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WO2025248032A1 - Composés d'indazole à action pesticide - Google Patents

Composés d'indazole à action pesticide

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Publication number
WO2025248032A1
WO2025248032A1 PCT/EP2025/064886 EP2025064886W WO2025248032A1 WO 2025248032 A1 WO2025248032 A1 WO 2025248032A1 EP 2025064886 W EP2025064886 W EP 2025064886W WO 2025248032 A1 WO2025248032 A1 WO 2025248032A1
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WO
WIPO (PCT)
Prior art keywords
formula
spp
methyl
hydrogen
compounds
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/064886
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English (en)
Inventor
Jagadeesh Prathap KILARU
Andre Jeanguenat
Michel Muehlebach
Christopher Charles SCARBOROUGH
André Stoller
Rushil FERNANDES
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Syngenta Crop Protection AG Switzerland
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Syngenta Crop Protection AG Switzerland
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Publication of WO2025248032A1 publication Critical patent/WO2025248032A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • 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
    • A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
    • A01N43/647—Triazoles; Hydrogenated triazoles
    • A01N43/653—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • 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
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P5/00—Nematocides
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P7/00—Arthropodicides
    • A01P7/02—Acaricides
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P7/00—Arthropodicides
    • A01P7/04—Insecticides
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P9/00—Molluscicides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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 also relates to the preparation of these indazole compounds, to intermediates useful in the preparation of these indazole compounds, to the preparation of these intermediates, to agrochemical compositions which comprise at least one of these indazole compounds, to preparation of these compositions and to the use of these indazole compounds or compositions in agriculture or horticulture, for controlling animal pests, including arthropods, and in particular insects or representatives of the order Acarina.
  • BACKGROUND [0002] WO 2023/037249, WO 2023/285175, WO 2022/157188 and WO 2019/197468 describe certain fused heterobicyclic carboxamide derivatives with pesticidal activity.
  • novel indazole compounds have pesticidal activity. More specifically, certain novel indazole-4-carboxamide compounds and aza analogues thereof, have pesticidal activity.
  • the present invention accordingly relates, in a first aspect, to a compound of the formula (I) wherein A is CH or N; X is an oxygen atom or a sulfur atom; 109921
  • R 1 is hydrogen, C1-C6alkyl, C1-C6cyanoalkyl, C1-C3alkoxyC1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C4cycloalkylC1-C2alkyl, or C1-C6alkoxycarbonyl;
  • R 2a is hydrogen, C1-C4alkyl, C1-C3haloalkyl, C3-C4cycloalkyl, or cyclopropyl substituted with a single halogen or cyano;
  • R 2b is hydrogen, halogen, C1-C3haloalkyl, C
  • the present invention also provides a method of preparation of compounds of formula (I) as well as intermediate compounds useful in the preparation of compounds of formula (I). 109921
  • the present invention makes available a composition comprising a compound of formula (I) as defined in the first aspect, one or more auxiliaries and diluent, and optionally one or more other active ingredient.
  • the present invention makes available a method of combating and controlling pests, such as insects, acarines, nematodes, or molluscs, which comprises applying to a pest, to a locus of a pest, or to a plant susceptible to attack by a pest a pesticidally, such as insecticidally, acaricidally, nematicidally, or molluscicidally, effective amount of a compound as defined in the first aspect or of a composition as defined in the second aspect.
  • pests such as insects, acarines, nematodes, or molluscs
  • the present invention makes available a method for the protection of plant propagation material from the attack by a pest, such as insects, acarines, nematodes, or molluscs, which comprises treating the propagation material or the site where the propagation material is planted, with an effective amount of a compound of formula (I) as defined in the first aspect or of a composition as defined in the second aspect.
  • a pest such as insects, acarines, nematodes, or molluscs
  • the present invention makes available a plant propagation material, such as a seed, comprising, or treated with, or coated with, or adhered thereto, a compound of formula (I) as defined in the first aspect or of a composition as defined in the second aspect.
  • the present invention in a further aspect provides a method of controlling parasites in or on an animal in need thereof comprising administering an effective amount of a compound of formula (I) as defined in the first aspect.
  • the present invention further provides a method of controlling ectoparasites on an animal in need thereof comprising administering an effective amount of a compound of formula (I) as defined in the first aspect.
  • the present invention further provides a method for preventing and/or treating diseases transmitted by ectoparasites comprising administering an effective amount of a compound of formula (I) as defined in the first aspect, to an animal in need thereof.
  • Compounds of formula (I) which have at least one basic centre can form, for example, acid addition salts, for example with strong inorganic acids such as mineral acids, for example perchloric acid, sulfuric acid, nitric acid, nitrous acid, a phosphorus acid or a hydrohalic acid, with strong organic carboxylic acids, such as C1-C4alkanecarboxylic acids which are unsubstituted or substituted, for example by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid or phthalic acid, such as hydroxycarboxylic acids, for example ascorbic acid, lactic acid, malic acid, tartaric acid or citric acid, or such as benzoic acid, or with organic sulfonic acids, such as C1- C4alkane- or arylsulfonic acids
  • Compounds of formula (I) which have at least one acidic group can form, for example, salts with bases, for example mineral salts such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as mor-pholine, piperidine, pyrrolidine, a mono-, di- or tri-lower-alkylamine, for example ethyl-, diethyl-, triethyl- or dimethylpropylamine, or a mono-, di- or trihydroxy-lower-alkylamine, for example mono-, di- or triethanolamine.
  • bases for example mineral salts such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as mor-pholine, piperidine, pyrrolidine, a mono-, di- or tri-lower-alkylamine, for example ethyl-,
  • the compounds of formula (I) according to the invention are in free form, in oxidized form as a N-oxide or in salt form, e.g. an agronomically usable salt form.
  • N-oxides are oxidized forms of tertiary amines or oxidized forms of nitrogen containing heteroaromatic compounds. They are described for instance in the book "Heterocyclic N-oxides" by A. Albini and S. Pietra, CRC Press, Boca Raton 1991.
  • the compounds of formula (I) according to the invention also include hydrates which may be formed during the salt formation.
  • C1-Cnalkyl refers to a saturated straight-chain or branched hydrocarbon radical attached via any of the carbon atoms having 1 to n carbon atoms, for example, any one of the radicals methyl, ethyl, n-propyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, n-pentyl, 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,
  • C1-Cnhaloalkyl refers to a straight-chain or branched saturated alkyl radical attached via any of the carbon atoms having 1 to n carbon atoms (as mentioned above), where some or all of the hydrogen atoms in these radicals may be replaced by fluorine, chlorine, bromine and/or iodine, i.e., for example, any one of chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2- iodoethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoro
  • C1-C2fluoroalkyl refers to a C1-C2alkyl radical which carries 1, 2, 3, 4, or 5 fluorine atoms, for example, any one of difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl or pentafluoroethyl.
  • C1-Cnalkoxy refers to a straight-chain or branched saturated alkyl radical having 1 to n carbon atoms (as mentioned above) which is attached via an oxygen atom, i.e., for example, any one of the radicals methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy.
  • haloC1-Cnalkoxy refers to a C1-Cnalkoxy radical where one or more hydrogen atoms on the alkyl radical is replaced by the same or different halo atom(s) - examples include trifluoromethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 3,3,3-trifluoropropoxy, 4-chlorobutoxy.
  • C1-Cncyanoalkyl refers to a straight chain or branched saturated alkyl radical having 1 to n carbon atoms (as mentioned above), where one of the hydrogen atoms in these radicals is replaced by a cyano group: for example, cyanomethyl, 2-cyanoethyl, 2-cyanopropyl, 3-cyanopropyl, 1- (cyanomethyl)-2-ethyl, 1-(methyl)-2-cyanoethyl, 4-cyanobutyl, and the like.
  • C3-Cncycloalkyl refers to a saturated monocyclic hydrocarbon radical attached via any of the ring carbon atoms and having 3 to n carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • cyanoC3-Cncycloalkyl refers to a C3-Cncycloalkyl where one of the hydrogen atoms in these radicals is replaced by a cyano group.
  • C3-C4cycloalkylC1-C2alkyl refers to a cyclopropyl or cyclobutyl radical bonded via a methylene or ethylene bridge to the rest of the molecule.
  • the substituent(s) can be bonded to the C3-C4cycloalkyl radical and/or to the C1-C2alkyl bridge.
  • C1-Cnalkylsulfanyl refers to a C1-Cnalkyl moiety linked through a sulfur atom.
  • C1-Cnhaloalkylthio or “C1-Cnhaloalkylsulfanyl” as used herein refers to a C1- Cnhaloalkyl moiety linked through a sulfur atom.
  • C3-Cncycloalkylsulfanyl refers to 3-n membered cycloalkyl moiety linked through a sulfur atom.
  • C2-Cnalkenyl refers to a straight or branched alkenyl chain having from two to n carbon atoms and one or two double bonds, for example, ethenyl, prop-1-enyl, but-2-enyl.
  • C2-Cnalkynyl refers to a straight or branched alkynyl chain having from two to n carbon atoms and one triple bond, for example, ethynyl, prop-2-ynyl, but-3-ynyl.
  • Halogen or "halo" is generally fluorine, chlorine, bromine or iodine.
  • C 3 -C 4 cycloalkyl is optionally substituted with 1 or 2 halo atoms
  • C3-C4cycloalkyl means C3-C4cycloalkyl, C3-C4cycloalkyl substituted with 1 halo atom and C3-C4cycloalkyl substituted with 2 halo atoms.
  • controlling refers to reducing the number of pests, eliminating pests and/or preventing further pest damage such that damage to a plant or to a plant derived product is reduced.
