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US20150237859A1 - Thiazol-4-Carboxylic Acid Esters and Thioesters as Plant Protection Agents - Google Patents

Thiazol-4-Carboxylic Acid Esters and Thioesters as Plant Protection Agents Download PDF

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Publication number
US20150237859A1
US20150237859A1 US14/678,174 US201514678174A US2015237859A1 US 20150237859 A1 US20150237859 A1 US 20150237859A1 US 201514678174 A US201514678174 A US 201514678174A US 2015237859 A1 US2015237859 A1 US 2015237859A1
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Prior art keywords
plants
alkyl
formula
methyl
trifluoromethyl
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US14/678,174
Inventor
Pierre CRISTAU
Stefan Herrmann
Nicola Rahn
Arnd Voerste
Ulrike Wachendorff-Neumann
Tomoki Tsuchiya
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Bayer Intellectual Property GmbH
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Bayer Intellectual Property GmbH
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Publication of US20150237859A1 publication Critical patent/US20150237859A1/en
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
    • A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention relates to thiazole-4-carboxylic esters and thioesters or agrochemically active salts thereof, to their use and to methods and compositions for controlling phytopathogenic harmful fungi in and/or on plants or in and/or on seed of plants, to processes for preparing such compositions and to treated seed, and to their use for controlling phytopathogenic harmful fungi in agriculture, horticulture and forestry, in animal health, in the protection of materials and in the domestic and hygiene field.
  • the present invention furthermore relates to a process for preparing thiazole-4-carboxylic esters and thioesters.
  • WO 04/058751 describes piperidinyl-substituted thiazole-4-carboxylic esters and thioesters which can be used as pharmaceutics for modulating blood pressure.
  • WO 05/003128 describes further piperidinyl-substituted thiazole-4-carboxylic esters and thioesters which are likewise suitable for medicinal applications, here as inhibitors on the microsomal triglyceride transfer protein (MTP inhibitors).
  • MTP inhibitors microsomal triglyceride transfer protein
  • the invention relates to compounds of the formulas (I)
  • the thiazole-4-carboxylic esters and thioesters of the formula (I) according to the invention and their agrochemically active salts are highly suitable for controlling phytopathogenic harmful fungi.
  • the compounds according to the invention mentioned above have potent fungicidal activity and can be used both in crop protection, in the domestic and hygiene field and in the protection of materials.
  • the compounds of the formula (I) can be present both in pure form and as mixtures of various possible isomeric forms, in particular of stereoisomers, such as E and Z, threo and erythro, endo or exo, and also optical isomers, such as R and S isomers or atropisomers, and, if appropriate, also of tautomers.
  • stereoisomers such as E and Z, threo and erythro, endo or exo
  • optical isomers such as R and S isomers or atropisomers, and, if appropriate, also of tautomers.
  • What is claimed are both the E and the Z isomers, and also the threo and erythro, and also the optical isomers, any mixtures of these isomers, and also the possible tautomeric forms.
  • the compounds of the formula (I) have acidic or basic properties and can form salts, if appropriate also inner salts, or adducts with inorganic or organic acids or with bases or with metal ions. If the compounds of the formula (I) carry amino, alkylamino or other groups which induce basic properties, these compounds can be reacted with acids to give salts, or they are directly obtained as salts in the synthesis. If the compounds of the formula (I) carry hydroxyl, carboxyl or other groups which induce acidic properties, these compounds can be reacted with bases to give salts.
  • Suitable bases are, for example, hydroxides, carbonates, bicarbonates of the alkali metals and alkaline earth metals, in particular those of sodium, potassium, magnesium and calcium, furthermore ammonia, primary, secondary and tertiary amines having (C 1 -C 4 )-alkyl groups, mono-, di- and trialkanolamines of (C 1 -C 4 )-alkanols, choline and also chlorocholine.
  • the salts obtainable in this manner also have fungicidal properties.
  • inorganic acids examples include hydrohalic acids, such as hydrogen fluoride, hydrogen chloride, hydrogen bromide and hydrogen iodide, sulphuric acid, phosphoric acid and nitric acid, and acidic salts, such as NaHSO 4 and KHSO 4 .
  • Suitable organic acids are, for example, formic acid, carbonic acid and alkanoic acids, such as acetic acid, trifluoroacetic acid, trichloroacetic acid and propionic acid, and also glycolic acid, thiocyanic acid, lactic acid, succinic acid, citric acid, benzoic acid, cinnamic acid, oxalic acid, alkylsulphonic acids (sulphonic acids having straight-chain or branched alkyl radicals of 1 to 20 carbon atoms), arylsulphonic acids or aryldisulphonic acids (aromatic radicals, such as phenyl and naphthyl, which carry one or two sulphonic acid groups), alkylphosphonic acids (phosphonic acids having straight-chain or branched alkyl radicals of 1 to 20 carbon atoms), arylphosphonic acids or aryldiphosphonic acids (aromatic radicals, such as phenyl and naphthyl, which carry one or two phospho
  • Suitable metal ions are in particular the ions of the elements of the second main group, in particular calcium and magnesium, of the third and fourth main group, in particular aluminum, tin and lead, and also of the first to eighth transition group, in particular chromium, manganese, iron, cobalt, nickel, copper, zinc and others. Particular preference is given to the metal ions of the elements of the fourth period.
  • the metals can be present in various valencies that they can assume.
  • Optionally substituted groups can be mono- or polysubstituted, where in the case of polysubstitutions the substituents can be identical or different.
  • halogen fluorine, chlorine, bromine and iodine
  • aryl unsubstituted or optionally substituted 5- to 15S-membered partially or filly unsaturated mono-, bi- or tricyclic ring system having up to 3 ring members selected from the groups C(O), (C ⁇ S), where at least one of the rings of the ring system is fully unsaturated, such as, for example (but not limited to), benzene, naphthalene, tetrahydronaphthalene, anthracene, indane, phenantlirene, azulene; alkyl: saturated, straight-chain or branched hydrocarbon radicals having 1 to 10 carbon atoms, for example (but not limited thereto) methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl,
  • Ring structures having three or more adjacent oxygen atoms, for example, are excluded.
  • the present invention furthermore provides a process for preparing the thiazole-4-carboxylic esters and thioesters of the formula (I) according to the invention, which comprises at least one of steps (a) to (c) below:
  • the protective group is removed from compounds of the formula (VII), giving compounds of the formula (VI) or the corresponding salt (Scheme 1).
  • a compound of the formula (VI) or a corresponding salt is coupled with a substrate of the formula (V), which gives compounds of the formula (IV) (Scheme 2).
  • the hydrolysis of compounds of the formula (IV) leads to carboxylic acids of the formula (III) (Scheme 3), followed by a coupling reaction in the presence of an alcohol or thiol of the general formula (II), which gives compounds of the formula (I) (Scheme 4).
  • the hydrolysis of the compound of the formula (VII) leads to a carboxylic acid of the general formula (VIII) (Scheme 3), followed by a coupling reaction in the presence of an alcohol or thiol of the general formula (II), which gives a compound of the formula (IX) (Scheme 4).
  • the protective group marked PG of a compound of the formula (IX) is removed, so that a compound of the formula (X) or the corresponding salt is formed (Scheme 1).
  • a compound of the formula (X) or a corresponding salt is coupled with a substrate of the formula (V), which gives a compound of the formula (I) (Scheme 2).
  • a compound of the formula (VII) is converted into a compound of the formula (VI) a using suitable methods for removing protective groups, which methods are described in the literature (“Protective Groups in Organic Synthesis”; Third Edition; Theodora W. Greene, Peter G. M. Wuts; 494-653, and the literature cited therein).
  • tert-Butoxycarbonyl and benzyloxycarbonyl protective groups can be removed in an acidic medium (for example using hydrochloric acid or trifluoroacetic acid).
  • Acetyl protective groups can be removed under basic conditions (using, for example, potassium carbonate or cesium carbonate).
  • Benzylic protective groups can be removed hydrogenolytically using hydrogen in the presence of a catalyst (for example palladium on activated carbon).
  • Suitable for use as solvents are all customary solvents which are inert under the reaction conditions, such as, for example, alcohols (for example methanol, ethanol, propanol), cyclic and acyclic ethers (for example diethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (for example benzene, toluene, xylene), halogenated hydrocarbons (for example dichloromethane, chloroform, carbon tetrachloride), halogenated aromatic hydrocarbons (for example chlorobenzene, dichlorobenzene), nitriles (for example acetonitrile), carboxylic esters (for example ethyl acetate), amides (for example N,N-dimethylformamide, N,N-dimethylacetamide), dimethyl sulfoxide, 1,3-dimethyl-2-imidazolinone, water and acetic acid, or the reaction can be carried out
  • Acids which can be used for this reaction of deprotecting t-butoxycarbonyl and benzyloxycarbonyl groups are, for example, trifluoroacetic acid, hydrochloric acid or other acids, as described in the literature (for example “ Protective Groups in Organic Synthesis ”; Third Edition; Theodora W. Greene, Peter G. M. Wuts; pp. 494-653).
  • the reaction is usually carried out at temperatures of 0° C.-150° C. and preferably at room temperature, but it can also be carried out at the reflux temperature of the reaction mixture.
  • the reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between half an hour and 72 hours.
  • the compounds (VI) are removed from the reaction mixture using one of the customary separation techniques. If required, the compounds are purified by recrystallisation, distillation or chromatography, or they can, if appropriate, also be used for the next step without prior purification. Moreover, it is possible to isolate the compound of the general formula (VI) as a salt, for example as a salt of hydrochloric acid or trifluoroacetic acid.
  • C 1 -C 2 -Alkyl esters are known and can be prepared from commercially available precursors according to procedures described in the literature, for example from nitriles of the formula (XI), carboxylic acids of the formula (XII), carbonyl chlorides of the formula (XIII), amides of the formula (XIV) or thioamides of the formula (XV) (FIG. 1).
  • a preferred method is the Hantzsch thiazole synthesis.
  • a compound of the formula (IV) is synthesized by a coupling reaction of a compound of the formula (VI) with a substrate of the formula (V) where Z ⁇ Cl, if appropriate in the presence of an acid scavenger/a base.
  • Acid halides (V) (Z ⁇ Cl) or the corresponding carboxylic acids (V) (Z ⁇ OH) are commercially available or can be prepared by processes described in the literature (for examples see WO 07/014290 and the references cited therein). A preferred method is shown in Scheme 7.
  • Pyrazoles (XVIII) can be prepared from diketones (XXI) and commercially available hydrazine (XX) or the corresponding HCl salt in ethanol or in N,N-dimethylformamide, if appropriate in the presence of bases, for example triethylamine at reflux.
  • Compounds (XVI) can be prepared by alkylation of compounds (XVIII) with commercially available ⁇ -halo esters (XVII) in acetonitrile or in N,N-dimethylformamide in the presence of bases, for example potassium carbonate at room temperature.
  • compounds (XVI) can be prepared directly from diketones (XXI) and commercially available hydrazine (XIX) or the corresponding HCl salts in ethanol or in N,N-dimethylformamide, if appropriate in the presence of bases, for example triethylamine at reflux.
  • Carboxylic acids (V) (Z ⁇ OH) can be prepared by hydrolysis of the esters (XVI) in THF/water mixtures using lithium hydroxide at room temperature. Moreover, a substrate of the general formula (V) where Z ⁇ Cl can be prepared from the corresponding acid (Z ⁇ OH) by chlorination using processes known from the literature (for example Tetrahedron 2005, 61, 10827-10852, and the literature cited therein).
  • Suitable for use as solvents are all customary solvents which are inert under the reaction conditions, such as, for example, alcohols (for example methanol, ethanol, propanol), cyclic and acyclic ethers (for example diethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (for example benzene, toluene, xylene), halogenated hydrocarbons (for example dichloromethane, chloroform, carbon tetrachloride), halogenated aromatic hydrocarbons (for example chlorobenzene, dichlorobenzene) and nitriles (for example acetonitrile), or the reaction can be carried out in mixtures of two or more of these solvents.
  • the preferred solvents are tetrahydrofuran and dichloromethane.
  • At least one equivalent of an acid scavenger/a base for example Hünig base, triethylamine or commercially available polymeric acid scavengers
  • a base for example Hünig base, triethylamine or commercially available polymeric acid scavengers
  • the starting material is a salt
  • at least two equivalents of the acid scavenger are required.
  • the reaction is usually carried out at temperatures of 0° C.-100° C. and preferably at 20° C.-30° C., but it can also be carried out at the reflux temperature of the reaction mixture.
  • the reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between a few minutes and 48 hours.
  • the compounds (IV) are removed from the reaction mixture using one of the customary separation techniques. If required, the compounds are purified by recrystallisation, distillation or chromatography, or they can, if appropriate, also be used for the next step without prior purification.
  • a compound of the formula (IV) can also be synthesized from the corresponding compound of the formula (VI) using a substrate of the formula (V) where Z ⁇ OH in the presence of a coupling agent analogously to procedures described in the literature (for example Tetrahedron 2005, 61, 10827-10852, and the references cited therein).
  • Suitable coupling agents are, for example, peptide coupling agents (for example N-(3-dimethylaminopropyl)-N-ethylcarbodiimide mixed with 4-dimethylaminopyridine, N-(3-dimethylaminopropyl)-N-ethylcarbodiimide mixed with 1-hydroxybenzotriazole, bromotripyrrolidinophosphonium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, etc.).
  • peptide coupling agents for example N-(3-dimethylaminopropyl)-N-ethylcarbodiimide mixed with 4-dimethylaminopyridine, N-(3-dimethylaminopropyl)-N-ethylcarbodiimide mixed with 1-hydroxybenzotriazole, bromotri
  • a base such as, for example, triethylamine or Hünig base can be employed in the reaction.
  • Suitable for use as solvents are all customary solvents which are inert under the reaction conditions, such as, for example, alcohols (for example methanol, ethanol, propanol), cyclic and acyclic ethers (for example diethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbon s (for example benzene, toluene, xylene), halogenated hydrocarbons (for example dichloromethane, chloroform, carbon tetrachloride), halogenated aromatic hydrocarbons (for example chlorobenzene, dichlorobenzene), nitriles (for example acetonitrile) and amides (for example N,N-dimethylformamide, N,N-dimethylacetamide), or the reaction can be carried out in mixtures of two or more of these solvents.
  • the preferred solvent is dichloromethane.
  • the reaction is usually carried out at temperatures of 0° C.-100° C. and preferably at 0° C.-30° C., but it can also be carried out at the reflux temperature of the reaction mixture.
  • the reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between a few minutes and 48 hours.
  • the compounds (IV) are removed from the reaction mixture using one of the customary separation techniques. If required, the compounds are purified by recrystallisation, distillation or chromatography, or they can, if appropriate, also be used for the next step without prior purification.
  • the carboxylic acid of the formula (III) can be prepared by hydrolysis of the corresponding C 1 -C 2 -alkyl ester of the formula (IV). It is possible to use, for example, the method described in WO2007/014290.
  • Suitable for use as solvents are all customary solvents which are inert under the reaction conditions, such as, for example, alcohols (for example methanol, ethanol, propanol), cyclic and acyclic ethers (for example diethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (for example benzene, toluene, xylene), halogenated hydrocarbons (for example dichloromethane, chloroform, carbon tetrachloride) and halogenated aromatic hydrocarbons (for example chlorobenzene, dichlorobenzene), or the reaction can be carried out in mixtures of two or more of these solvents.
  • alcohols for example methanol, ethanol, propanol
  • cyclic and acyclic ethers for example diethyl ether, tetrahydrofuran, dioxane
  • aromatic hydrocarbons for example benzene, toluene, xylene
  • Suitable alkali metal hydroxides are, for example, LiOH, NaOH or KOH, usually in the presence of water together with a cosolvent, preferably THF and/or methanol, to facilitate dissolution of the ester.
  • a cosolvent preferably THF and/or methanol
  • the starting material and the alkali metal hydroxide are employed in equimolar amounts; however, the alkali metal hydroxide may, if required, also be used in excess.
  • the carboxylate salt formed is converted into the free acid by treatment with a slight excess of mineral acids, such as, for example, hydrochloric acid or sulfuric acid.
  • the reaction is usually carried out at temperatures of 0° C.-60° C., but it can also be carried out at the reflux temperature of the reaction mixture.
  • the reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between a few minutes and 48 hours.
  • the compounds (Ill) are removed from the reaction mixture using one of the customary separation techniques. If required, the compounds are purified by recrystallisation, distillation or chromatography.
  • a compound of the formula (I) is synthesized by a coupling reaction of a compound of the formula (III) with a substrate of the formula (II), by chlorination using processes known from the literature (for example Tetrahedron 2005, 61, 10827-10852, and the literature cited therein), if appropriate in the presence of an acid scavenger/a base.
  • Suitable for use as solvents are all customary solvents which are inert under the reaction conditions, such as, for example, alcohols (for example methanol, ethanol, propanol), cyclic and acyclic ethers (for example diethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (for example benzene, toluene, xylene), halogenated hydrocarbons (for example dichloromethane, chloroform, carbon tetrachloride), halogenated aromatic hydrocarbons (for example chlorobenzene, dichlorobenzene) and nitriles (for example acetonitrile), or the reaction can be carried out in mixtures of two or more of these solvents.
  • the preferred solvents are tetrahydrofuran and dichloromethane.
  • At least one equivalent of an acid scavenger/a base for example Hünig base, triethylamine or commercially available polymeric acid scavengers
  • a base for example Hünig base, triethylamine or commercially available polymeric acid scavengers
  • the starting material is a salt
  • at least two equivalents of the acid scavenger are required.
  • the reaction is usually carried out at temperatures of 0° C.-100° C. and preferably at 20° C.-30° C., but it can also be carried out at the reflux temperature of the reaction mixture.
  • the reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between a few minutes and 48 hours.
  • the compounds (I) are removed from the reaction mixture using one of the customary separation techniques. If required, the compounds are purified by recrystallisation, distillation or chromatography, or they can, if appropriate, also be used for the next step without prior purification.
  • a compound of the formula (I) can also be synthesized from the corresponding compound of the formula (III) (Z ⁇ OH) using a substrate of the formula (II) in the presence of a coupling agent analogously to procedures described in the literature (for example Tetrahedron 2005, 61, 10827-10852, and the references cited therein).
  • Suitable coupling agents are, for example, peptide coupling agents (for example N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide mixed with 4-dimethylaminopyridine, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide mixed with 1-hydroxybenzotriazole, bromotripyrrolidinophosphonium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, etc.).
  • peptide coupling agents for example N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide mixed with 4-dimethylaminopyridine, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide mixed with 1-hydroxybenzotriazole,
  • a base such as, for example, triethylamine or Hünig base can be employed in the reaction.
  • Suitable for use as solvents are all customary solvents which are inert under the reaction conditions, such as, for example, alcohols (for example methanol, ethanol, propanol), cyclic and acyclic ethers (for example diethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (for example benzene, toluene, xylene), halogenated hydrocarbons (for example dichloromethane, chloroform, carbon tetrachloride), halogenated aromatic hydrocarbons (for example chlorobenzene, dichlorobenzene), nitriles (for example acetonitrile) and amides (for example N,N-dimethylformamide, N,N-dimethylacetamide), or the reaction can be carried out in mixtures of two or more of these solvents.
  • the preferred solvents are N,N-dimethylformamide and dichloromethane.
  • the reaction is usually carried out at temperatures of 0° C.-100° C. and preferably at 0° C.-30° C., but it can also be carried out at the reflux temperature of the reaction mixture.
  • the reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between a few minutes and 48 hours.
  • the compounds (I) are removed from the reaction mixture using one of the customary separation techniques. If required, the compounds are purified by recrystallisation, distillation or chromatography, or they can, if appropriate, also be used for the next step without prior purification.
  • Lawesson's reagent or, for example, phosphorus pentasulfide
  • Suitable for use as solvents are all customary solvents which are inert under the reaction conditions, such as, for example, alcohols (for example methanol, ethanol, propanol), cyclic and acyclic ethers (for example diethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (for example benzene, toluene, xylene), halogenated hydrocarbons (for example dichloromethane, chloroform, carbon tetrachloride), halogenated aromatic hydrocarbons (for example chlorobenzene, dichlorobenzene), nitriles (for example acetonitrile), carboxylic esters (for example ethyl acetate) and amides (for example N,N-dimethylformamide, N,N-dimethylacetamide), and the reaction can be carried out in mixtures of two or more of these solvents.
  • the preferred solvents are chloroform, toluene and
  • Suitable sulfurizing agents are, for example, Lawesson's reagent (see Tetrahedron 1986, 42, 6555-6564 , Tetrahedron Lett . 1993, 46, 7459-7462) and phosphorus pentasultide.
  • the starting material and the sulfurizing agent are employed in equimolar amounts; however, the sulfurizing agent may, if required, also be used in excess.
  • the reaction is usually carried out at temperatures of 0° C.-150° C. and preferably at 0° C.-100° C., but it can also be carried out at the reflux temperature of the reaction mixture.
  • the reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between a few minutes and 48 hours.
  • the compounds (I) are removed from the reaction mixture using one of the customary separation techniques. If required, the compounds are purified by recrystallisation, distillation or chromatography.
  • the invention furthermore provides the non-medicinal use of the thiazole-4-carboxylic esters and thioesters according to the invention or mixtures thereof for controlling unwanted microorganisms.
  • the invention furthermore relates to a composition for controlling unwanted microorganisms which comprises at least one thiazole-4-carboxylic ester or thioester according to the present invention.
  • the invention relates to a method for controlling unwanted microorganisms, characterized in that the thiazole-4-carboxylic esters and thioesters according to the invention are applied to the microorganisms and/or in their habitat.
  • the invention furthermore relates to seed treated with at least one thiazole-4-carboxylic ester or thioester according to the invention.
  • a last subject matter of the invention relates to a method for protecting seed against unwanted microorganisms by using seed treated with at least one thiazole-4-carboxylic ester or thioester according to the present invention.
  • the substances according to the invention have potent microbicidal activity and can be employed for controlling unwanted microorganisms, such as fungi and bacteria, in crop protection and in the protection of materials.
  • the thiazole-4-carboxylic esters and thioesters of the formula (I) according to the invention have very good fungicidal properties and can be used in crop protection, for example, for controlling Plasmodiophoromycetes, Oomycetes, Chytridiomycetes, Zygomycetes, Ascomycetes, Basidiomycetes and Deuteromycctcs.
  • Bactericides can be employed in crop protection, for example, for controlling Pseudomonadaceae, Rhizobiaceae, Enterobacteriaceae, Corynebacteriaceae and Streptomycetaceae.
  • the fungicidal compositions according to the invention can be used for the curative or protective control of phytopathogenic fungi. Accordingly, the invention also relates to curative and protective methods for controlling phytopathogenic fungi using the active compounds or compositions according to the invention, which are applied to the seed, the plant or plant parts, the fruit or the soil in which the plants grow.
  • compositions according to the invention for controlling phytopathogenic fungi in crop protection comprise an effective, but non-phytotoxic amount of the active compounds according to the invention.
  • Effective, but non-phytotoxic amount means an amount of the composition according to the invention which is sufficient to control the fungal disease of the plant in a satisfactory manner or to eradicate the fungal disease completely, and which, at the same time, does not cause any significant symptoms of phytotoxicity.
  • this application rate may vary within a relatively wide range. It depends on a plurality of factors, for example on the fungus to be controlled, the plant, the climatic conditions and the ingredients of the compositions according to the invention.
  • plants and plant parts can be treated in accordance with the invention.
  • plants are understood here all plants and plant populations such as desired and undesired wild plants or crop plants (including naturally occurring crop plants).
  • Crop plants can be plants which can be obtained by conventional breeding and optimization methods or by biotechnological and genetic engineering methods or combinations of these methods, including the transgenic plants and including the plant varieties which can or cannot be protected by varietal property rights.
  • Plant parts are to be understood as meaning all parts and organs of plants above and below the ground, such as shoot, leaf, flower and root, examples which may be mentioned being leaves, needles, stalks, stems, flowers, fruit bodies, fruits, seeds, roots, tubers and rhizomes.
  • Parts of plants also include harvested plants and vegetative and generative propagation material, for example seedlings, tubers, rhizomes, cuttings and seeds.
  • plants which can be treated according to the invention cotton, flax, grapevines, fruit, vegetables, such as Rosaceae sp. (for example pomaceous fruit, such as apples and pears, but also stone fruit, such as apricots, cherries, almonds and peaches and soft fruit such as strawberries), Ribesioidae sp., Juglandaceae sp., Betulaceae sp., Anacardiaceae sp., Fagaceae sp., Moraceae sp., Oleaceae sp., Actinidaceae sp., Lauraceae sp., Musaceae sp.
  • Rosaceae sp. for example pomaceous fruit, such as apples and pears, but also stone fruit, such as apricots, cherries, almonds and peaches and soft fruit such as strawberries
  • Rosaceae sp. for example pomaceous fruit, such as apples and pears, but also stone fruit,
  • Rubiaceae sp. for example coffee
  • Theaceae sp. Sterculiceae sp.
  • Rutaceae sp. for example lemons, oranges and grapefruit
  • Solanaceae sp. for example tomatoes
  • Liliaceae sp. Asteraceae sp.
  • Umbelliferae sp. for example Cruciferae sp.
  • Chenopodiaceae sp. Cucurbitaceae sp. (for example cucumbers), Alliaceae sp. (for example leek, onions), Papilionaceae sp.
  • peas for example peas
  • major crop plants such as Gramineae sp. (for example maize, lawn, cereals such as wheat, rye, rice, barley, oats, millet and triticale), Asteraceae sp. (for example sunflowers), Brassicaceae sp. (for example white cabbage, red cabbage, broccoli, cauliflowers, brussels sprouts, pak choi, kohlrabi, garden radish, and also oilseed rape, mustard, horseradish and cress), Fabacae sp. (for example beans, peanuts), Papilionaceae sp. (for example soya beans), Solanaceae sp.
  • Gramineae sp. for example maize, lawn, cereals such as wheat, rye, rice, barley, oats, millet and triticale
  • Asteraceae sp. for example sunflowers
  • Brassicaceae sp. for example white cabbage
  • diseases caused by powdery mildew pathogens such as, for example, Blumeria species, such as, for example, Blumeria graminis; Podosphaera species, such as, for example, Podosphacra leuco - tricha; Sphaerotheca species, such as, for example, Sphaerotheca fuliginea; Uncinula species, such as, for example, Uncinula necator , diseases caused by rust disease pathogens, such as, for example, Gymnosporangium species, such as, for example, Gymnosporangium sabinae; Hemileia species, such as, for example, Hemileia vastatrix; Phakopsora species, such as, for example, Phakopsora pachyrhizi and Phakopsora meibomiae; Puccinia species, such as, for example, Puccinia recondita or Puccinia triticina; Uromyces species, such as,
  • Phytophthora species such as, for example, Phytophthora infestans
  • Plasmopara species such as, for example, Plasmopara viticola
  • Pseudoperonospora species such as, for example, Pseudoperonospora humuli or Pseudoperonospora cubensis
  • Pythium species such as, for example, Pythium ultimum
  • Cercospora species such as, for example, Cercospora beticola
  • Cladiosporium species such as, for example, Cladiosporium cucumerinum
  • Cochliobolus species such as, for example, Cochliobolus sativus (conidia form: Drechslera , syn: Helminthosporium ); Colleto
  • Phaeosphaeria species such as, for example, Phaeosphaeria nodorum
  • Pyrenophora species such as, for example, Pyrenophora teres
  • Ramularia species such as, for example, Ramularia collo - cygni
  • Rhynchosporium species such as, for example, Rhynchosporium secalis
  • Septoria species such as, for example, Septoria apii
  • Typhula species such as, for example, Typhula incamata
  • Venturia species such as, for example, Venturia inaequalis
  • root and stem diseases caused, for example, by Corticium species such as, for example, Corticium graminearum
  • Fusarium species such as, for example, Fusarium oxysporum
  • Gaeumannomyces species such as, for example, Gaeumannomyces graminis
  • Rhizoctonia species such as, for example Rhizoctonia
  • Urocystis species such as, for example, Urocystis occulta
  • Ustilago species such as, for example, Ustilago nuda, U. nuda tritici
  • Botrytis species such as, for example, Botrytis cinerea
  • Penicillium species such as, for example, Penicillium expansum and P.
  • Sclerotinia species such as, for example, Sclerotinia sclerotiorum
  • Verticilium species such as, for example, Verticilium alboatrum
  • seed- and soil-borne rot and wilt diseases, and also diseases of seedlings caused, for example, by Fusarium species, such as, for example, Fusarium culmorum
  • Phytophthora species such as, for example, Phytophthora cactorum
  • Pythium species such as, for example, Pythium ultimum
  • Rhizoctonia species such as, for example, Rhizoctonia solani
  • Sclerotium species such as, for example, Sclerotium rolfsii
  • cancerous diseases, galls and witches' broom caused, for example, by Nectria species, such as, for example, Nectria galligena
  • wilt diseases caused, for example, by Monilinia species such as, for example, Monilinia species,
  • Pseudomonas species such as, for example, Pseudomonas syringae pv. lachrymans
  • Erwinia species such as, for example, Erwinia amylovora
  • Rhizoctonia solani sclerotinia stem decay ( Sclerotinia sclerotiorum ), sclerotinia southern blight ( Sclerotinia rolfsii ), thielaviopsis root rot ( Thielaviopsis basicola ).
  • the active compounds according to the invention also have very good fortifying action in plants. Accordingly, they can be used for mobilizing the defenses of the plant against attack by undesirable microorganisms.
  • Plant-strengthening (resistance-inducing) substances are to be understood as meaning, in the present context, those substances which are capable of stimulating the defense system of plants in such a way that the treated plants, when subsequently inoculated with undesired microorganisms, develop a high degree of resistance to these microorganisms.
  • the substances according to the invention can be used to protect plants for a certain period after the treatment against attack by the pathogens mentioned.
  • the period for which protection is provided generally extends over 1 to 10 days, preferably 1 to 7 days, after the treatment of the plants with the active compounds.
  • the active compounds according to the invention can be employed particularly successfully for controlling diseases in viticulture and fruit and vegetable growing such as, for example, against Botrytis, Venturia, Sphaerotheca, Podosphaera, Phythophthora and Plasmopara species.
  • the active compounds according to the invention are also suitable for increasing the yield of crops. In addition, they show reduced toxicity and are well tolerated by plants.
  • the compounds according to the invention can, at certain concentrations or application rates, also be used as herbicides, safeners, growth regulators or agents to improve plant properties, or as microbicidcs, for example as fungicides, antimycotics, bactericides, viricides (including agents against viroids) or as agents against MLO ( Mycoplasma -like organisms) and RLO ( Rickettsia -like organisms). If appropriate, they can also be used as intermediates or precursors for the synthesis of other active compounds.
  • the active compounds according to the invention can also be employed in specific concentrations and application rates as herbicides, for influencing plant growth, and for controlling animal pests. If appropriate, they can also be used as intermediates and precursors for the synthesis of further active compounds.
  • the active compounds according to the invention in combination with good plant tolerance and favourable toxicity to warm-blooded animals and being tolerated well by the environment, are suitable for protecting plants and plant organs, for increasing the harvest yields, for improving the quality of the harvested material and for controlling animal pests, in particular insects, arachnids, helminths, nematodes and molluscs, which are encountered in agriculture, in horticulture, in animal husbandry, in forests, in gardens and leisure facilities, in the protection of stored products and of materials, and in the hygiene sector. They may be preferably employed as plant protection agents.
  • the treatment according to the invention of the plants and plant parts with the active compounds or compositions is carried out directly or by action on their surroundings, habitat or storage space using customary treatment methods, for example by dipping, spraying, atomizing, irrigating, evaporating, dusting, fogging, broadcasting, foaming, painting, spreading-on, watering (drenching), drip irrigating and, in the case of propagation material, in particular in the case of seeds, furthermore as a powder for dry seed treatment, a solution for seed treatment, a water-soluble powder for slurry treatment, by incrusting, by coating with one or more coats, etc. It is furthermore possible to apply the active compounds by the ultra-low volume method or to inject the active compound preparation or the active compound itself into the soil.
  • the active compounds according to the invention can also be used as defoliants, desiccants, haulm killers and, especially, as weedkillers. Weeds in the broadest sense are understood to mean all plants which grow in locations where they are undesired. Whether the substances according to the invention act as total or selective herbicides depends essentially on the amount used.
  • the active compounds or compositions according to the invention can be employed for protecting industrial materials against attack and destruction by unwanted microorganisms, such as, for example, fungi.
  • Industrial materials in the present context are understood as meaning non-living materials which have been prepared for use in industry.
  • industrial materials which are intended to be protected by active compounds according to the invention from microbial change or destruction can be adhesives, sizes, paper and board, textiles, leather, wood, paints and plastic articles, cooling lubricants and other materials which can be infected with, or destroyed by, microorganisms.
  • Parts of production plants, for example cooling-water circuits, which may be impaired by the proliferation of microorganisms may also be mentioned within the scope of the materials to be protected.
  • Industrial materials which may be mentioned within the scope of the present invention are preferably adhesives, sizes, paper and board, leather, wood, paints, cooling lubricants and heat-transfer liquids particularly preferably wood.
  • the active compounds or compositions according to the invention may prevent disadvantageous effects, such as rotting, decay, discoloration, decoloration or formation of mold.
  • storage goods are to be understood as meaning natural substances of vegetable or animal origin or processed products thereof of natural origin, for which long-term protection is desired.
  • Storage goods of vegetable origin such as, for example, plants or plant parts, such as stems, leaves, tubers, seeds, fruits, grains, can be protected freshly harvested or after processing by (pre)drying, moistening, comminuting, grinding, pressing or roasting.
  • Storage goods also include timber, both unprocessed, such as construction timber, electricity poles and barriers, or in the form of finished products, such as furniture.
  • Storage goods of animal origin are, for example, hides, leather, furs and hairs.
  • the active compounds according to the invention may prevent disadvantageous effects, such as rotting, decay, discoloration, decoloration or formation of mold.
  • Microorganisms capable of degrading or changing the industrial materials are, for example, bacteria, fungi, yeasts, algae and slime organisms.
  • the active compounds according to the invention preferably act against fungi, in particular molds, wood-discoloring and wood-destroying fungi (Basidiomycetes), and against slime organisms and algae.
  • Microorganisms of the following genera may be mentioned as examples: Alternaria , such as Alternaria tenuis; Aspergillus , such as Aspergillus niger, Chaetomium , such as Chaetomium globosum; Coniophora , such as Coniophora puetana; Lentinus , such as Lentinus tigrinus; Penicillium , such as Penicillium glaucum; Polyporus , such as Polyporus versicolor, Aureobasidium , such as Aureobasidium pullulans; Sclerophoma , such as Sclerophoma pityophila; Trichoderma , such as Trichoderma viride; Escherichia , such as Escherichia coli; Pseudomonas , such as Pseudomonas aeruginosa; Staphylococcus , such as Staphylococcus aureus.
  • the present invention furthermore relates to a composition for controlling unwanted microorganisms, which composition comprises at least one of the thiazole-4-carboxylic ester or thiocsters according to the invention.
  • compositions for controlling unwanted microorganisms which composition comprises at least one of the thiazole-4-carboxylic ester or thiocsters according to the invention.
  • fungicidal composition which comprise agriculturally suitable auxiliaries, solvents, carriers, surfactants or extenders.
  • a carrier is a natural or synthetic organic or inorganic substance with which the active compounds are mixed or bonded for better applicability, in particular for application to plants or plant parts or seed.
  • the carrier which may be solid or liquid, is generally inert and should be suitable for use in agriculture.
  • solid carriers these are suitable: for example ammonium salts and ground natural minerals such as kaolins, clays, talc, chalk, quartz, attapulgite, niontmorillonite or diatomaceous earth, and ground synthetic materials such as highly-disperse silica, alumina and silicates;
  • suitable solid carriers for granules are: for example, crushed and fractionated natural rocks such as calcite, marble, pumice, sepiolite and dolomite, and also synthetic granules of inorganic and organic meals, and granules of organic material such as paper, sawdust, coconut shells, maize cobs and tobacco stalks;
  • suitable emulsifiers and/or foam-formers are: for example, nonionic and anionic emulsifiers, such as polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, for example alkylaryl polyglycol ethers, alkylsulfonates, alkyl s
  • oligo- or polymers for example those derived from vinylic monomers, from acrylic acid, from EO and/or PO alone or in combination with, for example, (poly)alcohols or (poly)amines. It is also possible to employ lignin and its sulphonic acid derivatives, unmodified and modified celluloses, aromatic and/or aliphatic sulphonic acids and their adducts with formaldehyde.
  • the active compounds can be converted into the customary formulations, such as solutions, emulsions, wettable powders, water- and oil-based suspensions, powders, dusts, pastes, soluble powders, soluble granules, granules for broadcasting, suspoemulsion concentrates, natural compounds impregnated with active compound, synthetic substances impregnated with active compound, fertilizers and also microencapsulations in polymeric substances.
  • customary formulations such as solutions, emulsions, wettable powders, water- and oil-based suspensions, powders, dusts, pastes, soluble powders, soluble granules, granules for broadcasting, suspoemulsion concentrates, natural compounds impregnated with active compound, synthetic substances impregnated with active compound, fertilizers and also microencapsulations in polymeric substances.
  • the active compounds can be applied as such, in the form of their formulations or the use forms prepared therefrom, such as ready-to-use solutions, emulsions, water- or oil-based suspensions, powders, wettable powders, pastes, soluble powders, dusts, soluble granules, granules for broadcasting, suspoemulsion concentrates, natural products impregnated with active compound, synthetic materials impregnated with active compound, fertilizers and also microencapsulations in polymeric substances.
  • Application is carried out in a customary manner, for example by watering, spraying, atomizing, broadcasting, dusting, foaming, spreading, etc. It is furthermore possible to apply the active compounds by the ultra-low volume method, or to inject the active compound preparation or the active compound itself into the soil. It is also possible to treat the seeds of the plants.
  • the formulations mentioned can be prepared in a manner known per se, for example by mixing the active compounds with at least one customary extender, solvent or diluent, emulsifier, dispersant, and/or binder or fixative, wetting agent, water-repellent, if appropriate desiccants and UV stabilizers and, if appropriate, dyes and pigments, defoamers, preservatives, secondary thickeners, adhesives, gibberellins and also further processing auxiliaries.
  • compositions according to the invention include not only formulations which are already ready for use and can be applied with a suitable apparatus to the plant or the seed, but also commercial concentrates which have to be diluted with water prior to use.
  • the active compounds according to the invention can be present as such or in their (commercial) formulations and in the use forms prepared from these formulations as a mixture with other (known) active compounds, such as insecticides, attractants, sterilants, bactericides, acaricides, nematicides, fungicides, growth regulators, herbicides, fertilizers, safeners and/or semiochemicals.
  • active compounds such as insecticides, attractants, sterilants, bactericides, acaricides, nematicides, fungicides, growth regulators, herbicides, fertilizers, safeners and/or semiochemicals.
  • auxiliaries are substances which are suitable for imparting to the composition itself and/or to preparations derived therefrom (for example spray liquors, seed dressings) particular properties such as certain technical properties and/or also particular biological properties.
  • suitable auxiliaries are: extenders, solvents and carriers.
  • Suitable extenders are, for example, water, polar and nonpolar organic chemical liquids, for example from the classes of the aromatic and non-aromatic hydrocarbons (such as paraffins, alkylbenzenes, alkylnaphthalenes, chlorobenzenes), the alcohols and polyols (which, if appropriate, may also be substituted, etherified and/or esterified), the ketones (such as acetone, cyclohexanone), esters (including fats and oils) and (poly)ethers, the unsubstituted and substituted amines, amides, lactams (such as N-alkylpyrrolidones) and lactones, the sulphones and sulphoxides (such as dimethyl sulphoxide).
  • aromatic and non-aromatic hydrocarbons such as paraffins, alkylbenzenes, alkylnaphthalenes, chlorobenzenes
  • the alcohols and polyols
  • Liquefied gaseous extenders or carriers are to be understood as meaning liquids which are gaseous at standard temperature and under atmospheric pressure, fix example aerosol propellants such as halogenated hydrocarbons, or else butane, propane, nitrogen and carbon dioxide.
  • Tackifiers such as carboxymethylcellulose and natural and synthetic polymers in the form of powders, granules or latices, such as gum arabic, polyvinyl alcohol and polyvinyl acetate, or else natural phospholipids such as cephalins and lecithins and synthetic phospholipids can be used in the formulations.
  • Other possible additives are mineral and vegetable oils.
  • suitable liquid solvents are: aromatics such as xylene, toluene or alkylnaphthalenes, chlorinated aromatics or chlorinated aliphatic hydrocarbons such as chlorobenzenes, chloroethylenes or methylene chloride, aliphatic hydrocarbons such as cyclohexane or paraffins, for example petroleum fractions, alcohols such as butanol or glycol and their ethers and esters, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone, strongly polar solvents such as dimethylformamide or dimethyl sulphoxide, or else water.
  • aromatics such as xylene, toluene or alkylnaphthalenes
  • chlorinated aromatics or chlorinated aliphatic hydrocarbons such as chlorobenzenes, chloroethylenes or methylene chloride
  • aliphatic hydrocarbons such as cyclohe
  • compositions according to the invention may comprise additional further components, such as, for example, surfactants.
  • surfactants are emulsifiers and/or foam formers, dispersants or wetting agents having ionic or nonionic properties, or mixtures of these surfactants.
  • salts of polyacrylic acid salts of lignosulphonic acid, salts of phenolsulphonic acid or naphthalenesulphonic acid, polycondensates of ethylene oxide with fatty alcohols or with fatty acids or with fatty amines, substituted phenols (preferably alkylphenols or arylphenols), salts of sulphosuccinic esters, taurine derivatives (preferably alkyl taurates), phosphoric esters of polyethoxylated alcohols or phenols, fatty esters of polyols, and derivatives of the compounds containing sulphates, sulphonates and phosphates, for example alkylaryl polyglycol ethers, alkylsulphonates, alkyl sulphates, arylsulphonates, protein hydrolysates, lignosulphite waste liquors and methylcellulose.
  • the presence of a surfactant is required if one of the active compounds and/or one of the inert carriers is insoluble in water and when the application takes place in water.
  • the proportion of surfactants is between 5 and 40 per cent by weight of the composition according to the invention.
  • colorants such as inorganic pigments, for example iron oxide, titanium oxide and Prussian Blue, and organic dyestuffs such as alizarin dyestuffs, azo dyestuffs and metal phthalocyanine dyestuffs, and trace nutrients such as salts of iron, manganese, boron, copper, cobalt, molybdenum and zinc.
  • inorganic pigments for example iron oxide, titanium oxide and Prussian Blue
  • organic dyestuffs such as alizarin dyestuffs, azo dyestuffs and metal phthalocyanine dyestuffs
  • trace nutrients such as salts of iron, manganese, boron, copper, cobalt, molybdenum and zinc.