  • pest refers to insects, and molluscs that are found in agriculture, horticulture, forestry, the storage of products of vegetable origin (such as fruit, grain and timber); and those pests associated with the damage of man-made structures. The term pest encompasses all stages in the life cycle of the pest.
  • the term “effective amount” refers to the amount of the compound, or a salt thereof, which, upon single or multiple applications provides the desired effect.
  • an effective amount is readily determined by the skilled person in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount a number of factors are considered including, but not limited to: the type of plant or derived product to be applied; the pest to be controlled & its lifecycle; the particular compound applied; the type of application; and other relevant circumstances.
  • compounds of formula (I) contain a stereogenic centre which is indicated with an asterisk in formula (I*) below: where A, R1, R2a, R2b, R3, Q and X are as defined in the first aspect.
  • the present invention contemplates both racemates and individual enantiomers.
  • Particularly preferred compounds of the present invention are compounds of formula (I’), where A, R1, R2a, R2b, R3, Q and X are as defined in the first aspect, and stereoisomers, enantiomers, tautomers and N- oxides of the compounds of formula (I’), and agrochemically acceptable salts thereof.
  • Particularly preferred compounds of formula (I’) include compounds of formula (I’a) as shown below, where X is oxygen, and A, R1, R2a, R2b, R3 and Q are as defined in the first aspect, and stereoisomers, enantiomers, tautomers and N-oxides of the compounds of formula (I*a), and agrochemically acceptable salts thereof: 109921
  • Particularly preferred compounds of the present invention are compounds of formula (I), (I*), (I*a), and preferred compounds thereof of the formula (I’) and (I’a), where A is CH, X is oxygen, and where R1, R2a, R 2b , R 3 , and Q are as defined in the first aspect, as shown with formula (I*b) and (I’b) below: [0039] Embodiments according to the invention are provided as set out below.
  • A is N.
  • the moiety containing A is a pyrazolo[4,3-b]pyridine group.
  • A is CH.
  • A is CH.
  • the moiety containing A is an indazole group.
  • X is oxygen (i.e. an oxygen atom).
  • X is S (i.e. a sulfur atom).
  • R1 is as follows: A.
  • R1 is hydrogen, C1-C6alkyl, C1-C6cyanoalkyl, C1-C3alkoxyC1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C4cycloalkylC1-C2alkyl, or C1-C6alkoxycarbonyl; or B .
  • R1 is hydrogen, methyl, ethyl, or cyclopropyl-methyl; or C.
  • R1 is hydrogen, methyl, or cyclopropylmethyl; or D.
  • R1 is hydrogen or methyl; or E. R1 is methyl; or F.
  • R1 is hydrogen.
  • R1 is hydrogen, methyl, or cyclopropylmethyl; or R1 is hydrogen or methyl. More preferably, R1 is hydrogen or methyl. Most preferably, R 1 is hydrogen.
  • R2a is as follows: A. R2a is hydrogen, C1-C4alkyl, C1-C3haloalkyl, C3-C4cycloalkyl, or cyclopropyl substituted with a single halogen or cyano; or 109921
  • R2a is hydrogen, C1-C3alkyl, C1-C3fluoroalkyl, cyclopropyl, cyclobutyl, or cyclopropyl substituted with a single fluoro or cyano; or C .
  • R2a is hydrogen, methyl, ethyl, difluoromethyl, trifluoromethyl, cyclopropyl, 1-fluorocyclopropyl, or 1- cyanocyclopropyl; or D .
  • R2a is hydrogen, methyl, ethyl, cyclopropyl, 1-fluorocyclopropyl, or 1-cyanocyclopropyl; or E.
  • R2a is methyl, ethyl, cyclopropyl, 1-fluorocyclopropyl, or 1-cyanocyclopropyl; or F. R2a is methyl, ethyl, or cyclopropyl; or G. R2a is methyl or cyclopropyl; or H. R2a is cyclopropyl. [0045] In preferred embodiments of each aspect of the invention, R2a is hydrogen, methyl, ethyl, cyclopropyl, 1-fluorocyclopropyl, or 1-cyanocyclopropyl.
  • R 2a is methyl, ethyl, cyclopropyl, 1-fluorocyclopropyl, or 1-cyanocyclopropyl. Most preferably, R 2a is methyl, ethyl, or cyclopropyl. For instance, R 2a is cyclopropyl. [0046] In an embodiment of each aspect of the invention, R2b is as follows: A.
  • R2b is hydrogen, halogen, C1-C3haloalkyl, C1-C3haloalkoxy, cyano, SF5, C1-C3alkylsulfanyl, C1- C3alkylsulfinyl, C1-C3alkylsulfonyl, C1-C3haloalkylsulfanyl, C1-C3haloalkylsulfinyl, C1- C 3haloalkylsulfonyl, C1-C5cyanoalkyl, C1-C5cyanoalkoxy, C3-C4cycloalkylC1-C2alkyl, C3-C4cycloalkylC1- C2haloalkyl, C3-C4cycloalkylcarbonyl, or C3-C4cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of halogen, -CN, C1-C3alky
  • R2b is hydrogen, halogen, C1-C3haloalkyl, C1-C3haloalkoxy, cyano, C1-C3alkylsulfonyl, C1- C3haloalkylsulfonyl, C1-C5cyanoalkyl, C1-C5cyanoalkoxy, C3-C4cycloalkylC1-C2alkyl, cyclopropyl, or cyclopropyl substituted with one or two substituents independently selected from the group consisting of halogen, -CN, methyl, and trifluoromethyl; or C .
  • R2b is halogen, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3alkylsulfonyl, C1-C3haloalkylsulfonyl, C1- C5cyanoalkyl, C3-C4cycloalkylC1-C2alkyl, or cyclopropyl; or D .
  • R2b is chloro, bromo, C1-C3fluoroalkyl, C1-C3fluoroalkoxy, C1-C3fluoroalkylsulfonyl, or cyclopropyl; or E.
  • R2b is chloro, bromo, iodo, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, difluoromethylsulfonyl, trifluoromethylsulfonyl, or cyclopropyl; or F .
  • R2b is chloro, bromo, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, difluoromethylsulfonyl, trifluoromethylsulfonyl, or cyclopropyl; or G .
  • R2b is chloro, difluoromethyl, difluoromethoxy, difluoromethylsulfonyl, or cyclopropyl; or H. R2b is chloro, bromo, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, difluoromethylsulfonyl, trifluoromethylsulfonyl, or cyclopropyl; or I . R2b is chloro, bromo, cyclopropyl, difluoromethyl, or trifluoromethyl; or J. R2b is chloro, bromo, cyclopropyl, or trifluoromethyl; or K.
  • R2b is chloro, bromo, or trifluoromethyl; or L. R2b is chloro or cyclopropyl; or M. R2b is chloro or trifluoromethyl; or 109921
  • R2b is chloro, bromo, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, difluoromethylsulfonyl, trifluoromethylsulfonyl, or cyclopropyl. More preferably, R 2b is chloro, bromo, difluoromethyl, trifluoromethyl, or cyclopropyl, or R 2b is bromo, difluoromethyl, trifluoromethyl or difluoromethoxy. Even more preferably, R2b is chloro, trifluoromethyl, or cyclopropyl. Most preferably, R2b is trifluoromethyl.
  • R3 is as follows: A. R3 is C1-C3alkyl or C1-C3haloalkyl; or B. R3 is methyl or trifluoromethyl; or C. R3 is methyl. [0049] In preferred embodiments of each aspect of the invention, R3 is methyl. [0050] In an embodiment of aspects of the invention where Q is Qa, R5 is as follows: D. R5 is hydrogen, halogen, C1-C3alkyl, C1-C3alkyloxy, or C3-C4cycloalkyl; or E. R5 is hydrogen, halogen, C1-C3alkyl, or C3-C4cycloalkyl; or F.
  • R5 is hydrogen, fluoro, chloro, bromo, iodo, methoxy, or ethoxy; or G. R5 is hydrogen, fluoro, chloro, bromo, iodo, or cyclopropyl; or H. R5 is hydrogen, fluoro, chloro, bromo, iodo, methyl, or ethyl; or I. R5 is hydrogen, chloro, bromo, methyl, ethyl, cyclopropyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, or 2,2,2-trifluoroethoxy; or J .
  • R5 is hydrogen, bromo, iodo, methyl, cyclopropyl; or K. R5 is hydrogen, bromo, iodo, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, or ethoxy; or L. R5 is hydrogen; or M. R5 is hydrogen, bromo, methyl, ethyl, cyclopropyl, methoxy, or ethoxy; or N. R5 is hydrogen, bromo, methyl, ethyl, cyclopropyl, or methoxy. [0051] In preferred embodiments where Q is Qa, R5 is as follows: A.
  • R5 is hydrogen, bromo, iodo, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, or ethoxy; or B. R5 is hydrogen, bromo, methyl, cyclopropyl, methoxy, or ethoxy; or C. R5 is hydrogen, cyclopropyl, or methoxy; or D. R5 is hydrogen; or E. R5 is hydrogen, bromo, methyl, ethyl, cyclopropyl, methoxy, or ethoxy; or F. R5 is hydrogen, bromo, methyl, ethyl, cyclopropyl, or methoxy.
  • Qa is selected from Qa-1 to Qa-16 109921
  • Q is Q a -1, or Q a -15.
  • Q is Q a -1.
  • Q a is Q a -1, Q a -4, Q a -5, Q a -10, Q a -15, or Q a -16;
  • R5a and R5b are as follows: A.
  • R5a and R5b are independently hydrogen, halogen, C1-C3alkyl, C1-C3alkyloxy, or C3-C4cycloalkyl; or B. R5a and R5b are independently hydrogen, halogen, C1-C3alkyl, or C3-C4cycloalkyl; or C. R5a and R5b are independently hydrogen, fluoro, chloro, bromo, iodo, methoxy, or ethoxy; or D. R5a and R5b are independently hydrogen, fluoro, chloro, bromo, iodo, or cyclopropyl; or E.
  • R5a and R5b are independently hydrogen, methyl, cyclopropyl, methoxy, or trifluoromethyl; or 109921
  • R5a and R5b are differently hydrogen, fluoro, chloro, methyl, cyclopropyl, methoxy, difluoromethoxy, or trifluoromethyl; or J .
  • R5a or R5b is hydrogen, and the other is hydrogen, fluoro, chloro, methyl, cyclopropyl, methoxy, difluoromethoxy, or trifluoromethyl; or K .
  • R5a and R5b are both hydrogen or fluoro; or L.
  • R5a and R5b are hydrogen.
  • R5a is hydrogen, chloro, fluoro, cyclopropyl, trifluoromethyl, methoxy, or difluoromethoxy and R5b is hydrogen, fluoro, or methoxy; or B .
  • R5a is hydrogen, fluoro, cyclopropyl, trifluoromethyl, or difluoromethoxy, and R5b is hydrogen, chloro, fluoro, or methoxy; or C .
  • R5a is hydrogen, fluoro, cyclopropyl, trifluoromethyl, or difluoromethoxy, and R5b is hydrogen, fluoro, or methoxy; or D .
  • R5a is hydrogen, fluoro, cyclopropyl, trifluoromethyl, or difluoromethoxy and R5b is hydrogen; or E. R5a is hydrogen, and R5b is hydrogen, fluoro, or methoxy; or F. R5a and R5b are hydrogen.
  • Qb is selected from Qb-1 to Qb-13: a n or or 1, Q b -2, Q b -3, Q b -5, Q b -8, Q b -10, and Q b -11.
  • Q b is Q b -1, Q b -3, Q b -5, Q b -10, or Q b -11.
  • Q b is Q b -1.
  • R4 is Qc-1, Qc-2, Qc-3, Qc-4, Qc-5, Qc-6, or Qc-9; or D.
  • R4 is Qc-1, Qc-2, Qc-3, Qc-4, or Qc-9; or E.
  • R4 is Qc-1, Qc-2, or Qc-3; or F.
  • R4 is 5-cyano-2-pyridyl, pyrimidin-2-yl, 5-bromopyrimidin-2-yl, 6-cyanopyrimidin-4-yl, 6- carbamoylpyrimidin-4-yl, 6-(cyanomethylcarbamoyl)pyrimidin-4-yl, 6-[cyanomethyl(methyl)carbamoyl]- pyrimidin-4-yl, 6-(methylcarbamoyl)pyrimidin-4-yl, 6-(dimethylcarbamoyl)pyrimidin-4-yl, 6- (methoxycarbonylamino)pyrimidin-4-yl, pyrazin-2-yl, 6-chloropyridazin-3-yl, 5-bromopyrazin-2-yl, 6- m ethoxypyridazin-3-yl, 6-ethoxypyridazin-3-yl, 1-methyl-6-oxo-pyridazin-3-yl, 5-cyanothiazol-2-
  • R4 is 5-cyano-2-pyridyl, pyrimidin-2-yl, 5-bromopyrimidin-2-yl, 6-cyanopyrimidin-4-yl, 6- carbamoylpyrimidin-4-yl, 6-(cyanomethylcarbamoyl)pyrimidin-4-yl, 6-[cyanomethyl(methyl)carbamoyl]- pyrimidin-4-yl, 6-(methylcarbamoyl)pyrimidin-4-yl, 6-(dimethylcarbamoyl)pyrimidin-4-yl, 6- (methoxycarbonylamino)pyrimidin-4-yl, pyrazin-2-yl, 5-bromopyrazin-2-yl, 6-methoxypyridazin-3-yl, 1- m ethyl-6-oxo-pyridazin-3-yl, 5-cyanothiazol-2-yl, or 5-carbamoyl-thiazol-2-yl; or H.
  • R4 is 5-cyano-2-pyridyl, pyrimidin-2-yl, 5-bromopyrimidin-2-yl, 6-cyanopyrimidin-4-yl, 6- carbamoylpyrimidin-4-yl, 6-(cyanomethylcarbamoyl)pyrimidin-4-yl, 6-(methylcarbamoyl)pyrimidin-4-yl, pyrazin-2-yl, 5-bromopyrazin-2-yl, 6-methoxypyridazin-3-yl, 1-methyl-6-oxo-pyridazin-3-yl, or 5- cyanothiazol-2-yl; or I .
  • R4 is 5-cyano-2-pyridyl, pyrimidin-2-yl, 6-cyanopyrimidin-4-yl, 6-carbamoylpyrimidin-4-yl, 6- (cyanomethylcarbamoyl)pyrimidin-4-yl, 6-(methylcarbamoyl)pyrimidin-4-yl, pyrazin-2-yl, 6- methoxypyridazin-3-yl, 1-methyl-6-oxo-pyridazin-3-yl, or 5-cyanothiazol-2-yl; or 109921
  • R4 is 5-cyano-2-pyridyl, pyrimidin-2-yl, 6-cyanopyrimidin-4-yl, pyrazin-2-yl, 6-methoxypyridazin-3-yl, or 5-cyanothiazol-2-yl; or K.
  • R4 is 5-cyano-2-pyridyl, pyrimidin-2-yl, 5-fluoropyrimidin-2-yl, 5-chloropyrimidin-2-yl, 5- bromopyrimidin-2-yl, 6-cyanopyrimidin-4-yl, 6-carbamoylpyrimidin-4-yl, 6- ( cyanomethylcarbamoyl)pyrimidin-4-yl, 6-[cyanomethyl(methyl)carbamoyl]-pyrimidin-4-yl, 6- (methylcarbamoyl)pyrimidin-4-yl, 6-(dimethylcarbamoyl)pyrimidin-4-yl, 6- (methoxycarbonylamino)pyrimidin-4-yl, pyrazin-2-yl, 6-chloropyridazin-3-yl, 5-bromopyrazin-2-yl, 6- methoxypyridazin-3-yl, 6-ethoxypyridazin-3-yl, 1-methyl-6-
  • R4 is 5-cyano-2-pyridyl, pyrimidin-2-yl, 5-fluoropyrimidin-2-yl, 5-chloropyrimidin-2-yl, 5- bromopyrimidin-2-yl, 6-cyanopyrimidin-4-yl, 6-carbamoylpyrimidin-4-yl, 6- ( cyanomethylcarbamoyl)pyrimidin-4-yl, 6-[cyanomethyl(methyl)carbamoyl]-pyrimidin-4-yl, 6- (methylcarbamoyl)pyrimidin-4-yl, 6-(dimethylcarbamoyl)pyrimidin-4-yl, 6- (methoxycarbonylamino)pyrimidin-4-yl, pyrazin-2-yl, 5-bromopyrazin-2-yl, 6-methoxypyridazin-3-yl, 1- m ethyl-6-oxo-pyridazin-3-yl, 5-carbamoylpyr
  • R4 is 5-cyano-2-pyridyl, pyrimidin-2-yl, 5-fluoropyrimidin-2-yl, 5-chloropyrimidin-2-yl, 5- bromopyrimidin-2-yl, 6-cyanopyrimidin-4-yl, 6-carbamoylpyrimidin-4-yl, 6- ( cyanomethylcarbamoyl)pyrimidin-4-yl, 6-(methylcarbamoyl)pyrimidin-4-yl, pyrazin-2-yl, 5-bromopyrazin- 2-yl, 6-methoxypyridazin-3-yl, 1-methyl-6-oxo-pyridazin-3-yl, 5-carbamoylpyrazin-2-yl, or 5-cyanothiazol- 2-yl; or O .
  • R4 is 5-cyano-2-pyridyl, pyrimidin-2-yl, 5-fluoropyrimidin-2-yl, 5-chloropyrimidin-2-yl, 5- bromopyrimidin-2-yl, 6-cyanopyrimidin-4-yl, 6-carbamoylpyrimidin-4-yl, 6- ( cyanomethylcarbamoyl)pyrimidin-4-yl, 6-(methylcarbamoyl)pyrimidin-4-yl, pyrazin-2-yl, 6- methoxypyridazin-3-yl, 1-methyl-6-oxo-pyridazin-3-yl, 5-carbamoylpyrazin-2-yl, or 5-cyanothiazol-2-yl; or P .
  • R4 is 5-cyano-2-pyridyl, pyrimidin-2-yl, 5-fluoropyrimidin-2-yl, 5-chloropyrimidin-2-yl, 5- bromopyrimidin-2-yl, 6-cyanopyrimidin-4-yl, 6-carbamoylpyrimidin-4-yl, 6- ( cyanomethylcarbamoyl)pyrimidin-4-yl, 6-[cyanomethyl(methyl)carbamoyl]-pyrimidin-4-yl, 6- (methylcarbamoyl)pyrimidin-4-yl, 6-(dimethylcarbamoyl)pyrimidin-4-yl, 6- (methoxycarbonylamino)pyrimidin-4-yl, pyrazin-2-yl, 6-chloropyridazin-3-yl, 5-chloropyrazin-2-yl, 5- bromopyrazin-2-yl, 6-methoxypyridazin-3-yl, 6-ethoxypyri
  • R4 is 5-cyano-2-pyridyl, pyrimidin-2-yl, 5-fluoropyrimidin-2-yl, 5-chloropyrimidin-2-yl, 5- bromopyrimidin-2-yl, 6-cyanopyrimidin-4-yl, 6-carbamoylpyrimidin-4-yl, 6- 109921
  • R4 is Qc-1, Qc-2, Qc-3, Qc-4, Qc-5, Qc-6, or Qc-9; or R4 is Qc-1, Qc-2, Qc-3, Qc-4, Qc-5, or Qc-9. More preferably, R4 is Qc-1, Qc-2, Qc-3, or Qc-9.