  • perfumes mineral or vegetable, optionally modified oils, waxes and nutrients (including trace nutrients), such as salts of iron, manganese, boron, copper, cobalt, molybdenum and zinc.
  • Stabilizers such as low-temperature stabilizers, preservatives, antioxidants, light stabilizers or other agents which improve chemical and/or physical stability may also be present.
  • additional components may also be present, for example protective colloids, binders, adhesives, thickeners, thixotropic substances, penetrants, stabilizers, sequestering agents, complex formers.
  • the active compounds can be combined with any solid or liquid additive customarily used for formulation purposes.
  • the formulations generally comprise between 0.05 and 99% by weight. 0.01 and 98% by weight, preferably between 0.1 and 95% by weight, particularly preferably between 0.5 and 90% of active compound, very particularly preferably between 10 and 70% by weight.
  • the formulations described above can be used in a method according to the invention for controlling unwanted microorganisms, where the thiazole-4-carboxylic esters and thioestcrs according to the invention are applied to the microorganisms and/or to their habitat.
  • the active compounds according to the invention can be used as such or in their formulations, also in a mixture with known fungicides, bactericides, acaricides, nematicides or insecticides, to broaden, for example, the activity spectrum or to prevent development of resistance.
  • Suitable mixing partners are, for example, known fungicides, insecticides, acaricides, nematicides or else bactericides (see also Pesticide Manual, 13th ed.).
  • a mixture with other known active compounds, such as herbicides, or with fertilizers and growth regulators, safeners and/or semiochemicals is also possible.
  • the invention furthermore includes a method for treating seed.
  • a further aspect of the present invention relates in particular to seed treated with at least one of the thiazole-4-carboxylic esters or thioesters according to the invention.
  • the seed according to the invention is used in methods for protecting seed against animal pests and/or phytopathogenic harmful fungi. In these methods, seed treated with at least one active compound according to the invention is employed.
  • the active compounds or compositions according to the invention are also suitable for treating seed.
  • a large part of the damage to crop plants caused by harmful organisms is triggered by the infection of the seed during storage or after sowing both during and after germination of the plant.
  • This phase is particularly critical since the roots and shoots of the growing plant are particularly sensitive, and even small damage may result in the death of the plant. Accordingly, there is great interest in protecting the seed and the germinating plant by using appropriate compositions.
  • the present invention also relates to a method for protecting seed and germinating plants against attack by animal pests and/or phytopathogenic harmful fungi by treating the seed with a composition according to the invention.
  • the invention also relates to the use of the compositions according to the invention for treating seed for protecting the seed and the germinating plant against phytopathogenic fungi.
  • the invention relates to seed treated with a composition according to the invention for protection against phytopathogenic fungi.
  • compositions according to the invention treatment of the seed with these compositions not only protects the seed itself, but also the resulting plants after emergence, from animal pests and/or phytopathogenic harmful fungi. In this manner, the immediate treatment of the crop at the time of sowing or shortly thereafter can be dispensed with.
  • the active compounds or compositions according to the invention can be used irn particular also for transgenic seed where the plant growing from this seed is capable of expressing a protein which acts against pests.
  • the active compounds or compositions according to the invention By treating such seed with the active compounds or compositions according to the invention, even by the expression of the, for example, insecticidal protein, certain pests may be controlled.
  • a further synergistic effect may be observed here, which additionally increases the effectiveness of the protection against attack by pests.
  • compositions according to the invention are suitable for protecting seed of any plant variety which is employed in agriculture, in the greenhouse, in forests or in horticulture.
  • this takes the form of seed of cereals (such as wheat, barley, rye, millet and oats), maize, cotton, soybeans, rice, potatoes, sunflowers, beans, coffee, beets (for example sugarbeets and fodder beets), peanuts, vegetables (such as such as tomatoes, cucumbers, onions and lettuce), lawn and ornamental plants.
  • cereals such as wheat, barley, rye, millet and oats
  • maize cotton, soybeans, rice, potatoes, sunflowers, beans, coffee, beets (for example sugarbeets and fodder beets)
  • peanuts such as tomatoes, cucumbers, onions and lettuce
  • lawn and ornamental plants such as tomatoes, cucumbers, onions and lettuce
  • transgenic seed As also described further below, the treatment of transgenic seed with the active compounds or compositions according to the invention is of particular importance.
  • the heterologous gene in transgenic seed can originate, for example, from microorganisms of the species Bacillus, Rhizobium, Pseudomonas, Serratia, Trichoderma, Clavibacter, Glomus or Gliocladium .
  • this heterologous gene is from Bacillus sp., the gene product having activity against the European corn borer and/or the Western corn rootworm.
  • the heterologous gene originates from Bacillus thuringiensis.
  • the composition according to the invention is applied to the seed either alone or in suitable formulation.
  • the seed is treated in a state in which it is stable enough to avoid damage during treatment.
  • the seed may be treated at any point in time between harvest and sowing.
  • the seed usually used has been separated from the plant and freed from cobs, shells, stalks, coats, hairs or the flesh of the fruits.
  • seed which has been harvested, cleaned and dried has been separated from the plant and freed from cobs, shells, stalks, coats, hairs or the flesh of the fruits.
  • the amount of the composition according to the invention applied to the seed and/or the amount of further additives is chosen in such a way that the germination of the seed is not adversely affected, or that the resulting plant is not damaged. This must be borne in mind in particular in the case of active compounds which can have phytotoxic effects at certain application rates.
  • compositions according to the invention can be applied directly, i.e. without any other components and undiluted. In general, it is preferred to apply the compositions to the seed in the form of a suitable formulation.
  • suitable formulations and methods for treating seed are known to the person skilled in the art and are described, for example, in the following documents: U.S. Pat. No. 4,272,417 A, U.S. Pat. No. 4,245,432 A, U.S. Pat. No. 4,808,430 A, U.S. Pat. No. 5,876,739 A, US 2003/0176428 A1, WO 2002/080675 A1, WO 2002/028186 A2.
  • the active compounds which can be used in accordance with the invention can be converted into the customary seed-dressing formulations, such as solutions, emulsions, suspensions, powders, foams, slurries or other coating compositions for seed, and also ULV formulations
  • customary additives such as, for example, customary extenders and also solvents or diluents, colorants, wetting agents, dispersants, emulsifiers, antifoams, preservatives, secondary thickeners, adhesives, gibberellins and also water.
  • Colorants which may be present in the seed-dressing formulations which can be used in accordance with the invention are all colorants which are customary for such purposes.
  • pigments which are sparingly soluble in water, but also dyes, which are soluble in water, may be used. Examples which may be mentioned are the colorants known by the names Rhodamin B, C.I. Pigment Red 112 and C.I. Solvent Red 1.
  • Suitable wetting agents which may be present in the seed-dressing formulations which can be used in accordance with the invention are all substances which promote wetting and which are conventionally used for the formulation of agrochemical active compounds. Preference is given to using alkylnaphthalenesulphonates, such as diisopropyl- or diisobutylnaphthalenesulphonates.
  • Suitable dispersants and/or emulsifiers which may be present in the seed-dressing formulations which can be used in accordance with the invention are all nonionic, anionic and cationic dispersants conventionally used for the formulation of agrochemical active compounds. Preference is given to using nonionic or anionic dispersants or mixtures of nonionic or anionic dispersants.
  • Suitable nonionic dispersants which may be mentioned are, in particular, ethylene oxide/propylene oxide block polymers, alkylphenol polyglycol ethers and tristryrylphenol polyglycol ether, and their phosphated or sulphated derivatives.
  • Suitable anionic dispersants are, in particular, lignlosulphonates, polyacrylic acid salts and arylsulphonate/formaldehyde condensates.
  • Antifoams which may be present in the seed-dressing formulations which can be used in accordance with the invention are all foam-inhibiting substances conventionally used for the formulation of agrochemical active compounds. Silicone antifoams and magnesium stearate can preferably be used.
  • Preservatives which may be present in the seed-dressing formulations which can be used in accordance with the invention are all substances which can be employed for such purposes in agrochemical compositions. Dichlorophene and benzyl alcohol hemiformal may be mentioned by way of example.
  • Secondary thickeners which may be present in the seed-dressing formulations which can be used in accordance with the invention are all substances which can be employed for such purposes in agrochemical compositions. Cellulose derivatives, acrylic acid derivatives, xanthan, modified clays and finely divided silica are preferred.
  • Adhesives which may be present in the seed-dressing formulations which can be used in accordance with the invention are all customary binders which can be employed in seed-dressing products.
  • Polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol and tylose may be mentioned as being preferred.
  • the gibberellins are known (cf. R. Wegler “Chemie der convinced Schdlingsbehimmpfungsstoff” [Chemistry of plant protection agents and pesticides], vol. 2, Springer Verlag, 1970, p. 401-412).
  • the seed-dressing formulations which can be used in accordance with the invention can be employed for the treatment of a wide range of seed, either directly or after previously having been diluted with water.
  • the concentrates or the preparations obtainable therefrom by dilution with water may be used to dress the seed of cereals, such as wheat, barley, rye, oats, and triticale, and also the seed of maize, rice, oilseed rape, peas, beans, cotton, sunflowers, and beets, or else vegetable seed of any of a very wide variety of kinds.
  • the seed-dressing formulations which can be used according to the invention or their dilute preparations may also be used to dress seed of transgenic plants. In this context, additional synergistic effects may also occur in cooperation with the substances formed by expression.
  • All mixers which can conventionally be employed for the seed-dressing operation are suitable for treating seed with the seed-dressing formulations which can be used in accordance with the invention or with the preparations prepared therefrom by addition of water. Specifically, a procedure is followed during the seed-dressing operation in which the seed is placed into a mixer, the specific desired amount of seed-dressing formulations, either as such or after previously having been diluted with water, is added, and everything is mixed until the formulation is distributed uniformly on the seed. If appropriate, this is followed by a drying process.
  • the application rate of the seed dressing formulations which can be used according to the invention may be varied within a relatively wide range. It depends on the respective content of the active compounds in the formulations and on the seed.
  • the active compound combination application rates are generally between 0.001 and 50 g per kilogram of seed, preferably between 0.01 and 15 g per kilogram of seed.
  • the compounds of the formula (I) according to the invention also have very good antimycotic activity. They have a very broad antimycotic activity spectrum in particular against dermatophytes and yeasts, molds and diphasic fungi, (for example against Candida species, such as Candida albicans, Candida glabrata ), and Epidermophyton floccosum, Aspergillus species, such as Aspergillus niger and Aspergillus fumigatus, Trichophyton species, such as Trichophyton mentagrophytes, Microsporon species such as Microsporon canis and audouinii .
  • Candida species such as Candida albicans, Candida glabrata
  • Epidermophyton floccosum Aspergillus species, such as Aspergillus niger and Aspergillus fumigatus
  • Trichophyton species such as Trichophyton mentagrophytes
  • Microsporon species such as Microsporon canis and audouinii .
  • the active compounds of the formula (I) according to the invention can be used both in medical and in non-medical applications.
  • the active compounds can be used as such, in the form of their formulations or the use forms prepared therefrom, such as ready-to-use solutions, suspensions, wettable powders, pastes, soluble powders, dusts and granules.
  • Application is carried out in a customary manner, for example by watering, spraying, atomizing, broadcasting, dusting, foaming, spreading, etc. It is furthermore possible to apply the active compounds by the ultra-low volume method, or to inject the active compound preparation or the active compound itself into the soil. It is also possible to treat the seed of the plants.
  • the application rates can be varied within a relatively wide range, depending on the kind of application.
  • the application rate of the active compounds according to the invention is
  • the compounds according to the invention can at the same time be employed for protecting objects which come into contact with saltwater or brackish water, such as hulls, screens, nets, buildings, moorings and signaling systems, against fouling.
  • the compounds according to the invention can be used alone or in combinations with other active compounds as antifouling compositions.
  • the method of treatment according to the invention can be used in the treatment of genetically modified organisms (GMOs), e.g. plants or seeds.
  • GMOs genetically modified organisms
  • Genetically modified plants are plants in which a heterologous gene has been stably integrated into the genome.
  • the expression “heterologous gene” essentially means a gene which is provided or assembled outside the plant and when introduced in the nuclear, chloroplastic or hypochondrial genome gives the transformed plant new or improved agronomic or other properties by expressing a protein or polypeptide of interest or by downregulating or silencing other gene(s) which are present in the plant (using for example antisense technology, cosuppression technology or RNAi technology [RNA interference]).
  • a heterologous gene that is located in the genome is also called a transgene.
  • a transgene that is defined by its particular location in the plant genome is called a transformation or transgenic event.
  • the treatment according to the invention may also result in superadditive (“synergistic”) effects.
  • superadditive encompasses the following effects which exceed the effects which were to be expected: reduced application rates and/or a widening of the activity spectrum and/or an increase in the activity of the active compounds and compositions which can be used according to the invention, better plant growth, increased tolerance to high or low temperatures, increased tolerance to drought or to water or soil salt content, increased flowering performance, easier harvesting, accelerated maturation, higher harvest yields, bigger fruits, larger plant height, greener leaf color, earlier flowering, higher quality and/or a higher nutritional value of the harvested products, higher sugar concentration within the fruits, better storage stability and/or processability of the harvested products.
  • the active compound combinations according to the invention may also have a strengthening effect in plants. Accordingly, they are suitable for mobilizing the defense system of the plant against attack by unwanted phytopathogenic fungi and/or microorganisms and/or viruses. This may, if appropriate, be one of the reasons for the enhanced activity of the combinations according to the invention, for example against fungi.
  • Plant-strengthening (resistance-inducing) substances are to be understood as meaning, in the present context, also those substances or combinations of substances which are capable of stimulating the defence system of plants in such a way that, when subsequently inoculated with unwanted phytopathogenic fungi and/or microorganisms and/or viruses, the treated plants display a substantial degree of resistance to there unwanted phytopathogenic fungi and/or microorganisms and/or viruses.
  • unwanted phytopathogenic fungi and/or microorganisms and/or viruses are understood as meaning phytopathogenic fungi, bacteria and viruses.
  • the substances according to the invention can be employed for protecting plants against attack by the abovementioned pathogens within a certain period of time after the treatment.
  • the period within which protection is brought about generally extends from 1 to 10 days, preferably 1 to 7 days, after the treatment of the plants with the active compounds.
  • Plants and plant varieties which are preferably treated according to the invention include all plants which have genetic material which imparts particularly advantageous, useful traits to these plants (whether obtained by breeding and/or biotechnological means).
  • Plants and plant varieties which are also preferably treated according to the invention are resistant against one or more biotic stresses, i.e. said plants have a better defence against animal and microbial pests, such as against nematodes, insects, mites, phytopathogcnic fungi, bacteria, viruses and/or viroids.
  • Plants and plant varieties which may also be treated according to the invention are those plants which are resistant to one or more abiotic stress factors.
  • Abiotic stress conditions may include, for example, drought, cold temperature exposure, heat exposure, osmotic stress, waterlogging, increased soil salinity, increased exposure to minerals, exposure to ozone, exposure to strong light. limited availability of nitrogen nutrients, limited availability of phosphorus nutrients or shade avoidance.
  • Plants and plant varieties which may also be treated according to the invention are those plants characterized by enhanced yield characteristics.
  • Enhanced yield in said plants can be the result of, for example, improved plant physiology, growth and development, such as water use efficiency, water retention efficiency, improved nitrogen use, enhanced carbon assimilation, improved photosynthesis, increased germination efficiency and accelerated maturation.
  • Yield can furthermore be affected by improved plant architecture (under stress and non-stress conditions), including early flowering, flowering control for hybrid seed production, seedling vigour, plant size, internode number and distance, root growth, seed size, fruit size, pod size, pod or ear number, seed number per pod or ear, seed mass, enhanced seed filling, reduced seed dispersal, reduced pod dehiscence and lodging resistance.
  • Further yield traits include seed composition, such as carbohydrate content, protein content, oil content and composition, nutritional value, reduction in anti-nutritional compounds, improved processability and better storage stability.
  • Plants that may be treated according to the invention are hybrid plants that already express the characteristics of heterosis, or hybrid vigour, which results in generally higher yield, vigour, health and resistance towards biotic and abiotic stress factors. Such plants are typically made by crossing an inbred male-sterile parent line (the female parent) with another inbred male-fertile parent line (the male parent). Hybrid seed is typically harvested from the male sterile plants and sold to growers. Male sterile plants can sometimes (e.g. in corn) be produced by detasseling (i.e. the mechanical removal of the male reproductive organs or male flowers) but, more typically, male sterility is the result of genetic determinants in the plant genome.
  • detasseling i.e. the mechanical removal of the male reproductive organs or male flowers
  • male fertility in the hybrid plants which contain the genetic determinants responsible for male sterility, is fully restored.
  • This can be accomplished by ensuring that the male parents have appropriate fertility restorer genes which are capable of restoring the male fertility in hybrid plants that contain the genetic determinants responsible for male sterility.
  • Genetic determinants for male sterility may be located in the cytoplasm. Examples of cytoplasmic male sterility (CMS) were for instance described for Brassica species. However, genetic determinants for male sterility can also be located in the nuclear genome. Male sterile plants can also be obtained by plant biotechnology methods such as genetic engineering.
  • a particularly useful means of obtaining male sterile plants is described in WO 89/10396 in which, for example, a ribonuclease such as barnase is selectively expressed in the tapetum cells in the stamens. Fertility can then be restored by expression in the tapetum cells of a ribonuclease inhibitor such as barstar.
  • Plants or plant varieties obtained by plant biotechnology methods such as genetic engineering which may be treated according to the invention are herbicide-tolerant plants, i.e. plants made tolerant to one or more given herbicides. Such plants can be obtained either by genetic transformation, or by selection of plants containing a mutation imparting such herbicide tolerance.
  • Herbicide-tolerant plants are for example glyphosate-tolerant plants, i.e. plants made tolerant to the herbicide glyphosate or salts thereof.
  • glyphosate-tolerant plants can be obtained by transforming the plant with a gene encoding the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS).
  • EPSPS 5-enolpyruvylshikimate-3-phosphate synthase
  • EPSPS 5-enolpyruvylshikimate-3-phosphate synthase
  • EPSPS genes are the AroA gene (mutant CT7) of the bacterium Salmonella typhimurium , the CP4 gene of the bacterium Agrobacterium sp., the genes encoding a petunia EPSPS, a tomato EPSPS, or an Eleusine EPSPS. It can also be a mutated EPSPS.
  • Glyphosate-tolerant plants can also be obtained by expressing a gene that encodes a glyphosate oxidoreductase enzyme. Glyphosate-tolerant plants can also be obtained by expressing a gene that encodes a glyphosate acetyl transferase enzyme. Glyphosate-tolerant plants can also be obtained by selecting plants containing naturally-occurring mutations of the above-mentioned genes.
  • herbicide-resistant plants are for example plants which have been made tolerant to herbicides inhibiting the enzyme glutamine synthase, such as bialaphos, phosphinothricin or glufosinate.
  • Such plants can be obtained by expressing an enzyme detoxifying the herbicide or a mutant glutamine synthase enzyme that is resistant to inhibition.
  • One such efficient detoxifying enzyme is, for example, an enzyme encoding a phosphinothricin acetyltransferase (such as the bar or pat protein from Streptomyces species). Plants expressing an exogenous phosphinothricin acetyltransferase have been described.
  • hydroxyphenylpyruvatedioxygenase HPPD
  • Hydroxyphenylpyruvatedioxygenases are enzymes that catalyse the reaction in which para-hydroxyphenylpyruvate (HPP) is transformed into homogentisate.
  • Plants tolerant to HPPD-inhibitors can be transformed with a gene encoding a naturally-occurring resistant HPPD enzyme, or a gene encoding a mutated HPPD enzyme.
  • Tolerance to HPPD-inhibitors can also be obtained by transforming plants with genes encoding certain enzymes enabling the formation of homogentisate despite the inhibition of the native HPPD enzyme by the HPPD-inhibitor. Tolerance of plants to HPPD inhibitors can also be improved by transforming plants with a gene encoding an enzyme prephenate dehydrogenase in addition to a gene encoding an HPPD-tolerant enzyme.
  • ALS inhibitors include, for example, sulphonylurea, imidazolinone, triazolopyrimidines, pyrimidinyloxy(thio)benzoates, and/or sulphonylaminocarbonyltriazolinone herbicides.
  • Different mutations in the ALS enzyme also known as acetohydroxyacid synthase, AHAS
  • AHAS acetohydroxyacid synthase
  • plants tolerant to imidazolinone and/or sulphonylurea can be obtained by induced mutagenesis, by selection in cell cultures in the presence of the herbicide or by mutation breeding.
  • Plants or plant varieties obtained by plant biotechnology methods such as genetic engineering which may also be treated according to the invention are insect-resistant transgenic plants, i.e. plants made resistant to attack by certain target insects. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such insect resistance.
  • insect-resistant transgenic plant includes any plant containing at least one transgene comprising a coding sequence encoding:
  • insect-resistant transgenic plants also include any plant comprising a combination of genes encoding the proteins of any one of the above classes 1 to 8.
  • an insect-resistant plant contains more than one transgene encoding a protein of any one of the above classes 1 to 8, to expand the range of target insect species affected or to delay insect resistance development to the plants, by using different proteins insecticidal to the same target insect species but having a different mode of action, such as binding to different receptor binding sites in the insect.
  • Plants or plant varieties obtained by plant biotechnology methods such as genetic engineering which may also be treated according to the invention are tolerant to abiotic stress factors. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such stress resistance. Particularly useful stress-tolerant plants include the following:
  • Plants or plant varieties obtained by plant biotechnology methods such as genetic engineering which may also be treated according to the invention show altered quantity, quality and/or storage-stability of the harvested product and/or altered properties of specific ingredients of the harvested product such as, for example:
  • Plants or plant varieties obtained by plant biotechnology methods such as genetic engineering which may also be treated according to the invention are plants, such as cotton plants, with altered fiber characteristics.
  • plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such altered fiber characteristics and include:
  • Plants or plant cultivars which may also be treated according to the invention are plants, such as oilseed rape or related Brassica plants, with altered oil profile characteristics.
  • Such plants can be obtained by genetic transformation or by selection of plants containing a mutation imparting such altered oil characteristics and include:
  • transgenic plants which comprise one or more genes which encode one or more toxins are the transgenic plants available under the following trade names: YIELD GARD® (for example maize, cotton, soya beans), KnockOut® (for example maize), BiteGard® (for example maize), BT-Xtra® (for example maize), StarLink® (for example maize), Bollgard® (cotton), Nucotn® (cotton), Nucotn 33B® (cotton), NatureGard® (for example maize), Protecta® and NewLeaf@(potato).
  • YIELD GARD® for example maize, cotton, soya beans
  • KnockOut® for example maize
  • BiteGard® for example maize
  • BT-Xtra® for example maize
  • StarLink® for example maize
  • Bollgard® cotton
  • Nucotn® cotton
  • Nucotn 33B® cotton
  • NatureGard® for example maize
  • herbicide-tolerant plants examples include maize varieties, cotton varieties and soya bean varieties which are available under the following trade names: Roundup Ready® (tolerance to glyphosate, for example maize, cotton, soya beans), Liberty Link® (tolerance to phosphinothricin, for example oilseed rape), IMI® (tolerance to imidazolinone) and SCS® (tolerance to sulphonylurea, for example maize).
  • Herbicide-resistant plants plants bred in a conventional manner for herbicide tolerance
  • Clearfield® for example maize.
  • transgenic plants which may be treated according to the invention are plants containing transformation events, or a combination of transformation events, that are listed for example in the databases for various national or regional regulatory agencies (see for example http://gmoinfo.jrc.it/gmp_browse.aspx and http://www.agbios.com/dbase.php).
  • the plants listed can be treated according to the invention in a particularly advantageous manner with the compounds of the general formula (I) and/or the active compound mixtures according to the invention.
  • the preferred ranges stated above for the active compounds or mixtures also apply to the treatment of these plants. Particular emphasis is given to the treatment of plants with the compounds or mixtures specifically mentioned in the present text.
  • the active compounds or compositions according to the invention can thus be employed for protecting plants for a certain period of time after treatment against attack by the pathogens mentioned.
  • the period for which protection is provided extends generally for 1 to 28 days, preferably 1 to 14 days, particularly preferably for 1 to 10 days, very particularly preferably for 1 to 7 days after the treatment of the plants with the active compounds, or up to 200 days after a seed treatment.
  • Ethyl 2-(1- ⁇ [3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl ⁇ piperidin-4-yl)-1,3-thiazole-4-carboxylate (IV-1, 13.3 g) is dissolved in tetrahydrofuran (80 ml). LiOH monohydrate (1.86 g) dissolved in water (20 ml) is then added. After 3 hours, water is added, the pH is adjusted to 2-3 with dilute hydrochloric acid (1M), the mixture is then extracted with ethyl acetate and the combined organic phases are dried with sodium sulfate. The solid is filtered off and the solvent is removed by distillation.
  • cyclohexanol (2.17 g), dimethylaminopyridine (0.20 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (3.35 g) are added to a solution of 2-(1- ⁇ [3,5-bis(difluoromethyl)-H-pyrazol-1-yl]acetyl ⁇ piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-1, 7.00 g) in dichloromethane (80 ml). The mixture is stirred overnight, and water is then added. The aqueous phase is separated off and extracted with ethyl acetate.
  • Oxalyl chloride (189 mg) and a drop of N,N-dimethylformamide are added to a solution of 2-(1- ⁇ [5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl ⁇ piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-4, 200 mg) in dichloromethane (2 ml).
  • the reaction mixture is stirred at room temperature overnight, and excess oxalyl chloride is then removed under reduced pressure.
  • the residue is re-dissolved in dichloromethane (2 ml) and added to a solution of 1-naphthol (79 mg) and pyridine (489 mg) in dichloromethane (4 ml).
  • lithium hydroxide monohydrate (8.88 g) is added in one portion to a solution of tert-butyl 4-[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (24.0 g) in tetrahydrofuran (240 ml) and water (60 ml).
  • the mixture is stirred for 4 hours and then stirred with dilute hydrochloric acid (1M) (100 ml) and ethyl acetate (100 ml).
  • the aqueous phase is separated off and extracted with ethyl acetate, and the combined organic phases are then dried with sodium sulfate.
  • the solid is filtered off and the solvent is removed by distillation. This gives 2-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-1,3-thiazole-4-carboxylic acid (21 g, 94%)
  • Oxalyl chloride (6.78 g) and a drop of N,N-dimethylformamide are added to a solution of [3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetic acid (10.8 g) in dichloromethane (150 ml). The reaction mixture is stirred at room temperature overnight, and excess oxalyl chloride is then removed under reduced pressure.
  • Table 1 shows the compounds of the formula (I) whose use as fungicides is claimed.
  • the LC-MS determination in the acidic range is carried out at pH 2.7 using the mobile phases 0.1% aqueous formic acid and acetonitrile (contains 0.1% formic acid) linear gradient from 10% acetonitrile to 95% acetonitrile
  • the LC-MS determination in the neutral range is carried out at pH 7.8 using the mobile phases 0.001 molar aqueous ammonium bicarbonate solution and acetonitrile linear gradient from 10% acetonitrile to 95% acetonitrile.
  • the calibration is carried out using unbranched alkan-2-ones (having 3 to 16 carbon atoms) with known logP values (determination of the logP values by the retention times using linear interpolation between two successive alkanones).
  • the lambda-maX values were determined in the maxima of the chromatographic signals using the UV spectra from 200 nm to 400 nm.
  • active compound 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
  • the compounds according to the invention of the formulae below show, at an active compound concentration of 100 ppm, an efficacy of 70% or more.
  • active compound 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
  • young plants are sprayed with the preparation of active compound at the stated application rate. After the spray coating has dried on, the plants are inoculated with an aqueous spore suspension of Plasmopara viticola and then remain in an incubation cabin at about 20° C. and 100% relative atmospheric humidity for 1 day. The plants are then placed in a greenhouse at about 21 C and about 90% atmospheric humidity for 4 days. The plants are then moistened and placed in an incubation cabin for 1 day.
  • the compounds according to the invention of the formulae below show, at an active compound concentration of 100 ppm, an efficacy of 70% or more.
  • active compound 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
  • active compound 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
  • Evaluation is carried out 6 days after the inoculation. 0% means an efficacy which corresponds to that of the control, whereas an efficacy of 100/% means that no infection is observed.
  • active compound 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
  • the plants are moistened and placed in an incubation cabin for 1 day.

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Abstract

The use of thiazole-4-carboxylic esters and thioesters of the formula (I)
Figure US20150237859A1-20150827-C00001
in which
  • R1, R2, R3, R4, R5, R6, R7, Y1, Y2, Y3, W, X and G have the meanings given in the description, and also of agrochemically active salts thereof, as fungicides.

Description

  • The invention relates to thiazole-4-carboxylic esters and thioesters or agrochemically active salts thereof, to their use and to methods and compositions for controlling phytopathogenic harmful fungi in and/or on plants or in and/or on seed of plants, to processes for preparing such compositions and to treated seed, and to their use for controlling phytopathogenic harmful fungi in agriculture, horticulture and forestry, in animal health, in the protection of materials and in the domestic and hygiene field. The present invention furthermore relates to a process for preparing thiazole-4-carboxylic esters and thioesters.
  • It is already known that certain piperidinyl-substituted thiazole-4-carboxamides can be used as fungicidal crop protection agents (see WO 07/014290, WO08/091594). However, in particular at relatively low application rates, the fungicidal activity of these compounds is not always sufficient.
  • Furthermore, in many cases the activity spectrum of these amides is insufficient. Moreover, some carboxylic esters are described as intermediates; however, a biological activity is not described.
  • WO 04/058751 describes piperidinyl-substituted thiazole-4-carboxylic esters and thioesters which can be used as pharmaceutics for modulating blood pressure.
  • WO 05/003128 describes further piperidinyl-substituted thiazole-4-carboxylic esters and thioesters which are likewise suitable for medicinal applications, here as inhibitors on the microsomal triglyceride transfer protein (MTP inhibitors). However, an effect on fungal pathogens is not described.
  • Since the ecological and economical demands made on modern crop protection agents are increasing constantly, for example with respect to activity spectrum, toxicity, selectivity, application rate, formation of residues and favorable manufacture, and there can furthermore be problems, for example, with resistances, there is a constant need to develop novel crop protection agents which, at least in some areas, have advantages over the known ones.
  • Surprisingly, it has now been found that the present thiazole-4-carboxylic esters and thioesters achieve at least some aspects of the objects mentioned and are suitable for use as crop protection agents, in particular as fungicides.
  • The invention relates to compounds of the formulas (I)
  • Figure US20150237859A1-20150827-C00002
  • in which the symbols have the following meanings:
    • R1 and R3 independently of one another are H, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-cycloalkyl, C3-C6-halocycloalkyl, optionally substituted phenyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, (C1-C4-alkyl)carbonyl, formyl, CR8═NOR9, CONR10R11, (C1-C4-alkoxy)carbonyl, COOH, halogen, hydroxyl or cyano
    • R2 is H, substituted or unsubstituted phenyl, C1-C4-alkyl, C2-C4-alkenyl. C2-C4-alkynyl, C3-C6-cycloalkyl, C3-C6-halocycloalkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, (C1-C4-alkyl)carbonyl, formyl, CR8═NOR9, CONR10R11, (C1-C4-alkoxy)carbonyl, COOH, halogen, hydroxyl, cyano, nitro or NR10R11
      or
    • R1 and R2 or R2 and R3 together with the carbon atoms to which they are attached form a 5- to 7-membered unsubstituted or substituted, partially saturated or unsaturated cycle which may contain up to three further heteroatoms selected from the group consisting of N, O and S, where two oxygen atoms are not adjacent,
      possible substituents independently of one another being selected from the group consisting of C1-C4-alkyl, C1-C4-alkoxy, oxo, hydroxyl and halogen
    • R4 and R5 independently of one another are H, C1-C4-alkyl, C3-C6-cycloalkyl or C1-C4-haloalkyl,
      or
    • R4 and R5 together with the carbon atom to which they are attached form a 3- to 7-membered unsubstituted or substituted saturated cycle which may contain up to three heteroatoms selected from the group consisting of N, O and S, where two oxygen atoms are not adjacent, possible substituents independently of one another being selected from the group consisting of C1-C4-alkyl, C1-C4-alkoxy, oxo, hydroxyl, halogen
    • Y1, Y2, Y3 independently of one another are sulfur or oxygen
    • X is a direct bond or an unsubstituted or substituted C1- to C3-carbon chain, where the carbon atoms carry, independently of one another, H, C1-C4-alkyl or oxo as substituents
    • W is an unsubstituted or substituted C1- to C3-carbon chain, where the carbon atoms carry, independently of one another, H, C1-C4-alkyl or oxo as substituents
    • R6 is H, C1-C4-alkyl, C1-C4-haloalkyl, (C1-C4-alkyl)carbonyl, formyl, CR8═NOR9, CONR10R11, (C1-C4-alkoxy)carbonyl, COOH, NR10R11, nitro, halogen or cyano
    • G is (C(R12)2)m
      where m=0 to 6
    • R7 is unsubstituted or substituted C5-C10-alkyl, C2-C16-alkenyl, C2-C16-alkynyl, C3-C15-cycloalkyl, C5-C15-cycloalkenyl, C3-C15-heterocyclyl, aryl, hetaryl or Si(C1-C4-alkyl)3,
      possible substituents independently of one another being selected from the list below:
      halogen, cyano, nitro, nitroso, C1-C4-alkyl, C1-C4-haloalkyl, arylalkyl, arylhaloalkyl, hydroxyl, oxo, C1-C4-alkoxy, O(C1-C6-alkyl)mOC1-C6-alkyl, O—C3-C6-cycloalkyl, O-phenyl, C1-C4-haloalkoxy, SH, C1-C6-thioalkyl, C1-C6-thiohaloalkyl, S-phenyl, SO2—C1-C6-alkyl, SO2—C1-C6-haloalkyl, SO—C1-C6-alkyl, SO—C1-C6-haloalkyl, CO2H, (C1-C4-alkyl)carbonyl, (C1-C4-haloalkyl)carbonyl, formyl, CR8═NOR9, CONR10R11, (C1-C4-alkoxy)carbonyl, COOH, NR10R11, cyclopropylamino, CH2COCH3, (CH2)mO—C1-C6-alkyl, CH2OH, CH2SMe, (CH2)2SMe, C3-C6-cycloalkyl, 1-methoxycyclopropyl, 1-chlorocyclopropyl, cyclohexylmethyl, C2-C6-alkenyl, C2-C6-alkynyl, Si(C1-C4-alkyl)3, phenyl or benzyl
      or
      two adjacent substituents form an optionally methyl- or halogen-substituted dioxolane or dioxane ring,
    • R8, R9, R10, R11 independently of one another are H, C1-C4-alkyl or C3-C6-cycloalkyl,
      or
    • R10 and R11 together with the nitrogen atom to which they are attached form a 3- to 7-membered unsubstituted or substituted saturated cycle which may contain up to two further heteroatoms selected from the group consisting of N, O and S, where two oxygen atoms are not adjacent,
      possible substituents independently of one another being selected from the group consisting of C1-C4-alkyl, C1-C4-alkoxy, halogen and oxo
    • R12 is identical or different independently of one another H, halogen, C1-C4-alkyl, C1-C4-alkoxy, C3-C6-cycloalkyl or C1-C4-haloalkyl,
      or
      two or four R12, in each case on two adjacent carbon atoms, are direct bonds,
      and also agrochemically active salts thereof.
  • The thiazole-4-carboxylic esters and thioesters of the formula (I) according to the invention and their agrochemically active salts are highly suitable for controlling phytopathogenic harmful fungi. The compounds according to the invention mentioned above have potent fungicidal activity and can be used both in crop protection, in the domestic and hygiene field and in the protection of materials.
  • The compounds of the formula (I) can be present both in pure form and as mixtures of various possible isomeric forms, in particular of stereoisomers, such as E and Z, threo and erythro, endo or exo, and also optical isomers, such as R and S isomers or atropisomers, and, if appropriate, also of tautomers. What is claimed are both the E and the Z isomers, and also the threo and erythro, and also the optical isomers, any mixtures of these isomers, and also the possible tautomeric forms.
  • Preference is given to compounds of the formula (I) in which one or more of the symbols have one of the meanings below:
    • R1 and R3 independently of one another are H, C1-C4-alkyl, C3-C6-cycloalkyl, C1-C3-alkoxy, C1-C3-haloalkyl, C1-C3-haloalkoxy, halogen, hydroxyl, cyano or phenyl,
    • R2 is H, phenyl, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-cycloalkyl, C1-C3-alkoxy, C1-C3-haloalkyl, C1-C3-haloalkoxy, halogen, hydroxyl, cyano or NR10R11.
      or
    • R1 and R2 together with the carbon atoms to which they are attached form a phenyl ring,
    • R4 and R5 independently of one another are H, C1-C3-alkyl, cyclopropyl, cyclopentyl, cylohexyl, or C1-C3-haloalkyl,
      or
    • R4 and R5 together with the carbon atom to which they are attached form a cyclopropyl ring,
    • Y1 and Y2 are oxygen,
    • Y3 is sulfur or oxygen,
    • X is a direct bond, CH2 or CH2CH2,
    • W is CH2, CH2CH2 or CH2CH2CH2,
    • R6 is H, C1-C3-alkyl, C1-C3-haloalkyl, NH2, NHMe, NMe2, chlorine, fluorine or cyano,
    • G is (C(R12)2)m.
      where m=0 to 4
    • R7 is unsubstituted or substituted C5-C10-alkyl, C2-C16-alkenyl, C2-C16-alkynyl, C3-C15-cycloalkyl, C5-C15-cycloalkenyl, C3-C15-heterocyclyl, aryl, hetaryl or Si(C1-C4-alkyl)3,
      possible substituents independently of one another being selected from the list below:
      fluorine, chlorine, bromine, iodine, cyano, nitro, CF3, CFH2, CF2H, C2F5, CCl3, hydroxyl, OMe, OEt, OPr, OisoPr, OBu, OsecBu, OlsoBu, OtertBu, O(CH2)2OCH3, O(CH2)3OCH3, O-cyclohexyl, O-cylopentyl, O-cyclopropyl, O-phenyl, OCF3, OCF2H, OCH2CF3, OCF2CF3, SH, SMe, SEt, SCF3, SCF2H, S-phenyl, SO2Me, SO2CF3, SOMe, SOEt, CO2H, CO2CH3, CO2Et, CO2Pr, CO2isoPr, CO2tertBu, COMe, COCF3, NH2, NHMe, NMe2, NHEt, NEt2, NHPr, NHisoPr, NHnBu, NHtertBu, NHisoBu, NHsecBu, cyclopropylamino, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, aziridinyl, azetidinyl, formyl, CH2COCH3, CH2OMe, (CH2)2OMe, (CH2)3OMe, CH2OH, CH2SMe, (CH2)2SMe, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, 1-methoxycyclopropyl, 1-chlorocyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, prop-2-en-1-yl, 1-methylprop-2-en-1-yl, but-3-en-1-yl, trimethylsilyl)methyl, phenyl, benzyl, —CH═CH2, —CH2CH═CH2, —CH(CH3)CH—CH2, —CH2C≡CH, —C≡CH,
      or
      two adjacent substituents form an optionally methyl- or halogen-substituted dioxolane or dioxane ring,
    • R10,R11 independently of one another are H, methyl, ethyl, isopropyl or cyclopropyl,
      or
    • R10 and R11 together with the nitrogen atom to which they are attached form an aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl ring,
    • R12 is identical or different independently of one another H, methyl, ethyl, chlorine, fluorine, trifluoromethyl, methoxy or cyclopropyl,
      or
      two or four R12, in each case on two adjacent carbon atoms, are direct bonds,
      and the agrochemically active salts thereof.
  • Particular preference is given to compounds of the formula (I) in which one or more of the symbols have one of the meanings below:
    • R1 is C1-C2-alkyl or C1-C2-haloalkyl,
    • R2 is H, C1-C2-haloalkyl or halogen,
      or
    • R1 and R2 together with the carbon atoms to which they are attached form a phenyl ring,
    • R3 is H, C1-C2-alkyl, C1-C2-haloalkyl or phenyl,
    • R4 is H, C1-C2-alkyl or C1-C2-haloalkyl,
    • R5 is H, C1-C2-alkyl, C1-C2-haloalkyl or cyclopropyl,
      or
    • R4 and R5 together with the carbon atom to which they are attached form a cyclopropyl ring,
    • Y1 is oxygen,
    • Y2 is oxygen,
    • Y3 is sulfur or oxygen,
    • X is CH2 or CH2CH2,
    • W is CH2, CH2CH2 or CH2CH2CH2,
    • R6 is H or methyl,
    • G is (C(R12)),
      where m=0 to 4
    • R7 is unsubstituted or substituted C5-C10-alkyl, C2-C16-alkenyl, C2-C16-alkynyl, C3-C15-cycloalkyl, C5-C15-cycloalkenyl, C3-C15-heterocyclyl, aryl, hetaryl or Si(C1-C4-alkyl)3,
      possible substituents independently of one another being selected from the list below:
      fluorine, chlorine, bromine, iodine, cyano, nitro, CF3, hydroxyl, OMe, O-phenyl, OCF3, OCF2H, OCH2CF3, OCF2CF3, SMe, S-phenyl, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, phenyl, benzyl, —CH—CH2, —CH2CH—CH2 or —C≡CH,
    • R12 is identical or different independently of one another H, methyl or ethyl,
      and the agrochemically active salts thereof.
  • Very particular preference is given to compounds of the formula (I) in which one or more of the symbols have one of the meanings below:
    • R1 is methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, difluoromethyl, trifluoromethyl or pentafluoroethyl,
    • R2 is H or chlorine,
      or
    • R1 and R2 together with the carbon atoms to which they are attached form a phenyl ring,
    • R3 is H, methyl, 1,1-dimethylethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl or phenyl,
    • R4 is H or methyl,
    • R5 is H, methyl or cyclopropyl,
      or
    • R4 and R5 together with the carbon atom to which they are attached form a cyclopropyl ring,
    • Y1 is oxygen,
    • Y2 is oxygen,
    • Y3 is sulfur or oxygen,
    • X is CH2 or CH2CH2,
    • W is CH2, CH2CH2 or CH2CH2CH2,
    • R6 is H or methyl,
    • G is a direct bond, CH2, CH2CH2, CH(CH3), CH(CH2CH3) or CH(CF3),
    • R7 is methyl, tert-butyl, heptan-3-yl, octyl, (1Z)-prop-1-en-1-yl, (E)-2-phenylethenyl, hex-1-en-3-yl, diphenylmethyl, 1,2,3,4-tetrahydronaphthalen-1-yl, (1R)-1,2,3,4-tetrahydronaphthalen-1-yl, (1S)-1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl, 5,6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, decahydronaphthalen-1-yl, 1,4-dioxaspiro[4.5]dec-8-yl, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-2-yl, cyclopropyl, 2,2-dichlorocyclopropyl, cyclopentyl, 1-ethynylcyclopentyl, cyclohexyl, 2-methylcyclohexyl, 2,6-dimethylcyclohexyl, 4-tert-butylcyclohexyl, 5-methyl-2-(propan-2-yl)cyclohexyl, 3-methyl-5-(propan-2-yl)cyclohexyl, 1-cyanocyclohexyl, 1-ethynylcyclohexyl, cycloheptyl, cyclopropyl(phenyl)methyl, (1S,2R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl, phenyl, 4-fluorophenyl, 2-bromophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,4,6-trichlorophenyl, 2,4,6-trifluorophenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 2,6-dimethoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-nitrophenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 2-(trifluoromethoxy)phenyl, 4-(trifluoromcthoxy)phenyl, 4-tert-butylphenyl, biphenyl-2-yl, biphenyl-3-yl, biphenyl-4-yl, 3-phenoxyphenyl, 4-phenoxyphenyl, 2-[1-methoxy-2-(methylamino)-2-oxoethyl]phenyl, 2-[(methylaminoxoxo)acetyl]phenyl 1-naphthyl, 2-naphthyl, phenylethynyl, 2-thienyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-5-yl, 1,3-benzoxazol-4-yl, trifluoromethyl, morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, 4-methylpiperazin-1-yl, dimethylamino or trimethylsilyl,
      and the agrochemically active salts thereof.
  • Most preference is given to compounds of the formula (I) in which one or more of the symbols have one of the meanings below:
    • R1 is methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, difluoromethyl, trifluoromethyl or pentafluoroethyl,
    • R2 is H or chlorine,
    • R3 is H, methyl, 1,1-dimethylethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl or phenyl,
    • R4 is H or methyl,
    • R5 isH or methyl,
    • Y1 is oxygen,
    • Y2 is oxygen,
    • Y3 is sulfur or oxygen,
    • X is CH2 or CH2CH2,
    • W is CH2 or CH2CH2,
    • R6 is H,
    • G is a direct bond, CH2, CH2CH2, CH(CH3) or CH(CH2CH3),
    • R7 is heptan-3-yl, octyl, (1Z)-prop-1-en-1-yl, (E)-2-phenylethenyl, hex-1-en-3-yl, diphenylmethyl, 1,2,3,4-tetrahydronaphthalen-1-yl, (1R)-1,2,3,4-tetrahydronaphthalen-1-yl, (1S)-1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl, 5,6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, decahydronaphthalen-1-yl, 1,4-dioxaspiro[4.5]dec-8-yl, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-2-yl, cyclopropyl, cyclopentyl, 1-ethynylcyclopentyl, cyclohexyl, 2-methylcyclohexyl, 2,6-dimethylcyclohexyl, 4-tert-butylcyclohexyl, 5-methyl-2-(propan-2-yl)cyclohexyl, 3-methyl-5-(propan-2-yl)cyclohexyl. 1-cyanocyclohexyl, 1-ethynylcyclohexyl, cycloheptyl, cyclopropyl(phenyl)methyl, (1S,2R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,4,6-trichlorophenyl, 2,4,6-trifluorophenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 2,6-dimethoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-nitrophenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 2-(trifluoromethoxy)phenyl, 4-(trifluoromethoxy)phenyl, 4-tert-butylphenyl, biphenyl-2-yl, biphenyl-3-yl, biphenyl-4-yl, 3-phenoxyphenyl, 4-phenoxyphenyl, 1-naphthyl, 2-naphthyl, phenylethynyl, 2-thienyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-5-yl, 1,3-benzoxazol-4-yl, trifluoromethyl, dimethylamino or trimethylsilyl,
      and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which one or more of the symbols have one of the meanings below:
    • R1 is C1-C4-alkyl or C1-C2-haloalkyl,
    • R2 is H and
    • R3 is C1-C4-alkyl or C1-C2-haloalkyl,
      where the other substituents have one or more of the meanings mentioned above,
      and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which one or more of the symbols have one of the meanings below:
    • R1 is methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, difluoromethyl, trifluoromethyl or pentafluoroethyl,
    • R2 is H and
    • R3 is methyl, 1,1-dimethylethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl or phenyl,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which one or more of the symbols have one of the meanings below:
    • X is CH2CH2 and
    • W is CH2,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which
    • Y3 is oxygen,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which
    • R6 is H,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which
    • G is CH2, CH2CH2, CH(CH3) or CH(CH2CH3).
      where the other substituents have one or more of the meanings mentioned above, and the agrochcmically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which
    • R7 is C5-C10-alkyl,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which
    • R7 is C5-C8-alkyl,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Very particular preference is furthermore given to compounds of the formula (I) in which
    • R7 is heptan-3-yl or octyl,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which
    • R7 is C2-C16-alkenyl,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which
    • R7 is C2-C6-alkenyl,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which
    • R7 is (1Z)-prop-1-en-1-yl or hex-1-en-3-yl,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which
    • R7 is C2-C16-alkynyl,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which
    • R7 is C2-C6-alkynyl,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which
    • R7 is C3-C15-cycloalkyl,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which
    • R7 is C3-C8-cycloalkyl,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which
    • R7 is cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which
    • R7 is C5-C15-cycloalkenyl,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which
    • R7 is C5-C8-cycloalkenyl,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which
    • R7 is C3-C15-heterocyclyl,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which
    • R7 is C5-C6-heterocyclyl,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which
    • R7 is aryl,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which
    • R7 is phenyl, or saturated or partially or fully unsaturated unsubstituted or substituted naphthyl or indenyl,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which
    • R7 is phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydronaphthalen-1-yl, (1R)-1,2,3,4-tetrahydronaphthalen-1-yl, (1S)-1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl, 5,6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, decahydronaphthalen-1-yl, 2,3-dihydro-1H-inden-1-yl or 2,3-dihydro-1H-inden-2-yl,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which
    • R7 is hetaryl,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which
    • R7 is furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, indol-1-yl, indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, indazol-1-yl, indazol-3-yl, indazol-4-yl, indazol-5-yl, indazol-6-yl, indazol-7-yl, indazol-2-yl, 1-benzofuran-2-yl, 1-benzofuran-3-yl, 1-benzofuran-4-yl, 1-benzofuran-5-yl, 1-benzofuran-6-yl, 1-benzofuran-7-yl, 1-benzothiophen-2-yl, 1-benzothiophen-3-yl, 1-benzothiophen-4yl, 1-benzothiophen-5-yl, 1-benzothiophen-6-yl, 1-benzothiophen-7-yl. 1,3-bcnzothiazol-2-yl, 1,3-benzothiazol-4-yl, 1,3-benzothiazol-5-yl, 1,3-benzothiazol-6-yl, 1,3-benzothiazol-7-yl, 1,3-benzoxazol-2-yl, 1,3-benzoxazol-4-yl, 1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl, 1,3-benzoxazol-7-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl or isoquinolin-8-yl,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which
    • R7 is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-5-yl or 1,3-benzoxazol-4-yl,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which
    • R7 is Si(C1-C4-alkyl)3,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which
    • R7 is Si(C1-C2-alkyl)3,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Special preference is furthermore given to compounds of the formula (I) in which
    • R7 is trimethylsilyl,
      where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.
  • Depending on the nature of the substituents defined above, the compounds of the formula (I) have acidic or basic properties and can form salts, if appropriate also inner salts, or adducts with inorganic or organic acids or with bases or with metal ions. If the compounds of the formula (I) carry amino, alkylamino or other groups which induce basic properties, these compounds can be reacted with acids to give salts, or they are directly obtained as salts in the synthesis. If the compounds of the formula (I) carry hydroxyl, carboxyl or other groups which induce acidic properties, these compounds can be reacted with bases to give salts. Suitable bases are, for example, hydroxides, carbonates, bicarbonates of the alkali metals and alkaline earth metals, in particular those of sodium, potassium, magnesium and calcium, furthermore ammonia, primary, secondary and tertiary amines having (C1-C4)-alkyl groups, mono-, di- and trialkanolamines of (C1-C4)-alkanols, choline and also chlorocholine.
  • The salts obtainable in this manner also have fungicidal properties.
  • Examples of inorganic acids are hydrohalic acids, such as hydrogen fluoride, hydrogen chloride, hydrogen bromide and hydrogen iodide, sulphuric acid, phosphoric acid and nitric acid, and acidic salts, such as NaHSO4 and KHSO4. Suitable organic acids are, for example, formic acid, carbonic acid and alkanoic acids, such as acetic acid, trifluoroacetic acid, trichloroacetic acid and propionic acid, and also glycolic acid, thiocyanic acid, lactic acid, succinic acid, citric acid, benzoic acid, cinnamic acid, oxalic acid, alkylsulphonic acids (sulphonic acids having straight-chain or branched alkyl radicals of 1 to 20 carbon atoms), arylsulphonic acids or aryldisulphonic acids (aromatic radicals, such as phenyl and naphthyl, which carry one or two sulphonic acid groups), alkylphosphonic acids (phosphonic acids having straight-chain or branched alkyl radicals of 1 to 20 carbon atoms), arylphosphonic acids or aryldiphosphonic acids (aromatic radicals, such as phenyl and naphthyl, which carry one or two phosphonic acid radicals), where the alkyl and aryl radicals may carry further substituents, for example p-toluenesulphonic acid, salicylic acid, p-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, etc.
  • Suitable metal ions are in particular the ions of the elements of the second main group, in particular calcium and magnesium, of the third and fourth main group, in particular aluminum, tin and lead, and also of the first to eighth transition group, in particular chromium, manganese, iron, cobalt, nickel, copper, zinc and others. Particular preference is given to the metal ions of the elements of the fourth period. Here, the metals can be present in various valencies that they can assume.
  • Optionally substituted groups can be mono- or polysubstituted, where in the case of polysubstitutions the substituents can be identical or different.
  • In the definitions of the symbols given in the formulae above, collective terms were used which are generally representative of the following substituents:
  • halogen: fluorine, chlorine, bromine and iodine;
    aryl: unsubstituted or optionally substituted 5- to 15S-membered partially or filly unsaturated mono-, bi- or tricyclic ring system having up to 3 ring members selected from the groups C(O), (C═S), where at least one of the rings of the ring system is fully unsaturated, such as, for example (but not limited to), benzene, naphthalene, tetrahydronaphthalene, anthracene, indane, phenantlirene, azulene;
    alkyl: saturated, straight-chain or branched hydrocarbon radicals having 1 to 10 carbon atoms, for example (but not limited thereto) methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl, heptyl, 1-methylhexyl, octyl, 1,1-diniethylhexyl, 2-ethylbexyl, 1-ethylhexyl, nonyl, 1,2,2-trimethylhexyl, decyl;
    • haloalkyl: straight-chain or branched alkyl groups having 1 to 4 carbon atoms (as mentioned above), where in these groups some or all of the hydrogen atoms may be replaced by halogen atoms as mentioned above, for example (but not limited thereto) C1-C2-haloalkyl, such as chloro-methyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and 1,1,1-trifluoroprop-2-yl;
      alkenyl: unsaturated, straight-chain or branched hydrocarbon radicals having 2 to 16 carbon atoms and at least one double bond in any position, for example (but not limited thereto) C2-C6-alkenyl, such as ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3 methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl;
      alkynyl: straight-chain or branched hydrocarbon groups having 2 to 16 carbon atoms and at least one triple bond in any position, for example (but not limited thereto) C2-C6-alkynyl, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-1-pentynyl, 3-methyl-4-pentynyl, 4-methyl-1-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl;
      alkoxy: saturated, straight-chain or branched alkoxy radicals having 1 to 4 carbon atoms, for example (but not limited thereto) C1-C4-alkoxy, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy;
      haloalkoxy: straight-chain or branched alkoxy groups having 1 to 4 carbon atoms (as mentioned above), where in these groups some or all of the hydrogen atoms may be replaced by halogen atoms as mentioned above, for example (but not limited thereto) C1-C2-haloalkoxy, such as chloro-methoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 1-chloroethoxy, 1-bromoethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy. 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy and 1,1,1-trifluoroprop-2-oxy;
      thioalkyl: saturated, straight-chain or branched alkylthio radicals having 1 to 6 carbon atoms, for example (but not limited thereto) C1-C6-alkylthio, such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio, 1,1-dimethylethylthio, pentylthio, 1-methylbutylthio, 2-methylbutylthio, 3-methylbutylthio, 2,2-dimethylpropylthio, 1-ethylpropylthio, hexylthio, 1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 1-methylpentylthio, 2-methylpentylthio, 3-methylpentylthio, 4-methylpentylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,2-dimethylbutylthio, 2,3-dimethylbutylthio, 3,3-dimethylbutylthio, 1-ethylbutylthio, 2-ethylbutylthio, 1,1,2-trimethylpropylthio, 1,2,2-trimethyl-propylthio, 1-ethyl-1-methylpropylthio and 1-ethyl-2-methylpropylthio;
      thiohaloalkyl: straight-chain or branched alkylthio groups having 1 to 6 carbon atoms (as mentioned above), where in these groups some or all of the hydrogen atoms may be replaced by halogen atoms as mentioned above, for example (but not limited thereto) C1-C2-haloalkylthio, such as chloromethylthio, bromomethylthio, dichloromethylthio, trichloromethylthio, fluoromethylthio, difluoromethylthio, trifluoromethylthio, chlorofluoromethylthio, dichlorofluoromethylthio, chlorodifluoromethylthio, 1-chloroethylthio, 1-bromoethylthio, 1-fluoroethylthio, 2-fluoroethylthio. 2,2-difluoroethylthio, 2,2,2-trifluoroethylthio, 2-chloro-2-fluoroethylthio, 2-chloro-2,2-difluoroethylthio, 2,2-dichloro-2-fluoroethylthio, 2,2,2-trichloroethylthio, pentafluoroethylthio and 1,1,1-trifluoroprop-2-ylthio;
      cycloalkyl: mono-, bi- or tricyclic saturated hydrocarbon groups having 3 to 12 carbon ring members, for example (but not limited thereto) cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, bicyclo[1.0.1]butane, decalinyl, norbornyl:
      cycloalkenyl: mono-, bi- or tricyclic non-aromatic hydrocarbon groups having 5 to 15 carbon ring members and at least one double bond, for example (but not limited thereto) cyclopenten-1-yl, cyclohexen-1-yl, cyclohepta-1,3-dien-1-yl, norbornen-1-yl;
      (alkoxy)carbonyl: an alkoxy group having 1 to 4 carbon atoms (as mentioned above) which is attached to the skeleton via a carbonyl group (—CO—);
      heterocyclyl: a three- to fifteen-membered saturated or partially unsaturated heterocycle which contains one to four heteroatoms from the group consisting of oxygen, nitrogen and sulfur: mono-, bi- or tricyclic heterocycles which contain, in addition to carbon ring members, one to three nitrogen atoms and/or one oxygen or sulphur atom or one or two oxygen and/or sulphur atoms; if the ring contains a plurality of oxygen atoms, these are not directly adjacent; such as, for example (but not limited thereto), oxiranyl, aziridinyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 3-isothiazolidinyl, 4-isothiazolidinyl, 5-isothiazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 2-thiazolidinyl, 4-thiazolidinyl, 5-thiazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1,2,4-oxadiazolidin-3-yl, 1,2,4-oxadiazolidin-5-yl, 1,2,4-thiadiazolidin-3-yl, 1,2,4-thiadiazolidin-5-yl, 1,2,4-triazolidin-3-yl, 1,3,4-oxadiazolidin-2-yl, 1,3,4-thiadiazolidin-2-yl, 1,3,4-triazolidin-2-yl, 2,3-dihydrofur-2-yl, 2,3-dihydrofur-3-yl, 2,4-dihydrofur-2-yl, 2,4-dihydrofur-3-yl, 2,3-dihydrothien-2-yl, 2,3-dihydrothien-3-yl, 2,4-dihydrothien-2-yl, 2,4-dihydrothien-3-yl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4-isoxazolin-3-yl, 2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin-4-yl, 2-isoxazolin-5-yl, 3-isoxazolin-5-yl, 4-isoxazolin-5-yl, 2-isothiazolin-3-yl, 3-isothiazolin-3-yl, 4-isothiazolin-3-yl, 2-isothiazolin-4-yl, 3-isothiazolin-4-yl, 4-isothiazolin-4-yl, 2-isothiazolin-5-yl, 3-isothiazolin-5-yl, 4-isothiazolin-5-yl, 2,3-dihydropyrazol-1-yl, 2,3-dihydropyrazol-2-yl, 2,3-dihydropyrazol-3-yl, 2,3-dihydropyrazol-4-yl, 2,3-dihydropyrazol-5-yl, 3,4-dihydropyrazol-1-yl, 3,4-dihydropyrazol-3-yl, 3,4-dihydropyrazol-4-yl, 3,4-dihydropyrazol-5-yl, 4,5-dihydropyrazol-1-yl, 4,5-dihydropyrazol-3-yl, 4,5-dihydropyrazol-4-yl, 4,5-dihydropyrazol-5-yl, 2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-3-yl, 2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 3,4-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 2.piperidinyl, 3-piperidinyl, 4-piperidinyl, 1,3-dioxan-5-yl, 2-tetra-hydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, 3-hexahydropyridazinyl, 4-hexahy-dropyridazinyl, 2-hexahydropyrimidinyl, 4-hexahydropyrimidinyl, 5-hexahydropyrimidinyl, 2-piperazinyl, 1,3,5-hexahydrotriazin-2-yl and 1,2,4-hexahydrotriazin-3-yl;
      hetaryl: an unsubstituted or optionally substituted 5- to 15-membered partially or fully unsaturated mono-, bi- or tricyclic ring system where at least one of the rings of the ring system is fully unsaturated and which contains one to four heteroatoms from the group consisting of oxygen, nitrogen and sulfur; if the ring contains a plurality of oxygen atoms, these are not directly adjacent;
      such as, for example (but not limited thereto)
      • 5-membered heteroaryl which contains one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom: 5-membered heteroaryl groups which, in addition to carbon atoms, may contain one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom as ring members, for example 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-imidazolyl, 4-imidazolyl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,4-triazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl and 1,3,4-triazol-2-yl;
      • benzo-fused 5-membered heteroaryl which contains one to three nitrogen atoms or one nitrogen atom and one oxygen or sulfur atom: 5-membered heteroaryl groups which, in addition to carbon atoms, may contain one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom as ring members and in which two adjacent carbon ring members or one nitrogen and one adjacent carbon ring member may be bridged by a buta-1,3-diene-1,4-diyl group in which one or two carbon atoms may be replaced by nitrogen atoms; for example benzindolyl, benzimidazolyl, benzothiazolyl, benzopyrazolyl, benzofuryl;
      • 5-membered heteroaryl which contains one to four nitrogen atoms and is attached via nitrogen or benzo-fused 5-membered heteroaryl which contains one to three nitrogen atoms and is attached via nitrogen: 5-membered heteroaryl groups which, in addition to carbon atoms, may contain one to four nitrogen atoms or one to three nitrogen atoms as ring members and in which two adjacent carbon ring members or one nitrogen and one adjacent carbon ring member may be bridged by a buta-1,3-diene-1,4-diyl group in which one or two carbon atoms may be replaced by nitrogen atoms, where these rings are attached to the skeleton via one of the nitrogen ring members, for example 1-pyrrolyl, 1-pyrazolyl, 1,2,4-triazol-1-yl, 1-imidazolyl, 1,2,3-triazol-1-yl, 1,3,4-triazol-1-yl;
      • 6-membered heteroaryl which contains one to three or one to four nitrogen atoms: 6-membered heteroaryl groups which, in addition to carbon atoms, may contain, respectively, one to three and one to four nitrogen atoms as ring members, for example 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl and 1,2,4-triazin-3-yl;
  • Not included are combinations which are against natural laws and which the person skilled in the art would therefore exclude based on his/her expert knowledge. Ring structures having three or more adjacent oxygen atoms, for example, are excluded.
  • The present invention furthermore provides a process for preparing the thiazole-4-carboxylic esters and thioesters of the formula (I) according to the invention, which comprises at least one of steps (a) to (c) below:
    • (a) the conversion of a compound of the formula (VII) or (IX) into a compound of the formula (VI) or (X), optionally in each case in the presence of a solvent and, if appropriate, in the presence of an acid or, if appropriate, in the presence of a base or, if appropriate, in the presence of a hydrogen source, according to the reaction scheme below (Scheme 1):
  • Figure US20150237859A1-20150827-C00003
  • where
      • L=—O—C1-C2-alkyl for compounds of the formulae (VII) and (VI),
      • L=—Y3−G-R7 for compounds of the formulae (IX) and (X),
      • PG=acetyl, C1-C4-alkoxycarbonyl, benzyl or benzyloxycarbonyl,
      • W, X and R6 are as defined above for formula (I).
    • (b) the reaction of a compound of the formula (VI) or (X) with a compound of the formula (V) to give a compound of the formula (IV) or (I), in each case, if appropriate, in the presence of a coupling agent, a base and a solvent, according to the reaction scheme below (Scheme 2):
  • Figure US20150237859A1-20150827-C00004
      • where
      • Z═Cl or OH,
      • L=—O—C1-C2-alkyl for compounds of the formulae (VI) and (IV),
      • L=—Y3-G-R7 for compounds of the formulae (X) and (I),
      • W, X, Y3, G, R, R2, R3, R4, R5, R6 and R7 are as defined above for formula (I).
    • (c) the conversion of a compound of the formula (IV) or (VII) into a compound of the formula (III) or (VIII), in each case by hydrolysis in the presence of a base and, if appropriate, in the presence of a solvent, according to the reaction scheme below (Scheme 3):
  • Figure US20150237859A1-20150827-C00005
      • where
  • Figure US20150237859A1-20150827-C00006
  • for compounds of the formulae (IV) and (III),
      • Q=acetyl, C1-C4-alkoxycarbonyl, benzyl or benzyloxycarbonyl (corresponds to PG), for compounds of the formulae (VII) and (VIII),
      • W, X, R1, R2, R3, R4, R5 and R6 are as defined above for formula (I).
    • (d) the reaction of a compound of the formula (III) or (VIII) with a compound of the formula
  • (II) to give a compound of the formula (I) or (IX), in each case, if appropriate, in the presence of a coupling agent, a base and a solvent, according to the reaction scheme below (Scheme 4):
  • Figure US20150237859A1-20150827-C00007
  • where
  • Figure US20150237859A1-20150827-C00008
  • for compounds of the formulae (III) and (I),
      • Q=acetyl, C1-C4-alkoxycarbonyl, benzyl or benzyloxycarbonyl (corresponds to PG), for compounds of the formulae (VIII) and (IX),
      • Z═OH or chlorine,
      • W, X, Y3, G, R, R2, R3, R4, R5, R6 and R7 are as defined above for formula (I).
    • (e) the conversion of a compound of the formula (I) into a compound of the formula (I) in the presence of a sulfurizing agent and, if appropriate, in the presence of a solvent, according to the reaction scheme below (Scheme 5):
  • Figure US20150237859A1-20150827-C00009
      • where
      • Y1=sulfur or oxygen,
      • Y2=sulfur or oxygen,
      • W, X, Y3, G, R1, R2, R3, R4, R5, R6 and R7 are as defined above for formula (I).
  • A general overview of the synthesis paths is given in Scheme 6.
  • The protective group is removed from compounds of the formula (VII), giving compounds of the formula (VI) or the corresponding salt (Scheme 1). A compound of the formula (VI) or a corresponding salt is coupled with a substrate of the formula (V), which gives compounds of the formula (IV) (Scheme 2). The hydrolysis of compounds of the formula (IV) leads to carboxylic acids of the formula (III) (Scheme 3), followed by a coupling reaction in the presence of an alcohol or thiol of the general formula (II), which gives compounds of the formula (I) (Scheme 4). Alternatively, the hydrolysis of the compound of the formula (VII) leads to a carboxylic acid of the general formula (VIII) (Scheme 3), followed by a coupling reaction in the presence of an alcohol or thiol of the general formula (II), which gives a compound of the formula (IX) (Scheme 4). The protective group marked PG of a compound of the formula (IX) is removed, so that a compound of the formula (X) or the corresponding salt is formed (Scheme 1). A compound of the formula (X) or a corresponding salt is coupled with a substrate of the formula (V), which gives a compound of the formula (I) (Scheme 2). A sulfurizing agent is added to a compound of the formula (I) to form a compound of the formula (I) (Y1=sulfur or oxygen, Y2=sulfur or oxygen) (Scheme 5).
  • Figure US20150237859A1-20150827-C00010
  • One way of preparing the intermediate (VI) from corresponding compounds (VII) is shown in Scheme 1.
  • A compound of the formula (VII) is converted into a compound of the formula (VI) a using suitable methods for removing protective groups, which methods are described in the literature (“Protective Groups in Organic Synthesis”; Third Edition; Theodora W. Greene, Peter G. M. Wuts; 494-653, and the literature cited therein).
  • tert-Butoxycarbonyl and benzyloxycarbonyl protective groups can be removed in an acidic medium (for example using hydrochloric acid or trifluoroacetic acid). Acetyl protective groups can be removed under basic conditions (using, for example, potassium carbonate or cesium carbonate). Benzylic protective groups can be removed hydrogenolytically using hydrogen in the presence of a catalyst (for example palladium on activated carbon).
  • Suitable for use as solvents are all customary solvents which are inert under the reaction conditions, such as, for example, alcohols (for example methanol, ethanol, propanol), cyclic and acyclic ethers (for example diethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (for example benzene, toluene, xylene), halogenated hydrocarbons (for example dichloromethane, chloroform, carbon tetrachloride), halogenated aromatic hydrocarbons (for example chlorobenzene, dichlorobenzene), nitriles (for example acetonitrile), carboxylic esters (for example ethyl acetate), amides (for example N,N-dimethylformamide, N,N-dimethylacetamide), dimethyl sulfoxide, 1,3-dimethyl-2-imidazolinone, water and acetic acid, or the reaction can be carried out in mixtures of two or more of these solvents.
  • Acids which can be used for this reaction of deprotecting t-butoxycarbonyl and benzyloxycarbonyl groups are, for example, trifluoroacetic acid, hydrochloric acid or other acids, as described in the literature (for example “Protective Groups in Organic Synthesis”; Third Edition; Theodora W. Greene, Peter G. M. Wuts; pp. 494-653).
  • The reaction is usually carried out at temperatures of 0° C.-150° C. and preferably at room temperature, but it can also be carried out at the reflux temperature of the reaction mixture. The reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between half an hour and 72 hours.
  • After the reaction has ended, the compounds (VI) are removed from the reaction mixture using one of the customary separation techniques. If required, the compounds are purified by recrystallisation, distillation or chromatography, or they can, if appropriate, also be used for the next step without prior purification. Moreover, it is possible to isolate the compound of the general formula (VI) as a salt, for example as a salt of hydrochloric acid or trifluoroacetic acid.
  • The same process is used to convert a compound of the formula (IX) into a compound of the formula (X).
  • C1-C2-Alkyl esters (VII) are known and can be prepared from commercially available precursors according to procedures described in the literature, for example from nitriles of the formula (XI), carboxylic acids of the formula (XII), carbonyl chlorides of the formula (XIII), amides of the formula (XIV) or thioamides of the formula (XV) (FIG. 1). A preferred method is the Hantzsch thiazole synthesis. Starting with (XIV) and commercially available ethyl or methyl halpyruvate in ethanol or in N,N-dimethylformamide in the presence of, for example, triethylamine at room temperature (for examples see WO 07/014290 and the references cited therein).
  • Figure US20150237859A1-20150827-C00011
  • where
      • Q=H or acid-labile amine protective groups, such as, for example, t-butoxycarbonyl (tBoc) or benzyloxycarbonyl (Cbz), or a benzyl protective group, such as, for example, benzyl (Bn).
        W and X are as defined above for formula (I).
  • One way of preparing compounds of the formula (IV) from corresponding compounds (VI) is shown in Scheme 2.
  • A compound of the formula (IV) is synthesized by a coupling reaction of a compound of the formula (VI) with a substrate of the formula (V) where Z═Cl, if appropriate in the presence of an acid scavenger/a base.
  • Acid halides (V) (Z═Cl) or the corresponding carboxylic acids (V) (Z═OH) are commercially available or can be prepared by processes described in the literature (for examples see WO 07/014290 and the references cited therein). A preferred method is shown in Scheme 7. Pyrazoles (XVIII) can be prepared from diketones (XXI) and commercially available hydrazine (XX) or the corresponding HCl salt in ethanol or in N,N-dimethylformamide, if appropriate in the presence of bases, for example triethylamine at reflux. Compounds (XVI) can be prepared by alkylation of compounds (XVIII) with commercially available α-halo esters (XVII) in acetonitrile or in N,N-dimethylformamide in the presence of bases, for example potassium carbonate at room temperature. Alternatively, compounds (XVI) can be prepared directly from diketones (XXI) and commercially available hydrazine (XIX) or the corresponding HCl salts in ethanol or in N,N-dimethylformamide, if appropriate in the presence of bases, for example triethylamine at reflux. Carboxylic acids (V) (Z═OH) can be prepared by hydrolysis of the esters (XVI) in THF/water mixtures using lithium hydroxide at room temperature. Moreover, a substrate of the general formula (V) where Z═Cl can be prepared from the corresponding acid (Z═OH) by chlorination using processes known from the literature (for example Tetrahedron 2005, 61, 10827-10852, and the literature cited therein).
  • Figure US20150237859A1-20150827-C00012
  • Suitable for use as solvents are all customary solvents which are inert under the reaction conditions, such as, for example, alcohols (for example methanol, ethanol, propanol), cyclic and acyclic ethers (for example diethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (for example benzene, toluene, xylene), halogenated hydrocarbons (for example dichloromethane, chloroform, carbon tetrachloride), halogenated aromatic hydrocarbons (for example chlorobenzene, dichlorobenzene) and nitriles (for example acetonitrile), or the reaction can be carried out in mixtures of two or more of these solvents. The preferred solvents are tetrahydrofuran and dichloromethane.
  • At least one equivalent of an acid scavenger/a base (for example Hünig base, triethylamine or commercially available polymeric acid scavengers), based on the starting material of the general formula (V), is employed. If the starting material is a salt, at least two equivalents of the acid scavenger are required.
  • The reaction is usually carried out at temperatures of 0° C.-100° C. and preferably at 20° C.-30° C., but it can also be carried out at the reflux temperature of the reaction mixture. The reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between a few minutes and 48 hours.
  • After the reaction has ended, the compounds (IV) are removed from the reaction mixture using one of the customary separation techniques. If required, the compounds are purified by recrystallisation, distillation or chromatography, or they can, if appropriate, also be used for the next step without prior purification.
  • Alternatively, a compound of the formula (IV) can also be synthesized from the corresponding compound of the formula (VI) using a substrate of the formula (V) where Z═OH in the presence of a coupling agent analogously to procedures described in the literature (for example Tetrahedron 2005, 61, 10827-10852, and the references cited therein).
  • Suitable coupling agents are, for example, peptide coupling agents (for example N-(3-dimethylaminopropyl)-N-ethylcarbodiimide mixed with 4-dimethylaminopyridine, N-(3-dimethylaminopropyl)-N-ethylcarbodiimide mixed with 1-hydroxybenzotriazole, bromotripyrrolidinophosphonium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, etc.).
  • If appropriate, a base, such as, for example, triethylamine or Hünig base can be employed in the reaction.
  • Suitable for use as solvents are all customary solvents which are inert under the reaction conditions, such as, for example, alcohols (for example methanol, ethanol, propanol), cyclic and acyclic ethers (for example diethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbon s (for example benzene, toluene, xylene), halogenated hydrocarbons (for example dichloromethane, chloroform, carbon tetrachloride), halogenated aromatic hydrocarbons (for example chlorobenzene, dichlorobenzene), nitriles (for example acetonitrile) and amides (for example N,N-dimethylformamide, N,N-dimethylacetamide), or the reaction can be carried out in mixtures of two or more of these solvents. The preferred solvent is dichloromethane.
  • The reaction is usually carried out at temperatures of 0° C.-100° C. and preferably at 0° C.-30° C., but it can also be carried out at the reflux temperature of the reaction mixture. The reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between a few minutes and 48 hours.
  • After the reaction has ended, the compounds (IV) are removed from the reaction mixture using one of the customary separation techniques. If required, the compounds are purified by recrystallisation, distillation or chromatography, or they can, if appropriate, also be used for the next step without prior purification.
  • Analogously, it is possible to convert compounds of the formula (X) into compounds of the formula (I).
  • One way of preparing the intermediate (III) from corresponding compounds (IV) is shown in Scheme 3.
  • The carboxylic acid of the formula (III) can be prepared by hydrolysis of the corresponding C1-C2-alkyl ester of the formula (IV). It is possible to use, for example, the method described in WO2007/014290.
  • Suitable for use as solvents are all customary solvents which are inert under the reaction conditions, such as, for example, alcohols (for example methanol, ethanol, propanol), cyclic and acyclic ethers (for example diethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (for example benzene, toluene, xylene), halogenated hydrocarbons (for example dichloromethane, chloroform, carbon tetrachloride) and halogenated aromatic hydrocarbons (for example chlorobenzene, dichlorobenzene), or the reaction can be carried out in mixtures of two or more of these solvents.
  • Suitable alkali metal hydroxides are, for example, LiOH, NaOH or KOH, usually in the presence of water together with a cosolvent, preferably THF and/or methanol, to facilitate dissolution of the ester. The starting material and the alkali metal hydroxide are employed in equimolar amounts; however, the alkali metal hydroxide may, if required, also be used in excess. The carboxylate salt formed is converted into the free acid by treatment with a slight excess of mineral acids, such as, for example, hydrochloric acid or sulfuric acid.
  • The reaction is usually carried out at temperatures of 0° C.-60° C., but it can also be carried out at the reflux temperature of the reaction mixture. The reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between a few minutes and 48 hours.
  • After the reaction has ended, the compounds (Ill) are removed from the reaction mixture using one of the customary separation techniques. If required, the compounds are purified by recrystallisation, distillation or chromatography.
  • Analogously, it is possible to convert compounds of the formula (VII) into compounds of the formula (VIII).
  • One way of preparing compounds of the formula (I) from corresponding compounds (III) is shown in Scheme 4.
  • A compound of the formula (I) is synthesized by a coupling reaction of a compound of the formula (III) with a substrate of the formula (II), by chlorination using processes known from the literature (for example Tetrahedron 2005, 61, 10827-10852, and the literature cited therein), if appropriate in the presence of an acid scavenger/a base.
  • Substrates of the general formula (II) are commercially available or can be prepared by processes described in the literature (see, for example, “The Chemistry of Functional groups”; “The Chemistry of the Thiol Group”; John Wiley & Sons, 1974, 163-269, and the references cited therein).
  • Suitable for use as solvents are all customary solvents which are inert under the reaction conditions, such as, for example, alcohols (for example methanol, ethanol, propanol), cyclic and acyclic ethers (for example diethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (for example benzene, toluene, xylene), halogenated hydrocarbons (for example dichloromethane, chloroform, carbon tetrachloride), halogenated aromatic hydrocarbons (for example chlorobenzene, dichlorobenzene) and nitriles (for example acetonitrile), or the reaction can be carried out in mixtures of two or more of these solvents. The preferred solvents are tetrahydrofuran and dichloromethane.
  • At least one equivalent of an acid scavenger/a base (for example Hünig base, triethylamine or commercially available polymeric acid scavengers), based on the starting material of the general formula (II), is employed. If the starting material is a salt, at least two equivalents of the acid scavenger are required.
  • The reaction is usually carried out at temperatures of 0° C.-100° C. and preferably at 20° C.-30° C., but it can also be carried out at the reflux temperature of the reaction mixture. The reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between a few minutes and 48 hours.
  • After the reaction has ended, the compounds (I) are removed from the reaction mixture using one of the customary separation techniques. If required, the compounds are purified by recrystallisation, distillation or chromatography, or they can, if appropriate, also be used for the next step without prior purification.
  • Alternatively, a compound of the formula (I) can also be synthesized from the corresponding compound of the formula (III) (Z═OH) using a substrate of the formula (II) in the presence of a coupling agent analogously to procedures described in the literature (for example Tetrahedron 2005, 61, 10827-10852, and the references cited therein).
  • Suitable coupling agents are, for example, peptide coupling agents (for example N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide mixed with 4-dimethylaminopyridine, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide mixed with 1-hydroxybenzotriazole, bromotripyrrolidinophosphonium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, etc.).
  • If appropriate, a base, such as, for example, triethylamine or Hünig base can be employed in the reaction.
  • Suitable for use as solvents are all customary solvents which are inert under the reaction conditions, such as, for example, alcohols (for example methanol, ethanol, propanol), cyclic and acyclic ethers (for example diethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (for example benzene, toluene, xylene), halogenated hydrocarbons (for example dichloromethane, chloroform, carbon tetrachloride), halogenated aromatic hydrocarbons (for example chlorobenzene, dichlorobenzene), nitriles (for example acetonitrile) and amides (for example N,N-dimethylformamide, N,N-dimethylacetamide), or the reaction can be carried out in mixtures of two or more of these solvents. The preferred solvents are N,N-dimethylformamide and dichloromethane.
  • The reaction is usually carried out at temperatures of 0° C.-100° C. and preferably at 0° C.-30° C., but it can also be carried out at the reflux temperature of the reaction mixture. The reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between a few minutes and 48 hours.
  • After the reaction has ended, the compounds (I) are removed from the reaction mixture using one of the customary separation techniques. If required, the compounds are purified by recrystallisation, distillation or chromatography, or they can, if appropriate, also be used for the next step without prior purification.
  • The same process can be used to convert a compound of the general formula (VIII) into a compound of the general formula (IX).
  • One way to prepare compounds of the formula (I) in which Y1 and Y2═S from corresponding compounds (I) in which Y1 and Y2═O is shown in Scheme 5.
  • A sulfurizing agent, such as, for example, Lawesson's reagent or, for example, phosphorus pentasulfide, is added to a compound of the formula (I) to form a compound of the formula (I) (Y1 and Y2=sulfur). Here, it is possible, for example, to use the method described in Tetrahedron Lett 2002, 43 (3), 371-373.
  • Suitable for use as solvents are all customary solvents which are inert under the reaction conditions, such as, for example, alcohols (for example methanol, ethanol, propanol), cyclic and acyclic ethers (for example diethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (for example benzene, toluene, xylene), halogenated hydrocarbons (for example dichloromethane, chloroform, carbon tetrachloride), halogenated aromatic hydrocarbons (for example chlorobenzene, dichlorobenzene), nitriles (for example acetonitrile), carboxylic esters (for example ethyl acetate) and amides (for example N,N-dimethylformamide, N,N-dimethylacetamide), and the reaction can be carried out in mixtures of two or more of these solvents. The preferred solvents are chloroform, toluene and 1,2-dimethoxyethane.
  • Suitable sulfurizing agents are, for example, Lawesson's reagent (see Tetrahedron 1986, 42, 6555-6564, Tetrahedron Lett. 1993, 46, 7459-7462) and phosphorus pentasultide. The starting material and the sulfurizing agent are employed in equimolar amounts; however, the sulfurizing agent may, if required, also be used in excess.
  • The reaction is usually carried out at temperatures of 0° C.-150° C. and preferably at 0° C.-100° C., but it can also be carried out at the reflux temperature of the reaction mixture. The reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between a few minutes and 48 hours.
  • After the reaction has ended, the compounds (I) are removed from the reaction mixture using one of the customary separation techniques. If required, the compounds are purified by recrystallisation, distillation or chromatography.
  • The compound of the formula (XVIII-1)
  • Figure US20150237859A1-20150827-C00013
  • and salts thereof are novel.
  • The compounds of the formulae (XVI-1), (XVI-2), (XVI-3), (XVI-4) and (XVI-5),
  • Figure US20150237859A1-20150827-C00014
  • and salts thereof are novel.
  • The compounds of the formulae (V-1), (V-2), (V-3), (V-4) and (V-5),
  • Figure US20150237859A1-20150827-C00015
  • and salts thereof novel.
  • The compounds of the formulae (IV-1), (IV-2) and (IV-3),
  • Figure US20150237859A1-20150827-C00016
  • and salts thereof are novel.
  • The compounds of the formulae (III-1), (III-2) and (III-3) in which
  • Figure US20150237859A1-20150827-C00017
  • Z═OH or chlorine
    and salts thereof are novel.
  • The compounds of the formula (IX) in which
  • Figure US20150237859A1-20150827-C00018
  • the symbols have the meanings below
    • PG is acetyl, C1-C2-alkoxycarbonyl, benzyl or benzyloxycarbonyl,
    • W, X, Y3, G, R6 and R7 have the general, preferred, particularly preferred or very particularly preferred meanings given above
      and salts thereof are novel.
  • Figure US20150237859A1-20150827-C00019
  • The compounds of the formula (X) in which
  • Figure US20150237859A1-20150827-C00020
  • the symbols have the meanings below
    • W, X, Y3, G, R6 and R7 have the general, preferred, particularly preferred or very particularly preferred meanings given above
      and salts thereof are novel.
  • Figure US20150237859A1-20150827-C00021
  • The invention furthermore provides the non-medicinal use of the thiazole-4-carboxylic esters and thioesters according to the invention or mixtures thereof for controlling unwanted microorganisms.
  • The invention furthermore relates to a composition for controlling unwanted microorganisms which comprises at least one thiazole-4-carboxylic ester or thioester according to the present invention.
  • Moreover, the invention relates to a method for controlling unwanted microorganisms, characterized in that the thiazole-4-carboxylic esters and thioesters according to the invention are applied to the microorganisms and/or in their habitat.
  • The invention furthermore relates to seed treated with at least one thiazole-4-carboxylic ester or thioester according to the invention.
  • A last subject matter of the invention relates to a method for protecting seed against unwanted microorganisms by using seed treated with at least one thiazole-4-carboxylic ester or thioester according to the present invention.
  • The substances according to the invention have potent microbicidal activity and can be employed for controlling unwanted microorganisms, such as fungi and bacteria, in crop protection and in the protection of materials.
  • The thiazole-4-carboxylic esters and thioesters of the formula (I) according to the invention have very good fungicidal properties and can be used in crop protection, for example, for controlling Plasmodiophoromycetes, Oomycetes, Chytridiomycetes, Zygomycetes, Ascomycetes, Basidiomycetes and Deuteromycctcs.
  • Bactericides can be employed in crop protection, for example, for controlling Pseudomonadaceae, Rhizobiaceae, Enterobacteriaceae, Corynebacteriaceae and Streptomycetaceae.