  • R 4 is 5-cyano-2-pyridyl, pyrimidin-2-yl, 5-bromopyrimidin-2-yl, 6-cyanopyrimidin-4-yl, 6-carbamoylpyrimidin-4- yl, 6-(cyanomethylcarbamoyl)pyrimidin-4-yl, 6-(methylcarbamoyl)pyrimidin-4-yl, pyrazin-2-yl, 5-bromopyrazin- 2-yl, 6-methoxypyridazin-3-yl, 1-methyl-6-oxo-pyridazin-3-yl, or 5-cyanothiazol-2-yl.
  • R 4 is 5- cyano-2-pyridyl, pyrimidin-2-yl, 6-cyanopyrimidin-4-yl, 6-carbamoylpyrimidin-4-yl, 6- (cyanomethylcarbamoyl)pyrimidin-4-yl, 6-(methylcarbamoyl)pyrimidin-4-yl, pyrazin-2-yl, 6-methoxypyridazin-3- yl, 1-methyl-6-oxo-pyridazin-3-yl, or 5-cyanothiazol-2-yl.
  • R4 is 5-cyano-2-pyridyl, pyrimidin-2-yl, 5-fluoropyrimidin-2-yl, 5-chloropyrimidin-2-yl, 5- bromopyrimidin-2-yl, 6-cyanopyrimidin-4-yl, 6-carbamoylpyrimidin-4-yl, 6-(cyanomethylcarbamoyl)pyrimidin-4- yl, 6-(methylcarbamoyl)pyrimidin-4-yl, pyrazin-2-yl, 6-methoxypyridazin-3-yl, 1-methyl-6-oxo-pyridazin-3-yl, 5- carbamoylpyrazin-2-yl, or 5-cyanothiazol-2-yl.
  • R4 is 5-cyano-2-pyridyl, pyrimidin-2-yl, 5- fluoropyrimidin-2-yl, 5-chloropyrimidin-2-yl, 5-bromopyrimidin-2-yl, 6-cyanopyrimidin-4-yl, 6- carbamoylpyrimidin-4-yl, 6-(cyanomethylcarbamoyl)pyrimidin-4-yl, 6-(methylcarbamoyl)pyrimidin-4-yl, pyrazin- 2-yl, 6-methoxypyridazin-3-yl, 1-methyl-6-oxo-pyridazin-3-yl, 5-chloropyrazin-2-yl, 5-bromopyrazin-2-yl, 5- carbamoylpyrazin-2-yl, or 5-cyanothiazol-2-yl.
  • R4 is Qc-1, Qc-2, or Qc-3.
  • R 4 is 5-cyano-2-pyridyl, pyrimidin-2-yl, 6-cyanopyrimidin-4-yl, or 6-carbamoylpyrimidin-4-yl.
  • Q is Qb
  • R4a is as follows: A.
  • R4a is pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl, pyrazol-1-yl, or N-linked triazolyl, each of which, independently of each other, is optionally substituted with a single substituent R 4b ; or R 4a is oxo- p yridazinyl optionally N-substituted with a single substituent R4c; or B.
  • R4a is Qc-1, Qc-2, Qc-3, Qc-4, Qc-5, Qc-6, Qc-7, Qc-8, Qc-9, Qc-10, or Qc-11: 109921
  • R4a is Qc-1, Qc-2, Qc-3, Qc-4, or Qc-9; or B. R4a is Qc-1, Qc-2, or Qc-3; or C. R4a is Qc-1; or D.
  • R4a is 5-cyano-2-pyridyl, pyrimidin-2-yl, 5-bromopyrimidin-2-yl, 6-cyanopyrimidin-4-yl, 6- carbamoylpyrimidin-4-yl, 6-(cyanomethylcarbamoyl)pyrimidin-4-yl, 6-[cyanomethyl(methyl)carbamoyl]- pyrimidin-4-yl, 6-(methylcarbamoyl)pyrimidin-4-yl, 6-(dimethylcarbamoyl)pyrimidin-4-yl, 6- (methoxycarbonylamino)pyrimidin-4-yl, pyrazin-2-yl, 6-chloropyridazin-3-yl, 5-bromopyrazin
  • R4a is 5-cyano-2-pyridyl or pyrimidin-2-yl; or F.
  • R4a is 5-cyano-2-pyridyl; i.e. R4a is Qc-1, with cyano as R4b.
  • R4a is Qc-1, Qc-2, Qc-3, Qc-4, or Qc-9, such as R 4a is Q c -1, Q c -2, or Q c -3. More preferably, R 4a is Q c -1.
  • the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, and oxo-pyridazinyl rings of R 4 and R 4a are each connected to the remainder of the compound via a carbon atom.
  • a carbon atom of the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, or oxo-pyridazinyl rings of R 4 and R 4a is linked to Q a or Q b , respectively.
  • R4b is as follows: A. R4b is hydrogen, halogen, cyano, hydroxy, C1-C3haloalkyl, C1-C3alkoxy, C1- C3haloalkoxy, -C(O)NR 10 R 11 , -N(R 11 )C(O)OR 10 , or -N(R 11 )C(O)R 10 ; or B .
  • R4b is hydrogen, halogen, cyano, hydroxy, C1-C3alkyl, C1-C3fluoroalkyl, C1-C3alkoxy, C1- C3fluoroalkoxy, -C(O)NR 10 R 11 , or -NHC(O)R 10 ; or C .
  • R4b is hydrogen, bromo, fluoro, chloro, iodo, cyano, C1-C3alkyl, C1-C3alkoxy, -C(O)NR10R11, -NHC(O)R 10 or -N(CH3)C(O)R 10 ; or D .
  • R4b is hydrogen, cyano, C1-C3alkyl, methoxy, -C(O)NHR11, -NHC(O)R10 or -N(CH3)C(O)R10; or G.
  • R4b is hydrogen, bromo, chloro, cyano, methyl, ethyl, methoxy, ethoxy, -C(O)NHR11, -C(O)N(CH3)R11, -NHC(O)R 10 or -N(CH3)C(O)R 10 ; or H .
  • R4b is hydrogen, bromo, chloro, cyano, methyl, methoxy, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -C(O)NHCH2CN, -C(O)N(CH3)CH2CN, or -NHC(O)OCH3; or I .
  • R4b is hydrogen, bromo, chloro, cyano, methoxy, -C(O)NH2, or -C(O)NHCH3; or J.
  • R4b is hydrogen, cyano, methoxy, -C(O)NH2, or -C(O)NHCH3; or K.
  • R4b is hydrogen, cyano, -C(O)NH2, or -C(O)NHCH3; or L. R4b is hydrogen or cyano; or M. R4b is cyano, -C(O)NH2, or -C(O)NHCH3; or N. R4b is hydrogen; or 109921
  • R4b is hydrogen, fluoro, chloro, bromo, cyano, methyl, methoxy, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -C(O)NHCH2CN, -C(O)N(CH3)CH2CN, or -NHC(O)OCH3; or Q .
  • R4b is hydrogen, fluoro, chloro, bromo, cyano, methoxy, -C(O)NH2, -C(O)NHCH3, or -C(O)NHCH2CN.
  • R10 is as follows: A. R10 is hydrogen, C1-C3alkyl, C3-C6cycloalkyl, C3-C4cycloalkylC1-C2alkyl, C1-C3cyanoalkyl, cyanoC3- C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, or C1-C4haloalkyl; or B.
  • R10 is hydrogen, C1-C3alkyl, C3-C4cycloalkyl, cyclopropylC1-C2alkyl, C1-C3cyanoalkyl, cyanoC3- C4cycloalkyl, C1-C3alkoxyC1-C3alkyl, or C1-C4haloalkyl; or C.
  • R10 is hydrogen, C1-C3alkyl, cyclopropyl, cyclopropylmethyl, cyanomethyl, 2-cyanoethyl, cyanoC3- C4cycloalkyl, or C1-C3alkoxyC1-C3alkyl; or D .
  • R11 is hydrogen, hydroxy, C1-C3alkyl, C3-C4cycloalkyl, cyanoC3-C6cycloalkyl, C1-C3cyanoalkyl, C1- C3alkoxyC1-C3alkyl, C1-C3haloalkyl, or C1-C3alkoxy; or B .
  • R11 is hydrogen, hydroxy, C1-C3alkyl, C1-C3cyanoalkyl, cyanoC3-C4cycloalkyl, C1-C3alkoxyC1-C3alkyl, or C1-C3alkoxy; or C .
  • R11 is hydrogen, C1-C3alkyl, C3-C4cycloalkyl, C1-C3cyanoalkyl, or C1-C3alkoxy; or D. R11 is hydrogen, C1-C3alkyl, cyanocyclopropyl, C1-C3alkoxyC1-C3alkyl, or methoxy; or E. R11 is hydrogen, C1-C3alkyl, cyanomethyl, 2-cyanoethyl, methoxymethyl, or C1-C3alkoxy; or F. R11 is hydrogen, C1-C3alkyl, cyclopropyl, or C1-C3alkoxy; or G.
  • R11 is hydrogen, C1-C3alkyl, cyclopropyl, or methoxy; or H. R11 is hydrogen, methyl, ethyl, cyanomethyl, 2-cyanoethyl, cyclopropyl, 1-cyanocyclopropyl, or methoxy; or I . R11 is hydrogen or methyl; or J. R11 is hydrogen; or K. R11 is hydrogen, C1-C3alkyl, cyclopropyl, cyanomethyl, or C1-C3alkoxy; or L. R11 is hydrogen, methyl, or cyanomethyl. [0067] In preferred embodiments of each aspect of the invention, R10 is hydrogen, methyl, or cyanomethyl, such as R 10 is hydrogen or methyl.
  • R 11 is hydrogen, methyl, or cyanomethyl, or R 11 is hydrogen or methyl, such as R 11 is hydrogen. 109921
  • R4b is hydrogen, fluoro, chloro, bromo, cyano, methyl, methoxy, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -C(O)NHCH2CN, -C(O)N(CH3)CH2CN, or - N HC(O)OCH3; or R4b is hydrogen, chloro, cyano, methyl, methoxy, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - C(O)NHCH2CN, -C(O)N(CH3)CH2CN, or -NHC(O)OCH3.
  • R 4b is hydrogen, fluoro, chloro, bromo, cyano, methoxy, -C(O)NH2, -C(O)NHCH3, or-C(O)NHCH2CN; or R 4b is hydrogen, chloro, cyano, methoxy, -C(O)NH2, or -C(O)NHCH3.
  • the group R4b is in the meta or para position with respect to the link of R 4 or R 4a to the remainder of the compound, i.e. to the Q a or Q b ring, respectively.
  • R4c is as follows: A.
  • R4c is C1-C3alkyl, C1-C3haloalkyl, allyl, propargyl, or C3-C6cycloalkylC1-C4alkyl; or B. R4c is C1-C3alkyl, C1-C3haloalkyl, or C3-C6cycloalkylC1-C4alkyl; or C. R4c is methyl, ethyl, difluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoromethyl, allyl, propargyl, or cyclopropylmethyl; or D .
  • R4c is methyl, ethyl, allyl, propargyl, or cyclopropylmethyl; or E. R4c is methyl, ethyl, or cyclopropylmethyl; or F. R4c is methyl or cyclopropylmethyl; or G. R4c is methyl or ethyl; or H. R4c is methyl. [0071] In preferred embodiments of each aspect of the invention, R4c is methyl or ethyl. For instance, R4c is methyl.
  • R4 and R4a are selected from QQ-1 to QQ-23, where the staggered line represents the connection to Qa or Qb: 109921
  • R4 and R4a are selected from QQ-1, QQ-2, QQ-3, QQ-4, QQ-5, QQ- 6, QQ-9, QQ-12, QQ-13, QQ-15, QQ-18, QQ-19, QQ-20, Q-21, Q-22, and Q-23.
  • R4 and R4a are selected from QQ-1, QQ-2, QQ-3, QQ-4, QQ-5, QQ-6, QQ-9, QQ-12, QQ-13, QQ-15, QQ-18, QQ-19, QQ-20, and Q-21, or R 4 and R 4a , as the case may be, are selected from QQ-1, QQ-2, QQ-3, Q Q-4, QQ-5, QQ-6, QQ-9, QQ-12, QQ-13, and QQ-15.
  • R4 and R4a are selected from QQ-1, QQ-2, and QQ-12. In other preferred embodiments, R4 and R4a are selected from QQ-1, QQ-2, and QQ-5.
  • the present invention makes available a compound of formula (I) having the substituents A, Q (i.e. Qa with R4 and R5, or Qb with R4a, R5a and R5b), R1, R2a, R2b, R3, R10, R11, and X as defined above, in all combinations and each permutation.
  • 83176 FF cyano; R 2b is hydrogen, halogen, C1-C3haloalkyl, C1-C3haloalkoxy, cyano,
  • A is CH or N, preferably A is CH;
  • X is oxygen;
  • R 1 is hydrogen, C1-C6alkyl, C1-C6cyanoalkyl, C1-C3alkoxyC1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C4cycloalkylC1-C2alkyl, or C1-C6alkoxycarbonyl;
  • R2a is hydrogen, C1-C3alkyl, C1-C3fluoroalkyl, cyclopropyl, cyclobutyl, or cyclopropyl substituted with a single fluoro or cyano;
  • R 2b is halogen, C1-C3haloalkyl, C1- C3haloalkoxy, C1-C3alkylsulfonyl, C1-C3haloalkylsulfonyl, C1-C
  • A is CH or N, preferably A is CH;
  • X is oxygen;
  • R 1 is hydrogen, C1-C6alkyl, C1-C6cyanoalkyl, C1-C3alkoxyC1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C4cycloalkylC1-C2alkyl, or C1-C6alkoxycarbonyl;
  • R2a is hydrogen, C1-C3alkyl, C1-C3fluoroalkyl, cyclopropyl, cyclobutyl, or cyclopropyl substituted with a single fluoro or cyano;
  • R 2b is halogen, C 1 -C 3 haloalkyl, C 1 - C3haloalkoxy, C1-C3alkylsulfonyl, C1-C3haloalkylsulfonyl, C
  • A is CH or N, preferably A is CH;
  • X is oxygen;
  • R1 is hydrogen, methyl, or cyclopropylmethyl;
  • R2a is hydrogen, C1-C3alkyl, C1- C3fluoroalkyl, cyclopropyl, cyclobutyl, or cyclopropyl substituted with a single fluoro or cyano;
  • R2b is halogen, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3alkylsulfonyl, C1-C3haloalkylsulfonyl, C1-C5cyanoalkyl, C3- C4cycloalkylC1-C2alkyl, or cyclopropyl;
  • R 3 is C1-C3alkyl or C1-C3haloalkyl; preferably R 3 is methyl or trifluoromethyl; such as R 3
  • A is CH or N, preferably A is CH;
  • X is oxygen;
  • R 1 is hydrogen, methyl, or cyclopropylmethyl;
  • R 2a is hydrogen, C1-C3alkyl, C1- C3fluoroalkyl, cyclopropyl, cyclobutyl, or cyclopropyl substituted with a single fluoro or cyano;
  • R2b is halogen, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3alkylsulfonyl, C1-C3haloalkylsulfonyl, C1-C5cyanoalkyl, C3- C4cycloalkylC1-C2alkyl, or cyclopropyl;
  • R 3 is C1-C3alkyl or C1-C3haloalkyl; preferably R 3 is methyl or trifluoromethyl; such as R 3
  • A is CH; X is oxygen or sulfur; preferably X is oxygen; R 1 is hydrogen, methyl, or cyclopropylmethyl; R 2a is hydrogen, methyl, ethyl, difluoromethyl, trifluoromethyl, cyclopropyl, 1-fluorocyclopropyl, or 1-cyanocyclopropyl; R 2b is halogen, C1-C3haloalkyl, C1- C3haloalkoxy, C1-C3alkylsulfonyl, C1-C3haloalkylsulfonyl, C1-C5cyanoalkyl, C3-C4cycloalkylC1-C2alkyl, or cyclopropyl; R 3 is C1-C3alkyl or C1-C3haloalkyl; preferably R 3 is methyl or trifluoromethyl; such as R 3 is methyl; Q is Q
  • A is CH; X is oxygen or sulfur; preferably X is oxygen; R 1 is hydrogen, methyl, or cyclopropylmethyl; R 2a is hydrogen, methyl, ethyl, difluoromethyl, trifluoromethyl, cyclopropyl, 1-fluorocyclopropyl, or 1-cyanocyclopropyl; R 2b is halogen, C1-C3haloalkyl, C1- C3haloalkoxy, C1-C3alkylsulfonyl, C1-C3haloalkylsulfonyl, C1-C5cyanoalkyl, C3-C4cycloalkylC1-C2alkyl, or cyclopropyl; R 3 is C1-C3alkyl or C1-C3haloalkyl; preferably R 3 is methyl or trifluoromethyl; such as R 3 is methyl; Q is Q
  • A is CH; X is oxygen or sulfur; preferably X is oxygen; R 1 is hydrogen, methyl, or cyclopropylmethyl; R 2a is hydrogen, methyl, ethyl, difluoromethyl, trifluoromethyl, cyclopropyl, 1-fluorocyclopropyl, or 1-cyanocyclopropyl; R 2b is halogen, C1-C3haloalkyl, C1- C3haloalkoxy, C1-C3alkylsulfonyl, C1-C3haloalkylsulfonyl, C1-C5cyanoalkyl, C3-C4cycloalkylC1-C2alkyl, or cyclopropyl; R 3 is C1-C3alkyl or C1-C3haloalkyl; preferably R 3 is methyl or trifluoromethyl; such as R 3 is methyl; Q is Qb
  • A is CH; X is oxygen or sulfur; preferably X is oxygen; R 1 is hydrogen, methyl, or cyclopropylmethyl; R 2a is hydrogen, methyl, ethyl, difluoromethyl, trifluoromethyl, cyclopropyl, 1-fluorocyclopropyl, or 1-cyanocyclopropyl; R 2b is halogen, C1-C3haloalkyl, C1- 109921
  • A is CH or N, preferably A is CH; X is oxygen or sulfur; preferably X is oxygen; R 1 is hydrogen or methyl; R 2a is hydrogen, methyl, ethyl, cyclopropyl, 1-fluorocyclopropyl, or 1-cyanocyclopropyl; R 2b is chloro, bromo, difluoromethyl, trifluoromethyl, or cyclopropyl; R 3 is methyl or trifluoromethyl; preferably, R 3 is methyl; Q is Q a ;-1; R 4 is 5-cyano-2-pyridyl, pyrimidin-2-yl, 5- bromopyrimidin-2-yl, 6-cyanopyrimidin-4-yl, 6-carbamoylpyrimidin-4-yl, 6-(cyanomethylcarbamoyl)pyrimidin-4- yl, 6-[cyanomethyl(methyl)carbamoyl]-pyrimidin-4
  • A is CH or N, preferably A is CH; X is oxygen or sulfur; preferably X is oxygen; R 1 is hydrogen or methyl; R 2a is hydrogen, methyl, ethyl, cyclopropyl, 1- fluorocyclopropyl, or 1-cyanocyclopropyl; R 2b is chloro, bromo, difluoromethyl, trifluoromethyl, difluoromethoxy, or cyclopropyl; R 3 is methyl or trifluoromethyl; preferably, R 3 is methyl; Q is Q a ;-1, Q a -4, Q a -5, Q a -10, Q a -15, or Q a -16; R 4 is 5-cyano-2-pyridyl, pyrimidin-2-yl, 5-fluoropyrimidin-2-yl, 5-chloropyrimidin-2-yl, 5-bromopyrimidin- 2-yl, 6-cyanopyr
  • A is CH or N, preferably A is CH; X is oxygen or sulfur; preferably X is oxygen; R 1 is hydrogen or methyl; R 2a is hydrogen, methyl, ethyl, cyclopropyl, 1- 109921
  • A is CH or N, preferably A is CH; X is oxygen or sulfur; preferably X is oxygen; R 1 is hydrogen or methyl; R 2a is hydrogen, methyl, ethyl, cyclopropyl, 1-fluorocyclopropyl, or 1-cyanocyclopropyl; R 2b is chloro, bromo, difluoromethyl, trifluoromethyl, or cyclopropyl; R 3 is methyl or trifluoromethyl; preferably, R 3 is methyl; Q is Q a -1, Q a -4, Q a -5, Q a -10, Q a -15, or Q a -16; R 4 is 5- cyano-2-pyridyl, pyrimidin-2-yl, 5-bromopyrimidin-2-yl, 6-cyanopyrimidin-4-yl, 6-carbamoylpyrimidin-4-yl, 6- (cyanomethylcarbamoy
  • Compounds of the formula (I) can be made, for example, by reaction of a compound of the formula (II), wherein X 1 is hydroxy or a leaving group, such as a halogen or sulfonate, for instance chloride, and wherein T has the meaning given above, with a compound of formula (III), or a salt thereof (such as a hydrohalide salt, preferably a hydrochloride or a hydrobromide salt, or a trifluoroacetic acid salt, or any other equivalent salt), wherein R1, R3 and Q have the same meaning as given above for compounds of the formula (I).