  • The fungicidal compositions according to the invention can be used for the curative or protective control of phytopathogenic fungi. Accordingly, the invention also relates to curative and protective methods for controlling phytopathogenic fungi using the active compounds or compositions according to the invention, which are applied to the seed, the plant or plant parts, the fruit or the soil in which the plants grow.
  • The compositions according to the invention for controlling phytopathogenic fungi in crop protection comprise an effective, but non-phytotoxic amount of the active compounds according to the invention. “Effective, but non-phytotoxic amount” means an amount of the composition according to the invention which is sufficient to control the fungal disease of the plant in a satisfactory manner or to eradicate the fungal disease completely, and which, at the same time, does not cause any significant symptoms of phytotoxicity. In general, this application rate may vary within a relatively wide range. It depends on a plurality of factors, for example on the fungus to be controlled, the plant, the climatic conditions and the ingredients of the compositions according to the invention.
  • All plants and plant parts can be treated in accordance with the invention. By plants are understood here all plants and plant populations such as desired and undesired wild plants or crop plants (including naturally occurring crop plants). Crop plants can be plants which can be obtained by conventional breeding and optimization methods or by biotechnological and genetic engineering methods or combinations of these methods, including the transgenic plants and including the plant varieties which can or cannot be protected by varietal property rights. Plant parts are to be understood as meaning all parts and organs of plants above and below the ground, such as shoot, leaf, flower and root, examples which may be mentioned being leaves, needles, stalks, stems, flowers, fruit bodies, fruits, seeds, roots, tubers and rhizomes. Parts of plants also include harvested plants and vegetative and generative propagation material, for example seedlings, tubers, rhizomes, cuttings and seeds.
  • The following plants may be mentioned as plants which can be treated according to the invention: cotton, flax, grapevines, fruit, vegetables, such as Rosaceae sp. (for example pomaceous fruit, such as apples and pears, but also stone fruit, such as apricots, cherries, almonds and peaches and soft fruit such as strawberries), Ribesioidae sp., Juglandaceae sp., Betulaceae sp., Anacardiaceae sp., Fagaceae sp., Moraceae sp., Oleaceae sp., Actinidaceae sp., Lauraceae sp., Musaceae sp. (for example banana trees and plantations), Rubiaceae sp. (for example coffee), Theaceae sp., Sterculiceae sp., Rutaceae sp. (for example lemons, oranges and grapefruit), Solanaceae sp. (for example tomatoes), Liliaceae sp., Asteraceae sp. (for example lettuce), Umbelliferae sp., Cruciferae sp., Chenopodiaceae sp., Cucurbitaceae sp. (for example cucumbers), Alliaceae sp. (for example leek, onions), Papilionaceae sp. (for example peas); major crop plants, such as Gramineae sp. (for example maize, lawn, cereals such as wheat, rye, rice, barley, oats, millet and triticale), Asteraceae sp. (for example sunflowers), Brassicaceae sp. (for example white cabbage, red cabbage, broccoli, cauliflowers, brussels sprouts, pak choi, kohlrabi, garden radish, and also oilseed rape, mustard, horseradish and cress), Fabacae sp. (for example beans, peanuts), Papilionaceae sp. (for example soya beans), Solanaceae sp. (for example potatoes), Chenopodiaceae sp. (for example sugarbeet, fodderbeet, swiss chard, beetroot); crop plants and ornamental plants in garden and forest; and also in each case genetically modified varieties of these plants. Preference is given to treating cereal plants according to the invention.
  • Some pathogens of fungal diseases which can be treated according to the invention may be mentioned by way of example, but not by way of limitation:
  • diseases caused by powdery mildew pathogens, such as, for example, Blumeria species, such as, for example, Blumeria graminis; Podosphaera species, such as, for example, Podosphacra leuco-tricha; Sphaerotheca species, such as, for example, Sphaerotheca fuliginea; Uncinula species, such as, for example, Uncinula necator, diseases caused by rust disease pathogens, such as, for example, Gymnosporangium species, such as, for example, Gymnosporangium sabinae; Hemileia species, such as, for example, Hemileia vastatrix; Phakopsora species, such as, for example, Phakopsora pachyrhizi and Phakopsora meibomiae; Puccinia species, such as, for example, Puccinia recondita or Puccinia triticina; Uromyces species, such as, for example, Uromyces appendiculatus;
    diseases caused by pathogens from the group of the Oomycetes, such as, for example, Bremia species, such as, for example, Bremia lactucae; Peronospora species, such as, for example, Peronospora pisi or P. brassicae; Phytophthora species, such as, for example, Phytophthora infestans; Plasmopara species, such as, for example, Plasmopara viticola; Pseudoperonospora species, such as, for example, Pseudoperonospora humuli or Pseudoperonospora cubensis; Pythium species, such as, for example, Pythium ultimum;
    leaf blotch diseases and leaf wilt diseases caused, for example, by Alternaria species, such as, for example, Alternaria solani; Cercospora species, such as, for example, Cercospora beticola; Cladiosporium species, such as, for example, Cladiosporium cucumerinum; Cochliobolus species, such as, for example, Cochliobolus sativus (conidia form: Drechslera, syn: Helminthosporium); Colletotrichum species, such as, for example, Colletotrichum lindemuthanium; Cycloconium species, such as, for example, Cycloconium oleaginum; Diaporthe species, such as, for example, Diaporthe citri; Elsinoe species, such as, for example, Elsinoe fawcettii; Gloeosporium species, such as, for example, Gloeosporium laeticolor, Glomerella species, such as, for example, Glomerella cingulata: Guignardia species, such as, for example, Guignardia bidwelli; Leptosphaeria species, such as, for example, Leptosphaeria maculans; Magnaporthe species, such as, for example, Magnaporthe grisea; Microdochium species, such as, for example, Microdochium nivale; Mycosphaerella species, such as, for example, Mycosphaerella graminicola and M. fijiensis; Phaeosphaeria species, such as, for example, Phaeosphaeria nodorum; Pyrenophora species, such as, for example, Pyrenophora teres; Ramularia species, such as, for example, Ramularia collo-cygni; Rhynchosporium species, such as, for example, Rhynchosporium secalis; Septoria species, such as, for example, Septoria apii; Typhula species, such as, for example, Typhula incamata; Venturia species, such as, for example, Venturia inaequalis;
    root and stem diseases caused, for example, by Corticium species, such as, for example, Corticium graminearum; Fusarium species, such as, for example, Fusarium oxysporum; Gaeumannomyces species, such as, for example, Gaeumannomyces graminis; Rhizoctonia species, such as, for example Rhizoctonia solani; Tapesia species, such as, for example, Tapesia acuformis; Thielaviopsis species, such as, for example, Thielaviopsis basicola;
    ear and panicle diseases (including corn cobs) caused, for example, by Alternaria species, such as, for example, Alternaria spp.; Aspergillus species, such as, for example, Aspergillus flavus; Cladosporium species, such as, for example, Cladosporium cladosporioides; Claviceps species, such as, for example, Claviceps purpurea; Fusarium species, such as, for example, Fusarium culmorum; Gibberella species, such as, for example, Gibberella zeae; Monographella species, such as, for example, Monographella nivalis; Septoria species, such as, for example, Septoria nodorum; diseases caused by smut fungi, such as, for example, Sphacclotheca species, such as, for example, Sphacelotheca reiliana; Tilletia species, such as, for example, Tilletia caries, T. controversa; Urocystis species, such as, for example, Urocystis occulta; Ustilago species, such as, for example, Ustilago nuda, U. nuda tritici;
    Fruit rot caused, for example, by Aspergillus species, such as, for example, Aspergillus flavus; Botrytis species, such as, for example, Botrytis cinerea; Penicillium species, such as, for example, Penicillium expansum and P. purpurogenum; Sclerotinia species, such as, for example, Sclerotinia sclerotiorum;
    Verticilium species, such as, for example, Verticilium alboatrum;
    seed- and soil-borne rot and wilt diseases, and also diseases of seedlings, caused, for example, by Fusarium species, such as, for example, Fusarium culmorum; Phytophthora species, such as, for example, Phytophthora cactorum; Pythium species, such as, for example, Pythium ultimum; Rhizoctonia species, such as, for example, Rhizoctonia solani; Sclerotium species, such as, for example, Sclerotium rolfsii;
    cancerous diseases, galls and witches' broom caused, for example, by Nectria species, such as, for example, Nectria galligena;
    wilt diseases caused, for example, by Monilinia species, such as, for example, Monilinia laxa;
    deformations of leaves, flowers and fruits caused, for example, by Taphrina species, such as, for example, Taphrina deformans;
    degenerative diseases of woody plants caused, for example, by Esca species, such as, for example, Phaeomoniella chlamydospora and Phaeoacremonium aleophilum and Fomitiporia mediterranea; diseases of flowers and seeds caused, for example, by Botrytis species, such as, for example, Botrytis cinerea;
    diseases of plant tubers caused, for example, by Rhizoctonia species, such as, for example, Rhizoctonia solani; Helminthosporium species, such as, for example, Helminthosporium solani;
    diseases caused by bacterial pathogens, such as, for example, Xanthomonas species, such as, for example, Xanthomonas campestris pv. oryzae; Pseudomonas species, such as, for example, Pseudomonas syringae pv. lachrymans; Erwinia species, such as, for example, Erwinia amylovora;
  • Preference is given to controlling the following diseases of soybeans:
  • Fungal diseases on leaves, stems, pods and seeds caused, for example, by alternaria leaf spot (Alternaria spec. atrans tenuissima), anthracnose (Colletotrichum gloeosporoides dematium var. truncatum), brown spot (Septoria glycines), cercospora leaf spot and blight (Cercospora kikuchii), choanephora leaf blight (Choanephora infundibulifera trispora (Syn.)), dactuliophora leaf spot (Dactuliophora glycines), downy mildew (Peronospora manshurica), drechslera blight (Drechslera glycini), frogeye leaf spot (Cercospora sojina), leptosphaerulina leaf spot (Leptosphaerulina trifolii), phyllostica leaf spot (Phyllosticta sojaecola), pod and stem blight (Phomopsis sojae), powdery mildew (Microsphaera diffusa), pyrenochaeta leaf spot (Pyrenochaeta glycines), rhizoctonia aerial, foliage, and web blight (Rhizoctonia solani), rust (Phakopsora pachyrhizi Phakopsora meibomiae), scab (Sphaceloma glycines), stemphylium leaf blight (Stemphylium botryosum), target spot (Corynespora cassiicola).
  • Fungal diseases on roots and the stem base caused, for example, by black root rot (Calonectria crotalariae), charcoal rot (Macrophomina phaseolina), fusarium blight or wilt, root rot, and pod and collar rot (Fusarium oxysporum, Fusarium orthoceras, Fusarium semitectum, Fusarium equiseti), mycoleptodiscus root rot (Mycoleptodiscus terrestris), neocosmospora (Neocosmospora vasinfecta), pod and stem blight (Diaporthe phaseolorum), stem canker (Diaporthe phaseolorum var. caulivora), phytophthora rot (Phytophthora megasperma), brown stem rot (Phialophora gregata), pythium rot (Pythium aphanidcrmatum, Pythium irregulare, Pythium debaryanum, Pythium myriotylum, Pythium ultimum), rhizoctonia root rot, stem decay, and damping-off (Rhizoctonia solani), sclerotinia stem decay (Sclerotinia sclerotiorum), sclerotinia southern blight (Sclerotinia rolfsii), thielaviopsis root rot (Thielaviopsis basicola).
  • The active compounds according to the invention also have very good fortifying action in plants. Accordingly, they can be used for mobilizing the defenses of the plant against attack by undesirable microorganisms.
  • Plant-strengthening (resistance-inducing) substances are to be understood as meaning, in the present context, those substances which are capable of stimulating the defense system of plants in such a way that the treated plants, when subsequently inoculated with undesired microorganisms, develop a high degree of resistance to these microorganisms.
  • In the present case, undesirable microorganisms are to be understood as meaning phytopathogenic fungi and bacteria. Accordingly, the substances according to the invention can be used to protect plants for a certain period after the treatment against attack by the pathogens mentioned. The period for which protection is provided generally extends over 1 to 10 days, preferably 1 to 7 days, after the treatment of the plants with the active compounds.
  • The fact that the active compounds are well tolerated by plants at the concentrations required for controlling plant diseases permits the treatment of above-ground parts of plants, of propagation stock and seeds, and of the soil.
  • The active compounds according to the invention can be employed particularly successfully for controlling diseases in viticulture and fruit and vegetable growing such as, for example, against Botrytis, Venturia, Sphaerotheca, Podosphaera, Phythophthora and Plasmopara species.
  • The active compounds according to the invention are also suitable for increasing the yield of crops. In addition, they show reduced toxicity and are well tolerated by plants.
  • If appropriate, the compounds according to the invention can, at certain concentrations or application rates, also be used as herbicides, safeners, growth regulators or agents to improve plant properties, or as microbicidcs, for example as fungicides, antimycotics, bactericides, viricides (including agents against viroids) or as agents against MLO (Mycoplasma-like organisms) and RLO (Rickettsia-like organisms). If appropriate, they can also be used as intermediates or precursors for the synthesis of other active compounds.
  • If appropriate, the active compounds according to the invention can also be employed in specific concentrations and application rates as herbicides, for influencing plant growth, and for controlling animal pests. If appropriate, they can also be used as intermediates and precursors for the synthesis of further active compounds.
  • The active compounds according to the invention, in combination with good plant tolerance and favourable toxicity to warm-blooded animals and being tolerated well by the environment, are suitable for protecting plants and plant organs, for increasing the harvest yields, for improving the quality of the harvested material and for controlling animal pests, in particular insects, arachnids, helminths, nematodes and molluscs, which are encountered in agriculture, in horticulture, in animal husbandry, in forests, in gardens and leisure facilities, in the protection of stored products and of materials, and in the hygiene sector. They may be preferably employed as plant protection agents.
  • The treatment according to the invention of the plants and plant parts with the active compounds or compositions is carried out directly or by action on their surroundings, habitat or storage space using customary treatment methods, for example by dipping, spraying, atomizing, irrigating, evaporating, dusting, fogging, broadcasting, foaming, painting, spreading-on, watering (drenching), drip irrigating and, in the case of propagation material, in particular in the case of seeds, furthermore as a powder for dry seed treatment, a solution for seed treatment, a water-soluble powder for slurry treatment, by incrusting, by coating with one or more coats, etc. It is furthermore possible to apply the active compounds by the ultra-low volume method or to inject the active compound preparation or the active compound itself into the soil.
  • The active compounds according to the invention can also be used as defoliants, desiccants, haulm killers and, especially, as weedkillers. Weeds in the broadest sense are understood to mean all plants which grow in locations where they are undesired. Whether the substances according to the invention act as total or selective herbicides depends essentially on the amount used.
  • Moreover, in the protection of materials, the active compounds or compositions according to the invention can be employed for protecting industrial materials against attack and destruction by unwanted microorganisms, such as, for example, fungi.
  • Industrial materials in the present context are understood as meaning non-living materials which have been prepared for use in industry. For example, industrial materials which are intended to be protected by active compounds according to the invention from microbial change or destruction can be adhesives, sizes, paper and board, textiles, leather, wood, paints and plastic articles, cooling lubricants and other materials which can be infected with, or destroyed by, microorganisms. Parts of production plants, for example cooling-water circuits, which may be impaired by the proliferation of microorganisms may also be mentioned within the scope of the materials to be protected. Industrial materials which may be mentioned within the scope of the present invention are preferably adhesives, sizes, paper and board, leather, wood, paints, cooling lubricants and heat-transfer liquids particularly preferably wood. The active compounds or compositions according to the invention may prevent disadvantageous effects, such as rotting, decay, discoloration, decoloration or formation of mold.
  • The method according to the invention for controlling unwanted fungi can also be employed for protecting storage goods. Here, storage goods are to be understood as meaning natural substances of vegetable or animal origin or processed products thereof of natural origin, for which long-term protection is desired. Storage goods of vegetable origin, such as, for example, plants or plant parts, such as stems, leaves, tubers, seeds, fruits, grains, can be protected freshly harvested or after processing by (pre)drying, moistening, comminuting, grinding, pressing or roasting. Storage goods also include timber, both unprocessed, such as construction timber, electricity poles and barriers, or in the form of finished products, such as furniture. Storage goods of animal origin are, for example, hides, leather, furs and hairs. The active compounds according to the invention may prevent disadvantageous effects, such as rotting, decay, discoloration, decoloration or formation of mold.
  • Microorganisms capable of degrading or changing the industrial materials which may be mentioned are, for example, bacteria, fungi, yeasts, algae and slime organisms. The active compounds according to the invention preferably act against fungi, in particular molds, wood-discoloring and wood-destroying fungi (Basidiomycetes), and against slime organisms and algae. Microorganisms of the following genera may be mentioned as examples: Alternaria, such as Alternaria tenuis; Aspergillus, such as Aspergillus niger, Chaetomium, such as Chaetomium globosum; Coniophora, such as Coniophora puetana; Lentinus, such as Lentinus tigrinus; Penicillium, such as Penicillium glaucum; Polyporus, such as Polyporus versicolor, Aureobasidium, such as Aureobasidium pullulans; Sclerophoma, such as Sclerophoma pityophila; Trichoderma, such as Trichoderma viride; Escherichia, such as Escherichia coli; Pseudomonas, such as Pseudomonas aeruginosa; Staphylococcus, such as Staphylococcus aureus.
  • The present invention furthermore relates to a composition for controlling unwanted microorganisms, which composition comprises at least one of the thiazole-4-carboxylic ester or thiocsters according to the invention. These are preferably fungicidal composition which comprise agriculturally suitable auxiliaries, solvents, carriers, surfactants or extenders.
  • According to the invention, a carrier is a natural or synthetic organic or inorganic substance with which the active compounds are mixed or bonded for better applicability, in particular for application to plants or plant parts or seed. The carrier, which may be solid or liquid, is generally inert and should be suitable for use in agriculture.
  • As solid carriers these are suitable: for example ammonium salts and ground natural minerals such as kaolins, clays, talc, chalk, quartz, attapulgite, niontmorillonite or diatomaceous earth, and ground synthetic materials such as highly-disperse silica, alumina and silicates; suitable solid carriers for granules are: for example, crushed and fractionated natural rocks such as calcite, marble, pumice, sepiolite and dolomite, and also synthetic granules of inorganic and organic meals, and granules of organic material such as paper, sawdust, coconut shells, maize cobs and tobacco stalks; suitable emulsifiers and/or foam-formers are: for example, nonionic and anionic emulsifiers, such as polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, for example alkylaryl polyglycol ethers, alkylsulfonates, alkyl sulphates, arylsulfonates and also protein hydrolysates; suitable dispersants are nonionic and/or ionic substances, for example from the classes of the alcohol-POE and/or -POP ethers, acid and/or POP POE esters, alkylaryl and/or POP POE ethers, fat and/or POP POE adducts, POE- and/or POP-polyol derivatives, POE- and/or POP-sorbitan or -sugar adducts, alkyl or aryl sulphates, alkyl- or arylsulphonates and alkyl or aryl phosphates or the corresponding PO-ether adducts. Furthermore, suitable oligo- or polymers, for example those derived from vinylic monomers, from acrylic acid, from EO and/or PO alone or in combination with, for example, (poly)alcohols or (poly)amines. It is also possible to employ lignin and its sulphonic acid derivatives, unmodified and modified celluloses, aromatic and/or aliphatic sulphonic acids and their adducts with formaldehyde.
  • The active compounds can be converted into the customary formulations, such as solutions, emulsions, wettable powders, water- and oil-based suspensions, powders, dusts, pastes, soluble powders, soluble granules, granules for broadcasting, suspoemulsion concentrates, natural compounds impregnated with active compound, synthetic substances impregnated with active compound, fertilizers and also microencapsulations in polymeric substances.
  • The active compounds can be applied as such, in the form of their formulations or the use forms prepared therefrom, such as ready-to-use solutions, emulsions, water- or oil-based suspensions, powders, wettable powders, pastes, soluble powders, dusts, soluble granules, granules for broadcasting, suspoemulsion concentrates, natural products impregnated with active compound, synthetic materials impregnated with active compound, fertilizers and also microencapsulations in polymeric substances. Application is carried out in a customary manner, for example by watering, spraying, atomizing, broadcasting, dusting, foaming, spreading, etc. It is furthermore possible to apply the active compounds by the ultra-low volume method, or to inject the active compound preparation or the active compound itself into the soil. It is also possible to treat the seeds of the plants.
  • The formulations mentioned can be prepared in a manner known per se, for example by mixing the active compounds with at least one customary extender, solvent or diluent, emulsifier, dispersant, and/or binder or fixative, wetting agent, water-repellent, if appropriate desiccants and UV stabilizers and, if appropriate, dyes and pigments, defoamers, preservatives, secondary thickeners, adhesives, gibberellins and also further processing auxiliaries.
  • The compositions according to the invention include not only formulations which are already ready for use and can be applied with a suitable apparatus to the plant or the seed, but also commercial concentrates which have to be diluted with water prior to use.
  • The active compounds according to the invention can be present as such or in their (commercial) formulations and in the use forms prepared from these formulations as a mixture with other (known) active compounds, such as insecticides, attractants, sterilants, bactericides, acaricides, nematicides, fungicides, growth regulators, herbicides, fertilizers, safeners and/or semiochemicals.
  • Suitable for use as auxiliaries are substances which are suitable for imparting to the composition itself and/or to preparations derived therefrom (for example spray liquors, seed dressings) particular properties such as certain technical properties and/or also particular biological properties. Typical suitable auxiliaries are: extenders, solvents and carriers.
  • Suitable extenders are, for example, water, polar and nonpolar organic chemical liquids, for example from the classes of the aromatic and non-aromatic hydrocarbons (such as paraffins, alkylbenzenes, alkylnaphthalenes, chlorobenzenes), the alcohols and polyols (which, if appropriate, may also be substituted, etherified and/or esterified), the ketones (such as acetone, cyclohexanone), esters (including fats and oils) and (poly)ethers, the unsubstituted and substituted amines, amides, lactams (such as N-alkylpyrrolidones) and lactones, the sulphones and sulphoxides (such as dimethyl sulphoxide).
  • Liquefied gaseous extenders or carriers are to be understood as meaning liquids which are gaseous at standard temperature and under atmospheric pressure, fix example aerosol propellants such as halogenated hydrocarbons, or else butane, propane, nitrogen and carbon dioxide.
  • Tackifiers such as carboxymethylcellulose and natural and synthetic polymers in the form of powders, granules or latices, such as gum arabic, polyvinyl alcohol and polyvinyl acetate, or else natural phospholipids such as cephalins and lecithins and synthetic phospholipids can be used in the formulations. Other possible additives are mineral and vegetable oils.
  • If the extender used is water, it is also possible to employ, for example, organic solvents as auxiliary solvents. Essentially, suitable liquid solvents are: aromatics such as xylene, toluene or alkylnaphthalenes, chlorinated aromatics or chlorinated aliphatic hydrocarbons such as chlorobenzenes, chloroethylenes or methylene chloride, aliphatic hydrocarbons such as cyclohexane or paraffins, for example petroleum fractions, alcohols such as butanol or glycol and their ethers and esters, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone, strongly polar solvents such as dimethylformamide or dimethyl sulphoxide, or else water.
  • The compositions according to the invention may comprise additional further components, such as, for example, surfactants. Suitable surfactants are emulsifiers and/or foam formers, dispersants or wetting agents having ionic or nonionic properties, or mixtures of these surfactants. Examples of these are salts of polyacrylic acid, salts of lignosulphonic acid, salts of phenolsulphonic acid or naphthalenesulphonic acid, polycondensates of ethylene oxide with fatty alcohols or with fatty acids or with fatty amines, substituted phenols (preferably alkylphenols or arylphenols), salts of sulphosuccinic esters, taurine derivatives (preferably alkyl taurates), phosphoric esters of polyethoxylated alcohols or phenols, fatty esters of polyols, and derivatives of the compounds containing sulphates, sulphonates and phosphates, for example alkylaryl polyglycol ethers, alkylsulphonates, alkyl sulphates, arylsulphonates, protein hydrolysates, lignosulphite waste liquors and methylcellulose. The presence of a surfactant is required if one of the active compounds and/or one of the inert carriers is insoluble in water and when the application takes place in water. The proportion of surfactants is between 5 and 40 per cent by weight of the composition according to the invention.
  • It is possible to use colorants such as inorganic pigments, for example iron oxide, titanium oxide and Prussian Blue, and organic dyestuffs such as alizarin dyestuffs, azo dyestuffs and metal phthalocyanine dyestuffs, and trace nutrients such as salts of iron, manganese, boron, copper, cobalt, molybdenum and zinc.
  • Other possible additives are perfumes, mineral or vegetable, optionally modified oils, waxes and nutrients (including trace nutrients), such as salts of iron, manganese, boron, copper, cobalt, molybdenum and zinc.
  • Stabilizers, such as low-temperature stabilizers, preservatives, antioxidants, light stabilizers or other agents which improve chemical and/or physical stability may also be present.
  • If appropriate, other additional components may also be present, for example protective colloids, binders, adhesives, thickeners, thixotropic substances, penetrants, stabilizers, sequestering agents, complex formers. In general, the active compounds can be combined with any solid or liquid additive customarily used for formulation purposes.
  • The formulations generally comprise between 0.05 and 99% by weight. 0.01 and 98% by weight, preferably between 0.1 and 95% by weight, particularly preferably between 0.5 and 90% of active compound, very particularly preferably between 10 and 70% by weight. The formulations described above can be used in a method according to the invention for controlling unwanted microorganisms, where the thiazole-4-carboxylic esters and thioestcrs according to the invention are applied to the microorganisms and/or to their habitat.
  • The active compounds according to the invention can be used as such or in their formulations, also in a mixture with known fungicides, bactericides, acaricides, nematicides or insecticides, to broaden, for example, the activity spectrum or to prevent development of resistance.
  • Suitable mixing partners are, for example, known fungicides, insecticides, acaricides, nematicides or else bactericides (see also Pesticide Manual, 13th ed.).
  • A mixture with other known active compounds, such as herbicides, or with fertilizers and growth regulators, safeners and/or semiochemicals is also possible.
  • The compounds are employed in a customary manner appropriate for the use forms.
  • The invention furthermore includes a method for treating seed.
  • A further aspect of the present invention relates in particular to seed treated with at least one of the thiazole-4-carboxylic esters or thioesters according to the invention. The seed according to the invention is used in methods for protecting seed against animal pests and/or phytopathogenic harmful fungi. In these methods, seed treated with at least one active compound according to the invention is employed.
  • The active compounds or compositions according to the invention are also suitable for treating seed. A large part of the damage to crop plants caused by harmful organisms is triggered by the infection of the seed during storage or after sowing both during and after germination of the plant.
  • This phase is particularly critical since the roots and shoots of the growing plant are particularly sensitive, and even small damage may result in the death of the plant. Accordingly, there is great interest in protecting the seed and the germinating plant by using appropriate compositions.
  • The control of animal pests and/or phytopatlogenic harmful fungi by tr-eating the seed of plants has been known for a long time and is the subject of continuous improvements. However, the treatment of seed entails a series of problems which cannot always be solved in a satisfactory manner. Thus, it is desirable to develop methods for protecting the seed and the germinating plant which dispense with, or at least reduce considerably, the additional application of crop protection agents after planting or after emergence of the plants. It is furthermore desirable to optimize the amount of active compound employed in such a way as to provide optimum protection for the seed and the germinating plant from attack by phytopathogenic fungi, but without damaging the plant itself by the active compound employed. In particular, methods for the treatment of seed should also take into consideration the intrinsic fungicidal properties of transgenic plants in order to achieve optimum protection of the seed and the germinating plant with a minimum of crop protection agents being employed.
  • Accordingly, the present invention also relates to a method for protecting seed and germinating plants against attack by animal pests and/or phytopathogenic harmful fungi by treating the seed with a composition according to the invention. The invention also relates to the use of the compositions according to the invention for treating seed for protecting the seed and the germinating plant against phytopathogenic fungi. Furthermore, the invention relates to seed treated with a composition according to the invention for protection against phytopathogenic fungi.
  • The control of animal pests and/or phytopathogenic harmful fungi which damage plants post-emergence is carried out primarily by treating the soil and the above-ground parts of plants with plant protection agents. Owing to the concerns regarding a possible impact of the plant protection agent on the environment and the health of humans and animals, there are efforts to reduce the amount of active compounds applied.
  • One of the advantages of the present invention is that, because of the particular systemic properties of the compositions according to the invention, treatment of the seed with these compositions not only protects the seed itself, but also the resulting plants after emergence, from animal pests and/or phytopathogenic harmful fungi. In this manner, the immediate treatment of the crop at the time of sowing or shortly thereafter can be dispensed with.
  • It is also considered to be advantageous that the active compounds or compositions according to the invention can be used irn particular also for transgenic seed where the plant growing from this seed is capable of expressing a protein which acts against pests. By treating such seed with the active compounds or compositions according to the invention, even by the expression of the, for example, insecticidal protein, certain pests may be controlled. Surprisingly, a further synergistic effect may be observed here, which additionally increases the effectiveness of the protection against attack by pests.
  • The compositions according to the invention are suitable for protecting seed of any plant variety which is employed in agriculture, in the greenhouse, in forests or in horticulture. In particular, this takes the form of seed of cereals (such as wheat, barley, rye, millet and oats), maize, cotton, soybeans, rice, potatoes, sunflowers, beans, coffee, beets (for example sugarbeets and fodder beets), peanuts, vegetables (such as such as tomatoes, cucumbers, onions and lettuce), lawn and ornamental plants. The treatment of the seed of cereals (such as wheat, barley, rye and oats), maize and rice is of particular importance.
  • As also described further below, the treatment of transgenic seed with the active compounds or compositions according to the invention is of particular importance. This refers to the seed of plants containing at least one heterologous gene which allows the expression of a polypeptide or protein having insecticidal properties. The heterologous gene in transgenic seed can originate, for example, from microorganisms of the species Bacillus, Rhizobium, Pseudomonas, Serratia, Trichoderma, Clavibacter, Glomus or Gliocladium. Preferably, this heterologous gene is from Bacillus sp., the gene product having activity against the European corn borer and/or the Western corn rootworm. Particularly preferably, the heterologous gene originates from Bacillus thuringiensis.
  • Within the context of the present invention, the composition according to the invention is applied to the seed either alone or in suitable formulation. Preferably, the seed is treated in a state in which it is stable enough to avoid damage during treatment. In general, the seed may be treated at any point in time between harvest and sowing. The seed usually used has been separated from the plant and freed from cobs, shells, stalks, coats, hairs or the flesh of the fruits. Thus, it is possible to use, for example, seed which has been harvested, cleaned and dried to a moisture content of less than 15% by weight. Alternatively, it is also possible to use seed which, after drying, has been treated, for example, with water and then dried again.
  • When treating the seed, care must generally be taken that the amount of the composition according to the invention applied to the seed and/or the amount of further additives is chosen in such a way that the germination of the seed is not adversely affected, or that the resulting plant is not damaged. This must be borne in mind in particular in the case of active compounds which can have phytotoxic effects at certain application rates.
  • The compositions according to the invention can be applied directly, i.e. without any other components and undiluted. In general, it is preferred to apply the compositions to the seed in the form of a suitable formulation. Suitable formulations and methods for treating seed are known to the person skilled in the art and are described, for example, in the following documents: U.S. Pat. No. 4,272,417 A, U.S. Pat. No. 4,245,432 A, U.S. Pat. No. 4,808,430 A, U.S. Pat. No. 5,876,739 A, US 2003/0176428 A1, WO 2002/080675 A1, WO 2002/028186 A2.
  • The active compounds which can be used in accordance with the invention can be converted into the customary seed-dressing formulations, such as solutions, emulsions, suspensions, powders, foams, slurries or other coating compositions for seed, and also ULV formulations These formulations are prepared in a known manner, by mixing the active compounds or active compound combinations with customary additives such as, for example, customary extenders and also solvents or diluents, colorants, wetting agents, dispersants, emulsifiers, antifoams, preservatives, secondary thickeners, adhesives, gibberellins and also water.
  • Colorants which may be present in the seed-dressing formulations which can be used in accordance with the invention are all colorants which are customary for such purposes. In this context, not only pigments, which are sparingly soluble in water, but also dyes, which are soluble in water, may be used. Examples which may be mentioned are the colorants known by the names Rhodamin B, C.I. Pigment Red 112 and C.I. Solvent Red 1.
  • Suitable wetting agents which may be present in the seed-dressing formulations which can be used in accordance with the invention are all substances which promote wetting and which are conventionally used for the formulation of agrochemical active compounds. Preference is given to using alkylnaphthalenesulphonates, such as diisopropyl- or diisobutylnaphthalenesulphonates.
  • Suitable dispersants and/or emulsifiers which may be present in the seed-dressing formulations which can be used in accordance with the invention are all nonionic, anionic and cationic dispersants conventionally used for the formulation of agrochemical active compounds. Preference is given to using nonionic or anionic dispersants or mixtures of nonionic or anionic dispersants. Suitable nonionic dispersants which may be mentioned are, in particular, ethylene oxide/propylene oxide block polymers, alkylphenol polyglycol ethers and tristryrylphenol polyglycol ether, and their phosphated or sulphated derivatives. Suitable anionic dispersants are, in particular, lignlosulphonates, polyacrylic acid salts and arylsulphonate/formaldehyde condensates.
  • Antifoams which may be present in the seed-dressing formulations which can be used in accordance with the invention are all foam-inhibiting substances conventionally used for the formulation of agrochemical active compounds. Silicone antifoams and magnesium stearate can preferably be used.
  • Preservatives which may be present in the seed-dressing formulations which can be used in accordance with the invention are all substances which can be employed for such purposes in agrochemical compositions. Dichlorophene and benzyl alcohol hemiformal may be mentioned by way of example.
  • Secondary thickeners which may be present in the seed-dressing formulations which can be used in accordance with the invention are all substances which can be employed for such purposes in agrochemical compositions. Cellulose derivatives, acrylic acid derivatives, xanthan, modified clays and finely divided silica are preferred.
  • Adhesives which may be present in the seed-dressing formulations which can be used in accordance with the invention are all customary binders which can be employed in seed-dressing products. Polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol and tylose may be mentioned as being preferred.
  • Gibberellins which can be present in the seed-dressing formulations which can be used in accordance with the invention are preferably the gibberellins A1, A3 (=gibberellic acid), A4 and A7; gibberellic acid is especially preferably used. The gibberellins are known (cf. R. Wegler “Chemie der Pflanzenschutz-und Schdlingsbekämpfungsmittel” [Chemistry of plant protection agents and pesticides], vol. 2, Springer Verlag, 1970, p. 401-412).
  • The seed-dressing formulations which can be used in accordance with the invention can be employed for the treatment of a wide range of seed, either directly or after previously having been diluted with water. Thus, the concentrates or the preparations obtainable therefrom by dilution with water may be used to dress the seed of cereals, such as wheat, barley, rye, oats, and triticale, and also the seed of maize, rice, oilseed rape, peas, beans, cotton, sunflowers, and beets, or else vegetable seed of any of a very wide variety of kinds. The seed-dressing formulations which can be used according to the invention or their dilute preparations may also be used to dress seed of transgenic plants. In this context, additional synergistic effects may also occur in cooperation with the substances formed by expression.
  • All mixers which can conventionally be employed for the seed-dressing operation are suitable for treating seed with the seed-dressing formulations which can be used in accordance with the invention or with the preparations prepared therefrom by addition of water. Specifically, a procedure is followed during the seed-dressing operation in which the seed is placed into a mixer, the specific desired amount of seed-dressing formulations, either as such or after previously having been diluted with water, is added, and everything is mixed until the formulation is distributed uniformly on the seed. If appropriate, this is followed by a drying process.
  • The application rate of the seed dressing formulations which can be used according to the invention may be varied within a relatively wide range. It depends on the respective content of the active compounds in the formulations and on the seed. The active compound combination application rates are generally between 0.001 and 50 g per kilogram of seed, preferably between 0.01 and 15 g per kilogram of seed.
  • In addition, the compounds of the formula (I) according to the invention also have very good antimycotic activity. They have a very broad antimycotic activity spectrum in particular against dermatophytes and yeasts, molds and diphasic fungi, (for example against Candida species, such as Candida albicans, Candida glabrata), and Epidermophyton floccosum, Aspergillus species, such as Aspergillus niger and Aspergillus fumigatus, Trichophyton species, such as Trichophyton mentagrophytes, Microsporon species such as Microsporon canis and audouinii. The list of these fungi by no means limits the mycotic spectrum covered, but is only for illustration.
  • Accordingly, the active compounds of the formula (I) according to the invention can be used both in medical and in non-medical applications.
  • The active compounds can be used as such, in the form of their formulations or the use forms prepared therefrom, such as ready-to-use solutions, suspensions, wettable powders, pastes, soluble powders, dusts and granules. Application is carried out in a customary manner, for example by watering, spraying, atomizing, broadcasting, dusting, foaming, spreading, etc. It is furthermore possible to apply the active compounds by the ultra-low volume method, or to inject the active compound preparation or the active compound itself into the soil. It is also possible to treat the seed of the plants.
  • When using the active compounds according to the invention as fungicides, the application rates can be varied within a relatively wide range, depending on the kind of application. The application rate of the active compounds according to the invention is
      • when treating plant parts, for example leaves: from 0,1 to 10 000 g/ha, preferably from 10 to 1 000 g/ha, particularly preferably from 50 to 300 g/ha (when the application is carried out by watering or dripping, it is even possible to reduce the application rate, especially when inert substrates such as rock wool or perlite are used);
      • when treating seed: from 2 to 200 g per 100 kg of seed, preferably from 3 to 150 g per 100 kg of seed, particularly preferably from 2.5 to 25 g per 100 kg of seed, very particularly preferably from 2.5 to 12.5 g per 100 kg of seed;
      • when treating the soil: from 0.1 to 10 000 g/ha, preferably from 1 to 5000 g/ha.
  • These application rates are mentioned only by way of example and are not limiting in the sense of the invention.
  • With respect to possible additional partners for mixing, reference is made to the insecticides and fungicides mentioned above.
  • The compounds according to the invention can at the same time be employed for protecting objects which come into contact with saltwater or brackish water, such as hulls, screens, nets, buildings, moorings and signaling systems, against fouling.
  • Furthermore, the compounds according to the invention can be used alone or in combinations with other active compounds as antifouling compositions.
  • The method of treatment according to the invention can be used in the treatment of genetically modified organisms (GMOs), e.g. plants or seeds. Genetically modified plants (or transgenic plants) are plants in which a heterologous gene has been stably integrated into the genome. The expression “heterologous gene” essentially means a gene which is provided or assembled outside the plant and when introduced in the nuclear, chloroplastic or hypochondrial genome gives the transformed plant new or improved agronomic or other properties by expressing a protein or polypeptide of interest or by downregulating or silencing other gene(s) which are present in the plant (using for example antisense technology, cosuppression technology or RNAi technology [RNA interference]). A heterologous gene that is located in the genome is also called a transgene. A transgene that is defined by its particular location in the plant genome is called a transformation or transgenic event.
  • Depending on the plant species or plant varieties, their location and growth conditions (soils, climate, vegetation period, diet), the treatment according to the invention may also result in superadditive (“synergistic”) effects. Possible are thus, for example, the following effects which exceed the effects which were to be expected: reduced application rates and/or a widening of the activity spectrum and/or an increase in the activity of the active compounds and compositions which can be used according to the invention, better plant growth, increased tolerance to high or low temperatures, increased tolerance to drought or to water or soil salt content, increased flowering performance, easier harvesting, accelerated maturation, higher harvest yields, bigger fruits, larger plant height, greener leaf color, earlier flowering, higher quality and/or a higher nutritional value of the harvested products, higher sugar concentration within the fruits, better storage stability and/or processability of the harvested products.
  • At certain application rates, the active compound combinations according to the invention may also have a strengthening effect in plants. Accordingly, they are suitable for mobilizing the defense system of the plant against attack by unwanted phytopathogenic fungi and/or microorganisms and/or viruses. This may, if appropriate, be one of the reasons for the enhanced activity of the combinations according to the invention, for example against fungi. Plant-strengthening (resistance-inducing) substances are to be understood as meaning, in the present context, also those substances or combinations of substances which are capable of stimulating the defence system of plants in such a way that, when subsequently inoculated with unwanted phytopathogenic fungi and/or microorganisms and/or viruses, the treated plants display a substantial degree of resistance to there unwanted phytopathogenic fungi and/or microorganisms and/or viruses. In the present case, unwanted phytopathogenic fungi and/or microorganisms and/or viruses are understood as meaning phytopathogenic fungi, bacteria and viruses. Thus, the substances according to the invention can be employed for protecting plants against attack by the abovementioned pathogens within a certain period of time after the treatment. The period within which protection is brought about generally extends from 1 to 10 days, preferably 1 to 7 days, after the treatment of the plants with the active compounds.
  • Plants and plant varieties which are preferably treated according to the invention include all plants which have genetic material which imparts particularly advantageous, useful traits to these plants (whether obtained by breeding and/or biotechnological means).
  • Plants and plant varieties which are also preferably treated according to the invention are resistant against one or more biotic stresses, i.e. said plants have a better defence against animal and microbial pests, such as against nematodes, insects, mites, phytopathogcnic fungi, bacteria, viruses and/or viroids.
  • Plants and plant varieties which may also be treated according to the invention are those plants which are resistant to one or more abiotic stress factors. Abiotic stress conditions may include, for example, drought, cold temperature exposure, heat exposure, osmotic stress, waterlogging, increased soil salinity, increased exposure to minerals, exposure to ozone, exposure to strong light. limited availability of nitrogen nutrients, limited availability of phosphorus nutrients or shade avoidance.
  • Plants and plant varieties which may also be treated according to the invention are those plants characterized by enhanced yield characteristics. Enhanced yield in said plants can be the result of, for example, improved plant physiology, growth and development, such as water use efficiency, water retention efficiency, improved nitrogen use, enhanced carbon assimilation, improved photosynthesis, increased germination efficiency and accelerated maturation. Yield can furthermore be affected by improved plant architecture (under stress and non-stress conditions), including early flowering, flowering control for hybrid seed production, seedling vigour, plant size, internode number and distance, root growth, seed size, fruit size, pod size, pod or ear number, seed number per pod or ear, seed mass, enhanced seed filling, reduced seed dispersal, reduced pod dehiscence and lodging resistance. Further yield traits include seed composition, such as carbohydrate content, protein content, oil content and composition, nutritional value, reduction in anti-nutritional compounds, improved processability and better storage stability.
  • Plants that may be treated according to the invention are hybrid plants that already express the characteristics of heterosis, or hybrid vigour, which results in generally higher yield, vigour, health and resistance towards biotic and abiotic stress factors. Such plants are typically made by crossing an inbred male-sterile parent line (the female parent) with another inbred male-fertile parent line (the male parent). Hybrid seed is typically harvested from the male sterile plants and sold to growers. Male sterile plants can sometimes (e.g. in corn) be produced by detasseling (i.e. the mechanical removal of the male reproductive organs or male flowers) but, more typically, male sterility is the result of genetic determinants in the plant genome. In that case, and especially when seed is the desired product to be harvested from the hybrid plants, it is typically useful to ensure that male fertility in the hybrid plants, which contain the genetic determinants responsible for male sterility, is fully restored. This can be accomplished by ensuring that the male parents have appropriate fertility restorer genes which are capable of restoring the male fertility in hybrid plants that contain the genetic determinants responsible for male sterility. Genetic determinants for male sterility may be located in the cytoplasm. Examples of cytoplasmic male sterility (CMS) were for instance described for Brassica species. However, genetic determinants for male sterility can also be located in the nuclear genome. Male sterile plants can also be obtained by plant biotechnology methods such as genetic engineering. A particularly useful means of obtaining male sterile plants is described in WO 89/10396 in which, for example, a ribonuclease such as barnase is selectively expressed in the tapetum cells in the stamens. Fertility can then be restored by expression in the tapetum cells of a ribonuclease inhibitor such as barstar.
  • Plants or plant varieties (obtained by plant biotechnology methods such as genetic engineering) which may be treated according to the invention are herbicide-tolerant plants, i.e. plants made tolerant to one or more given herbicides. Such plants can be obtained either by genetic transformation, or by selection of plants containing a mutation imparting such herbicide tolerance.
  • Herbicide-tolerant plants are for example glyphosate-tolerant plants, i.e. plants made tolerant to the herbicide glyphosate or salts thereof. For example, glyphosate-tolerant plants can be obtained by transforming the plant with a gene encoding the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS). Examples of such EPSPS genes are the AroA gene (mutant CT7) of the bacterium Salmonella typhimurium, the CP4 gene of the bacterium Agrobacterium sp., the genes encoding a petunia EPSPS, a tomato EPSPS, or an Eleusine EPSPS. It can also be a mutated EPSPS. Glyphosate-tolerant plants can also be obtained by expressing a gene that encodes a glyphosate oxidoreductase enzyme. Glyphosate-tolerant plants can also be obtained by expressing a gene that encodes a glyphosate acetyl transferase enzyme. Glyphosate-tolerant plants can also be obtained by selecting plants containing naturally-occurring mutations of the above-mentioned genes.
  • Other herbicide-resistant plants are for example plants which have been made tolerant to herbicides inhibiting the enzyme glutamine synthase, such as bialaphos, phosphinothricin or glufosinate. Such plants can be obtained by expressing an enzyme detoxifying the herbicide or a mutant glutamine synthase enzyme that is resistant to inhibition. One such efficient detoxifying enzyme is, for example, an enzyme encoding a phosphinothricin acetyltransferase (such as the bar or pat protein from Streptomyces species). Plants expressing an exogenous phosphinothricin acetyltransferase have been described.
  • Further herbicide-tolerant plants are also plants that are made tolerant to the herbicides inhibiting the enzyme hydroxyphenylpyruvatedioxygenase (HPPD). Hydroxyphenylpyruvatedioxygenases are enzymes that catalyse the reaction in which para-hydroxyphenylpyruvate (HPP) is transformed into homogentisate. Plants tolerant to HPPD-inhibitors can be transformed with a gene encoding a naturally-occurring resistant HPPD enzyme, or a gene encoding a mutated HPPD enzyme. Tolerance to HPPD-inhibitors can also be obtained by transforming plants with genes encoding certain enzymes enabling the formation of homogentisate despite the inhibition of the native HPPD enzyme by the HPPD-inhibitor. Tolerance of plants to HPPD inhibitors can also be improved by transforming plants with a gene encoding an enzyme prephenate dehydrogenase in addition to a gene encoding an HPPD-tolerant enzyme.
  • Further herbicide-resistant plants are plants that have been made tolerant to acetolactate synthase (ALS) inhibitors. Known ALS inhibitors include, for example, sulphonylurea, imidazolinone, triazolopyrimidines, pyrimidinyloxy(thio)benzoates, and/or sulphonylaminocarbonyltriazolinone herbicides. Different mutations in the ALS enzyme (also known as acetohydroxyacid synthase, AHAS) are known to confer tolerance to different herbicides and groups of herbicides. The production of sulphonylurea-tolerant plants and imidazolinone-tolerant plants has been described in the international publication WO 1996/033270. Further sulphonylurea- and imidazolinone-tolerant plants have also been described, for example in WO 2007/024782.
  • Other plants tolerant to imidazolinone and/or sulphonylurea can be obtained by induced mutagenesis, by selection in cell cultures in the presence of the herbicide or by mutation breeding.
  • Plants or plant varieties (obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention are insect-resistant transgenic plants, i.e. plants made resistant to attack by certain target insects. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such insect resistance.
  • In the present context, the term “insect-resistant transgenic plant” includes any plant containing at least one transgene comprising a coding sequence encoding:
    • 1) an insecticidal crystal protein from Bacillus thuringiensis or an insecticidal portion thereof, such as the insecticidal crystal proteins listed online at: http://www.lifesci.sussex.ac.uk/Home/Neil_Crickmore/Bt/, or insecticidal portions thereof, for example proteins of the Cry protein classes Cry1Ab, Cry1Ac, Cry1F, Cry2Ab, Cry3Ae or Cry3Bb or insecticidal portions thereof; or
    • 2) a crystal protein from Bacillus thuringiensis or a portion thereof which is insecticidal in the presence of a second other crystal protein from Bacillus thuringiensis or a portion thereof, such as the binary toxin made up of the Cy34 and Cy35 crystal proteins; or
    • 3) a hybrid insecticidal protein comprising parts of two different insecticidal crystal proteins from Bacillus thuringiensis, such as a hybrid of the proteins of 1) above or a hybrid of the proteins of 2) above, for example the Cry1A.105 protein produced by maize event MON98034 (WO 2007/027777): or
    • 4) a protein of any one of 1) to 3) above wherein some, particularly 1 to 10, amino acids have been replaced by another amino acid to obtain a higher insecticidal activity to a target insect species, and/or to expand the range of target insect species affected, and/or because of changes induced in the encoding DNA during cloning or transformation, such as the Cry3Bbl protein in maize events MON863 or MON88017, or the Cry3A protein in maize event MIR604;
    • 5) an insecticidal secreted protein from Bacillus thuringiensis or Bacillus cereus, or an insecticidal portion thereof, such as the vegetative insecticidal proteins (VIP) listed at: http://www.lifesci.sussex.ac.uk/home/Neil_Crickmore/Bt/vip.html, for example proteins from the VIP3Aa protein class; or
    • 6) a secreted protein from Bacillus thuringiensis or Bacillus cereus which is insecticidal in the presence of a second secreted protein from Bacillus thuringiensis or B. cereus, such as the binary toxin made up of the VIP1A and VIP2A proteins.
    • 7) a hybrid insecticidal protein comprising parts from different secreted proteins from Bacillus thuringiensis or Bacillus cereus, such as a hybrid of the proteins in 1) above or a hybrid of the proteins in 2) above; or
    • 8) a protein of any one of 1) to 3) above wherein some, particularly 1 to 10, amino acids have been replaced by another amino acid to obtain a higher insecticidal activity to a target insect species, and/or to expand the range of target insect species affected, and/or because of changes induced in the encoding DNA during cloning or transformation (while still encoding an insecticidal protein), such as the VIP3Aa protein in cotton event COT102.
  • Of course, insect-resistant transgenic plants, as used herein, also include any plant comprising a combination of genes encoding the proteins of any one of the above classes 1 to 8. In one embodiment, an insect-resistant plant contains more than one transgene encoding a protein of any one of the above classes 1 to 8, to expand the range of target insect species affected or to delay insect resistance development to the plants, by using different proteins insecticidal to the same target insect species but having a different mode of action, such as binding to different receptor binding sites in the insect.
  • Plants or plant varieties (obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention are tolerant to abiotic stress factors. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such stress resistance. Particularly useful stress-tolerant plants include the following:
      • a. plants which contain a transgene capable of reducing the expression and/or the activity of the poly(ADP-ribose)polymerase (PARP) gene in the plant cells or plants.
      • b. plants which contain a stress tolerance-enhancing transgcne capable of reducing the expression and/or the activity of the PARG encoding genes of the plants or plants cells;
      • c. plants which contain a stress tolerance-enhancing transgene coding for a plant-functional enzyme of the nicotinamide adenine dinucleotide salvage biosynthesis pathway, including nicotinamidase, nicotinate phosphoribosyltransferase, nicotinic acid mononucleotide adenyl transferase, nicotinamide adenine dinucleotide synthetase or nicotinamide phosphoribosyltransferase.
  • Plants or plant varieties (obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention show altered quantity, quality and/or storage-stability of the harvested product and/or altered properties of specific ingredients of the harvested product such as, for example:
    • 1) Transgenic plants which synthesize a modified starch which is altered with respect to its chemophysical traits, in particular the amylose content or the amylose/amylopectin ratio, the degree of branching, the average chain length, the distribution of the side chains, the viscosity behavior, the gel resistance, the grain size and/or grain morphology of the starch in comparison to the synthesized starch in wild-type plant cells or plants, such that this modified starch is better suited for certain applications.
    • 2) Transgenic plants which synthesize non-starch carbohydrate polymers or which synthesize non-starch carbohydrate polymers with altered properties in comparison to wild type plants without genetic modification. Examples are plants which produce polyfructose, especially of the inulin and levan type, plants which produce alpha-1,4-glucans, plants which produce alpha-1,6 branched alpha-1,4-glucans, and plants producing alternan.
    • 3) Transgenic plants which produce hyaluronan.
  • Plants or plant varieties (obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention are plants, such as cotton plants, with altered fiber characteristics. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such altered fiber characteristics and include:
    • a) plants, such as cotton plants, which contain an altered form of cellulose synthase genes,
    • b) plants, such as cotton plants, which contain an altered form of rsw2 or rsw3 homologous nucleic acids;
    • c) plants, such as cotton plants, with an increased expression of sucrose phosphate synthase;
    • d) plants, such as cotton plants, with an increased expression of sucrose synthase;
    • e) plants, such as cotton plants, wherein the timing of the plasmodesmatal gating at the basis of the fiber cell is altered, for example through downregulation of fiber-selective β-1,3-glucanase;
    • f) plants, such as cotton plants, which have fibers with altered reactivity, for example through the expression of the N-acetylglucosaminetransferase gene including nodC and chitin synthase genes.
  • Plants or plant cultivars (that can be obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention are plants, such as oilseed rape or related Brassica plants, with altered oil profile characteristics. Such plants can be obtained by genetic transformation or by selection of plants containing a mutation imparting such altered oil characteristics and include:
    • a) plants, such as oilseed rape plants, which produce oil having a high oleic acid content;
    • b) plants, such as oilseed rape plants, which produce oil having a low linolenic acid content.
    • c) plants, such as oilseed rape plants, which produce oil having a low level of saturated fatty acids.
  • Particularly useful transgenic plants which may be treated according to the invention are plants which comprise one or more genes which encode one or more toxins are the transgenic plants available under the following trade names: YIELD GARD® (for example maize, cotton, soya beans), KnockOut® (for example maize), BiteGard® (for example maize), BT-Xtra® (for example maize), StarLink® (for example maize), Bollgard® (cotton), Nucotn® (cotton), Nucotn 33B® (cotton), NatureGard® (for example maize), Protecta® and NewLeaf@(potato). Examples of herbicide-tolerant plants which may be mentioned are maize varieties, cotton varieties and soya bean varieties which are available under the following trade names: Roundup Ready® (tolerance to glyphosate, for example maize, cotton, soya beans), Liberty Link® (tolerance to phosphinothricin, for example oilseed rape), IMI® (tolerance to imidazolinone) and SCS® (tolerance to sulphonylurea, for example maize). Herbicide-resistant plants (plants bred in a conventional manner for herbicide tolerance) which may be mentioned include the varieties sold under the name Clearfield® (for example maize).
  • Particularly useful transgenic plants which may be treated according to the invention are plants containing transformation events, or a combination of transformation events, that are listed for example in the databases for various national or regional regulatory agencies (see for example http://gmoinfo.jrc.it/gmp_browse.aspx and http://www.agbios.com/dbase.php).
  • The plants listed can be treated according to the invention in a particularly advantageous manner with the compounds of the general formula (I) and/or the active compound mixtures according to the invention. The preferred ranges stated above for the active compounds or mixtures also apply to the treatment of these plants. Particular emphasis is given to the treatment of plants with the compounds or mixtures specifically mentioned in the present text.
  • The active compounds or compositions according to the invention can thus be employed for protecting plants for a certain period of time after treatment against attack by the pathogens mentioned. The period for which protection is provided extends generally for 1 to 28 days, preferably 1 to 14 days, particularly preferably for 1 to 10 days, very particularly preferably for 1 to 7 days after the treatment of the plants with the active compounds, or up to 200 days after a seed treatment.
  • The preparation and the use of the active compounds of the formula (I) according to the invention is illustrated by the examples below. However, the invention is not limited to these examples.
  • General note: Unless indicated otherwise, all chromatographic purification and separation steps are carried out on silica gel and using a solvent gradient of from 0:100 ethyl acetate/cyclohexane to 100:0 ethyl acetate/cyclohexane.
  • General note: Unless indicated otherwise, all chromatographic purification and separation steps are carried out on silica gel and using a solvent gradient of from 0:100 ethyl acetate/hexane to 100:0 ethyl acetate/hexane.
    • Preparation of Starting Materials of the Formula (XVIII) 3-tert-Butyl-5-(pentafluoroethyl)-1H-pyrazole (XVIII-1)
  • At room temperature, hydrazine hydrate (2.06 g) is added to a solution of 1,1,1,2,2-pentafluoro-6,6-dimethylheptane-3,5-dione (10.1 g) in ethanol (100 ml). The reaction mixture is stirred at room temperature overnight. After removal of the solvents under reduced pressure, 3-tert-butyl-5-(pentafluoroethyl)-1H-pyrazole (7.9 g, 79%) is obtained.
  • log P (pH 2.7): 3.23
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.30 (s, 9H), 6.40 (s, 1H) 13.3 (s, 1H)
  • MS (ESI): 243 ([M+H]+)
    • 5-tert-Butyl-3-(trifluoromethyl)-1H-pyrazole (XVIII-2)
  • 1,1,1-Trifluoro-5,5-dimethylhexane-2,4-dione (14.1 g) is reacted analogously to Example XVIII-1 with hydrazine hydrate (3.61 g). This gives 5-tert-butyl-3-(trifluoromethyl)-1H-pyrazole (10.7 g. 77%)
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.30 (s, 9H), 6.39 (s, 1H), 13.1 (s, 1H)
  • MS (ESI): 192 ([M]+)
    • 3-Isopropyl-5-(trifluoromethyl)-1H-pyrazole (XVIII-3)
  • 1,1,1-Trifluoro-5-methylhexane-2,4-dione (24.9 g) is reacted analogously to Example XVIII-1 with hydrazine hydrate (6.84 g). This gives 3-isopropyl-5-(trifluoromethyl)-1H-pyrazole (19 g, 78%)
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.23 (d, 6H), 3.02 (septet, 1H), 6.39 (s, 1H), 13.1 (s, 1H)
  • MS (ESI): 178 ([M]+)
    • Preparation of Starting Materials of the Formula (XVI) Ethyl [3-tert-butyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (XVI-1) and ethyl [5-tert-butyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (XVI-2)
  • Potassium carbonate (15.4 g) is added to a solution of 5-tert-butyl-3-(trifluoromethyl)-1H-pyrazole (XVIII-2, 10.7 g) in acetonitrile (150 ml). Ethyl bromoacetate (13.9 g) is then added dropwise at room temperature. The reaction mixture is stirred at room temperature overnight and then filtered and concentrated under reduced pressure. The residue is purified chromatographically. This gives ethyl [3-tert-butyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (7.84 g, 50%) and ethyl[5-tert-butyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (4.53 g, 29%).
  • Ethyl [3-tert-butyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (XVI-1)
  • log P (pH 2.7): 3.89
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.18 (t, 3H), 1.26 (s, 9H), 4.15 (q, 2H), 5.06 (s, 2H), 6.79 (s, 1H)
  • MS (ESI): 279 ([M+H]+)
  • Ethyl [5-tert-butyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (XVI-2)
  • log P (pH 2.7): 3.48
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.20 (t, 3H), 1.31 (s, 9H), 4.17 (q, 2H), 5.18 (s, 2H), 6.47 (s, 1H)
  • MS (ESI): 279 ([M+H]+)
    • Ethyl [3-tert-butyl-5-(pentafluoroethyl)-1H-pyrazol-1-yl]acetate (XVI-3) and ethyl [5-tert-butyl-3-(pentafluoroethyl)-1H-pyrazol-1-yl]acetate (XVI-4)
  • 3-tert-Butyl-5-(pentafluoroethyl)-1H-pyrazole (XVIII-1, 7.90 g) is reacted analogously to Examples XVI-1 and XVI-2 with ethyl bromoacetate (8.17 g). This gives, after chromatographic purification, ethyl[3-tert-butyl-5-(pentafluoroethyl)-1H-pyrazol-1-yl]acetate (2.50 g, 23%) and ethyl[5-tert-butyl-3-(pentafluoroethyl)-1H-pyrazol-1-yl]acetate (4.80 g, 45%).
  • Ethyl [3-tert-butyl-5-(pentafluoroethyl)-1H-pyrazol-1-yl]acetate (XVI-3)
  • log P (pH 2.7): 4.45
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.18 (t, 3H), 1.26 (s, 9H), 4.15 (q, 2H), 5.07 (s, 2H), 6.75 (s, 1H)
  • MS (ESI): 329 ([M+H]+)
    • Ethyl [5-tert-butyl-3-(pentafluoroethyl)-1H-pyrazol-1-yl]acetate (XVI-4)
  • log P (pH 2.7): 4.05
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.18 (t, 3H), 1.32 (s, 9H), 4.16 (q, 2H), 5.20 (s, 2H), 6.47 (s, 1H)
  • MS (ESI): 329 ([M+H]+)
    • Ethyl [3-isopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (XVI-5)
  • 3-Isopropyl-5-(trifluoromethyl)-1H-pyrazole (XVIII-3, 19.3 g) is reacted analogously to Examples XVI-1 and XVI-2 with ethyl bromoacetate (27.1 g). This gives ethyl[3-isopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (26.2 g, 92%)
  • log P (pH 2.7): 3.22
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.18-1.22 (m, 3H), 1.20 (d, 6H), 3.0 (septet, 1H), 4.17 (q, 2H), 5.11 (s, 2H), 6.54 (s, 1H)
  • MS (ESI): 265 ([M+H]+)
    • Ethyl [4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (XVI-6)
  • 4-Chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazole (14.9 g) is reacted analogously to Examples XVI-1 and XVI-2 with ethyl bromoacetate (20.3 g). This gives ethyl[4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (19.5 g, 89%)
  • log P (pH 2.7): 3.11
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.22 (t, 311), 2.25 (s, 311), 4.18 (q, 2H), 5.24 (s, 2H) MS (ESI): 271 ([M+H]+)
    • Preparation of Starting Materials of the Formula (V) [3-tert-Butyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (V−1)
  • At room temperature, a solution of lithium hydroxide monohydrate (2.35 g) in water (20 ml) is added dropwise to a solution of ethyl[3-tert-butyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (XVI-1, 7.80 g) in tetrahydrofuran (80 ml). The reaction mixture is stirred for 2 hours. After removal of the solvent under reduced pressure, the residue is, at 0° C., slowly adjusted to pH 2-3 using dilute hydrochloric acid (1M). This gives, after filtration and drying, [3-tert-butyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid as a white solid (7.1 g, 100%).
  • log P (pH 2.7): 2.45
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.26 (s, 9H), 4.95 (s, 2H), 6.76 (s, 1H)
  • MS (ESI): 251 ([M+H]+)
    • [5-tert-Butyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (V-2)
  • Ethyl [5-tert-butyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (XVI-2, 4.50 g) is reacted analogously to Example V-1. This gives, after filtration and drying, [5-tert-butyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (3.9 g, 95%).
  • log P (pH 2.7): 2.45
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.26 (s, 9H), 4.95 (s, 2H), 6.76 (s, 1H) MS (ESI): 251 ([M+H]+)
    • [3-tert-Butyl-5-(pentafluoroethyl)-1H-pyrazol-1-yl]acetic acid (V-3)
  • Ethyl [3-tert-butyl-5-(pentafluoroethyl)-1H-pyrazol-1-yl]acetate (XVI-3, 2.50 g) is reacted analogously to Example V-1. This gives, after filtration and drying. [3-tert-butyl-5-(pentafluoroethyl)-1H-pyrazol-1-yl]acetic acid (1.8 g. 79%).
  • log P (pH 2.7): 2.92
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.27 (s, 9H), 4.96 (s, 2H), 6.72 (s, 1H)
  • MS (ESI): 301 ([M+H]+)
    • [5-tert-Butyl-3-(pentafluoroethyl)-1H-pyrazol-1-yl]acetic acid (V-4)
  • Ethyl [5-tert-butyl-3-(pentafluoroethyl)-1H-pyrazol-1-yl]acetate (XVI-4, 4.80 g) is reacted analogously to Example V-1. This gives, after filtration and drying, [5-tert-butyl-3-(pentafluoroethyl)-1H-pyrazol-1-yl]acetic acid (3.5 g, 80%).
  • log P (pH 2.7): 2.75
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.33 (s, 9H), 5.09 (s, 2H), 6.45 (s, 1H)
  • MS (ESI): 301 ([M+H]+)
    • [3-Isopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (V-5)
  • Ethyl [3-isopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (XVI-5, 26.2 g) is reacted analogously to Example V-1. This gives, after filtration and drying [3-isopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (22 g, 94%).
  • log P (pH 2.7): 2.05
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.21 (d, 6H), 2.99 (septet, 1H), 4.99 (s, 2H), 6.51 (s, 1H)
  • MS (ESI): 237 ([M+H]+)
    • [4-Chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (V-6)
  • Ethyl [4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazo-1-yl]acetate (XVI-6, 18.0 g) is reacted analogously to Example V-1. This gives, after filtration and drying, [4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (15.5 g, 96%).
  • log P (pH 7.8): 0.68
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 2.24 (s, 3H), 3.13 (bs, 1H), 5.04 (s, 2H)
    • Preparation of Starting Materials of the Formula (VI) 4-[4-(Ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (VI-1)
  • Under argon and at 0° C., a 2-molar solution of hydrogen chloride in diethyl ether (370 ml) is added dropwise to a solution of tert-butyl 4-[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (25.0 g) in diethyl ether (200 ml). The reaction mixture is stirred at 0° C. and then slowly warmed to room temperature. After stirring overnight, the solvent and excess hydrogen chloride are removed. This gives 4-[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (20.0 g, 98%)
  • log P (pH 2.7): 0.42
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.31 (t, 3H), 1.97-2.04 (m, 2H), 2.18-2.23 (m, 2H), 2.98-3.08 (m, 2H), 3.31-3.39 (m, 2H), 3.42 (m, 1H), 4.30 (q, 2H), 839 (s, 1H). 8.90 (bs, 1H), 9.13 (bs, 1H)
  • MS (ESI): 241 ([M−Cl]+)
    • 3-[4-(Ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (VI-2)
  • tert-Butyl 3-[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (13.8 g) is reacted analogously to Example VI-1. This gives 3-[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (10.4 g, 93%)
  • log P (pH 2.7): 0.54
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.31 (t, 3H). 1.75-1.82 (m. 1H), 1.87-1.92 (m, 2H), 2.17-2.20 (m, 1H), 2.90-2.94 (m, 111), 3.10-3.25 (m, 1H), 3.25-3.28 (m, 1H), 3.57 (m, 1H), 3.62 (m, 1H), 4.30 (q, 2H), 8.43 (s, 1H), 9.29-9.34 (m, 2H)
  • MS (ESI): 241 ([M−Cl]+)
    • Preparation of Starting Materials of the Formula (IV) Ethyl 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (IV-1)
  • Oxalyl chloride (6.91 g) and a drop of N,N-dimethylformamide are added to a solution of [3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetic acid (8.00 g) in dichloromethane (200 ml). The reaction mixture is stirred at room temperature overnight, and excess oxalyl chloride is then removed under reduced pressure. The residue is redissolved in dichloromethane (20 ml) and added to a solution of 4-[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (VI-1, 7.53 g) and Hünig base (10.6 g) in dichloromethane (80 ml). The reaction mixture is stirred at room temperature for 24 hours, added to a mixture of ice and water, neutralized with saturated bicarbonate solution and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The residue is purified chromatographically. This gives ethyl 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (10 g, 63%).
  • log P (pH 2.7): 2.52
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.31 (t, 3H), 1.55-1.85 (m, 2H), 2.10 (m, 2H), 3.20-3.60 (m, 4H), 3.99 (bs, 1H), 4.30 (q, 2H), 5.35 (s, 2H), 6.83-7.30 (m, 3H), 8.37 (s, 1H)
  • MS (ESI): 449 ([M+H]+)
    • Ethyl 2-(1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (IV-2)
  • 4-[4-(Ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (VI-1, 5.50 g) is reacted analogously to Example IV-1 with [3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (3.86 g). This gives, after chromatographic purification, ethyl 2-(1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (5.1 g, 62%).
  • log P (pH 2.7): 2.41
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.31 (t, 3H), 1.63 (bs, 1H), 1.75 (bs, 1H), 2.05-2.15 (m, 2H), 2.88 (bs, 1H), 3.26 (bs, 1H). 3.36 (m, 1H), 3.98 (bs, 1H), 4.30 (q, 2H), 4.35 (bs, 1H), 5.28 (s, 2H), 6.67 (d. 1H), 7.85 (dd, 1H), 8.36 (s, 1H)
  • MS (ESI): 417 ([M+H]+)
    • Ethyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-3-yl)-1,3-thiazole-4-carboxylate (IV-3)
  • 3-[4-(Ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (VI-2, 5.32 g) is reacted analogously to Example IV-1 with [5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (4.00 g). This gives, after chromatographic purification, ethyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-3-yl)-1,3-thiazole-4-carboxylate (5.7 g, 69%).
  • log P (pH 2.7): 2.78
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.29 (t, 3H), 1.50-1.74 (m, 2H), 1.79-1.89 (m, 2H), 2.20 (s, 3H), 3.18 (m, 1H), 3.39 (m, 0.5H), 3,69 (m, 0.5H), 3.86-3.89 (m, 1H), 4.00 (m, 0.5H), 4.30 (q, 2H), 4.45 (m, 0.5H), 4.90 (m, 1H), 5.25-5.30 (m, 2H), 6.44 (s, 1H), 8.40 (s, 1H)
  • MS (ESI): 431 ([M+H]+)
    • Ethyl 2-{1-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-2-methylpropanoyl]piperidin-4-yl}-1,3-thiazole-4-carboxylate (IV-4)
  • 4-[4-(Ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (VI-1, 8.23 g) is reacted analogously to Example IV-1 with 2-(3,5-dimethyl-1H-pyrazol-1-yl)-2-methylpropanoic acid (5.42 g). This gives, after chromatographic purification, ethyl 2-{1-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-2-methylpropanoyl]piperidin-4-yl}-1,3-thiazole-4-carboxylate (9.64 g, 80%) log P (pH 7.8): 2.34
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.29 (t, 3H), 1.41 (m, 2H), 1.66 (s, 6H), 1.90 (m, 2H), 2.11 (s, 3H), 2.12 (s, 3H), 2.81 (m, 2H), 3.22 (m, 1H), 3.59 (m, 1H), 4,10 (m, 1H), 4.28 (q, 2H), 5.89 (s, 1H), 8.32 (s, 1H)
  • MS (ESI): 405 ([M+H]+)
    • Ethyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidn-4-yl)-1,3-thazole-4-carboxylate (IV-5)
  • 4-[4-(Ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (VI-1, 4.65 g) is reacted analogously to Example IV-1 with [5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (3.50 g). This gives, after chromatographic purification, ethyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (5.00 g, 69%).
  • log P (pH 2.7): 2.62
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.31 (t, 3H), 1.62 (bs, 1H), 1.80 (bs, 1H), 2.06-2.16 (m, 2H), 2.22 (s, 3H), 2.88 (bs, 1H), 3.28 (bs, 1H), 3.37 (m, 1H), 3.99 (bs, 1H), 4.30 (q, 2H), 4.33 (bs, 1H), 5.22 (bs, 2H), 6.45 (s, 1H), 8.37 (s, 1H)
  • MS (ESI): 431 ([M+H]+)
    • Ethyl 2-(1-{[4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (IV-6)
  • 4-[4-(Ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (VI-1, 5.50 g) is reacted analogously to Example IV-1 with [4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (4.82 g). This gives, after chromatographic purification, ethyl 2-(1-{[4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (6.00 g, 65%).
  • log P (pH 2.7): 3.17
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.31 (t, 3H), 1.61 (bs, 1H), 1.81 (bs, 1H), 2.05-2.15 (m, 2H), 2.20 (s, 3H), 2.88 (bs, 1H), 3.27 (bs, 1H), 3.37 (m, 1H), 3.95 (bs, 1H), 4.30 (q, 2H), 4.32 (bs, 1H), 5.27-5.35 (3, 2H), 8.37 (s, 1H)
  • MS (ESI): 465 ([M+H]+)
    • Preparation of Starting Materials of the Formula (III) 2-(1-{[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-1)
  • Ethyl 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (IV-1, 13.3 g) is dissolved in tetrahydrofuran (80 ml). LiOH monohydrate (1.86 g) dissolved in water (20 ml) is then added. After 3 hours, water is added, the pH is adjusted to 2-3 with dilute hydrochloric acid (1M), the mixture is then extracted with ethyl acetate and the combined organic phases are dried with sodium sulfate. The solid is filtered off and the solvent is removed by distillation. This gives 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (11.7 g, 94%).
  • log P (pH 2.7): 1.71
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.55-1.85 (m, 2H), 2.09-2.13 (m, 2H), 2.80-3.30 (m, 3H), 3.36 (m, 1H), 3.99 (bs, 1H), 4.30 (bs, 1H), 5.34 (s, 2H), 6.85 (s, 1H), 6.98 (t, 1H), 7.14 (t, 1H), 8.29 (s, 1H)
  • MS (ESI): 421 ([M+H]+)
    • 2-(1-{[3-(Trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-2)
  • Ethyl 2-(1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (IV-2, 5.20 g) is reacted analogously to Example III-1. This gives, after drying, 2-(1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (4.6 g, 95%).
  • log P (pH 2.7): 1.65
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.64 (bs, 1H), 1.76 (bs, 1H), 2.05-2.15 (m, 2H), 2.88 (bs, 1H), 3.23 (bs, 1H), 3.36 (m, 1H), 3.98 (bs, 1H), 4.34 (bs, 1H), 5.28 (s, 2H), 6.67 (d, 1H), 7.85 (dd. 1H), 8.29 (s, 1H)
  • MS (ESI): 389 ([M+H]+)
    • 2-(1-{[5-Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-3-yl)-1,3-thiazole-4-carboxylic acid (III-3)
  • Ethyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-3-yl)-1,3-thiazole-4-carboxylate (IV-3, 5.70 g) is reacted analogously to Example III-1. This gives, after drying, 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-3-yl)-1,3-thiazole-4-carboxylic acid (5.4 g, 100%).
  • log P (pH 2.7): 1.90
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.48-1.88 (m. 4H), 2.20 (s, 3H), 3.38 (m, 0.5H), 3.60 (m, 0.5H), 3.87 (m, 2H), 4.01 (m, 0.5H), 4.45 (m, 0.5H), 5.24-5.28 (m, 3H), 6.44 (s, 1H), 8.32 (s, 1H)
  • MS (ESI): 403 ([M+H])
    • 2-(1-{[5-Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-4)
  • Ethyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-5-yl)-1,3-thiazole-4-carboxylate (IV-3, 5.10 g) is reacted analogously to Example III-1. This gives, after drying, 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (4.63 g, 97%).
  • log P (pH 2.7): 1.82
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.62 (bs, 1H), 1.79 (bs, 1H), 2.06-2.16 (m, 2H), 2.22 (s, 3H), 2.88 (bs, 1H), 3.28 (bs, 1H), 3.37 (m, 1H), 3.99 (bs, 1H), 4.33 (bs, 1H), 5.21 (bs, 2H), 6.45 (d, 1H), 8.30 (s, 1H)
  • MS (ESI): 403 ([M+H]+)
    • 2-(1-{[4-Chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-5)
  • Ethyl 2-(1-{[4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-5-yl)-1,3-thiazole-4-carboxylate (IV-6, 6.00 g) is reacted analogously to Example III-1. This gives, after drying, 2-(1-{[4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (3.10 g, 55%).
  • log P (pH 2.7): 2.26
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.61 (bs, 1H), 1.81 (bs, 1H), 2.05-2.17 (m, 2H), 2.20 (s, 3H), 2.89 (bs, 1H), 3.27 (bs, 1H), 3.37 (m, 1H), 3.95 (bs, 1H), 4.32 (bs, 1H), 5.27-5.34 (m, 2H), 8.29 (s, 1H)
  • MS (ESI): 437 ([M+H]+)
    • Preparation of the compounds of the formula (I) Cyclohexyl 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (I-811)
  • At room temperature, cyclohexanol (2.17 g), dimethylaminopyridine (0.20 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (3.35 g) are added to a solution of 2-(1-{[3,5-bis(difluoromethyl)-H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-1, 7.00 g) in dichloromethane (80 ml). The mixture is stirred overnight, and water is then added. The aqueous phase is separated off and extracted with ethyl acetate. The combined organic phases are dried with sodium sulfate. The solid is filtered off and the solvent is removed by distillation. The residue is purified chromatographically. This gives cyclohexyl 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (2.83 g, 34%).
  • log P (pH 2.7): 3.64
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.29-1.90 (m, 12H), 2.09-2.12 (m, 2H), 2.88 (bs, 1H), 3.25 (bs, 1H), 3.39 (m, 1H), 4.01 (bs, 1H), 4.30 (bs, 1H), 4.88-4.93 (m, 1H), 5.35 (s, 2H), 6.85 (s, 1H), 6.96 (t, 1H), 7.14 (t, 1H), 8.34 (s, 1H) MS (ESI): 503 ([M+H])
    • 1-Naphthyl 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (I-813)
  • 2-(1-{[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-1, 7.00 g) is reacted analogously to Example I-811 with 1-naphthol (3.12 g). This gives, after chromatographic purification, 1-naphthyl-2-(1l-{[3,5-bis(difluoromcthyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (4.0 g, 44%).
  • log P (pH 2.7): 3.64
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.70 (bs, 1H), 1.87 (bs, 1H), 2.18 (m, 2H), 2.91 (bs, 1H), 3.31 (bs, 1H), 3.48 (m, 1H), 4.03 (bs, 1H), 4.36 (bs, 1H), 5.36 (s, 2H), 6.85 (s, 1H), 6.97 (t, 1H), 7.15 (t, 1H), 7.45 (dd, 1H), 7.54-7.61 (m, 3H), 7.89 (m, 2H), 8.01 (m, 1H), 8.84 (s, 1H)
  • MS (ESI): 547 ([M+H]+)
    • 1-Naphthyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (I-227)
  • Oxalyl chloride (189 mg) and a drop of N,N-dimethylformamide are added to a solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-4, 200 mg) in dichloromethane (2 ml). The reaction mixture is stirred at room temperature overnight, and excess oxalyl chloride is then removed under reduced pressure. The residue is re-dissolved in dichloromethane (2 ml) and added to a solution of 1-naphthol (79 mg) and pyridine (489 mg) in dichloromethane (4 ml). The mixture is stirred at room temperature for one hour, and dilute hydrochloric acid (1M) is then added. The aqueous phase is separated off and extracted with ethyl acetate, and the combined organic phases are then dried with sodium sulfate. The solid is filtered off and the solvent is removed by distillation. The residue is purified chromatographically. This gives 1-naphthyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (100 mg, 38%).
  • log P (pH 2.7): 3.75
  • 1H NMR (CD3CN, 400 MHz): δppm: 1.72-2.00 (m, 2H), 2.19-2.27 (m, 2H), 2.24 (s, 3H), 2.92 (bs, 1H), 3.34 (bs, 1H), 3.42 (m, 1H), 3.98 (bs, 1H), 4.49 (bs, 1H), 5.06 (bs, 2H), 6.37 (s, 1H), 7.40 (d. 1H), 7.52-7.60 (m, 3H), 7.86 (d, 1H), 7.92-7.99 (m, 2H), 8.55 (s, 1H)
  • MS (ESI): 529 ([M+H])
    • 1,2,3,4-Tetrahydronaphthalen-1-yl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (I-224)
  • At room temperature, 1,2,3,4-tetrahydronaphthalen-1-ol (155 mg) and triphenylphosphine (758 mg) are added to a solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-4, 380 mg) in tetrahydrofuran (2.5 ml). The mixture is stirred at 0 C under argon for 5 minutes, and diethyldiazene 1,2-dicarboxylate (383 mg) is then added dropwise. The reaction mixture is slowly warmed to room temperature. After 2 hours, the solvent is removed under reduced pressure and the residue is purified chromatographically. This gives 1,2,3,4-tetrahydronaphthalen-1-yl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (196 mg, 39%).
  • log P (pH 2.7): 4.01
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.52-1.88 (m, 3H), 1.88-2.15 (m, 4H), 2.22 (s, 3H), 2.70-2.99 (m, 4H), 3.25 (bs, 1H), 3.38 (m, 1H), 3.98 (bs, 1H), 4.33 (bs, 1H), 5.21 (bs, 2H), 6.12 (t, 1H), 6.44 (s, 1H), 7.15-7.19 (m, 2H), 7.21-7.30 (m, 2H), 8.35 (s, 1H)
  • MS (ESI): 403 ([M+H-1,2,3,4-tetrahydronaphthalen-1-ol]+)
    • Cyclohexyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (I-220)
  • A solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-4, 6.00 g) is reacted analogously to Example I-811 with cyclohexanol (1.94 g). This gives, after chromatographic purification, cyclohexyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (5.00 g, 69%).
  • log P (pH 2.7): 3.74
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.25-1.48 (m, 3H), 1.50-2.00 (broad m, 2H), 1.50-1.51 (m, 3H). 1.70-1.80 (m, 2H), 1.85-1.92 (m, 2H), 2.06-2.16 (m, 2H), 2.22 (s, 3H), 2.88 (bs, 1H), 3.28 (bs, 1H), 3.38 (m, 1H), 3.98 (bs, 1H), 4.34 (bs, 1H). 4.91 (septet, 1H), 5.21 (bs, 2H), 6.44 (s, 1H), 8.34 (s, 1H)
  • MS (ESI): 485 ([M+H]+)
    • 2-Bromohenzyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (I-820)
  • A solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-4, 100 mg) is reacted analogously to Example I-811 with (2-bromophenyl)methanol (49.0 mg). This gives, after chromatographic purification, 2-bromobenzyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (123 mg, 89%).
  • log P (pH 2.7): 3.80
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.62 (bs, 1H), 1.80 (bs, 1H), 2.07-2.19 (m, 2H), 2.22 (s, 3H), 2.88 (bs, 1H), 3.27 (bs, 1H), 3.38 (m, 1H), 3.99 (bs, 1H), 4.43 (bs, 1H), 5.22 (bs, 2H), 5.38 (s, 2H), 6.44 (s, 1H), 7.32 (td, 1H), 7.43 (td, 1H), 7.56 (dd, 1H), 7.67 (dd, 1H), 8.46 (s, 1H) MS (ESI): 571, 573 ([M+H]−)
    • 3,3-Dimethylbutyl 2-(1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (I-767)
  • A solution of 2-(1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-2, 200 mg) is reacted analogously to Example I-811 with 3,3-dimethylbutan-1-ol (68.0 mg). This gives, after chromatographic purification, 3,3-dimethylbutyl 2-(1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (98 mg, 40%).
  • log P (pH 2.7): 3.82
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 0.96 (s, 9H), 1.50-1.85 (broad m+t, 4H), 2.06-2.13 (m, 2H), 2.88 (bs, 1H), 3.28 (bs, 1H), 3.38 (m, 1H), 3.98 (bs, 1H), 4.31 (t, 2H), 4.34 (bs, 1H), 5.28 (bs, 21H), 6.66 (d, 1H), 7.85 (s, 1H), 8.34 (s, 1H)
  • MS (ESI): 473 ([M+H]+)
    • S-(4-Fluorobenzyl) 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbothioate (I-27)
  • A solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-4, 200 mg) is reacted analogously to Example I-227 with (4-fluorophenyl)methanethiol (78.0 mg). This gives, after chromatographic purification, S-(4-fluorobenzyl) 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbothioate (110 mg, 42%).
  • log P (pH 2.7): 4.00
  • 1H NMR (CD3CN, 400 MHz): δppm: 1.64-1.88 (broad m, 2H), 2.12-2.18 (m, 2H), 2.23 (s, 3H), 2.92 (bs, 1H), 3.30 (bs, 1H), 3.33 (m, 1H), 3.97 (bs, 1H), 4.24 (s, 2H), 4.41 (bs, 1H), 5.04 (bs, 2H), 6.36 (s, 1H), 7.00-7.07 (m, 2H), 7.36-7.42 (m, 2H), 8.11 (s, 1H)
  • MS (ESI): 527 ([M+H])
    • S-Cyclohexyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbothioate (I-76)
  • A solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (Ill-4, 200 mg) is reacted analogously to Example I-227 with cyclohexanethiol (64.0 mg). This gives, after chromatographic purification, S-cyclohexyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbothioate (110 mg, 44%).
  • log P (pH 2.7): 4.51
  • 1H NMR (CD3CN, 400 MHz): δppm: 1.30-1.40 (m, 2H), 1.42-1.90 (m, 10H), 2.12-2.19 (m, 2H), 2.24 (s, 3H), 2.91 (bs, 1H), 3.30 (bs, 1H), 3.34 (m, 1H), 3.65 (m, 1H), 3.95 (bs, 1H), 4.44 (bs, 1H), 5.04 (bs, 2H), 6.36 (s, 1H), 8.05 (s, 1H)
  • MS (ESI): 501 ([M+H]+)
    • S-1-Naphthyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbothioate (I-77)
  • A solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-4, 200 mg) is reacted analogously to Example I-227 with naphthalene-1-thiol (88.0 mg). This gives, after chromatographic purification, S-1-naphthyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4.carbothioate (100 mg, 37%).