  • a compound of the formula (II) wherein X 1 is hydroxy or a leaving group, such as a halogen or sulfonate, for instance chloride, and wherein T has the meaning given above
  • a compound of formula (III), or a salt thereof such as a hydrohalide salt, preferably a hydrochloride or a hydrobromide salt, or a
  • a dehydration reagent for instance a peptide coupling reagent, such as, for example, a carbodiimide, HATU (1-[bis(dimethylamino)- methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, also known as Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium) or propanephosphonic acid cyclic anhydride (T3P®).
  • a dehydration reagent for instance a peptide coupling reagent, such as, for example, a carbodiimide, HATU (1-[bis(dimethylamino)- methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, also known as Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium) or propanephosphonic acid cyclic an
  • Such reactions can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, N,N- dimethylacetamide or N,N-dimethylformamide, in a temperature range of -100 to +300 °C, preferably between 109921
  • a solvent such as an organic solvent, for instance acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran,
  • compounds of the formula (II) are either known, or they can be prepared by methods known to a person skilled in the art.
  • compounds of the formula (II) wherein X 1 is a leaving group, such as a halogen, for instance chloride can be formed by treatment of compounds of formula (II) wherein X 1 is hydroxy with, for example, oxalyl chloride or thionyl chloride, in the presence of catalytic quantities of N,N-dimethylformamide (DMF), in inert solvents such as for instance dichloromethane (DCM) or tetrahydrofuran (THF), at temperatures between 0°C to 100°C, preferably around 25°C.
  • DMF N,N-dimethylformamide
  • DCM dichloromethane
  • THF tetrahydrofuran
  • the reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance acetonitrile, in a temperature range of -100 to +300 °C, preferably between ambient temperature and 200 °C, with or without the addition of a base, such as an inorganic base, for instance potassium carbonate, or an organic base, such as, for example, triethylamine.
  • a solvent such as an organic solvent, for instance acetonitrile
  • a base such as an inorganic base, for instance potassium carbonate
  • an organic base such as, for example, triethylamine.
  • This reaction is done in the presence of a reducing agent, such as for example hydrogen, or a hydride, such as sodium borohydride, with or without a catalyst, such as a hydrogenation catalyst, for example palladium on carbon, with or without the presence of an acid, such as acetic acid, or a Lewis acid, such as zinc bromide or titanium(IV) isopropoxide, in a solvent or without a solvent, such as, for instance, methanol.
  • a reducing agent such as for example hydrogen
  • a hydride such as sodium borohydride
  • a catalyst such as a hydrogenation catalyst, for example palladium on carbon
  • an acid such as acetic acid
  • a Lewis acid such as zinc bromide or titanium(IV) isopropoxide
  • 83176 FF alkylation of amines e.g. in the presence of NaBH(OAc)3 or NaBH3CN, in a suitable solvent, preferably in acetic acid, at room temperature, analogous to WO2002/088073; or alternatively, by the use of a combination of Ti(i- OiPr)4 and NaBH4 as described in Synthesis 2003 (14), 2206) are well known to a person skilled in the art.
  • the reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance acetonitrile, in a temperature range of -100 to +300 °C, preferably between ambient temperature and 200 °C, with or without the addition of a base, such as an inorganic base, for instance potassium carbonate, or an organic base, such as, for example, triethylamine.
  • a solvent such as an organic solvent, for instance acetonitrile
  • a base such as an inorganic base, for instance potassium carbonate
  • organic base such as, for example, triethylamine.
  • a compound of the formula (I) can be made by reaction of a compound of the formula (IVa), wherein T has the same meaning as given above in Scheme 1, with a compound of the formula (VII), wherein R3 and Q have the same meaning as given above for compounds of the formula (I).
  • This reaction is done in the presence of a reducing agent, such as for example hydrogen, or a hydride, such as sodium borohydride, with or without a catalyst, such as a hydrogenation catalyst, for example palladium on carbon, with or without the presence of an acid, such as acetic acid, or a Lewis acid, such as zinc bromide, in a solvent or without a solvent, such as, for instance, methanol.
  • the reaction can be done with or without exposure to visible light, or to UV light, and it can be conducted in a temperature range of -100 to +300 °C, preferably between ambient temperature and 200 °C.
  • a compound of the formula (VII) wherein R3 and Q have the same meaning as given above for compounds of the formula (I)
  • a compound of the formula (V) can be treated with a reducing agent, followed by reaction with a sulfonyl chloride, for instance methanesulfonyl chloride, to give a compound of the formula (V), wherein the leaving group X 2 is a sulfonate, for instance a mesylate.
  • This reaction can be done in a solvent, or without a solvent, in the presence of a base, such as an inorganic base, for instance potassium carbonate, or an organic base, such as an amine base, for instance trimethylamine, or without a base, and it can be conducted in a temperature range of -100 to +300 °C, preferably between ambient temperature and 200 °C.
  • a base such as an inorganic base, for instance potassium carbonate, or an organic base, such as an amine base, for instance trimethylamine, or without a base, and it can be conducted in a temperature range of -100 to +300 °C, preferably between ambient temperature and 200 °C.
  • a suitable reducing agent could be, for example, hydrogen, or a hydride, such as sodium borohydride, with or without a catalyst, such as a hydrogenation catalyst, for example palladium on carbon, with or without the presence of an acid, such as acetic acid, or a Lewis acid, such as zinc bromide, in a solvent or without a solvent, such as, for instance, methanol.
  • the reaction can be conducted in a temperature range of -100 to +300 °C, preferably between ambient temperature and 200 °C.
  • a leaving group such as a halogen or sulfonate, for instance a chloride, bromide, iodide or mesylate
  • This reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance acetonitrile, dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA), or mixtures thereof, in a temperature range of -100 to +300 °C, preferably between ambient temperature and 200 °C, with or without the addition of a base, such as an inorganic base, for instance sodium, potassium or cesium carbonate, or an organic base, such as, for example, triethylamine, diisopropylethylamine or pyridine.
  • a solvent such as an organic solvent, for instance acetonitrile, dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA), or mixtures thereof, in a temperature range of -100 to +300 °C, preferably between ambient temperature and 200 °
  • a dehydration reagent for instance a peptide coupling reagent, such as, for example, a carbodiimide, HATU (1- [bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, also known as Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium) or propanephosphonic acid cyclic anhydride (T3P®).
  • a dehydration reagent for instance a peptide coupling reagent, such as, for example, a carbodiimide, HATU (1- [bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, also known as Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium
  • T3P® propanephosphonic acid cycl
  • the reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, 109921
  • a solvent such as an organic solvent, 109921
  • This reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran or dioxane, in a temperature range of -100 to +300 °C, preferably between ambient temperature and 100 °C, or between ambient temperature and 50 °C, without a base or in the presence of a base, such as an inorganic base, for instance sodium, potassium or cesium carbonate, or an organic base, such as, for example, triethylamine, diisopropylethylamine or pyridine.