  • log P (pH 2.7): 4.22
  • 1H NMR (CD3CN, 400 MHz): δppm: 1.74-1.90 (m, 2H), 2.20-2.26 (m, 2H), 2.25 (s, 3H), 2.93 (bs, 1H), 3.34 (bs, 1H), 3.42 (m, 1H), 4.04 (bs, 1H), 4.48 (bs, 1H), 5.07 (bs, 2H), 6.37 (s, 1H), 7.54-7.60 (m, 3H), 7.80 (dd, 1H), 7.98 (dd, 1H), 8.05 (d, 1H), 8.13 (s, 1H), 8.20 (dd, 1H)
  • MS (ESI): 545 ([M+H]+)
    • Preparation of Starting Materials of the Formula (VIII) 2-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-1,3-thiazole-4-carboxylic acid (VIII-1)
  • At room temperature, lithium hydroxide monohydrate (8.88 g) is added in one portion to a solution of tert-butyl 4-[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (24.0 g) in tetrahydrofuran (240 ml) and water (60 ml). The mixture is stirred for 4 hours and then stirred with dilute hydrochloric acid (1M) (100 ml) and ethyl acetate (100 ml). The aqueous phase is separated off and extracted with ethyl acetate, and the combined organic phases are then dried with sodium sulfate. The solid is filtered off and the solvent is removed by distillation. This gives 2-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-1,3-thiazole-4-carboxylic acid (21 g, 94%)
  • log P (pH 2.7): 2.04
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.41 (s, 9H), 1.59 (qd, 2H), 2.02 (dd, 2H), 2.91 (m, 2H), 3.23 (m, 1H), 3.97-4.02 (m, 2H), 8.27 (s, 1H)
  • MS (ESI): 256 ([M+H−C(CH3)3] +)
    • Preparation of Starting Materials of the Formula (IX) tert-Butyl 4-{4-[(cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (IX-1)
  • At room temperature, cyclohexanol (1.21 g), dimethylaminopyridine (113 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (1.87 g) are added to a solution of 2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1,3-thiazole-4-carboxylic acid (VII-I, 2.90 g) in dichloromethane (30 ml). The mixture is stirred at room temperature overnight, and water is then added. The aqueous phase is separated off and extracted with ethyl acetate, and the combined organic phases are then dried with sodium sulfate. The solid is filtered off and the solvent is removed by distillation. The residue is purified chromatographically. This gives tert-butyl 4-{4-[(cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (2.63 g, 72%)
  • log P (pH 2.7): 4.62
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.13-1.81 (m+s, 21H), 2.02 (m, 2H), 2.90 (m, 2H), 3.40 (m, 1H), 3.98-4.01 (m, 2H), 4.90 (m, 1H), 8.32 (s, 1H)
  • MS (ESI): 339 ([M+2H−C(CH3)3]+)
    • tert-Butyl 4-{4-[(1-naphthyloxy)carbonyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (IX-2)
  • A solution of 2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1,3-thiazole-4-carboxylic acid (VIII-1, 12.0 g) is reacted analogously to Example IX-1 with 1-naphthol (7.20 g). This gives, after chromatographic purification, tert-butyl 4-{4-[(1-naphthyloxy)carbonyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (12.3 g, 73%)
  • log P (pH 2.7): 4.50
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.42 (s, 9H), 1.67 (qd, 2H), 2.10 (dd, 2H), 2.95 (m, 2H), 3.35 (m, 1H), 4.00-4.08 (m, 2H), 7.45 (dd, 1H), 7.55-7.62 (m, 3H), 7.89 (d, 2H), 8.01 (dd, 1H), 8.83 (s, 1H)
  • MS (ESI): 383 ([M+2H−C(CH3)3]+)
    • Preparation of Starting Materials of the Formula (X) 4-{4-[(Cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidinium chloride (X-1)
  • Under argon and at 0° C, a 2-molar solution of hydrogen chloride in diethyl ether (50 ml) is added dropwise to a solution of tert-butyl 4-{4-[(cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (IX-1, 2.63 g) in dioxane (20 ml). The reaction mixture is stirred at 0° C. and then slowly warmed to room temperature. After stirring overnight, the solvent and excess hydrogen chloride are removed. This gives 4-{4-[(cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidinium chloride (2.19 g, 99%)
  • log P (pH 2.7): 1.25
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.15-1.55 (m, 6H), 1.71-1.75 (m, 2H), 1.85-1.90 (m, 2H), 1.98-2.04 (m, 2H), 2.20 (dd, 2H), 3.01-3.03 (m, 2H), 3.14-3.34 (m, 2H), 3.40 (m, 1H), 4.90 (m, 1H), 8.36 (s, 1H), 9.05 (bs, 1H), 9.25 (bs, 1H) MS (ESI): 295 ([M−Cl]+)
    • 4-{4-[(1-Naphthyloxy)carbonyl]-1,3-thiazol-2-yl}piperidinium chloride (X-2)
  • tert-Butyl 4-{4-[(1-naphthyloxy)carbonyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (IX-2, 3.20 g) is reacted analogously to Example X-1. This gives, after drying, 4-{4-[(1-naphthyloxy)carbonyl]-1,3-thiazol-2-yl}piperidinium chloride (2.93 g, 100%)
  • log P (pH 2.7): 1.42
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 2.02-2.15 (m, 2H), 2.25-2.34 (m, 2H), 3.00-3.12 (m, 2H), 3.34-3.40 (m, 2H), 3.51 (m, 1H), 7.46 (dd, 1H), 7.53-7.62 (m, 3H), 7.89 (d, 2H), 8.00-5.05 (m, 1H), 8.87 (s, 1H), 9.05 (bs, 1H), 9.25 (bs, 1H)
  • MS (ESI): 339 ([M−Cl]+)
    • Preparation of the Compounds of the Formula (I)
  • Cyclohexyl 2-(1-({[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (I-772)
  • [3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (288 mg) and Hünig base (323 mg) are dissolved in dichloromethane (10 ml) and stirred at room temperature for 30 min. 4-{4-[(Cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidinium chloride (X-1, 330 mg) is added, and the mixture is stirred for a further 5 min before bromo-tris-pyrrolidinophosphonium hexafluorophosphate (559 mg) is added. The reaction mixture is stirred at room temperature overnight. After removal of the solvent under reduced pressure, the residue is purified chromatographically. This gives cyclohexyl 2-(1-{[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (348 mg, 65%).
  • log P (pH 2.7): 4.39
  • 1H NMR (DMSO-d6, 400 MHz): δ: 1.20-1.60 (m, 8H), 1.71-1.75 (m, 2H), 1.85-1.88 (m, 2H), 2.04 (m, 2H), 2.90 (bs, 1H), 3.30 (bs, 1H), 3.38 (m, 1H), 3.95 (bs, 1H), 4.30 (bs, 1H), 4.91 (m, 1H), 5.48 (bs, 2H), 7.47 (s, 1H), 8.34 (s, 1H)
  • MS (ESI): 539 ([M+H]+)
    • 1-Naphthyl 2-(1-{[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (I-771)
  • 4-{4-[(1-Naphthyloxy)carbonyl]-1,3-thiazol-2-yl}piperidinium chloride (X-2, 375 mg) is reacted analogously to Example I-772 with [3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (288 mg). This gives, after chromatographic purification, 1-naphthyl 2-(1-{[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (356 mg, 61%).
  • log P (pH 2.7): 4.35
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.65 (m, 1H), 1.90 (m, 1H), 2.19 (m, 2H), 2.95 (m, 1H), 3.32 (m, 1H), 3.48 (m, 1H), 4.01 (m, 1H), 4.35 (m, 1H), 5.50 (m, 2H), 7.45 (m, 2H), 7.56-7.61 (m, 3H), 7.89 (m, 2H), 8.02 (m, 1H), 8.84 (s, 1H)
  • MS (ESI): 583 ([M+H]+)
    • 1-Naphthyl 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (I-813)
  • Oxalyl chloride (6.78 g) and a drop of N,N-dimethylformamide are added to a solution of [3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetic acid (10.8 g) in dichloromethane (150 ml). The reaction mixture is stirred at room temperature overnight, and excess oxalyl chloride is then removed under reduced pressure. The residue is redissolved in dichloromethane (50 ml) and added to a solution of 4-{4-[(1-naphthyloxy)carbonyl]-1,3-thiazol-2-yl]piperidinium chloride (X-2, 7.25 g) and Hünig base (10.4 g) in dichloromethane (100 ml) at 0° C. The reaction mixture is stirred at room temperature overnight. After addition of cone ammonium chloride solution, the aqueous phase is separated off and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate. The solid is filtered off and the solvent is removed by distillation. The residue is purified chromatographically. This gives 1-naphthyl 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (11.3 g, 64%).
  • log P (pH 2.7): 3.64
  • 1H NMR (DMSO-d6, 400 MHz): δppm: 1.70 (bs, 1H), 1.87 (bs, 1H), 2.18 (m, 2H), 2.91 (bs, 1H), 3.31 (bs, 1H), 3.48 (m, 1H), 4.03 (bs, 1H), 4.36 (bs, 1H), 5.36 (s, 2H), 6.85 (s, 1H), 6.97 (t, 1H), 7.15 (t, 1H), 7.45 (dd, 1H): 7.54-7.61 (m, 3H), 7.89 (m, 2H), 8.01 (m, 1H), 8.84 (s, 1H)
  • MS (ESI): 547 ([M+H]+)
    • Cyclohexyl 2-(1-{2-[3,5-bis(diluoromethyl)-1H-pyrazol-1-yl]ethanethioyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (I-854)
  • At room temperature, 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (88 mg) is added to a solution of cyclohexyl 2-(l-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (I-811. 200 mg) in 1.2-dimethoxyethane (1 ml) and chloroform (0.4 ml). The reaction mixture is stirred at 70-80° C. overnight. After removal of the solvent under reduced pressure, the residue is purified chromatographically. This gives cyclohexyl 2-(1-{2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]ethanethioyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (80 mg, 39%).
  • log P (pH 2.7): 4.23
  • 1H NMR (DMSO-d6, 400 MHz): δppm; 1.30-1.58 (m, 6H), 1.75-1.92 (m, 4H), 2.10-2.30 (m, 4H), 3.32 (m, 1H), 3.50 (m, 2H), 4.39 (m, 1H), 4.93 (m, 1H), 5.39 (s, 2H), 5.42 (m, 1H), 6.79 (t, 1H), 6.83 (s, 1H), 7.01 (t, 1H), 8.16 (s, 1H)
  • MS (ESI): 519 ([M+H]+)
    • EXAMPLES
  • Table 1 shows the compounds of the formula (I) whose use as fungicides is claimed.
  • (I)
    Figure US20150237859A1-20150827-C00022
    EX NO R1 R2 R3 R4 R5 Y1 X
    1 CF3 H CH3 H H O —CH2CH2—
    2 CF3 H CH3 H H O —CH2CH2—
    3 CF3 H CH3 H H O —CH2CH2—
    4 CF3 H CH3 H H O —CH2CH2—
    5 CF3 H CH3 H H O —CH2CH2—
    6 CF3 H CH3 H H O —CH2CH2—
    7 CF3 H CH3 H H O —CH2CH2—
    8 CF3 H CH3 H H O —CH2CH2—
    9 CF3 H CH3 H H O —CH2CH2—
    10 CF3 H CH3 H H O —CH2CH2—
    11 CF3 H CH3 H H O —CH2CH2—
    12 CF3 H CH3 H H O —CH2CH2—
    13 CF3 H CH3 H H O —CH2CH2—
    14 CF3 H CH3 H H O —CH2CH2—
    15 CF3 H CH3 H H O —CH2CH2—
    16 CF3 H CH3 H H O —CH2CH2—
    17 CF3 H CH3 H H O —CH2CH2—
    18 CF3 H CH3 H H O —CH2CH2—
    19 CF3 H CH3 H H O —CH2CH2—
    20 CF3 H CH3 H H O —CH2CH2—
    21 CF3 H CH3 H H O —CH2CH2—
    22 CF3 H CH3 H H O —CH2CH2—
    23 CF3 H CH3 H H O —CH2CH2—
    24 CF3 H CH3 H H O —CH2CH2—
    25 CF3 H CH3 H H O —CH2CH2—
    26 CF3 H CH3 H H O —CH2CH2—
    27 CF3 H CH3 H H O —CH2CH2—
    28 CF3 H CH3 H H O —CH2CH2—
    29 CF3 H CH3 H H O —CH2CH2—
    30 CF3 H CH3 H H O —CH2CH2—
    31 CF3 H CH3 H H O —CH2CH2—
    32 CF3 H CH3 H H O —CH2CH2—
    33 CF3 H CH3 H H O —CH2CH2—
    34 CF3 H CH3 H H O —CH2CH2—
    35 CF3 H CH3 H H O —CH2CH2—
    36 CF3 H CH3 H H O —CH2CH2—
    37 CF3 H CH3 H H O —CH2CH2—
    38 CF3 H CH3 H H O —CH2CH2—
    39 CF3 H CH3 H H O —CH2CH2—
    40 CF3 H CH3 H H O —CH2CH2—
    41 CF3 H CH3 H H O —CH2CH2—
    42 CF3 H CH3 H H O —CH2CH2—
    43 CF3 H CH3 H H O —CH2CH2—
    44 CF3 H CH3 H H O —CH2CH2—
    45 CF3 H CH3 H H O —CH2CH2—
    46 CF3 H CH3 H H O —CH2CH2—
    47 CF3 H CH3 H H O —CH2CH2—
    48 CF3 H CH3 H H O —CH2CH2—
    49 CF3 H CH3 H H O —CH2CH2—
    50 CF3 H CH3 H H O —CH2CH2—
    51 CF3 H CH3 H H O —CH2CH2—
    52 CF3 H CH3 H H O —CH2CH2—
    53 CF3 H CH3 H H O —CH2CH2—
    54 CF3 H CH3 H H O —CH2CH2—
    55 CF3 H CH3 H H O —CH2CH2—
    56 CF3 H CH3 H H O —CH2CH2—
    57 CF3 H CH3 H H O —CH2CH2—
    58 CF3 H CH3 H H O —CH2CH2—
    59 CF3 H CH3 H H O —CH2CH2—
    60 CF3 H CH3 H H O —CH2CH2—
    61 CF3 H CH3 H H O —CH2CH2—
    62 CF3 H CH3 H H O —CH2CH2—
    63 CF3 H CH3 H H O —CH2CH2—
    64 CF3 H CH3 H H O —CH2CH2—
    65 CF3 H CH3 H H O —CH2CH2—
    66 CF3 H CH3 H H O —CH2CH2—
    67 CF3 H CH3 H H O —CH2CH2—
    68 CF3 H CH3 H H O —CH2CH2—
    69 CF3 H CH3 H H O —CH2CH2—
    70 CF3 H CH3 H H O —CH2CH2—
    71 CF3 H CH3 H H O —CH2CH2—
    72 CF3 H CH3 H H O —CH2CH2—
    73 CF3 H CH3 H H O —CH2CH2—
    74 CF3 H CH3 H H O —CH2CH2—
    75 CF3 H CH3 H H O —CH2CH2—
    76 CF3 H CH3 H H O —CH2CH2—
    77 CF3 H CH3 H H O —CH2CH2—
    78 CF3 H CH3 H H O —CH2CH2—
    79 CF3 H CH3 H H O —CH2CH2—
    80 CF3 H CH3 H H O —CH2CH2—
    81 CF3 H CH3 H H O —CH2CH2—
    82 CF3 H CH3 H H O —CH2CH2—
    83 CF3 H CH3 H H O —CH2CH2—
    84 CF3 H H H H O —CH2CH2—
    85 CF3 H H H H O —CH2CH2—
    86 CF3 H H H H O —CH2CH2—
    87 CF3 H H H H O —CH2CH2—
    88 CF3 H H H H O —CH2CH2—
    89 CF3 H H H H O —CH2CH2—
    90 CF3 H H H H O —CH2CH2—
    91 CF3 H H H H O —CH2CH2—
    92 CF3 H H H H O —CH2CH2—
    93 CF3 H H H H O —CH2CH2—
    94 CF3 H H H H O —CH2CH2—
    95 CF3 H H H H O —CH2CH2—
    96 CF3 H H H H O —CH2CH2—
    97 CF3 H H H H O —CH2CH2—
    98 CF3 H H H H O —CH2CH2—
    99 CF3 H H H H O —CH2CH2—
    100 CF3 H H H H O —CH2CH2—
    101 CF3 H H H H O —CH2CH2—
    102 CF3 H H H H O —CH2CH2—
    103 CF3 H H H H O —CH2CH2—
    104 CF3 H H H H O —CH2CH2—
    105 CF3 H H H H O —CH2CH2—
    106 CF3 H H H H O —CH2CH2—
    107 CF3 H H H H O —CH2CH2—
    108 CF3 H H H H O —CH2CH2—
    109 CF3 H H H H O —CH2CH2—
    110 CF3 H H H H O —CH2CH2—
    111 CF3 H H H H O —CH2CH2—
    112 CF3 H H H H O —CH2CH2—
    113 CF3 H H H H O —CH2CH2—
    114 CF3 H H H H O —CH2CH2—
    115 CF3 H H H H O —CH2CH2—
    116 CF3 H H H H O —CH2CH2—
    117 CF3 H H H H O —CH2CH2—
    118 CF3 H H H H O —CH2CH2—
    119 CF3 H H H H O —CH2CH2—
    120 CF3 H H H H O —CH2CH2—
    121 CF3 H H H H O —CH2CH2—
    122 CF3 H H H H O —CH2CH2—
    123 CF3 H H H H O —CH2CH2—
    124 CF3 H H H H O —CH2CH2—
    125 CF3 H H H H O —CH2CH2—
    126 CF3 H H H H O —CH2CH2—
    127 CF3 H H H H O —CH2CH2—
    128 CF3 H H H H O —CH2CH2—
    129 CF3 H H H H O —CH2CH2—
    130 CF3 H H H H O —CH2CH2—
    131 CF3 H H H H O —CH2CH2—
    132 CF3 H H H H O —CH2CH2—
    133 CF3 H H H H O —CH2CH2—
    134 CF3 H H H H O —CH2CH2—
    135 CF3 H H H H O —CH2CH2—
    136 CF3 H H H H O —CH2CH2—
    137 CF3 H H H H O —CH2CH2—
    138 CF3 H H H H O —CH2CH2—
    139 CF3 H H H H O —CH2CH2—
    140 CF3 H H H H O —CH2CH2—
    141 CF3 H H H H O —CH2CH2—
    142 CF3 H H H H O —CH2CH2—
    143 CF3 H H H H O —CH2CH2—
    144 CF3 chlorine CH3 H H O —CH2CH2—
    145 CF3 chlorine CH3 H H O —CH2CH2—
    146 CF3 chlorine CH3 H H O —CH2CH2—
    147 CF3 chlorine CH3 H H O —CH2CH2—
    148 CF3 chlorine CH3 H H O —CH2CH2—
    149 CF3 chlorine CH3 H H O —CH2CH2—
    150 CF3 chlorine CH3 H H O —CH2CH2—
    151 CF3 chlorine CH3 H H O —CH2CH2—
    152 CF3 chlorine CH3 H H O —CH2CH2—
    153 CF3 chlorine CH3 H H O —CH2CH2—
    154 CF3 chlorine CH3 H H O —CH2CH2—
    155 CF3 chlorine CH3 H H O —CH2CH2—
    156 CF3 chlorine CH3 H H O —CH2CH2—
    157 CF3 chlorine CH3 H H O —CH2CH2—
    158 CF3 chlorine CH3 H H O —CH2CH2—
    159 CF3 chlorine CH3 H H O —CH2CH2—
    160 CF3 chlorine CH3 H H O —CH2CH2—
    161 CF3 chlorine CH3 H H O —CH2CH2—
    162 CF3 chlorine CH3 H H O —CH2CH2—
    163 CF3 chlorine CH3 H H O —CH2CH2—
    164 CF3 chlorine CH3 H H O —CH2CH2—
    165 CF3 chlorine CH3 H H O —CH2CH2—
    166 CF3 chlorine CH3 H H O —CH2CH2—
    167 CF3 chlorine CH3 H H O —CH2CH2—
    168 CF3 chlorine CH3 H H O —CH2CH2—
    169 CF3 chlorine CH3 H H O —CH2CH2—
    170 CF3 chlorine CH3 H H O —CH2CH2—
    171 CF3 chlorine CH3 H H O —CH2CH2—
    172 CF3 chlorine CH3 H H O —CH2CH2—
    173 CF3 chlorine CH3 H H O —CH2CH2—
    174 CF3 chlorine CH3 H H O —CH2CH2—
    175 CF3 chlorine CH3 H H O —CH2CH2—
    176 CF3 chlorine CH3 H H O —CH2CH2—
    177 CF3 chlorine CH3 H H O —CH2CH2—
    178 CF3 chlorine CH3 H H O —CH2CH2—
    179 CF3 chlorine CH3 H H O —CH2CH2—
    180 CF3 chlorine CH3 H H O —CH2CH2—
    181 CF3 chlorine CH3 H H O —CH2CH2—
    182 CF3 chlorine CH3 H H O —CH2CH2—
    183 CF3 chlorine CH3 H H O —CH2CH2—
    184 CF3 chlorine CH3 H H O —CH2CH2—
    185 CF3 chlorine CH3 H H O —CH2CH2—
    186 CF3 chlorine CH3 H H O —CH2CH2—
    187 CF3 chlorine CH3 H H O —CH2CH2—
    188 CF3 chlorine CH3 H H O —CH2CH2—
    189 CF3 chlorine CH3 H H O —CH2CH2—
    190 CF3 chlorine CH3 H H O —CH2CH2—
    191 CF3 chlorine CH3 H H O —CH2CH2—
    192 CF3 chlorine CH3 H H O —CH2CH2—
    193 CF3 chlorine CH3 H H O —CH2CH2—
    194 CF3 chlorine CH3 H H O —CH2CH2—
    195 CF3 chlorine CH3 H H O —CH2CH2—
    196 CF3 chlorine CH3 H H O —CH2CH2—
    197 CF3 chlorine CH3 H H O —CH2CH2—
    198 CF3 chlorine CH3 H H O —CH2CH2—
    199 CF3 chlorine CH3 H H O —CH2CH2—
    200 CF3 chlorine CH3 H H O —CH2CH2—
    201 CF3 chlorine CH3 H H O —CH2CH2—
    202 CF3 chlorine CH3 H H O —CH2CH2—
    203 CF3 chlorine CH3 H H O —CH2CH2—
    204 CF3 chlorine CH3 H H O —CH2CH2—
    205 CF3 chlorine CH3 H H O —CH2CH2—
    206 CF3 chlorine CH3 H H O —CH2CH2—
    207 CF3 chlorine CH3 H H O —CH2CH2—
    208 CF3 chlorine CH3 H H O —CH2CH2—
    209 CF3 chlorine CH3 H H O —CH2CH2—
    210 CF3 chlorine CH3 H H O —CH2CH2—
    211 CF3 chlorine CH3 H H O —CH2CH2—
    212 CF3 chlorine CH3 H H O —CH2CH2—
    213 CF3 chlorine CH3 H H O —CH2CH2—
    214 CF3 chlorine CH3 H H O —CH2CH2—
    215 CF3 chlorine CH3 H H O —CH2CH2—
    216 CF3 chlorine CH3 H H O —CH2CH2—
    217 CF3 chlorine CH3 H H O —CH2CH2—
    218 CF3 chlorine CH3 H H O —CH2CH2—
    219 CF3 H CH3 H H O —CH2—
    220 CF3 H CH3 H H O —CH2—
    221 CF3 H CH3 H H O —CH2—
    222 CF3 H CH3 H H O —CH2—
    223 CF3 H CH3 H H O —CH2—
    224 CF3 H CH3 H H O —CH2—
    225 CF3 H CH3 H H O —CH2—
    226 CF3 H CH3 H H O —CH2—
    227 CF3 H CH3 H H O —CH2—
    228 CF3 H CH3 H H O —CH2—
    229 CF3 H CH3 H H O —CH2—
    230 CF3 H CH3 H H O —CH2—
    231 CF3 H CH3 H H O —CH2—
    232 CF3 H CH3 H H O —CH2—
    233 CF3 H CH3 H H O —CH2—
    234 CF3 H CH3 H H O —CH2—
    235 CF3 H CH3 H H O —CH2—
    236 CF3 H CH3 H H O —CH2—
    237 CF3 H CH3 H H O —CH2—
    238 CF3 H CH3 H H O —CH2—
    239 CF3 H CH3 H H O —CH2—
    240 CF3 H CH3 H H O —CH2—
    241 CF3 H CH3 H H O —CH2—
    242 CF3 H CH3 H H O —CH2—
    243 CF3 H CH3 H H O —CH2—
    244 CF3 H CH3 H H O —CH2—
    245 CF3 H CH3 H H O —CH2—
    246 CF3 H CH3 H H O —CH2—
    247 CF3 H CH3 H H O —CH2—
    248 CF3 H CH3 H H O —CH2—
    249 CF3 H CH3 H H O —CH2—
    250 CF3 H CH3 H H O —CH2—
    251 CF3 H CH3 H H O —CH2—
    252 CF3 H CH3 H H O —CH2—
    253 CF3 H CH3 H H O —CH2—
    254 CF3 H CH3 H H O —CH2—
    255 CF3 H CH3 H H O —CH2—
    256 CF3 H CH3 H H O —CH2—
    257 CF3 H CH3 H H O —CH2—
    258 CF3 H CH3 H H O —CH2—
    259 CF3 H CH3 H H O —CH2—
    260 CF3 H CH3 H H O —CH2—
    261 CF3 H CH3 H H O —CH2—
    262 CF3 H CH3 H H O —CH2—
    263 CF3 H CH3 H H O —CH2—
    264 CF3 H CH3 H H O —CH2—
    265 CF3 H CH3 H H O —CH2—
    266 CF3 H CH3 H H O —CH2—
    267 CF3 H CH3 H H O —CH2—
    268 CF3 H CH3 H H O —CH2—
    269 CF3 H CH3 H H O —CH2—
    270 CF3 H CH3 H H O —CH2—
    271 CF3 H CH3 H H O —CH2—
    272 CF3 H CH3 H H O —CH2—
    273 CF3 H CH3 H H O —CH2—
    274 CF3 H CH3 H H O —CH2—
    275 CF3 H CH3 H H O —CH2—
    276 CF3 H CH3 H H O —CH2—
    277 CF3 H CH3 H H O —CH2—
    278 CF3 H CH3 H H O —CH2—
    279 CF3 H CH3 H H O —CH2—
    280 CF3 H CH3 H H O —CH2—
    281 CF3 H CH3 H H O —CH2—
    282 CF3 H CH3 H H O —CH2—
    283 CF3 H CH3 H H O —CH2—
    284 CF3 H CH3 H H O —CH2—
    285 CF3 H CH3 H H O —CH2—
    286 CF3 H CH3 H H O —CH2—
    287 CF3 H CH3 H H O —CH2—
    288 CF3 H CH3 H H O —CH2—
    289 CF3 H CH3 H H O —CH2—
    290 CF3 H CH3 H H O —CH2—
    291 CF3 H CH3 H H O —CH2—
    292 CF3 H CH3 H H O —CH2—
    293 CF3 H CH3 H H O —CH2—
    294 CH3 H CH3 H H O —CH2CH2—
    295 CH3 H CH3 H H O —CH2CH2—
    296 CH3 H CH3 H H O —CH2CH2—
    297 CH3 H CH3 H H O —CH2CH2—
    298 CH3 H CH3 H H O —CH2CH2—
    299 CH3 H CH3 H H O —CH2CH2—
    300 CH3 H CH3 H H O —CH2CH2—
    301 CH3 H CH3 H H O —CH2CH2—
    302 CH3 H CH3 H H O —CH2CH2—
    303 CH3 H CH3 H H O —CH2CH2—
    304 CH3 H CH3 H H O —CH2CH2—
    305 CH3 H CH3 H H O —CH2CH2—
    306 CH3 H CH3 H H O —CH2CH2—
    307 CH3 H CH3 H H O —CH2CH2—
    308 CH3 H CH3 H H O —CH2CH2—
    309 CH3 H CH3 H H O —CH2CH2—
    310 CH3 H CH3 H H O —CH2CH2—
    311 CH3 H CH3 H H O —CH2CH2—
    312 CH3 H CH3 H H O —CH2CH2—
    313 CH3 H CH3 H H O —CH2CH2—
    314 CH3 H CH3 H H O —CH2CH2—
    315 CH3 H CH3 H H O —CH2CH2—
    316 CH3 H CH3 H H O —CH2CH2—
    317 CH3 H CH3 H H O —CH2CH2—
    318 CH3 H CH3 H H O —CH2CH2—
    319 CH3 H CH3 H H O —CH2CH2—
    320 CH3 H CH3 H H O —CH2CH2—
    321 CH3 H CH3 H H O —CH2CH2—
    322 CH3 H CH3 H H O —CH2CH2—
    323 CH3 H CH3 H H O —CH2CH2—
    324 CH3 H CH3 H H O —CH2CH2—
    325 CH3 H CH3 H H O —CH2CH2—
    326 CH3 H CH3 H H O —CH2CH2—
    327 CH3 H CH3 H H O —CH2CH2—
    328 CH3 H CH3 H H O —CH2CH2—
    329 CH3 H CH3 H H O —CH2CH2—
    330 CH3 H CH3 H H O —CH2CH2—
    331 CH3 H CH3 H H O —CH2CH2—
    332 CH3 H CH3 H H O —CH2CH2—
    333 CH3 H CH3 H H O —CH2CH2—
    334 CH3 H CH3 H H O —CH2CH2—
    335 CH3 H CH3 H H O —CH2CH2—
    336 CH3 H CH3 H H O —CH2CH2—
    337 CH3 H CH3 H H O —CH2CH2—
    338 CH3 H CH3 H H O —CH2CH2—
    339 CH3 H CH3 H H O —CH2CH2—
    340 CH3 H CH3 H H O —CH2CH2—
    341 CH3 H CH3 H H O —CH2CH2—
    342 CH3 H CH3 H H O —CH2CH2—
    343 CH3 H CH3 H H O —CH2CH2—
    344 CH3 H CH3 H H O —CH2CH2—
    345 CH3 H CH3 H H O —CH2CH2—
    346 CH3 H CH3 H H O —CH2CH2—
    347 CH3 H CH3 H H O —CH2CH2—
    348 CH3 H CH3 H H O —CH2CH2—
    349 CH3 H CH3 H H O —CH2CH2—
    350 CH3 H CH3 H H O —CH2CH2—
    351 CH3 H CH3 H H O —CH2CH2—
    352 CH3 H CH3 H H O —CH2CH2—
    353 CH3 H CH3 H H O —CH2CH2—
    354 CH3 H CH3 H H O —CH2CH2—
    355 CH3 H CH3 H H O —CH2CH2—
    356 CH3 H CH3 H H O —CH2CH2—
    357 CH3 H CH3 H H O —CH2CH2—
    358 CH3 H CH3 H H O —CH2CH2—
    359 CH3 H CH3 H H O —CH2CH2—
    360 CH3 H CH3 H H O —CH2CH2—
    361 CH3 H CH3 H H O —CH2CH2—
    362 CH3 H CH3 H H O —CH2CH2—
    363 CH3 H CH3 H H O —CH2CH2—
    364 CH3 H CH3 H H O —CH2CH2—
    365 CH3 H CH3 CH3 CH3 O —CH2CH2—
    366 CH3 H CH3 H H O —CH2CH2—
    367 CH3 H CH3 H H O —CH2CH2—
    368 CH3 H CH3 CH3 CH3 O —CH2CH2—
    369 CH3 H CH3 CH3 CH3 O —CH2CH2—
    370 CH3 H CH3 CH3 CH3 O —CH2CH2—
    371 CH3 H CH3 H H O —CH2CH2—
    372 CH3 H CH3 CH3 CH3 O —CH2CH2—
    373 CH3 H CH3 CH3 CH3 O —CH2CH2—
    374 CH3 H CH3 H H O —CH2CH2—
    375 CH3 H CH3 CH3 CH3 O —CH2CH2—
    376 CH3 H CH3 CH3 CH3 O —CH2CH2—
    377 CH3 H CH3 CH3 CH3 O —CH2CH2—
    378 CH3 H CH3 CH3 CH3 O —CH2CH2—
    379 CH3 H CH3 CH3 CH3 O —CH2CH2—
    380 CH3 H CH3 CH3 CH3 O —CH2CH2—
    381 CH3 H CH3 CH3 CH3 O —CH2CH2—
    382 CH3 H CH3 CH3 CH3 O —CH2CH2—
    383 CH3 H CH3 CH3 CH3 O —CH2CH2—
    384 CH3 H CH3 CH3 CH3 O —CH2CH2—
    385 CH3 H CH3 CH3 CH3 O —CH2CH2—
    386 CH3 H CH3 CH3 CH3 O —CH2CH2—
    387 CH3 H CH3 CH3 CH3 O —CH2CH2—
    388 CH3 H CH3 CH3 CH3 O —CH2CH2—
    389 CH3 H CH3 CH3 CH3 O —CH2CH2—
    390 CH3 H CH3 CH3 CH3 O —CH2CH2—
    391 CH3 H CH3 CH3 CH3 O —CH2CH2—
    392 CH3 H CH3 CH3 CH3 O —CH2CH2—
    393 CH3 H CH3 CH3 CH3 O —CH2CH2—
    394 CH3 H CH3 CH3 CH3 O —CH2CH2—
    395 CH3 H CH3 CH3 CH3 O —CH2CH2—
    396 CH3 H CH3 CH3 CH3 O —CH2CH2—
    397 CH3 H CH3 CH3 CH3 O —CH2CH2—
    398 CH3 H CH3 CH3 CH3 O —CH2CH2—
    399 CH3 H CH3 CH3 CH3 O —CH2CH2—
    400 CH3 H CH3 CH3 CH3 O —CH2CH2—
    401 CH3 H CH3 CH3 CH3 O —CH2CH2—
    402 CH3 H CH3 CH3 CH3 O —CH2CH2—
    403 CH3 H CH3 CH3 CH3 O —CH2CH2—
    404 CH3 H CH3 CH3 CH3 O —CH2CH2—
    405 CH3 H CH3 CH3 CH3 O —CH2CH2—
    406 CH3 H CH3 CH3 CH3 O —CH2CH2—
    407 CH3 H CH3 CH3 CH3 O —CH2CH2—
    408 CH3 H CH3 CH3 CH3 O —CH2CH2—
    409 CH3 H CH3 CH3 CH3 O —CH2CH2—
    410 CH3 H CH3 CH3 CH3 O —CH2CH2—
    411 CH3 H CH3 CH3 CH3 O —CH2CH2—
    412 CH3 H CH3 CH3 CH3 O —CH2CH2—
    413 CH3 H CH3 CH3 CH3 O —CH2CH2—
    414 CH3 H CH3 CH3 CH3 O —CH2CH2—
    415 CH3 H CH3 CH3 CH3 O —CH2CH2—
    416 CH3 H CH3 CH3 CH3 O —CH2CH2—
    417 CH3 H CH3 CH3 CH3 O —CH2CH2—
    418 CH3 H CH3 CH3 CH3 O —CH2CH2—
    419 CH3 H CH3 CH3 CH3 O —CH2CH2—
    420 CH3 H CH3 CH3 CH3 O —CH2CH2—
    421 CH3 H CH3 CH3 CH3 O —CH2CH2—
    422 CH3 H CH3 CH3 CH3 O —CH2CH2—
    423 CH3 H CH3 CH3 CH3 O —CH2CH2—
    424 CH3 H CH3 CH3 CH3 O —CH2CH2—
    425 CH3 H CH3 CH3 CH3 O —CH2CH2—
    426 CH3 H CH3 CH3 CH3 O —CH2CH2—
    427 CH3 H CH3 CH3 CH3 O —CH2CH2—
    428 CH3 H CH3 CH3 CH3 O —CH2CH2—
    429 CH3 H CH3 CH3 CH3 O —CH2CH2—
    430 CH3 H CH3 CH3 CH3 O —CH2CH2—
    431 CH3 H CH3 CH3 CH3 O —CH2CH2—
    432 CH3 H CH3 CH3 CH3 O —CH2CH2—
    433 CH3 H CH3 CH3 CH3 O —CH2CH2—
    434 CH3 H CH3 CH3 CH3 O —CH2CH2—
    435 CH3 H CH3 CH3 CH3 O —CH2CH2—
    436 CH3 H CH3 CH3 CH3 O —CH2CH2—
    437 CH3 H CH3 CH3 CH3 O —CH2CH2—
    438 CH3 H CH3 CH3 CH3 O —CH2CH2—
    439 CH3 H CH3 CH3 CH3 O —CH2CH2—
    440 CH3 H CH3 CH3 CH3 O —CH2CH2—
    441 CH3 H CH3 CH3 CH3 O —CH2CH2—
    442 CH3 H CH3 CH3 CH3 O —CH2CH2—
    443 CH3 H CH3 CH3 CH3 O —CH2CH2—
    444 CF3 H CH3 H H O —CH2CH2—
    445 CF3 H CH3 H H O —CH2CH2—
    446 CF3 H CH3 H H O —CH2CH2—
    447 CF3 H CH3 H H O —CH2CH2—
    448 CF3 H CH3 H H O —CH2CH2—
    449 CF3 H CH3 H H O —CH2CH2—
    450 CF3 H CH3 H H O —CH2CH2—
    451 CF3 H CH3 H H O —CH2CH2—
    452 CF3 H CH3 H H O —CH2CH2—
    453 CF3 H CH3 H H O —CH2CH2—
    454 CF3 H CH3 H H O —CH2CH2—
    455 CF3 H CH3 H H O —CH2CH2—
    456 CF3 H CH3 H H O —CH2CH2—
    457 CF3 H CH3 H H O —CH2CH2—
    458 CF3 H CH3 H H O —CH2CH2—
    459 CF3 H CH3 H H O —CH2CH2—
    460 CF3 H CH3 H H O —CH2CH2—
    461 CF3 H CH3 H H O —CH2CH2—
    462 CF3 H CH3 H H O —CH2CH2—
    463 CF3 H CH3 H H O —CH2CH2—
    464 CF3 H CH3 H H O —CH2CH2—
    465 CF3 H CH3 H H O —CH2CH2—
    466 CF3 H CH3 H H O —CH2CH2—
    467 CF3 H CH3 H H O —CH2CH2—
    468 CF3 H CH3 H H O —CH2CH2—
    469 CF3 H CH3 H H O —CH2CH2—
    470 CF3 H CH3 H H O —CH2CH2—
    471 CF3 H CH3 H H O —CH2CH2—
    472 CF3 H CH3 H H O —CH2CH2—
    473 CF3 H CH3 H H O —CH2CH2—
    474 CF3 H CH3 H H O —CH2CH2—
    475 CF3 H CH3 H H O —CH2CH2—
    476 CF3 H CH3 H H O —CH2CH2—
    477 CF3 H CH3 H H O —CH2CH2—
    478 CF3 H CH3 H H O —CH2CH2—
    479 CF3 H CH3 H H O —CH2CH2—
    480 CF3 H CH3 H H O —CH2CH2—
    481 CF3 H CH3 H H O —CH2CH2—
    482 CF3 H CH3 H H O —CH2CH2—
    483 CF3 H CH3 H H O —CH2CH2—
    484 CF3 H CH3 H H O —CH2CH2—
    485 CF3 H CH3 H H O —CH2CH2—
    486 CF3 H CH3 H H O —CH2CH2—
    487 CF3 H CH3 H H O —CH2CH2—
    488 CF3 H CH3 H H O —CH2CH2—
    489 CF3 H CH3 H H O —CH2CH2—
    490 CF3 H CH3 H H O —CH2CH2—
    491 CF3 H CH3 H H O —CH2CH2—
    492 CF3 H CH3 H H O —CH2CH2—
    493 CF3 H CH3 H H O —CH2CH2—
    494 CF3 H CH3 H H O —CH2CH2—
    495 CF3 H CH3 H H O —CH2CH2—
    496 CF3 H CH3 H H O —CH2CH2—
    497 CF3 H CH3 H H O —CH2CH2—
    498 CF3 H CH3 H H O —CH2CH2—
    499 CF3 H CH3 H H O —CH2CH2—
    500 CF3 H CH3 H H O —CH2CH2—
    501 CF3 H CH3 H H O —CH2CH2—
    502 CF3 H CH3 H H O —CH2CH2—
    503 CF3 H CH3 H H O —CH2CH2—
    504 CF3 H CH3 H H O —CH2CH2—
    505 CF3 H CH3 H H O —CH2CH2—
    506 CF3 H CH3 H H O —CH2CH2—
    507 CF3 H CH3 H H O —CH2CH2—
    508 CF3 H CH3 H H O —CH2CH2—
    509 CF3 H CH3 H H O —CH2CH2—
    510 CF3 H CH3 H H O —CH2CH2—
    511 CF3 H CH3 H H O —CH2CH2—
    512 CF3 H CH3 H H O —CH2CH2—
    513 CF3 H CH3 H H O —CH2CH2—
    514 CF3 H CH3 H H O —CH2CH2—
    515 CF3 H CH3 H H O —CH2CH2—
    516 CF3 H CH3 H H O —CH2CH2—
    517 CF3 H CH3 H H O —CH2CH2—
    518 CF3 H CH3 H H O —CH2CH2—
    519 CF3 H CH3 H H O —CH2CH2—
    520 CF3 H CH3 H H O —CH2CH2—
    521 CF3 H CH3 H H O bond
    522 CF3 H CH3 H H O bond
    523 CF3 H CH3 H H O bond
    524 CF3 H CH3 H H O bond
    525 CF3 H CH3 H H O bond
    526 CF3 H CH3 H H O bond
    527 CF3 H CH3 H H O bond
    528 CF3 H CH3 H H O bond
    529 CF3 H CH3 H H O bond
    530 CF3 H CH3 H H O bond
    531 CF3 H CH3 H H O bond
    532 CF3 H CH3 H H O bond
    533 CF3 H CH3 H H O bond
    534 CF3 H CH3 H H O bond
    535 CF3 H CH3 H H O bond
    536 CF3 H CH3 H H O bond
    537 CF3 H CH3 H H O bond
    538 CF3 H CH3 H H O bond
    539 CF3 H CH3 H H O bond
    540 CF3 H CH3 H H O bond
    541 CF3 H CH3 H H O bond
    542 CF3 H CH3 H H O bond
    543 CF3 H CH3 H H O bond
    544 CF3 H CH3 H H O bond
    545 CF3 H CH3 H H O bond
    546 CF3 H CH3 H H O bond
    547 CF3 H CH3 H H O bond
    548 CF3 H CH3 H H O bond
    549 CF3 H CH3 H H O bond
    550 CF3 H CH3 H H O bond
    551 CF3 H CH3 H H O bond
    552 CF3 H CH3 H H O bond
    553 CF3 H CH3 H H O bond
    554 CF3 H CH3 H H O bond
    555 CF3 H CH3 H H O bond
    556 CF3 H CH3 H H O bond
    557 CF3 H CH3 H H O bond
    558 CF3 H CH3 H H O bond
    559 CF3 H CH3 H H O bond
    560 CF3 H CH3 H H O bond
    561 CF3 H CH3 H H O bond
    562 CF3 H CH3 H H O bond
    563 CF3 H CH3 H H O bond
    564 CF3 H CH3 H H O bond
    565 CF3 H CH3 H H O bond
    566 CF3 H CH3 H H O bond
    567 CF3 H CH3 H H O bond
    568 CF3 H CH3 H H O bond
    569 CF3 H CH3 H H O bond
    570 CF3 H CH3 H H O bond
    571 CF3 H CH3 H H O bond
    572 CF3 H CH3 H H O bond
    573 CF3 H CH3 H H O bond
    574 CF3 H CH3 H H O bond
    575 CF3 H CH3 H H O bond
    576 CF3 H CH3 H H O bond
    577 CF3 H CH3 H H O bond
    578 CF3 H CH3 H H O bond
    579 CF3 H CH3 H H O bond
    580 CF3 H CH3 H H O bond
    581 CF3 H CH3 H H O bond
    582 CF3 H CH3 H H O bond
    583 CF3 H CH3 H H O bond
    584 CF3 H CH3 H H O bond
    585 CF3 H CH3 H H O bond
    586 CF3 H CH3 H H O bond
    587 CF3 H CH3 H H O bond
    588 CF3 H CH3 H H O bond
    589 CF3 H CH3 H H O bond
    590 CF3 H CH3 H H O bond
    591 CF3 H CH3 H H O bond
    592 CF3 H CH3 H H O bond
    593 CF3 H CH3 H H O bond
    594 CF3 H CH3 H H O bond
    595 CF3 H CH3 H H O bond
    596 CF3 H CH3 H H O bond
    597 CF3 H CH3 H H O bond
    598 CF3 H CH3 H CH3 O —CH2CH2—
    599 CF3 H CH3 H CH3 O —CH2CH2—
    600 CF3 H CH3 H CH3 O —CH2CH2—
    601 CF3 H CH3 H CH3 O —CH2CH2—
    602 CF3 H CH3 H CH3 O —CH2CH2—
    603 CF3 H CH3 H CH3 O —CH2CH2—
    604 CF3 H CH3 H CH3 O —CH2CH2—
    605 CF3 H CH3 H CH3 O —CH2CH2—
    606 CF3 H CH3 H CH3 O —CH2CH2—
    607 CF3 H CH3 H CH3 O —CH2CH2—
    608 CF3 H CH3 H CH3 O —CH2CH2—
    609 CF3 H CH3 H CH3 O —CH2CH2—
    610 CF3 H CH3 H CH3 O —CH2CH2—
    611 CF3 H CH3 H CH3 O —CH2CH2—
    612 CF3 H CH3 H CH3 O —CH2CH2—
    613 CF3 H CH3 H CH3 O —CH2CH2—
    614 CF3 H CH3 H CH3 O —CH2CH2—
    615 CF3 H CH3 H CH3 O —CH2CH2—
    616 CF3 H CH3 H CH3 O —CH2CH2—
    617 CF3 H CH3 H CH3 O —CH2CH2—
    618 CF3 H CH3 H CH3 O —CH2CH2—
    619 CF3 H CH3 H CH3 O —CH2CH2—
    620 CF3 H CH3 H CH3 O —CH2CH2—
    621 CF3 H CH3 H CH3 O —CH2CH2—
    622 CF3 H CH3 H CH3 O —CH2CH2—
    623 CF3 H CH3 H CH3 O —CH2CH2—
    624 CF3 H CH3 H CH3 O —CH2CH2—
    625 CF3 H CH3 H CH3 O —CH2CH2—
    626 CF3 H CH3 H CH3 O —CH2CH2—
    627 CF3 H CH3 H CH3 O —CH2CH2—
    628 CF3 H CH3 H CH3 O —CH2CH2—
    629 CF3 H CH3 H CH3 O —CH2CH2—
    630 CF3 H CH3 H CH3 O —CH2CH2—
    631 CF3 H CH3 H CH3 O —CH2CH2—
    632 CF3 H CH3 H CH3 O —CH2CH2—
    633 CF3 H CH3 H CH3 O —CH2CH2—
    634 CF3 H CH3 H CH3 O —CH2CH2—
    635 CF3 H CH3 H CH3 O —CH2CH2—
    636 CF3 H CH3 H CH3 O —CH2CH2—
    637 CF3 H CH3 H CH3 O —CH2CH2—
    638 CF3 H CH3 H CH3 O —CH2CH2—
    639 CF3 H CH3 H CH3 O —CH2CH2—
    640 CF3 H CH3 H CH3 O —CH2CH2—
    641 CF3 H CH3 H CH3 O —CH2CH2—
    642 CF3 H CH3 H CH3 O —CH2CH2—
    643 CF3 H CH3 H CH3 O —CH2CH2—
    644 CF3 H CH3 H CH3 O —CH2CH2—
    645 CF3 H CH3 H CH3 O —CH2CH2—
    646 CF3 H CH3 H CH3 O —CH2CH2—
    647 CF3 H CH3 H CH3 O —CH2CH2—
    648 CF3 H CH3 H CH3 O —CH2CH2—
    649 CF3 H CH3 H CH3 O —CH2CH2—
    650 CF3 H CH3 H CH3 O —CH2CH2—
    651 CF3 H CH3 H CH3 O —CH2CH2—
    652 CF3 H CH3 H CH3 O —CH2CH2—
    653 CF3 H CH3 H CH3 O —CH2CH2—
    654 CF3 H CH3 H CH3 O —CH2CH2—
    655 CF3 H CH3 H CH3 O —CH2CH2—
    656 CF3 H CH3 H CH3 O —CH2CH2—
    657 CF3 H CH3 H CH3 O —CH2CH2—
    658 CF3 H CH3 H CH3 O —CH2CH2—
    659 CF3 H CH3 H CH3 O —CH2CH2—
    660 CF3 H CH3 H CH3 O —CH2CH2—
    661 CF3 H CH3 H CH3 O —CH2CH2—
    662 CF3 H CH3 H CH3 O —CH2CH2—
    663 CF3 H CH3 H CH3 O —CH2CH2—
    664 CF3 H CH3 H CH3 O —CH2CH2—
    665 CF3 H CH3 H CH3 O —CH2CH2—
    666 CF3 H CH3 H CH3 O —CH2CH2—
    667 CF3 H CH3 H CH3 O —CH2CH2—
    668 CF3 H CH3 H CH3 O —CH2CH2—
    669 CF3 H CH3 H CH3 O —CH2CH2—
    670 CF3 H CH3 H CH3 O —CH2CH2—
    671 CF3 H CH3 H CH3 O —CH2CH2—
    672 CF3 H CH3 H CH3 O —CH2CH2—
    673 CF3 H CH3 H CH3 O —CH2CH2—
    674 CF3 H CH3 H CH3 O —CH2CH2—
    675 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    676 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    677 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    678 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    679 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    680 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    681 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    682 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    683 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    684 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    685 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    686 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    687 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    688 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    689 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    690 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    691 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    692 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    693 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    694 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    695 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    696 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    697 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    698 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    699 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    700 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    701 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    702 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    703 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    704 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    705 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    706 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    707 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    708 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    709 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    710 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    711 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    712 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    713 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    714 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    715 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    716 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    717 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    718 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    719 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    720 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    721 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    722 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    723 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    724 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    725 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    726 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    727 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    728 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    729 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    730 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    731 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    732 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    733 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    734 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    735 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    736 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    737 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    738 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    739 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    740 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    741 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    742 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    743 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    744 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    745 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    746 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    747 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    748 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    749 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    750 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    751 (1Z,3Z)-buta- CH3 H H O —CH2CH2—
    1,3-diene-1,4-diyl
    752 CF3 H CH3 —CH2CH2— O —CH2CH2—
    753 CF3 H CH3 —CH2CH2— O —CH2CH2—
    754 CF3 H CH3 —CH2CH2— O —CH2CH2—
    755 CF3 H CH3 —CH2CH2— O —CH2CH2—
    756 CF3 H CH3 —CH2CH2— O —CH2CH2—
    757 CF3 H CH3 —CH2CH2— O —CH2CH2—
    758 CF3 H CH3 —CH2CH2— O —CH2CH2—
    759 CF3 H CH3 H cyclopropyl O —CH2CH2—
    760 CF3 H CH3 H cyclopropyl O —CH2CH2—
    761 CF3 H CH3 H cyclopropyl O —CH2CH2—
    762 CF3 H CH3 H cyclopropyl O —CH2CH2—
    763 CF3 H CH3 H cyclopropyl O —CH2CH2—
    764 CF3 H CH3 H cyclopropyl O —CH2CH2—
    765 CF3 H CH3 H cyclopropyl O —CH2CH2—
    766 CF3 H CH3 H H O —CH2CH2—
    767 CF3 H H H H O —CH2CH2—
    768 CF3 chlorine CH3 H H O —CH2CH2—
    769 CF3 chlorine CH3 H CH3 O —CH2CH2—
    770 CF3 chlorine CH3 H CH3 O —CH2CH2—
    771 CF3 H CF3 H H O —CH2CH2—
    772 CF3 H CF3 H H O —CH2CH2—
    773 CF3 H H H CH3 O —CH2CH2—
    774 CF3 H H H CH3 O —CH2CH2—
    775 CF3 H CH3 H H O —CH2CH2—
    776 CF3 H CH3 H H O —CH2CH2—
    777 CF3 H phenyl H H O —CH2CH2—
    778 CF3 H ethyl H H O —CH2CH2—
    779 CF3 H CH3 H H O —CH2CH2—
    780 CF3 H CH3 H H O —CH2CH2—
    781 CF3 H CH3 H H O —CH2CH2—
    782 CF3 H CH3 H H O —CH2CH2—
    783 CF3 H CH3 H H O —CH2CH2—
    784 CF3 H CH3 H H O —CH2CH2—
    785 CF3 H CH3 H H O —CH2CH2—
    786 CF3 H CH3 H H O —CH2CH2—
    787 CF3 H CH3 H H O —CH2CH2—
    788 CF3 H CH3 H H O —CH2CH2—
    789 CF3 H CH3 H H O —CH2CH2—
    790 CF3 H CH3 H H O —CH2CH2—
    791 CF3 H CH3 H H O —CH2CH2—
    792 CF3 H CH3 H H O —CH2CH2—
    793 CF3 H CH3 H H O —CH2CH2—
    794 CF3 H CH3 H H O —CH2CH2—
    795 CF3 H CH3 H H O —CH2CH2—
    796 CH3 H difluoro- H H O —CH2CH2—
    methyl
    797 CH3 H CH3 CH3 CH3 O —CH2CH2—
    798 CH3 H CH3 CH3 CH3 O —CH2CH2—
    799 CH3 H CH3 CH3 CH3 O —CH2CH2—
    800 CH3 H CH3 CH3 CH3 O —CH2CH2—
    801 CH3 H CH3 CH3 CH3 O —CH2CH2—
    802 CH3 H CH3 CH3 CH3 O —CH2CH2—
    803 CH3 H CH3 CH3 CH3 O —CH2CH2—
    804 CH3 H CH3 CH3 CH3 O —CH2CH2—
    805 CH3 H CH3 CH3 CH3 O —CH2CH2—
    806 CH3 H CH3 CH3 CH3 O —CH2CH2—
    807 CF3 H CH3 H H O —CH2CH2—
    808 CF3 H CH3 H H O —CH2CH2—
    809 CF3 H CH3 H H O —CH2CH2—
    810 ethyl H ethyl H H O —CH2CH2—
    811 difluoro- H difluoro- H H O —CH2CH2—
    methyl methyl
    812 ethyl H ethyl H H O —CH2CH2—
    813 difluoro- H difluoro- H H O —CH2CH2—
    methyl methyl
    814 CF3 H CH3 H H O —CH2CH2—
    815 CF3 H CH3 H H O —CH2CH2—
    816 CF3 H CH3 H H O —CH2CH2—
    817 CF3 H CH3 H H O —CH2CH2—
    818 CF3 H CH3 H H O —CH2CH2—
    819 CF3 H CH3 H H O —CH2CH2—
    820 CF3 H CH3 H H O —CH2CH2—
    821 CF3 H CH3 H H O —CH2CH2—
    822 CF3 H CH3 H H O —CH2CH2—
    823 CF3 H CH3 H H O —CH2CH2—
    824 CF3 H CH3 H H O —CH2CH2—
    825 CF3 H CH3 H H O —CH2CH2—
    826 CF3 H CH3 H H O —CH2CH2—
    827 CF3 H CH3 H H O —CH2CH2—
    828 CF3 H CH3 H H O —CH2CH2—
    829 CF3 H CH3 H H O —CH2CH2—
    830 CF3 H CH3 H H O —CH2CH2—
    831 CF3 H CH3 H H O —CH2CH2—
    832 CF3 H CH3 H H O —CH2CH2—
    833 CF3 H CH3 H H O —CH2CH2—
    834 CF3 H CH3 H H O —CH2CH2—
    835 CF3 H CH3 H H O —CH2CH2—
    836 CF3 H CH3 H H O —CH2CH2—
    837 CF3 H CH3 H H O —CH2CH2—
    838 CF3 H CH3 H H O —CH2CH2—
    839 H CF3 CH3 H H O —CH2CH2—
    840 CF3 H H H H O —CH2CH2—
    841 CF3 chlorine CH3 H H O —CH2CH2—
    842 CH3 H CH3 CH3 CH3 O —CH2CH2—
    843 CF3 H CH3 H H O —CH2—
    844 CH3 H difluoro- H H O —CH2CH2—
    methyl
    845 CF3 H CH3 H H O —CH2CH2—
    846 CF3 H CH3 H H O —CH2CH2—
    847 tBu H CF3 H H O —CH2CH2—
    848 CF3 H tBu H H O —CH2CH2—
    849 tBu H CF2CF3 H H O —CH2CH2—
    850 CF2CF3 H tBu H H O —CH2CH2—
    851 iPr H CF3 H H O —CH2CH2—
    852 ethyl H CF3 H H O —CH2CH2—
    853 CF3 H CH3 H H O —CH2CH2—
    854 difluoro- H difluoro- H H S —CH2CH2—
    methyl methyl
    EX NO W R6 Y2 Y3 G R7 log p
    1 —CH2— H O O —CH2— trimethylsilyl
    2 —CH2— H O O bond cyclohexyl
    3 —CH2— H O O bond cyclopentyl 3.40*
    4 —CH2— H O O —CH2— cyclopropyl
    5 —CH2— H O O —CH2— 2,2-dicholoro-
    cyclopropyl
    6 —CH2— H O O bond 1,2,3,4-tetra- 4.01**
    hydronaphthalen-
    1-yl
    7 —CH2— H O O bond decahydro-
    naphthalen-1-yl
    8 —CH2— H O O bond 2,3-dihydro-1H- 3.76*
    inden-1-yl
    9 —CH2— H O O bond 1-naphthyl
    10 —CH2— H O O bond 2-naphthyl 3.84*
    11 —CH2— H O O —CH2CH2 morpholin-4-yl
    12 —CH2— H O O —CH2— 4-fluorophenyl 3.35*
    13 —CH2— H O O —CH2CH2 piperidin-1-yl
    14 —CH2— H O O —CH2CH2 pyrrolidin-1-yl
    15 —CH2— H O O —CH2— phenyl 3.37*
    16 —CH2— H O O —CH2CH2 4-methylpiperazin-
    1-yl
    17 —CH2— H O O —CH2— 4-chlorophenyl 3.73*
    18 —CH2— H O O —CH2— 4-methylphenyl 4.21*
    19 —CH2— H O O —CH2— 4-methoxyphenyl 3.30*
    20 —CH2— H O O —CH2— 2,4-dichlorophenyl 3.69*
    21 —CH2— H O O —CH2— 3,5-dichlorophenyl 4.24*
    22 —CH2— H O O —CH2— 2,6-dichlorophenyl 3.94*
    23 —CH2— H O O —CH2— 2-chlorophenyl 3.70*
    24 —CH2— H O O —CH2— 3-chlorophenyl 3.72*
    25 —CH2— H O O —CH2— 3-(trifluoromethyl) 3.81*
    phenyl
    26 —CH2— H O O —CH2— 3-methylphenyl 3.68*
    27 —CH2— H O S —CH2— 4-fluorophenyl 4.00*
    28 —CH2— H O O —CH2— 4-nitrophenyl 3.22*
    29 —CH2— H O O —CH2— 4-tert-butylphenyl 4.57*
    30 —CH2— H O S —CH2— phenyl
    31 —CH2— H O O —CH2— 2-methylphenyl 3.62*
    32 —CH2— H O S —CH2— 4-chlorophenyl
    33 —CH2— H O S —CH2— 4-methylphenyl
    34 —CH2— H O S —CH2— 4-methoxyphenyl
    35 —CH2— H O S —CH2— 2,4-dicholorphenyl
    36 —CH2— H O S —CH2— 3,5-dichlorophenyl
    37 —CH2— H O S —CH2— 2,6-dichlorophenyl
    38 —CH2— H O S —CH2— 2-chlorophenyl
    39 —CH2— H O S —CH2— 3-chlorophenyl
    40 —CH2— H O S —CH2— 3-(trifluoromethyl)
    phenyl
    41 —CH2— H O O —CH(CH3)— 4-fluorophenyl 3.60*
    42 —CH2— H O O —CH(CH2CH3)— 4-fluorophenyl 3.89*
    43 —CH2— H O O —CH2CH2— 4-fluorophenyl 3.55*
    44 —CH2— H O O bond phenyl 3.20*
    45 —CH2— H O O bond 4-fluorophenyl 3.26*
    46 —CH2— H O S —CH2— 2-methylphenyl
    47 —CH2— H O O —CH(CF3)— phenyl
    48 —CH2— H O S —CH2— 4-nitrophenyl
    49 —CH2— H O S —CH2— 4-tert-butlyphenyl
    50 —CH2— H O S —CH2— 3-methlyphenyl
    51 —CH2— H O O bond 4-chlorophenyl
    52 —CH2— H O O bond 4-methylphenyl
    53 —CH2— H O O bond 3-chlorophenyl
    54 —CH2— H O O bond 3,5-dichlorophenyl
    55 —CH2— H O O bond 3,4-dichlorophenyl
    56 —CH2— H O O bond 2,4-dichlorophenyl
    57 —CH2— H O O bond 2-chlorophenyl
    58 —CH2— H O O bond 2,6-dichlorophenyl
    59 —CH2— H O O bond 3-(trifluoromethyl)
    phenyl
    60 —CH2— H O O bond 3-methlyphenyl
    61 —CH2— H O O bond 2-methylphenyl
    62 —CH2— H O O bond 4-tert-butylphenyl
    63 —CH2— H O O bond 4-nitrophenyl
    64 —CH2— H O S bond phenyl
    65 —CH2— H O S bond 4-fluorophenyl
    66 —CH2— H O S bond 4-chlorophenyl
    67 —CH2— H O S bond 4-methylphenyl
    68 —CH2— H O S bond 3-chlorophenyl
    69 —CH2— H O S bond 3,5-dichlorophenyl
    70 —CH2— H O S bond 3,4-dichlorophenyl
    71 —CH2— H O S bond 2,4-dichlorophenyl
    72 —CH2— H O S bond 2-chlorophenyl
    73 —CH2— H O S bond 2,6-dichlorophenyl
    74 —CH2— H O S bond 3-(trifluoromethyl)
    phenyl
    75 —CH2— H O S bond 3-methylphenyl
    76 —CH2— H O S bond cyclohexyl 4.51*
    77 —CH2— H O S bond 1-naphthyl 4.22*
    78 —CH2— H O S bond 4-nitrophenyl
    79 —CH2— H O O —CH2— pyridin-4-yl
    80 —CH2— H O O —CH2— pyridin-2-yl 2.21*
    81 —CH2— H O O —CH2— 2-thienyl 3.22*
    82 —CH2— H O S bond 2-methylphenyl
    83 —CH2— H O S bond 4-tert-butylphenyl
    84 —CH2— H O O —CH2— trimethylsilyl 3.53*
    85 —CH2— H O O bond cyclohexyl 3.42*
    86 —CH2— H O O bond cyclopentyl
    87 —CH2— H O O —CH2— cyclopropyl
    88 —CH2— H O O —CH2— 2,2-dichlorocyclo-
    propyl
    89 —CH2— H O O bond 1,2,3,4-tetrahydro- 3.68*
    naphthalen-1-yl
    90 —CH2— H O O bond decahydro-
    naphthalen-1-yl
    91 —CH2— H O O bond 2,3-dihydro-1H- 3.37*
    inden-1-yl
    92 —CH2— H O O bond 1-naphthyl 3.42*
    93 —CH2— H O O bond 2-naphthyl
    94 —CH2— H O O —CH2— phenyl 2.99*
    95 —CH2— H O O —CH2— 4-fluorophenyl 3.04*
    96 —CH2— H O O —CH2— 4-chlorophenyl
    97 —CH2— H O O —CH2— 4-methylphenyl
    98 —CH2— H O O —CH2— 4-methoxyphenyl
    99 —CH2— H O O —CH2— 2,4-dichlorophenyl
    100 —CH2— H O O —CH2— 3,5-dichlorophenyl
    101 —CH2— H O O —CH2— 2,6-dichlorophenyl
    102 —CH2— H O O —CH2— 2-chlorophenyl
    103 —CH2— H O O —CH2— 3-chlorophenyl
    104 —CH2— H O O —CH2— 3-(trifluoromethyl)
    phenyl
    105 —CH2— H O O —CH2— 3-methylphenyl
    106 —CH2— H O O —CH2— 2-methylphenyl
    107 —CH2— H O O —CH2— 4-nitrophenyl
    108 —CH2— H O O —CH2— 4-tert-butylphenyl
    109 —CH2— H O S —CH2— phenyl
    110 —CH2— H O S —CH2— 4-fluorophenyl
    111 —CH2— H O S —CH2— 4-chlorophenyl
    112 —CH2— H O S —CH2— 4-methylphenyl
    113 —CH2— H O S —CH2— 4-methoxyphenyl
    114 —CH2— H O S —CH2— 2,4-dichlorophenyl
    115 —CH2— H O S —CH2— 3,5-dichlorophenyl
    116 —CH2— H O S —CH2— 2,6-dichlorophenyl
    117 —CH2— H O S —CH2— 2-chlorophenyl
    118 —CH2— H O S —CH2— 3-chlorophenyl
    119 —CH2— H O S —CH2— 3-(trifluoromethyl)
    phenyl
    120 —CH2— H O S —CH2— 3-methylphenyl
    121 —CH2— H O S —CH2— 2-methlyphenyl
    122 —CH2— H O S —CH2— 4-nitrophenyl
    123 —CH2— H O S —CH2— 4-tert-butylphenyl
    124 —CH2— H O O —CH(CH3)— 4-fluorophenyl 3.18*
    125 —CH2— H O O —CH(CH2CH3)— 4-fluorophenyl
    126 —CH2— H O O —CH2CH2— 4-fluorophenyl 3.27*
    127 —CH2— H O O bond phenyl 2.85*
    128 —CH2— H O O bond 4-fluorophenyl 2.89*
    129 —CH2— H O O bond 4-chlorophenyl
    130 —CH2— H O O bond 4-methylphenyl
    131 —CH2— H O O bond 3-chlorophenyl
    132 —CH2— H O O bond 3,5-dichlorophenyl
    133 —CH2— H O O bond 3,4-dichlorophenyl
    134 —CH2— H O O bond 2,4-dichlorophenyl
    135 —CH2— H O O bond 2-chlorophenyl
    136 —CH2— H O O bond 2,6-dichlorophenyl
    137 —CH2— H O O bond 3-(trifluoromethyl)
    phenyl
    138 —CH2— H O O bond 3-methylphenyl
    139 —CH2— H O O bond 2-methylphenyl
    140 —CH2— H O O bond 4-tert-butlyphenyl
    141 —CH2— H O O bond 4-nitrophenyl
    142 —CH2— H O O —CH2— pyridin-4-yl 1.32*
    143 —CH2— H O O —CH2— 2-thienyl 2.85*
    144 —CH2— H O O —CH2— trimethylsilyl 4.28*
    145 —CH2— H O O bond cyclohexyl 4.17*
    146 —CH2— H O O bond cyclopentyl 3.84*
    147 —CH2— H O O —CH2— cyclopropyl
    148 —CH2— H O O —CH2— 2,2-dichlorocyclo-
    propyl
    149 —CH2— H O O bond 1,2,3,4-tetrahydro- 4.40*
    naphthalen-1-yl
    150 —CH2— H O O bond decahydro- 5.44*
    naphthalen-1-yl
    151 —CH2— H O O bond 2,3-dihydro-1H- 4.17*
    inden-1-yl
    152 —CH2— H O O bond 1-naphthyl 4.17*
    153 —CH2— H O O bond 2-naphthyl 4.17*
    154 —CH2— H O O —CH2— phenyl 3.73*
    155 —CH2— H O O —CH2— 4-fluorophenyl 3.73*
    156 —CH2— H O O —CH2— 4-chlorophenyl
    157 —CH2— H O O —CH2— 4-methylphenyl
    158 —CH2— H O O —CH2— 4-methoxyphenyl
    159 —CH2— H O O —CH2— 2,4-dichlorophenyl
    160 —CH2— H O O —CH2— 3,5-dichlorophenyl
    161 —CH2— H O O —CH2— 2,6-dichlorophenyl
    162 —CH2— H O O —CH2— 2-chlorophenyl
    163 —CH2— H O O —CH2— 3-chlorophenyl
    164 —CH2— H O O —CH2— 3-(trifluoromethyl)
    phenyl
    165 —CH2— H O O —CH2— 3-methylphenyl
    166 —CH2— H O O —CH2— 2-methylphenyl
    167 —CH2— H O O —CH2— 4-nitrophenyl
    168 —CH2— H O O —CH2— 4-tert-butylphenyl
    169 —CH2— H O S —CH2— phenyl
    170 —CH2— H O S —CH2— 4-fluorophenyl
    171 —CH2— H O S —CH2— 4-chlorophenyl
    172 —CH2— H O S —CH2— 4-methylphenyl
    173 —CH2— H O S —CH2— 4-methoxyphenyl
    174 —CH2— H O S —CH2— 2,4-dichlorophenyl
    175 —CH2— H O S —CH2— 3,5-dichlorophenyl
    176 —CH2— H O S —CH2— 2,6-dichlorophenyl
    177 —CH2— H O S —CH2— 2-chlorophenyl
    178 —CH2— H O S —CH2— 3-chlorophenyl
    179 —CH2— H O S —CH2— 3-(trifluoromethyl)
    phenyl
    180 —CH2— H O S —CH2— 3-methylphenyl
    181 —CH2— H O S —CH2— 2-methylphenyl
    182 —CH2— H O S —CH2— 4-nitrophenyl
    183 —CH2— H O S —CH2— 4-tert-butylphenyl
    184 —CH2— H O O —CH(CH3)— 4-fluorophenyl 3.89*
    185 —CH2— H O O —CH(CH2CH3)— 4-fluorophenyl
    186 —CH2— H O O —CH2CH2— 4-fluorophenyl 3.94*
    187 —CH2— H O O bond phenyl 3.58*
    188 —CH2— H O O bond 4-fluorophenyl 3.63*
    189 —CH2— H O O bond 4-chlorophenyl
    190 —CH2— H O O bond 4-methylphenyl
    191 —CH2— H O O bond 3-chlorophenyl
    192 —CH2— H O O bond 3,5-dichlorophenyl
    193 —CH2— H O O bond 3,4-dichlorophenyl
    194 —CH2— H O O bond 2,4-dichlorophenyl
    195 —CH2— H O O bond 2-chlorophenyl
    196 —CH2— H O O bond 2,6-dichlorophenyl
    197 —CH2— H O O bond 3-(trifluoromethyl)
    phenyl
    198 —CH2— H O O bond 3-methylphenyl
    199 —CH2— H O O bond 2-methylphenyl
    200 —CH2— H O O bond 4-tert-butylphenyl
    201 —CH2— H O O bond 4-nitrophenyl
    202 —CH2— H O S bond phenyl
    203 —CH2— H O S bond 4-fluorophenyl
    204 —CH2— H O S bond 4-chlorophenyl
    205 —CH2— H O S bond 4-methylohenyl
    206 —CH2— H O S bond 3-chlorophenyl
    207 —CH2— H O S bond 3,5-dichlorophenyl
    208 —CH2— H O S bond 3,4-dichlorophenyl
    209 —CH2— H O S bond 2,4-dichlorophenyl
    210 —CH2— H O S bond 2-chlorophenyl
    211 —CH2— H O S bond 2,6-dichlorophenyl
    212 —CH2— H O S bond 3-(trifluoromethyl)
    phenyl
    213 —CH2— H O S bond 3-methylphenyl
    214 —CH2— H O S bond 2-methylphenyl
    215 —CH2— H O S bond 4-tert-butylphenyl
    216 —CH2— H O S bond 4-nitrophenyl
    217 —CH2— H O O —CH2— pyridin-4-yl 1.82*
    218 —CH2— H O O —CH2— 2-thienyl 3.58*
    219 —CH2CH2— H O O —CH2— trimethylsilyl 3.89*
    220 —CH2CH2— H O O bond cyclohexyl 3.74*
    221 —CH2CH2— H O O bond cyclopentyl 3.47*
    222 —CH2CH2— H O O —CH2— cyclopropyl
    223 —CH2CH2— H O O —CH2— 2,2-dichlorocyclo-
    propyl
    224 —CH2CH2— H O O bond 1,2,3,4-tetrahydro- 4.01*
    naphthalen-1-yl
    225 —CH2CH2— H O O bond decahydro- 5.08*
    naphthalen-1-yl
    226 —CH2CH2— H O O bond 2,3-dihydro-1H- 3.78*
    inden-1-yl
    227 —CH2CH2— H O O bond 1-naphthyl 3.75*
    228 —CH2CH2— H O O bond 2-naphthyl 3.84*
    229 —CH2CH2— H O O —CH2— phenyl 3.37*
    230 —CH2CH2— H O O —CH2— 4-fluorophenyl 3.37*
    231 —CH2CH2— H O O —CH2— 4-chlorophenyl
    232 —CH2CH2— H O O —CH2— 4-methylphenyl
    233 —CH2CH2— H O O —CH2— 4-methoxyphenyl
    234 —CH2CH2— H O O —CH2— 2,4-dichlorophenyl
    235 —CH2CH2— H O O —CH2— 3,5-dichlorophenyl
    236 —CH2CH2— H O O —CH2— 2,6-dichlorophenyl
    237 —CH2CH2— H O O —CH2— 2-chlorophenyl
    238 —CH2CH2— H O O —CH2— 3-chlorophenyl
    239 —CH2CH2— H O O —CH2— 3-(trifluoromethyl)
    phenyl
    240 —CH2CH2— H O O —CH2— 3-methylphenyl
    241 —CH2CH2— H O O —CH2— 2-methylphenyl
    242 —CH2CH2— H O O —CH2— 4-nitrophenyl
    243 —CH2CH2— H O O —CH2— 4-tert-butylphenyl
    244 —CH2CH2— H O S —CH2— phenyl
    245 —CH2CH2— H O S —CH2— 4-fluorophenyl
    246 —CH2CH2— H O S —CH2— 4-chlorophenyl
    247 —CH2CH2— H O S —CH2— 4-methylphenyl
    248 —CH2CH2— H O S —CH2— 4-methoxyphenyl
    249 —CH2CH2— H O S —CH2— 2,4-dichlorophenyl
    250 —CH2CH2— H O S —CH2— 3,5-dichlorophenyl
    251 —CH2CH2— H O S —CH2— 2,6-dichlorophenyl
    252 —CH2CH2— H O S —CH2— 2-chlorophenyl
    253 —CH2CH2— H O S —CH2— 3-chlorophenyl
    254 —CH2CH2— H O S —CH2— 3-(trifluoromethyl)
    phenyl
    255 —CH2CH2— H O S —CH2— 3-methylphenyl
    256 —CH2CH2— H O S —CH2— 2-methylphenyl
    257 —CH2CH2— H O S —CH2— 4-nitrophenyl
    258 —CH2CH2— H O S —CH2— 4-tert-butylphenyl
    259 —CH2CH2— H O O —CH(CH3)— 4-fluorophenyl 3.53*
    260 —CH2CH2— H O O —CH(CH2CH3)— 4-fluorophenyl
    261 —CH2CH2— H O O —CH2CH2— 4-fluorophenyl 3.63*
    262 —CH2CH2— H O O bond phenyl 3.18*
    263 —CH2CH2— H O O bond 4-fluorophenyl 3.27*
    264 —CH2CH2— H O O bond 4-chlorophenyl
    265 —CH2CH2— H O O bond 4-methylphenyl
    266 —CH2CH2— H O O bond 3-chlorophenyl
    267 —CH2CH2— H O O bond 3,5-dichlorophenyl
    268 —CH2CH2— H O O bond 3,4-dichlorophenyl
    269 —CH2CH2— H O O bond 2,4-dichlorophenyl
    270 —CH2CH2— H O O bond 2-chlorophenyl
    271 —CH2CH2— H O O bond 2,6-dichlorophenyl
    272 —CH2CH2— H O O bond 3-(trifluoromethyl)
    —CH2CH2— phenyl
    273 —CH2CH2— H O O bond 3-methylphenyl
    274 —CH2CH2— H O O bond 2-methylphenyl
    275 —CH2CH2— H O O bond 4-tert-butylphenyl
    276 —CH2CH2— H O O bond 4-nitrophenyl
    277 —CH2CH2— H O S bond phenyl
    278 —CH2CH2— H O S bond 4-fluorophenyl
    279 —CH2CH2— H O S bond 4-chlorophenyl
    280 —CH2CH2— H O S bond 4-methylphenyl
    281 —CH2CH2— H O S bond 3-chlorophenyl
    282 —CH2CH2— H O S bond 3,5-dichlorophenyl
    283 —CH2CH2— H O S bond 3,4-dichlorophenyl
    284 —CH2CH2— H O S bond 2,4-dichlorophenyl
    285 —CH2CH2— H O S bond 2-chlorophenyl
    286 —CH2CH2— H O S bond 2,6-dichlorophenyl
    287 —CH2CH2— H O S bond 3-(trifluoromethyl)
    phenyl
    288 —CH2CH2— H O S bond 3-methylphenyl
    289 —CH2CH2— H O S bond 2-methylphenyl
    290 —CH2CH2— H O S bond 4-tert-butylphenyl
    291 —CH2CH2— H O S bond 4-nitrophenyl
    292 —CH2CH2— H O O —CH2— pyridin-4-yl
    293 —CH2CH2— H O O —CH2— 2-thienyl
    294 —CH2— H O O —CH2— trimethylsilyl
    295 —CH2— H O O bond cyclohexyl
    296 —CH2— H O O bond cylcopentyl
    297 —CH2— H O O —CH2— cyclopropyl
    298 —CH2— H O O —CH2— 2,2-dichlorophenyl
    299 —CH2— H O O bond 1,2,3,4-tetrahydro-
    naphthalen-1-yl
    300 —CH2— H O O bond decahydro-
    naphthalen-1-yl
    301 —CH2— H O O bond 2,3-dihydro-1H-
    inden-1-yl
    302 —CH2— H O O bond 1-naphthyl
    303 —CH2— H O O bond 2-naphthyl
    304 —CH2— H O O —CH2— phenyl
    305 —CH2— H O O —CH2— 4-fluorophenyl
    306 —CH2— H O O —CH2— 4-chlorophenyl
    307 —CH2— H O O —CH2— 4-methylphenyl
    308 —CH2— H O O —CH2— 4-methoxyphenyl
    309 —CH2— H O O —CH2— 2,4-dichlorophenyl
    310 —CH2— H O O —CH2— 3,5-dichlorophenyl
    311 —CH2— H O O —CH2— 2,6-dichlorophenyl
    312 —CH2— H O O —CH2— 2-chlorophenyl
    313 —CH2— H O O —CH2— 3-chlorophenyl
    314 —CH2— H O O —CH2— 3-(trifluoromethyl)
    phenyl
    315 —CH2— H O O —CH2— 3-methylphenyl
    316 —CH2— H O O —CH2— 2-methylphenyl
    317 —CH2— H O O —CH2— 4-nitrophenyl
    318 —CH2— H O O —CH2— 4-tert-butylphenyl
    319 —CH2— H O S —CH2— phenyl
    320 —CH2— H O S —CH2— 4-fluorophenyl
    321 —CH2— H O S —CH2— 4-chlorophenyl
    322 —CH2— H O S —CH2— 4-methylphenyl
    323 —CH2— H O S —CH2— 4-methoxyphenyl
    324 —CH2— H O S —CH2— 2,4-dichlorophenyl
    325 —CH2— H O S —CH2— 3,5-dichlorophenyl
    326 —CH2— H O S —CH2— 2,6-dichlorophenyl
    327 —CH2— H O S —CH2— 2-chlorophenyl
    328 —CH2— H O S —CH2— 3-chlorophenyl
    329 —CH2— H O S —CH2— 3-(trifluoromethyl)
    phenyl
    330 —CH2— H O S —CH2— 3-methylphenyl
    331 —CH2— H O S —CH2— 2-methylphenyl
    332 —CH2— H O S —CH2— 4-nitrophenyl
    333 —CH2— H O S —CH2— 4-tert-butylphenyl
    334 —CH2— H O O —CH(CH3)— 4-fluorophenyl
    335 —CH2— H O O —CH(CH2CH3)— 4-fluorophenyl
    336 —CH2— H O O —CH2CH2— 4-fluorophenyl
    337 —CH2— H O O bond phenyl
    338 —CH2— H O O bond 4-fluorophenyl
    339 —CH2— H O O bond 4-chlorophenyl
    340 —CH2— H O O bond 4-methylphenyl
    341 —CH2— H O O bond 3-chlorophenyl
    342 —CH2— H O O bond 3,5-dichlorophenyl
    343 —CH2— H O O bond 3,4-dichlorophenyl
    344 —CH2— H O O bond 2,4-dichlorophenyl
    345 —CH2— H O O bond 2-chlorophenyl
    346 —CH2— H O O bond 2,6-dichlorophenyl
    347 —CH2— H O O bond 3-(trifluoromethyl)
    phenyl
    348 —CH2— H O O bond 3-methylphenyl
    349 —CH2— H O O bond 2-methylphenyl
    350 —CH2— H O O bond 4-tert-butylphenyl
    351 —CH2— H O O bond 4-nitrophenyl
    352 —CH2— H O S bond phenyl
    353 —CH2— H O S bond 4-fluorophenyl
    354 —CH2— H O S bond 4-chlorophenyl
    355 —CH2— H O S bond 4-methylphenyl
    356 —CH2— H O S bond 3-chlorophenyl
    357 —CH2— H O S bond 3,5-dichlorophenyl
    358 —CH2— H O S bond 3,4-dichlorophenyl
    359 —CH2— H O S bond 2,4-dichlorophenyl
    360 —CH2— H O S bond 2-chlorophenyl
    361 —CH2— H O S bond 2,6-dichlorophenyl
    362 —CH2— H O S bond 3-(trifluoromethyl)
    phenyl
    363 —CH2— H O S bond 3-methylphenyl
    364 —CH2— H O S bond 2-methylphenyl
    365 —CH2— H O O bond cyclopentyl
    366 —CH2— H O S bond 4-nitrophenyl
    367 —CH2— H O O —CH2— pyridin-4-yl
    368 —CH2— H O O bond 1,2,3,4-tetrahydro- 4.04*
    naphthalen-1-yl
    369 —CH2— H O O —CH2— trimethylsilyl 3.84*
    370 —CH2— H O O bond cyclohexyl 3.78*
    371 —CH2— H O S bond 4-tert-butylphenyl
    372 —CH2— H O O —CH2— cyclopropyl 3.86*
    373 —CH2— H O O —CH2— 2,2-dichlorocyclo-
    propyl
    374 —CH2— H O O —CH2— 2-thienyl
    375 —CH2— H O O bond decahydro-
    naphthalen-1-yl
    376 —CH2— H O O bond 2,3-dihydro-1H- 3.68*
    inden-1-yl
    377 —CH2— H O O bond 1-naphthyl 3.82*
    378 —CH2— H O O bond 2-naphthyl 3.73*
    379 —CH2— H O O —CH2— phenyl 3.19*
    380 —CH2— H O O —CH2— 4-fluorophenyl 3.35*
    381 —CH2— H O O —CH2— 4-chlorophenyl
    382 —CH2— H O O —CH2— 4-methylphenyl
    383 —CH2— H O O —CH2— 4-methoxyphenyl
    384 —CH2— H O O —CH2— 2,4-dichlorophenyl
    385 —CH2— H O O —CH2— 3,5-dichlorophenyl
    386 —CH2— H O O —CH2— 2,6-dichlorophenyl
    387 —CH2— H O O —CH2— 2-chlorophenyl
    388 —CH2— H O O —CH2— 3-chlorophenyl
    389 —CH2— H O O —CH2— 3-(trifluoromethyl)
    phenyl
    390 —CH2— H O O —CH2— 3-methylphenyl
    391 —CH2— H O O —CH2— 2-methylphenyl
    392 —CH2— H O O —CH2— 4-nitrophenyl
    393 —CH2— H O O —CH2— 4-tert-butylphenyl
    394 —CH2— H O S —CH2— phenyl
    395 —CH2— H O S —CH2— 4-fluorophenyl
    396 —CH2— H O S —CH2— 4-chlorophenyl
    397 —CH2— H O S —CH2— 4-methylphenyl
    398 —CH2— H O S —CH2— 4-methoxyphenyl
    399 —CH2— H O S —CH2— 2,4-dichlorophenyl
    400 —CH2— H O S —CH2— 3,5-dichlorophenyl
    401 —CH2— H O S —CH2— 2,6-dichlorophenyl
    402 —CH2— H O S —CH2— 2-chlorophenyl
    403 —CH2— H O O —CH(CH3)— 4-fluorophenyl 3.47*
    404 —CH2— H O O —CH(CH2CH3)— 4-fluorophenyl
    405 —CH2— H O O —CH2CH2— 4-fluorophenyl 3.42*
    406 —CH2— H O S —CH2— 2-methylphenyl
    407 —CH2— H O S —CH2— 4-nitrophenyl
    408 —CH2— H O S —CH2— 4-tert-butylphenyl
    409 —CH2— H O S —CH2— 3-chlorophenyl
    410 —CH2— H O S —CH2— 3-(trifluoromethyl)
    phenyl
    411 —CH2— H O S —CH2— 3-methylphenyl
    412 —CH2— H O O bond phenyl 3.06*
    413 —CH2— H O O bond 4-fluorophenyl 3.21*
    414 —CH2— H O O bond 4-chlorophenyl
    415 —CH2— H O O bond 4-methylphenyl
    416 —CH2— H O O bond 3-chlorophenyl
    417 —CH2— H O O bond 3,5-dichlorophenyl
    418 —CH2— H O O bond 3,4-dichlorophenyl
    419 —CH2— H O O bond 2,4-dichlorophenyl
    420 —CH2— H O O bond 2-chlorophenyl
    421 —CH2— H O O bond 2,6-dichlorophenyl
    422 —CH2— H O O bond 3-(trifluoromethyl)
    phenyl
    423 —CH2— H O O bond 3-methylphenyl
    424 —CH2— H O O bond 2-methylphenyl
    425 —CH2— H O O bond 4-tert-butylphenyl
    426 —CH2— H O O bond 4-nitrophenyl
    427 —CH2— H O S bond phenyl
    428 —CH2— H O S bond 4-fluorophenyl
    429 —CH2— H O S bond 4-chlorophenyl
    430 —CH2— H O S bond 4-methylphenyl
    431 —CH2— H O S bond 3-chlorophenyl
    432 —CH2— H O S bond 3,5-dichlorophenyl
    433 —CH2— H O S bond 3,4-dichlorophenyl
    434 —CH2— H O S bond 2,4-dichlorophenyl
    435 —CH2— H O S bond 2-chlorophenyl
    436 —CH2— H O S bond 2,6-dichlorophenyl
    437 —CH2— H O S bond 3-(trifluoromethyl)
    phenyl
    438 —CH2— H O S bond 3-methylphenyl
    439 —CH2— H O S bond 2-methylphenyl
    440 —CH2— H O S bond 4-tert-butylphenyl
    441 —CH2— H O S bond 4-nitrophenyl
    442 —CH2— H O O —CH2— pyridin-4-yl 1.33*
    443 —CH2— H O O —CH2— 2-thienyl 3.06*
    444 —CH2— CH3 O O —CH2— trimethylsilyl
    445 —CH2— CH3 O O bond cyclohexyl
    446 —CH2— CH3 O O bond cyclopentyl