  • a solvent such as an organic solvent, for instance dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran or dioxane
  • a base such as an inorganic base, for instance sodium, potassium or cesium carbonate
  • an organic base such as, for example, triethylamine, diisopropylethylamine
  • This reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance 1,4-dioxane, or acetic acid, or a mixture of 1,4-dioxane and acetic acid, in a temperature range of -100 to +300 °C, preferably between ambient temperature and 200 °C, or between ambient temperature and 80 °C.
  • a solvent such as an organic solvent, for instance 1,4-dioxane, or acetic acid, or a mixture of 1,4-dioxane and acetic acid
  • 83176 FF can be prepared by the reaction of an amine of the formula (IIIf), or a salt thereof wherein R1, R3, R4 and R5 are as described in formula (I), with a compound of the formula (IIa) wherein A, R2a and R2b are as described in formula (I) and X1 is hydroxy or a leaving group, such as a halogen or a sulfonate, for instance chloride, under conditions already described in Scheme 1.
  • 83176 FF [0110] Compounds of formula (Ic) can be made, for example, as shown in scheme 7.
  • This reaction is done in the presence of a reducing agent, such as for example hydrogen, or a hydride, such as sodium borohydride, with or without a catalyst, such as a hydrogenation catalyst, for example palladium on carbon, with or without the presence of an acid, such as acetic acid, or a Lewis acid, such as zinc bromide, in a solvent or without a solvent, such as, for instance, methanol.
  • a reducing agent such as for example hydrogen
  • a hydride such as sodium borohydride
  • a catalyst such as a hydrogenation catalyst, for example palladium on carbon
  • an acid such as acetic acid, or a Lewis acid, such as zinc bromide
  • a solvent or without a solvent such as, for instance, methanol.
  • R4a-M1 is a metal, such as for instance lithium, or –MgCl, or –ZnBr, or –B(OH)2; or R4a-M1 represents a boronate, such as a pinacol ester of a boronic acid, or a stannane such as R4a-Sn(n-Bu)3.
  • Such transformations are known to a person skilled in the art as Suzuki-, Kumada-, Negishi- or Stille-coupling reactions, respectively.
  • Such reactions are carried out in a temperature range of - 100 to +300 °C, preferably between ambient temperature and 200 °C, in the presence of a catalyst, such as a metal catalyst, for instance a palladium catalyst (for example palladium(II) acetate, 1,1’- bis(diphenylphosphino)ferrocene-palladium(II)dichloride or tetrakis(triphenyl-phosphine)palladium(0)), and optionally in the presence of an additional ligand, such as for example a phosphine ligand, or an N-heterocyclic carbene (NHC) ligand, or a phosphite ligand.
  • a catalyst such as a metal catalyst, for instance a palladium catalyst (for example palladium(II) acetate
  • the reaction can be done in the presence or absence of an additional metal catalyst, such as, for example, a copper salt, for instance CuI.
  • a base which can be an inorganic base, such as potassium carbonate, or sodium hydroxide, or cesium carbonate, or tribasic potassium phosphate, or an organic base, such as an amine base, for instance triethyl amine.
  • This reaction is done with or without a solvent, preferentially in a solvent, such as tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, toluene or N,N-dimethylformamide, optionally in the presence of water.
  • reaction can be conducted under microwave irradiation or with conventional heating, such as heating the reaction vessel in an oil bath.
  • compound (XVII) can be reacted with a compound of the formula (XV) to give intermediate (XVIII). This reaction is done essentially under in the same range of conditions as described for the transformation of intermediate (XIV) to the compound of formula (Ic).
  • the intermediate (XVIII) is reacted with a compound of the formula (IVb) to give a compound of the formula (Ic), wherein R1 is hydrogen and A, R2a, R2b, R3 and R4a have the same meaning as given above for compounds of the formula (I).
  • This reaction is done in the presence of a reducing agent, essentially under the same conditions as described above for the transformation of compound (XVII) to intermediate (XVI).
  • the intermediate compound of the formula (XVIII) can be reacted with an amine of the formula (XIX), or a salt thereof, to give the intermediate of the formula (IIIa), or a salt thereof.
  • the intermediate compounds of formulas (XIV), (XVI), (XVIII) and (IIIa) can be used as crude products for the respective subsequent step, or they can be purified, for instance by chromatography, and used in purified form for the next transformation.
  • Compounds of the formula (XVII) are known, or they can be prepared by methods known to a person skilled in the art.
  • Compounds of the formula (Id) can be prepared by the reaction of an amine of the formula (IIIb), or a salt thereof wherein R1, R3, R4a, R5a and R5b are as described in formula (I), with a compound of the formula (IIa) 109921
  • the chemistry is described in more detail in Scheme 8.
  • the reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance acetonitrile, in a temperature range of -100 to +300 °C, preferably between ambient temperature and 200 °C, with or without the presence of a catalyst, for instance a metal catalyst, such as a palladium complex, and with or without the addition of a base, such as an inorganic base, for instance potassium carbonate, or an organic base, such as, for example, triethylamine.
  • a solvent such as an organic solvent, for instance acetonitrile
  • Amines of formula (IIIc), or a salt thereof may be obtained by biocatalyzed deracemization of amines of formula (IIId), or a salt thereof. This may be done for instance using a lipase, e.g. Candida Antarctica lipase B or Pseudomonas fluorescens lipase, eventually in immobilized form (e.g. Novozym® 435) in presence of an acyl donor, e.g. ethyl methoxyacetate or vinyl acetate, in a suitable solvent such as acetonitrile or methyl tert- butyl ether at temperatures between 20 °C to 100 °C.
  • a lipase e.g. Candida Antarctica lipase B or Pseudomonas fluorescens lipase
  • an acyl donor e.g. ethyl methoxyacetate or vinyl acetate
  • suitable solvent such as acetonitrile or
  • compounds of formula (IIIc), or a salt thereof can be obtained from compounds of the formula (XXII), wherein R3, R4a, R5a, and R5b are as described in formula (I), following the synthesis described in Scheme 10.
  • Amines of formula (IIIc), or a salt thereof may be obtained from intermediates of formula (XXII), wherein R3, R4a, R5a, and R5b are as described in formula (I) and Z3 is -NPhth (N-phthalimide group) or -NBoc2 (N-bis(tert-butyloxycarbonyl) group), typically by treatment with either hydrazine (preferably hydrazine hydrate or hydrazine monohydrate) in an alcohol solvent such as ethanol or isopropanol (Z3 is -NPhth), or with an acid such as trifluoroacetic acid or hydrochloric acid in the presence of a suitable solvent such as dichloromethane, tetrahydrofuran or dioxane (Z 3 is -NBoc 2 ), under deprotection conditions known to a person skilled in the art, and described in the literature, such as for example in: Protective Groups in Organic Synthesis, 3rd Edition
  • Such intermediates of formula (XXII), wherein R3, R4a, R5a, and R5b are as described in formula (I) and Z 3 is -NPhth (N-phthalimide group) or -NBoc 2 (N-bis(tert-butyloxycarbonyl) group), can be obtained from alcohols of formula (XXI), wherein R3, R4a, R5a, and R5b are as described in formula (I), by a Mitsunobu reaction, which involves treating alcohols of formula (XXI) with an azodicarboxylate, such as diethyl azodicarboxylate or diisopropyl azodicarboxylate in the presence of a phosphine, such as triphenylphos
  • amines of formula (IIIc) may be obtained by reduction of azides of formula (XXIII), wherein R3, R4a, R5a, and R5b are as described in formula (I), by treatment with triphenylphosphine and water (Staudinger reaction) or by hydrogenation for example using a palladium catalyst in the presence of hydrogen.
  • Azides of formula (XXIII) may be obtained by treatment of alcohols of formula (XXI), wherein R3, R4a, R5a, 109921
  • an azidation reagent such as diphenyl phosphoryl azide in a solvent such as toluene or THF in presence of a base such as DBU.
  • Alcohols of formula (XXI) may be obtained by enantioselective reduction of ketones of formula (XXIV), wherein R3, R4a, R5a, and R5b are as described in formula (I).
  • reductions can be done using a catalyst, for instance a ruthenium or a rhodium catalyst with a chiral ligand such as RuCl[(R,R)-TsDPEN](mesitylene) or RuBF4[(R,R)-TsDPEN](p-cymene) in the presence of a hydrogen donor system such as for example HCOOH/Et3N or HCO2NH4.
  • a hydrogen donor system such as for example HCOOH/Et3N or HCO2NH4.
  • compounds of formula (IIIc) may also be prepared as outlined in Scheme 11.
  • Scheme 11 Amines of formula (IIIc), or a salt thereof (such as a hydrohalide salt, preferably a hydrochloride or a hydrobromide salt, or a trifluoroacetic acid salt, or any other equivalent salt), can be prepared by deprotection of amines of formula (XXV), wherein R3, R4a, R5a, and R5b are as described in formula (I), for instance using an acid such as trifluoroacetic acid or hydrochloric acid, optionally in the presence of a suitable solvent such as dichloromethane, tetrahydrofuran or dioxane.
  • a suitable solvent such as dichloromethane, tetrahydrofuran or dioxane.
  • Amines of formula (XXV) can be obtained by condensation of diamines of formula (XLVII), wherein R5a, and R5b are as described in formula (I), on diketones of formula (XXVI), wherein R3 and R4a are as described in formula (I). This condensation can take place in the presence of a suitable solvent such as ethanol or isopropanol in presence of an oxidant such as air or DDQ.
  • Diketones of formula (XXVI) may be formed by oxidation of hydroxyketones of formula (XXVII), wherein R3 and R4a are as described in formula (I).