    447 —CH2— CH3 O O —CH2— cyclopropyl
    448 —CH2— CH3 O O —CH2— 2,2-dichlorocyclo-
    propyl
    449 —CH2— CH3 O O bond 1,2,3,4-tetrahydro-
    naphthalen-1-yl
    450 —CH2— CH3 O O bond decahydro-
    naphthalen-1-yl
    451 —CH2— CH3 O O bond 2,3-dihydro-1H-
    inden-1-yl
    452 —CH2— CH3 O O bond 1-naphthyl
    453 —CH2— CH3 O O bond 2-naphthyl
    454 —CH2— CH3 O O —CH2— phenyl
    455 —CH2— CH3 O O —CH2— 4-fluorophenyl
    456 —CH2— CH3 O O —CH2— 4-chlorophenyl
    457 —CH2— CH3 O O —CH2— 4-methylphenyl
    458 —CH2— CH3 O O —CH2— 4-methoxyphenyl
    459 —CH2— CH3 O O —CH2— 2,4-dichlorophenyl
    460 —CH2— CH3 O O —CH2— 3,5-dichlorophenyl
    461 —CH2— CH3 O O —CH2— 2,6-dichlorophenyl
    462 —CH2— CH3 O O —CH2— 2-chlorophenyl
    463 —CH2— CH3 O O —CH2— 3-chlorophenyl
    464 —CH2— CH3 O O —CH2— 3-(trifluoromethyl)
    phenyl
    465 —CH2— CH3 O O —CH2— 3-methylphenyl
    466 —CH2— CH3 O O —CH2— 2-methylphenyl
    467 —CH2— CH3 O O —CH2— 4-nitrophenyl
    468 —CH2— CH3 O O —CH2— 4-tert-butylphenyl
    469 —CH2— CH3 O S —CH2— phenyl
    470 —CH2— CH3 O S —CH2— 4-fluorophenyl
    471 —CH2— CH3 O S —CH2— 4-chlorophenyl
    472 —CH2— CH3 O S —CH2— 4-methylphenyl
    473 —CH2— CH3 O S —CH2— 4-methoxyphenyl
    474 —CH2— CH3 O S —CH2— 2,4-dichlorophenyl
    475 —CH2— CH3 O S —CH2— 3,5-dichlorophenyl
    476 —CH2— CH3 O S —CH2— 2,6-dichlorophenyl
    477 —CH2— CH3 O S —CH2— 2-chlorophenyl
    478 —CH2— CH3 O S —CH2— 3-chlorophenyl
    479 —CH2— CH3 O S —CH2— 3-(trifluoromethyl)
    phenyl
    480 —CH2— CH3 O S —CH2— 3-methylphenyl
    481 —CH2— CH3 O S —CH2— 2-methylphenyl
    482 —CH2— CH3 O S —CH2— 4-nitrophenyl
    483 —CH2— CH3 O S —CH2— 4-tert-butylphenyl
    484 —CH2— CH3 O O —CH(CH3)— 4-fluorophenyl
    485 —CH2— CH3 O O —CH(CH2CH3)— 4-fluorophenyl
    486 —CH2— CH3 O O —CH2CH2— 4-fluorophenyl
    487 —CH2— CH3 O O bond phenyl
    488 —CH2— CH3 O O bond 4-fluorophenyl
    489 —CH2— CH3 O O bond 4-chlorophenyl
    490 —CH2— CH3 O O bond 4-methylphenyl
    491 —CH2— CH3 O O bond 3-chlorophenyl
    492 —CH2— CH3 O O bond 3,5-dichlorophenyl
    493 —CH2— CH3 O O bond 3,4-dichlorophenyl
    494 —CH2— CH3 O O bond 2,4-dichlorophenyl
    495 —CH2— CH3 O O bond 2-chlorophenyl
    496 —CH2— CH3 O O bond 2,6-dichlorophenyl
    497 —CH2— CH3 O O bond 3-(trifluoromethyl)
    498 —CH2— CH3 O O bond phenyl
    3-methylphenyl
    499 —CH2— CH3 O O bond 2-methylphenyl
    500 —CH2— CH3 O O bond 4-tert-butylphenyl
    501 —CH2— CH3 O O bond 4-nitrophenyl
    502 —CH2— CH3 O S bond phenyl
    503 —CH2— CH3 O S bond 4-fluorophenyl
    504 —CH2— CH3 O S bond 4-chlorophenyl
    505 —CH2— CH3 O S bond 4-methylphenyl
    506 —CH2— CH3 O S bond 3-chlorophenyl
    507 —CH2— CH3 O S bond 3,5-dichlorophenyl
    508 —CH2— CH3 O S bond 3,4-dichlorophenyl
    509 —CH2— CH3 O S bond 2,4-dichlorophenyl
    510 —CH2— CH3 O S bond 2-chlorophenyl
    511 —CH2— CH3 O S bond 2,6-dichlorophenyl
    512 —CH2— CH3 O S bond 3-(trifluoromethyl)
    phenyl
    513 —CH2— CH3 O S bond 3-methylphenyl
    514 —CH2— CH3 O S bond 2-methylphenyl
    515 —CH2— CH3 O S bond 4-tert-butylphenyl
    516 —CH2— CH3 O S bond 4-nitrophenyl
    517 —CH2— CH3 O O —CH2— pyridin-4-yl
    518 —CH2— CH3 O O —CH2— 2-thienyl
    519 —CH2— CH3 O S bond cyclohexyl
    520 —CH2— CH3 O S bond 1-naphthyl
    521 —CH2CH2CH2— H O O —CH2— trimethylsilyl
    522 —CH2CH2CH2— H O O bond cyclohexyl
    523 —CH2CH2CH2— H O O bond cyclopentyl
    524 —CH2CH2CH2— H O O —CH2— cyclopropyl
    525 —CH2CH2CH2— H O O —CH2— 2,2-dichlorocyclo-
    propyl
    526 —CH2CH2CH2— H O O bond 1,2,3,4-tetrahydro-
    naphthalen-1-yl
    527 —CH2CH2CH2— H O O bond decahydro-
    naphthalen-1-yl
    528 —CH2CH2CH2— H O O bond 2,3-dihydro-1H-
    inden-1-yl
    529 —CH2CH2CH2— H O O bond 1-naphthyl
    530 —CH2CH2CH2— H O O bond 2-naphthyl
    531 —CH2CH2CH2— H O O —CH2— phenyl
    532 —CH2CH2CH2— H O O —CH2— 4-fluorophenyl
    533 —CH2CH2CH2— H O O —CH2— 4-chlorophenyl
    534 —CH2CH2CH2— H O O —CH2— 4-methylphenyl
    535 —CH2CH2CH2— H O O —CH2— 4-methoxyphenyl
    536 —CH2CH2CH2— H O O —CH2— 2,4-dichlorophenyl
    537 —CH2CH2CH2— H O O —CH2— 3,5-dichlorophenyl
    538 —CH2CH2CH2— H O O —CH2— 2,6-dichlorophenyl
    539 —CH2CH2CH2— H O O —CH2— 2-chlorophenyl
    540 —CH2CH2CH2— H O O —CH2— 3-chlorophenyl
    541 —CH2CH2CH2— H O O —CH2— 3-(trifluoromethyl)
    phenyl
    542 —CH2CH2CH2— H O O —CH2— 3-methylphenyl
    543 —CH2CH2CH2— H O O —CH2— 2-methylphenyl
    544 —CH2CH2CH2— H O O —CH2— 4-nitrophenyl
    545 —CH2CH2CH2— H O O —CH2— 4-tert-butylphenyl
    546 —CH2CH2CH2— H O S —CH2— phenyl
    547 —CH2CH2CH2— H O S —CH2— 4-fluorophenyl
    548 —CH2CH2CH2— H O S —CH2— 4-chlorophenyl
    549 —CH2CH2CH2— H O S —CH2— 4-methylphenyl
    550 —CH2CH2CH2— H O S —CH2— 4-methoxyphenyl
    551 —CH2CH2CH2— H O S —CH2— 2,4-dichlorophenyl
    552 —CH2CH2CH2— H O S —CH2— 3,5-dichlorophenyl
    553 —CH2CH2CH2— H O S —CH2— 2,6-dichlorophenyl
    554 —CH2CH2CH2— H O S —CH2— 2-chlorophenyl
    555 —CH2CH2CH2— H O S —CH2— 3-chlorophenyl
    556 —CH2CH2CH2— H O S —CH2— 3-(trifluoromethyl)
    phenyl
    557 —CH2CH2CH2— H O S —CH2— 3-methylphenyl
    558 —CH2CH2CH2— H O S —CH2— 2-methylphenyl
    559 —CH2CH2CH2— H O S —CH2— 4-nitrophenyl
    560 —CH2CH2CH2— H O S —CH2— 4-tert-butylphenyl
    561 —CH2CH2CH2— H O O —CH(CH3)— 4-fluorophenyl
    562 —CH2CH2CH2— H O O —CH(CH2CH3)— 4-fluorophenyl
    563 —CH2CH2CH2— H O O —CH2CH2— 4-fluorophenyl
    564 —CH2CH2CH2— H O O bond phenyl
    565 —CH2CH2CH2— H O O bond 4-fluorophenyl
    566 —CH2CH2CH2— H O O bond 4-chlorophenyl
    567 —CH2CH2CH2— H O O bond 4-methylphenyl
    568 —CH2CH2CH2— H O O bond 3-chlorophenyl
    569 —CH2CH2CH2— H O O bond 3,5-dichlorophenyl
    570 —CH2CH2CH2— H O O bond 3,4-dichlorophenyl
    571 —CH2CH2CH2— H O O bond 2,4-dichlorophenyl
    572 —CH2CH2CH2— H O O bond 2-chlorophenyl
    573 —CH2CH2CH2— H O O bond 2,6-dichlorophenyl
    574 —CH2CH2CH2— H O O bond 3-(trifluoromethyl)
    phenyl
    575 —CH2CH2CH2— H O O bond 3-methylphenyl
    576 —CH2CH2CH2— H O O bond 2-methylphenyl
    577 —CH2CH2CH2— H O O bond 4-tert-butylphenyl
    578 —CH2CH2CH2— H O O bond 4-nitrophenyl
    579 —CH2CH2CH2— H O S bond phenyl
    580 —CH2CH2CH2— H O S bond 4-fluorophenyl
    581 —CH2CH2CH2— H O S bond 4-chlorophenyl
    582 —CH2CH2CH2— H O S bond 4-methylphenyl
    583 —CH2CH2CH2— H O S bond 3-chlorophenyl
    584 —CH2CH2CH2— H O S bond 3,5-dichlorophenyl
    585 —CH2CH2CH2— H O S bond 3,4-dichlorophenyl
    586 —CH2CH2CH2— H O S bond 2,4-dichlorophenyl
    587 —CH2CH2CH2— H O S bond 2-chlorophenyl
    588 —CH2CH2CH2— H O S bond 2,6-dichlorophenyl
    589 —CH2CH2CH2— H O S bond 3-(trifluoromethyl)
    —CH2CH2CH2— phenyl
    590 —CH2CH2CH2— H O S bond 3-methylphenyl
    591 —CH2CH2CH2— H O S bond 2-methylphenyl
    592 —CH2CH2CH2— H O S bond 4-tert-butylphenyl
    593 —CH2CH2CH2— H O S bond 4-nitrophenyl
    594 —CH2CH2CH2— H O O —CH2— pyridin-4-yl
    595 —CH2CH2CH2— H O O —CH2— 2-thienyl
    596 —CH2CH2CH2— H O S bond cyclohexyl
    597 —CH2CH2CH2— H O S bond 1-naphthyl
    598 —CH2— H O O —CH2— trimethylsilyl
    599 —CH2— H O O bond cyclohexyl
    600 —CH2— H O O bond cyclopentyl
    601 —CH2— H O O —CH2— cyclopropyl
    602 —CH2— H O O —CH2— 2,2-dichlorocyclo-
    propyl
    603 —CH2— H O O bond 1,2,3,4-tetrahydro-
    naphthalen-1-yl
    604 —CH2— H O O bond decahydro-
    naphthalen-1-yl
    605 —CH2— H O O bond 2,3-dihydro-1H-
    inden-1-yl
    606 —CH2— H O O bond 1-naphthyl
    607 —CH2— H O O bond 2-naphthyl
    608 —CH2— H O O —CH2— phenyl
    609 —CH2— H O O —CH2— 4-fluorophenyl
    610 —CH2— H O O —CH2— 4-chlorophenyl
    611 —CH2— H O O —CH2— 4-methylphenyl
    612 —CH2— H O O —CH2— 4-methoxyphenyl
    613 —CH2— H O O —CH2— 2,4-dichlorophenyl
    614 —CH2— H O O —CH2— 3,5-dichlorophenyl
    615 —CH2— H O O —CH2— 2,6-dichlorophenyl
    616 —CH2— H O O —CH2— 2-chlorophenyl
    617 —CH2— H O O —CH2— 3-chlorophenyl
    618 —CH2— H O O —CH2— 3-(trifluoromethyl)
    phenyl
    619 —CH2— H O O —CH2— 3-methylphenyl
    620 —CH2— H O O —CH2— 2-methylphenyl
    621 —CH2— H O O —CH2— 4-nitrophenyl
    622 —CH2— H O O —CH2— 4-tert-butylphenyl
    623 —CH2— H O S —CH2— phenyl
    624 —CH2— H O S —CH2— 4-fluorophenyl
    625 —CH2— H O S —CH2— 4-chlorophenyl
    626 —CH2— H O S —CH2— 4-methylphenyl
    627 —CH2— H O S —CH2— 4-methoxyphenyl
    628 —CH2— H O S —CH2— 2,4-dichlorophenyl
    629 —CH2— H O S —CH2— 3,5-dichlorophenyl
    630 —CH2— H O S —CH2— 2,6-dichlorophenyl
    631 —CH2— H O S —CH2— 2-chlorophenyl
    632 —CH2— H O S —CH2— 3-chlorophenyl
    633 —CH2— H O S —CH2— 3-(trifluoromethyl)
    phenyl
    634 —CH2— H O S —CH2— 3-methylphenyl
    635 —CH2— H O S —CH2— 2-methylphenyl
    636 —CH2— H O S —CH2— 4-nitrophenyl
    637 —CH2— H O S —CH2— 4-tert-butylphenyl
    638 —CH2— H O O —CH(CH3)— 4-fluorophenyl
    639 —CH2— H O O —CH(CH2CH3)— 4-fluorophenyl
    640 —CH2— H O O —CH2CH2— 4-fluorophenyl
    641 —CH2— H O O bond phenyl
    642 —CH2— H O O bond 4-fluorophenyl
    643 —CH2— H O O bond 4-chlorophenyl
    644 —CH2— H O O bond 4-methylphenyl
    645 —CH2— H O O bond 3-chlorophenyl
    646 —CH2— H O O bond 3,5-dichlorophenyl
    647 —CH2— H O O bond 3,4-dichlorophenyl
    648 —CH2— H O O bond 2,4-dichlorophenyl
    649 —CH2— H O O bond 2-chlorophenyl
    650 —CH2— H O O bond 2,6-dichlorophenyl
    651 —CH2— H O O bond 3-(trifluoromethyl)
    phenyl
    652 —CH2— H O O bond 3-methylphenyl
    653 —CH2— H O O bond 2-methylphenyl
    654 —CH2— H O O bond 4-tert-butylphenyl
    655 —CH2— H O O bond 4-nitrophenyl
    656 —CH2— H O S bond phenyl
    657 —CH2— H O S bond 4-fluorophenyl
    658 —CH2— H O S bond 4-chlorophenyl
    659 —CH2— H O S bond 4-methylphenyl
    660 —CH2— H O S bond 3-chlorophenyl
    661 —CH2— H O S bond 3,5-dichlorophenyl
    662 —CH2— H O S bond 3,4-dichlorophenyl
    663 —CH2— H O S bond 2,4-dichlorophenyl
    664 —CH2— H O S bond 2-chlorophenyl
    665 —CH2— H O S bond 2,6-dichlorophenyl
    666 —CH2— H O S bond 3-(trifluoromethyl)
    phenyl
    667 —CH2— H O S bond 3-methylphenyl
    668 —CH2— H O S bond 2-methylphenyl
    669 —CH2— H O S bond 4-tert-butylphenyl
    670 —CH2— H O S bond 4-nitrophenyl
    671 —CH2— H O O —CH2— pyridin-4-yl
    672 —CH2— H O O —CH2— 2-thienyl
    673 —CH2— H O S bond cyclohexyl
    674 —CH2— H O S bond 1-naphthyl
    675 —CH2— H O O —CH2— trimethylsilyl
    676 —CH2— H O O bond cyclohexyl
    677 —CH2— H O O bond cyclopentyl
    678 —CH2— H O O —CH2— cyclopropyl
    679 —CH2— H O O —CH2— 2,2-dichlorocyclo-
    propyl
    680 —CH2— H O O bond 1,2,3,4-tetrahydro-
    naphthalen-1-yl
    681 —CH2— H O O bond decahydro-
    naphthalen-1-yl
    682 —CH2— H O O bond 2,3-dihydro-1H-
    inden-1-yl
    683 —CH2— H O O bond 1-naphthyl
    684 —CH2— H O O bond 2-naphthyl
    685 —CH2— H O O —CH2— phenyl
    686 —CH2— H O O —CH2— 4-fluorophenyl
    687 —CH2— H O O —CH2— 4-chlorophenyl
    688 —CH2— H O O —CH2— 4-methylphenyl
    689 —CH2— H O O —CH2— 4-methoxyphenyl
    690 —CH2— H O O —CH2— 2,4-dichlorophenyl
    691 —CH2— H O O —CH2— 3,5-dichlorophenyl
    692 —CH2— H O O —CH2— 2,6-dichlorophenyl
    693 —CH2— H O O —CH2— 2-chlorophenyl
    694 —CH2— H O O —CH2— 3-chlorophenyl
    695 —CH2— H O O —CH2— 3-(trifluoromethyl)
    phenyl
    696 —CH2— H O O —CH2— 3-methylphenyl
    697 —CH2— H O O —CH2— 2-methylphenyl
    698 —CH2— H O O —CH2— 4-nitrophenyl
    699 —CH2— H O O —CH2— 4-tert-butylphenyl
    700 —CH2— H O S —CH2— phenyl
    701 —CH2— H O S —CH2— 4-fluorophenyl
    702 —CH2— H O S —CH2— 4-chlorophenyl
    703 —CH2— H O S —CH2— 4-methylphenyl
    704 —CH2— H O S —CH2— 4-methoxyphenyl
    705 —CH2— H O S —CH2— 2,4-dichlorophenyl
    706 —CH2— H O S —CH2— 3,5-dichlorophenyl
    707 —CH2— H O S —CH2— 2,6-dichlorophenyl
    708 —CH2— H O S —CH2— 2-chlorophenyl
    709 —CH2— H O S —CH2— 3-chlorophenyl
    710 —CH2— H O S —CH2— 3-(trifluoromethyl)
    phenyl
    711 —CH2— H O S —CH2— 3-methylphenyl
    712 —CH2— H O S —CH2— 2-methylphenyl
    713 —CH2— H O S —CH2— 4-nitrophenyl
    714 —CH2— H O S —CH2— 4-tert-butylphenyl
    715 —CH2— H O O —CH(CH3)— 4-fluorophenyl
    716 —CH2— H O O —CH(CH2CH3)— 4-fluorophenyl
    717 —CH2— H O O —CH2CH2— 4-fluorophenyl
    718 —CH2— H O O bond phenyl
    719 —CH2— H O O bond 4-fluorophenyl
    720 —CH2— H O O bond 4-chlorophenyl
    721 —CH2— H O O bond 4-methylphenyl
    722 —CH2— H O O bond 3-chlorophenyl
    723 —CH2— H O O bond 3,5-dichlorophenyl
    724 —CH2— H O O bond 3,4-dichlorophenyl
    725 —CH2— H O O bond 2,4-dichlorophenyl
    726 —CH2— H O O bond 2-chlorophenyl
    727 —CH2— H O O bond 2,6-dichlorophenyl
    728 —CH2— H O O bond 3-(trifluoromethyl)
    phenyl
    729 —CH2— H O O bond 3-methylphenyl
    730 —CH2— H O O bond 2-methylphenyl
    731 —CH2— H O O bond 4-tert-butylphenyl
    732 —CH2— H O O bond 4-nitrophenyl
    733 —CH2— H O S bond phenyl
    734 —CH2— H O S bond 4-fluorophenyl
    735 —CH2— H O S bond 4-chlorophenyl
    736 —CH2— H O S bond 4-methylphenyl
    737 —CH2— H O S bond 3-chlorophenyl
    738 —CH2— H O S bond 3,5-dichlorophenyl
    739 —CH2— H O S bond 3,4-dichlorophenyl
    740 —CH2— H O S bond 2,4-dichlorophenyl
    741 —CH2— H O S bond 2-chlorophenyl
    742 —CH2— H O S bond 2,6-dichlorophenyl
    743 —CH2— H O S bond 3-(trifluoromethyl)
    phenyl
    744 —CH2— H O S bond 3-methylphenyl
    745 —CH2— H O S bond 2-methylphenyl
    746 —CH2— H O S bond 4-tert-butylphenyl
    747 —CH2— H O S bond 4-nitrophenyl
    748 —CH2— H O O —CH2— pyridin-4-yl
    749 —CH2— H O O —CH2— 2-thienyl
    750 —CH2— H O S bond cylcohexyl
    751 —CH2— H O S bond 1-naphthyl
    752 —CH2— H O O bond cyclohexyl
    753 —CH2— H O O bond 1,2,3,4-tetrahydro-
    naphthalen-1-yl
    754 —CH2— H O O bond decahydro-
    naphthalen-1-yl
    755 —CH2— H O O bond 2,3-dihydro-1H-
    inden-1-yl
    756 —CH2— H O O bond 1-naphthyl
    757 —CH2— H O O bond 2-naphthyl
    758 —CH2— H O O —CH2— phenyl
    759 —CH2— H O O bond cyclohexyl
    760 —CH2— H O O bond 1,2,3,4-tetrahydro-
    naphthalen-1-yl
    761 —CH2— H O O bond decahydro-
    naphthalen-1-yl
    762 —CH2— H O O bond 2,3-dihydro-1H-
    inden-1-yl
    763 —CH2— H O O bond 1-naphthyl
    764 —CH2— H O O bond 2-naphthyl
    765 —CH2— H O O —CH2— phenyl
    766 —CH2— H O O —CH2CH2— tert-butyl
    767 —CH2— H O O —CH2CH2— tert-butyl 3.82*
    768 —CH2— H O O —CH2CH2— tert-butyl
    769 —CH2— H O O bond cyclohexyl 4.58*
    770 —CH2— H O O bond 1-naphthyl 4.50*
    771 —CH2— H O O bond 1-naphthyl 4.35*
    772 —CH2— H O O bond cyclohexyl 4.39*
    773 —CH2— H O O bond 1-naphthyl 3.87*
    774 —CH2— H O O bond cyclohexyl 3.88*
    775 —CH2— H O O —CH2— 3,4-dichlorophenyl 4.09*
    776 —CH2— H O O —CH2— 4-(trifluoromethyl) 3.86*
    phenyl
    777 —CH2— H O O bond 1-naphthyl 4.50*
    778 —CH2— H O O bond 1-naphthyl
    779 —CH2— H O O —CH2— (E)-2-phenylethenyl 3.74*
    780 —CH2— H O O —CH2— pyridin-3-yl 1.74*
    781 —CH2— H O O bond quinolin-7-yl 2.42*
    782 —CH2— H O O bond quinolin-8-yl 2.88*
    783 —CH2— H O O —CH2— 1-naphthyl 3.90*
    784 —CH2— H O O —CH2— 2-naphthyl 3.92*
    785 —CH2— H O O —CH(CH3)— 1-naphthyl 4.16*
    786 —CH2— H O O —CH(CH3)— 2-naphthyl 4.18*
    787 —CH2— H O O —CH2— phenylethynyl 3.70*
    788 —CH2— H O O bond cycloheptyl 4.09*
    789 —CH2— H O O bond 1,2,3,4-tetrahydro- 3.94*
    naphthalen-2-yl
    790 —CH2— H O O bond 5,6,7,8-tetrahydro- 4.21*
    naphthalen-1-yl
    791 —CH2— H O O bond 2,3-dihydro-1H- 3.67*
    inden-2-yl
    792 —CH2— H O O bond 5,6,7,8-tetrahydro- 4.30*
    naphthalen-2-yl
    793 —CH2— H O O bond quinolin-6-yl 2.37*
    794 —CH2— H O O bond isoquinolin-5-yl 2.18*
    795 —CH2— H O O bond (1R)-1,2,3,4-tetra- 4.06*
    hydronaphthalen-1-yl
    796 —CH2— H O O bond cyclohexyl 3.28*
    797 —CH2— H O O bond 5-methyl-2-(propan- 5.51*
    2-yl)cyclohexyl
    798 —CH2— H O O bond 1-ethynyl- 3.28*
    cyclopentyl
    799 —CH2— H O O —CH(CH2CH3)— (1Z)-prop-1-en-1-yl 3.78*
    800 —CH2— H O O bond (1S,2R)-1,7,7- 5.08*
    trimethylbicyclo
    [2.2.1]hept-2-yl
    801 —CH2— H O O bond hex-1-en-3-yl 3.78*
    802 —CH2— H O O bond 3-methyl-5-(propan- 5.58*
    2-yl)cyclohexyl
    803 —CH2— H O O —CH2CH2— dimethylamino 1.03*
    804 —CH2— H O O bond 1-ethynyl- 3.73*
    cyclohexyl
    805 —CH2— H O O —CH(CH3)— CF3 3.19*
    806 —CH2— H O O —CH2— heptan-3-yl 5.08*
    807 —CH2— H O O bond quinolin-5-yl 2.59*
    808 —CH2— H O O bond diphenylmethyl 4.17*
    809 —CH2— H O O bond 1,3-benzoxazol-4-yl 2.81*
    810 —CH2— H O O bond cyclohexyl
    811 —CH2— H O O bond cyclohexyl 3.64*
    812 —CH2— H O O bond 1-naphthyl
    813 —CH2— H O O bond 1-naphthyl 3.64*
    814 —CH2— H O O bond 2-methoxyphenyl 3.17*
    815 —CH2— H O O bond cyclopropyl(phenyl) 3.87*
    methyl
    816 —CH2— H O O bond 2,6-dimethoxyphenyl 3.12*
    817 —CH2— H O O —CH2— 2-methoxyphenyl 3.44*
    818 —CH2— H O O —CH2— 2,4,6-trichlorophenyl 4.53*
    819 —CH2— H O O —CH2— 4-(trifluoromethoxy) 3.99*
    phenyl
    820 —CH2— H O O —CH2— 2-bromophenyl 3.80*
    821 —CH2— H O O bond biphenyl-2-yl 3.96*
    822 —CH2— H O O bond biphenyl-3-yl 4.16*
    823 —CH2— H O O bond biphenyl-4-yl 4.17*
    824 —CH2— H O O bond 3-phenoxyphenyl 4.18*
    825 —CH2— H O O bond 4-phenoxyphenyl 4.14*
    826 —CH2— H O O bond 1-ethynylcyclohexyl 3.76*
    827 —CH2— H O O bond 1-cyanocyclohexyl 3.33*
    828 —CH2— H O O bond 4-tert-butylcyclohexl 5.19*
    829 —CH2— H O O bond 5-methyl-2-(propan- 5.22*
    2-yl)-cyclohexyl
    830 —CH2— H O O bond 1,4-dioxaspiro[4.5] 2.90*
    dec-8-yl
    831 —CH2— H O O bond 2,6-dimethylcyclo- 4.40*
    hexyl
    832 —CH2— H O O bond 2-methcyclohexyl 4.12*
    833 —CH2— H O O bond octyl 5.02*
    834 —CH2— H O O —CH2— 2,4-dimethoxyphenyl 3.33*
    835 —CH2— H O O —CH2— 2,4,6-trifluorophenyl 3..53*
    836 —CH2— H O O —CH2— 2-(trifluoromethyl) 3.84*
    phenyl
    837 —CH2— H O O —CH2— 2-(trifluoromethoxy) 3.95*
    phenyl
    838 —CH2— H O O —CH2— CH3
    839 —CH2— H O O —CH2— CH3
    840 —CH2— H O O —CH2— CH3
    841 —CH2— H O O —CH2— CH3
    842 —CH2— H O O —CH2— CH3
    843 —CH2CH2— H O O —CH2— CH3
    844 —CH2— H O O bond 1-naphthyl
    845 —CH2— H O O —CH2— 2-[1-methoxy-2-
    (methylamino)-2-
    oxoethyl]phenyl
    846 —CH2— H O O —CH2— 2-[(methylamino)-
    (oxo)acetyl]phenyl
    847 —CH2— H O O —CH2— cyclohexyl 4.75*
    848 —CH2— H O O —CH2— cyclohexyl 4.51*
    849 —CH2— H O O —CH2— cyclohexyl 5.08*
    850 —CH2— H O O —CH2— cyclohexyl 4.94*
    851 —CH2— H O O —CH2— cyclohexyl 4.35*
    852 —CH2— H O O —CH2— cyclohexyl 3.99*
    853 —CH2— H O O bond (1S)-1,2,3,4-tetra- 4.06*
    hydronaphthalen-1-yl
    854 —CH2— H O O bond cyclohexyl 4.23*
    The logP values were measured according to EEC directive 79/831 Annex V.A8 by HPLC (High Performance Liquid Chromatography) on reversed-phase columns (C 18), using the methods below:
    **The determination in the acidic range is carried out at pH 2.3 using the mobile phases 0.1% aqueous phosphoric acid and acetonitrile linear gradient from 10% acetonitrile to 95% acetonitrile.
    *The LC-MS determination in the acidic range is carried out at pH 2.7 using the mobile phases 0.1% aqueous formic acid and acetonitrile (contains 0.1% formic acid) linear gradient from 10% acetonitrile to 95% acetonitrile
    ***The LC-MS determination in the neutral range is carried out at pH 7.8 using the mobile phases 0.001 molar aqueous ammonium bicarbonate solution and acetonitrile linear gradient from 10% acetonitrile to 95% acetonitrile.
    The calibration is carried out using unbranched alkan-2-ones (having 3 to 16 carbon atoms) with known logP values (determination of the logP values by the retention times using linear interpolation between two successive alkanones). The lambda-maX values were determined in the maxima of the chromatographic signals using the UV spectra from 200 nm to 400 nm.
    • Use Examples Example A Phytophthora Test (Tomato)/Protective
  • Solvent: 24.5 parts by weight of acetone
      • 24.5 parts by weight of dimethylacetamide
        Emulsifier: 1 part by weight of alkylaryl polyglycol ether
  • To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
  • To test for protective activity, young plants are sprayed with the preparation of active compound at the stated application rate. After the spray coating has dried on, the plants are inoculated with an aqueous spore suspension of Phytophthora infestans. The plants are then placed in an incubation cabin at about 20° C. and 100% relative atmospheric humidity.
  • Evaluation is carried out 3 days after the inoculation. 0% means an efficacy which corresponds to that of the control, whereas an efficacy of 100% means that no infection is observed.
  • In this test, the compounds according to the invention of the formulae below show, at an active compound concentration of 100 ppm, an efficacy of 70% or more.
  • Ex. Nos. 44, 45, 8, 10, 766, 772, 771, 774, 773, 18, 20, 19, 775, 17, 23, 24, 776, 29, 21, 26, 28, 15, 31, 25, 778, 81, 3, 779, 781, 782, 783, 784, 785, 788, 790, 789, 791, 792, 795, 794, 796, 811, 813
    • Example B Plasmopara Test (Grapevine)/Protective
  • Solvent: 24.5 parts by weight of acetone
      • 24.5 parts by weight of dimethylacetamide
        Emulsifier: 1 part by weight of alkylaryl polyglycol ether
  • To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
  • To test for protective activity, young plants are sprayed with the preparation of active compound at the stated application rate. After the spray coating has dried on, the plants are inoculated with an aqueous spore suspension of Plasmopara viticola and then remain in an incubation cabin at about 20° C. and 100% relative atmospheric humidity for 1 day. The plants are then placed in a greenhouse at about 21 C and about 90% atmospheric humidity for 4 days. The plants are then moistened and placed in an incubation cabin for 1 day.
  • Evaluation is carried out 6 days after the inoculation. 0% means an efficacy which corresponds to that of the control, whereas an efficacy of 100% means that no infection is observed.
  • In this test, the compounds according to the invention of the formulae below show, at an active compound concentration of 100 ppm, an efficacy of 70% or more.
  • Ex. Nos. 44, 45, 8, 10, 766, 772, 771, 774, 773, 18, 20, 19, 775, 17, 23, 24, 776, 21, 26, 28, 15, 31, 25, 778, 81, 3, 779, 781, 782, 783, 784, 785, 788, 790, 789, 791, 792, 795, 794, 796, 811, 813
    • Example C Phytophthora Test (Tomato)/Protective
  • Solvent: 24.5 parts by weight of acetone
      • 24.5 parts by weight of dimethylacetamide
        Emulsifier: 1 part by weight of alkylaryl polyglycol ether
  • To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
  • To test for protective activity, young plants are sprayed with the preparation of active compound at the stated application rate. After the spray coating has dried on, the plants are inoculated with an aqueous spore suspension of Phytophthora Infestans. The plants are then placed in an incubation cabin at about 20° C. and 100% relative atmospheric humidity.
  • Evaluation is carried out 3 days after the inoculation. 0% means an efficacy which corresponds to that of the control, whereas an efficacy of 100% means that no infection is observed.
  • TABLE
    Phytophthora test (tomato) / protective
    Active
    compound
    application rate
    Active compound in ppm Efficacy in %
    Known from W02007014290
    Figure US20150237859A1-20150827-C00023
         		10 65
    According the invention:
    Ex. 23
    Figure US20150237859A1-20150827-C00024
         		10 94
    • Example D Plasmopara Test (Grapevine)/Protective
  • Solvent: 24.5 parts by weight of acetone
      • 24.5 parts by weight of dimethylacetamide
        Emulsifier: 1 part by weight of alkylaryl polyglycol ether
  • To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
  • To test for protective activity, young plants are sprayed with the preparation of active compound at the stated application rate. After the spray coating has dried on, the plants are inoculated with an aqueous spore suspension of Plasmopara viticola and then remain in an incubation cabin at about 20° C. and 100% relative atmospheric humidity for 1 day. The plants are then placed in a greenhouse at about 21° C. and about 90% atmospheric humidity for 4 days. The plants are then moistened and placed in an incubation cabin for 1 day.
  • Evaluation is carried out 6 days after the inoculation. 0% means an efficacy which corresponds to that of the control, whereas an efficacy of 100/% means that no infection is observed.
  • TABLE
    Plasmopara test (grapevine) / protective
    Active
    compound
    application rate
    Active compound in ppm Efficacy in %
    Known from W02007014290
    Figure US20150237859A1-20150827-C00025
         		1 72
    According the invention:
    Ex. 6
    Figure US20150237859A1-20150827-C00026
         		1 91
    • Example E Plasmopara Test (Grapevine)/Curative
  • Solvent: 24.5 parts by weight of acetone
      • 24.5 parts by weight of dimethylacetamide
        Emulsifier: 1 part by weight of alkylaryl polyglycol ether
  • To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
  • To test for curative activity, young plants are inoculated with an aqueous spore suspension of Plasmopara viticola. The plants remain in an incubation cabin at about 20° C. and 100% relative atmospheric humidity for 24 hours, and after a further 24 hours at about 21° C. and about 90% relative atmospheric humidity, the plants are sprayed with the active compound preparation at the stated application rate.
  • 5 days after the inoculation, the plants are moistened and placed in an incubation cabin for 1 day.
  • Evaluation is carried out 6 days after the inoculation. 0% means an efficacy which corresponds to that of the control, whereas an efficacy of 100% means that no infection is observed.
  • TABLE
    Plasmopara test (grapevine) / curative
    Active
    compound
    application rate
    Active compound in ppm Efficacy in %
    Known from W02007014290
    Figure US20150237859A1-20150827-C00027
         		100 37
    According the invention:
    Ex. 6
    Figure US20150237859A1-20150827-C00028
         		100 84

Claims (9)

1-6. (canceled)
7. A compound of formula (XVI-1), (XVI-2), (XVI-3), (XVI-4) or (XVI-5):
Figure US20150237859A1-20150827-C00029
or a salt thereof.
8. A compound of formula (V-1), (V-2), (V-3), (V-4) or (V-5):
Figure US20150237859A1-20150827-C00030
or a salt thereof.
9-10. (canceled)
11. A compound of formula (IX):
Figure US20150237859A1-20150827-C00031
in which
PG is acetyl, C1-C2-alkoxycarbonyl, benzyl or benzyloxycarbonyl;
W is an unsubstituted or substituted C1- to C3-carbon chain, where the carbon atoms carry, independently of one another, H, methyl, or oxo as substituents;
X is a direct bond or an unsubstituted or substituted C1- to C3-carbon chain, where the carbon atoms carry, independently of one another, H, methyl, or oxo as substituents;
Y3 is sulfur or oxygen;
G is (C(R12)2)m;
R12 is identical or different independently of one another H, chlorine, fluorine, C1-C3-alkyl, C1-C3-alkoxy, C3-C6-cycloalkyl, or trifluoromethyl,
or
two or four R12, in each case on two adjacent carbon atoms, are direct bonds
where m=0 to 6;
R6 is H, C1-C4-alkyl, C1-C4-haloalkyl, CONR10R11, (C1-C4-alkoxy)carbonyl, COOH, NR10R11, halogen, or cyano;
R10 and R11 independently of one another are H, C1-C3-alkyl, or cyclopropyl;
R7 is unsubstituted or substituted C5-C10-alkyl, C2-C16-alkenyl, C2-C16-alkynyl, C3-C15-cycloalkyl, C5-C15-cycloalkenyl, C3-C5-heterocyclyl, aryl, hetaryl, or Si(C1-C4-alkyl)3,
suitable substituents independently of one another are selected from:
halogen, cyano, nitro, nitroso, C1-C4-alkyl, C1-C4-haloalkyl, aryl-C1-C3-alkyl, aryl-C1-C3-haloalkyl, hydroxyl, oxo, C1-C4-alkoxy, O(C1-C6-alkyl)mOC1-C6-alkyl, O—C3-C6-cycloalkyl, O-phenyl, C1-C4-haloalkoxy, SH, C1-C4-thioalkyl, C1-C4-thiohaloalkyl, S-phenyl, SO2—C1-C6-alkyl, SO2—C1-C6-haloalkyl, SO—C1-C6-alkyl, C1-C3-alkoxy, C3-C6-cycloalkyl, or trifluoromethyl,
or a salt thereof.
12. A compound of formula (X):
Figure US20150237859A1-20150827-C00032
in which
W is an unsubstituted or substituted C1- to C3-carbon chain, where the carbon atoms carry, independently of one another, H, methyl, or oxo as substituents;
X is a direct bond or an unsubstituted or substituted C1- to C3-carbon chain, where the carbon atoms carry, independently of one another, H, methyl, or oxo as substituents;
Y3 is sulfur or oxygen;
G is (C(R12)2)m;
R12 is identical or different independently of one another H, chlorine, fluorine, C1-C3-alkyl, C1-C3-alkoxy, C3-C6-cycloalkyl, or trifluoromethyl,
or
two or four R12, in each case on two adjacent carbon atoms, are direct bonds
where m=0 to 6;
R6 is H, C1-C4-alkyl, C1-C4-haloalkyl, CONR10R11, (C1-C4-alkoxy)carbonyl, COOH, NR10R11, halogen, or cyano;
R10 and R11 independently of one another are H, C1-C3-alkyl, or cyclopropyl:
R7 is unsubstituted or substituted C5-C10-alkyl, C2-C16-alkenyl, C2-C16-alkynyl, C3-C15-cycloalkyl, C5-C15-cycloalkenyl, C3-C15-heterocyclyl, aryl, hetaryl, or Si(C1-C4-alkyl)3;
suitable substituents independently of one another are selected from:
halogen, cyano, nitro, nitroso, C1-C4-alkyl, C1-C4-haloalkyl, aryl-C1-C2-alkyl, aryl-C1-C3-haloalkyl, hydroxyl, oxo, C1-C4-alkoxy, O(C1-C6-alkyl)mOC1-C6-alkyl, O—C3-C6-cycloalkyl, O-phenyl, C1-C4-haloalkoxy, SH, C1-C4-thioalkyl, C1-C4-thiohaloalkyl, S-phenyl, SO2—C1-C6-alkyl, SO2—C1-C6-haloalkyl, SO—C1-C6-alkyl, C1-C3-alkoxy, C3-C6-cycloalkyl, or trifluoromethyl,
or a salt thereof.
13-14. (canceled)
15. A compound of formula (IX-1) or (IX-2) according to claim 11,
Figure US20150237859A1-20150827-C00033
16. A compound of formula (X-1) or (X-2) according to claim 12,
Figure US20150237859A1-20150827-C00034
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