  • This oxidation can involve for instance SO3-pyridine in presence of solvents such as dichloromethane or dimethyl sulfoxide DMSO, or mixtures thereof, and a base for instance triethylamine or alternatively sodium hypochlorite in presence of a catalyst such as 109921
  • solvents such as dichloromethane or dimethyl sulfoxide DMSO, or mixtures thereof
  • a base for instance triethylamine or alternatively sodium hypochlorite
  • a catalyst such as 109921
  • Hydroxyketones of formula (XXVII) may be synthesized by cross-benzoin condensation between aldehydes of formula (XXIX), wherein R4a is as described in formula (I), and aldehydes of formula (XXVIII), wherein R 3 is as described in formula (I).
  • Aldehydes of formula (XXVIII) are commercially available in chiral form, like for instance Boc-L- alaninal (CAS 79069-50-4) or tert-butyl N-[(1S)-1-(cyclopropylmethyl)-2-oxo-ethyl]carbamate (CAS 881902-36- 9).
  • Cross-benzoin condensations are done in the usual way by employing an organocatalyst such as a triazolium salt or a thiazolium salt, in the presence of a base such as potassium tert-butoxide or N,N- isopropylethylamine, in a suitable solvent such as DCM or THF, at a temperature between -20 °C and the boiling point of the solvent.
  • organocatalyst such as a triazolium salt or a thiazolium salt
  • a base such as potassium tert-butoxide or N,N- isopropylethylamine
  • a suitable solvent such as DCM or THF
  • Amines of formula (XXXIV) can be prepared by deracemization procedure method, which involves for example, a selective acylation of one enantiomer. Such an example is described in Scheme 13 more in details.
  • Chemoenzymatic resolution biocatalyst e.g. lipase or protease acylating agent e.g.
  • Amines of formula (XXXIV) may be obtained by biocatalyzed deracemization of amines of formula (XXXIVa), wherein R3, R5a, and R5b are as in formula (I) and X07 is a leaving group such as bromine, chlorine or iodine. This may be done for instance using a lipase, e.g.
  • acyl donor e.g. ethyl methoxyacetate or vinyl acetate
  • suitable solvent such as acetonitrile or methyl tert-butyl ether
  • Amines of formula (XXXIV) can be prepared from intermediates of formula (XXXVII), wherein R3, R5a, and R5b are as in compounds of the formula (I), X07 is a leaving group such as bromine, chlorine or iodine, and X12* is a chiral auxiliary, by treatment with acids such as HCl or bases such as NaOH.
  • Chiral auxiliaries of formula (XXXVI) are for instance mandelic acid or (1R)-menthylchloroformate.
  • Amines of formula (XXXIV), or a salt thereof may be obtained from intermediates of formula (XXIIa), wherein R3, R5a, and R5b are as described in formula (I), X07 is a leaving group such as a halogen or sulfonate, for instance bromide, and Z3 is -NPhth (N-phthalimide group) or -NBoc2 (N-bis(tert-butyloxycarbonyl) group), typically by treatment with either hydrazine (preferably hydrazine hydrate or hydrazine monohydrate) in an alcohol solvent such as ethanol or isopropanol (Z3 is -NPhth), or with an acid such as trifluoroacetic acid or 109921
  • Such intermediates of formula (XXIIa), wherein R3, R5a, and R5b are as described in formula (I), X07 is a leaving group such as a halogen or sulfonate, for instance bromide, and Z3 is -NPhth (N-phthalimide group) or -NBoc2 (N-bis(tert-butyloxycarbonyl) group), can be obtained from alcohols of formula (XXIa), wherein R3, R5a, and R5b are as described in formula (I) and X07 is a leaving group, by a Mitsunobu reaction, which involves treating alcohols of formula (XXIa) with an azodicarboxylate, such as diethyl azodicarboxylate
  • amines of formula (XXXIV) may be obtained by reduction of azides of formula (XXIIIa), wherein R3, R5a, and R5b are as described in formula (I) and X07 is a leaving group such as a halogen or sulfonate, for instance bromide, by treatment with triphenylphosphine and water (Staudinger reaction) or by hydrogenation for example using a palladium catalyst in the presence of hydrogen.
  • Azides of formula (XXIIIa) may be obtained by treatment of alcohols of formula (XXIa) with an azidation reagent such as diphenyl phosphoryl azide in a solvent such as toluene or THF in presence of a base such as DBU.
  • an azidation reagent such as diphenyl phosphoryl azide in a solvent such as toluene or THF in presence of a base such as DBU.
  • Alcohols of formula (XXIa) may be obtained by enantioselective reduction of ketones of formula (XXIVa), wherein R3, R5a, and R5b are as described in formula (I) and X07 is a leaving group such as a halogen or sulfonate, for instance bromide.
  • Such reductions can be done using catalysts, for instance a ruthenium or a rhodium catalyst with a chiral ligand such as RuCl[(R,R)-TsDPEN](mesitylene) or RuBF 4 [(R,R)-TsDPEN](p- cymene) in the presence of a hydrogen donor system such as for example HCOOH/Et3N or HCO2NH4.
  • a hydrogen donor system such as for example HCOOH/Et3N or HCO2NH4.
  • Compounds of the formula (IIa-1), wherein A, R2a and R2b are as described in formula (I), can be prepared by saponification of compounds of the formula (IIa-2), wherein A, R2a and R2b are as described in formula (I), and in which Ra is C1-C6alkyl or benzyl, under conditions known to a person skilled in the art (using for example conditions such as: aqueous sodium, potassium or lithium hydroxide in methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran or dioxane at room temperature, or up to refluxing conditions; or alternatively treating compounds of the formula (IIa-2) with an acid, such as for example a hydrohalide acid, preferably hydrochloride or hydrobromide acid, or trifluoroacetic acid, optionally in presence of a solvent, such as tetrahydrofuran, dioxane or dichloromethane, at temperatures between 0 and 150
  • Compounds of the formula (IIa-2), wherein A, R2a and R2b are as described in formula (I), and in which Ra is C1-C6alkyl or benzyl, can be prepared by means of a carbonylation reaction on compounds of the formula (XL), wherein A, R2a and R2b are as described in formula (I), and in which X3 is a halogen, preferably bromine, chlorine or iodine (even more preferably bromine or chlorine), in the presence of an alcohol RaOH, wherein Ra is C1-C6alkyl or benzyl.
  • the compounds of formula (XL) are reacted with carbon monoxide CO (usually under pressure, for example in the range of 5 to 200 bar), in the presence of a metal catalyst such as a palladium catalyst (for example: palladium(II) acetate, or 1,1’- bis(diphenylphosphino)ferrocene-palladium(II)dichloride (Pd(dppf)Cl2, optionally as a dichloromethane complex)), optionally in the presence of a phosphine ligand, preferably in the presence of a base such as triethylamine, diisopropylethylamine or pyridine, in an alcohol RaOH solvent (optionally in presence of an inert organic co-solvent), and at temperatures ranging between 0 and 250°C, preferably between room temperature and 200°C.
  • a metal catalyst such as a palladium catalyst (for example: palladium(II) acetate, or 1,1’- bis(diphen
  • compounds of the formula (IIa-1), wherein A, R2a and R2b are as described in formula (I) can be prepared by i. performing a lithium-halogen (Li-X3) exchange on compounds of the formula (XL), wherein A, R2a and R2b are as described in formula (I), and in which X3 is a halogen, preferably bromine, chlorine or iodine (even more preferably bromine or chlorine), followed by ii. quenching the formed organolithium species with carbon dioxide.
  • Li-X3 lithium-halogen
  • Such lithium-halogen exchange reactions can be performed using, for example, organolithium compounds such as butyllithium (BuLi), in an anhydrous aprotic solvent, such as tetrahydrofuran, 2-methyltetrahydrofuran or N,N′-dimethylpropylene-urea (DMPU), and at temperatures ranging from -120 to 0°C, preferably between -78 and 0°C.
  • organolithium compounds such as butyllithium (BuLi)
  • an anhydrous aprotic solvent such as tetrahydrofuran, 2-methyltetrahydrofuran or N,N′-dimethylpropylene-urea (DMPU)
  • DMPU N,N′-dimethylpropylene-urea
  • the formed lithiated intermediate is preferably quenched in situ with carbon dioxide (gasous, or alternatively solid carbon dioxide known as dry ice) to generate the compounds of the formula (IIa-1).
  • carbon dioxide gasous, or
  • the 1H-indazole formation may be conducted using an intramolecular Ullmann-type reaction, in the presence of copper salts, for instance copper bromide CuBr, preferably in sub-stoichiometric amounts, with for example 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a base, in for instance acetonitrile as a solvent, and at temperatures ranging from room temperature to the boiling point of the reaction mixture, as described for example in J. Org. Chem.2023, 88, 4209-4223.
  • copper salts for instance copper bromide CuBr
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • X3 is a halogen, preferably 109921
  • X4 is a leaving group, such as a halogen or sulfonate, for instance a fluoride, chloride, bromide or mesylate, preferably fluoride, chloride or bromide, followed by ii.
  • formylation agents such as formate esters, preferably methyl formate or ethyl formate, or N,N-disubstituted formamides, preferably N,N-dimethyl formamide or N-formylmorpholine.
  • Such metallation reactions can be performed using, for example, lithium diisopropylamide LDA as a base (alternatively lithium bis(trimethylsilyl)amide LiHMDS or lithium tetramethylpiperidide LiTMP, or other organolithium species such as n-butyllithium or tert-butyllithium), in an anhydrous aprotic solvent, such as tetrahydrofuran or 2-methyltetrahydrofuran, and at temperatures ranging from -120 to 0°C, preferably between -78 and 0°C.
  • lithium diisopropylamide LDA as a base
  • lithium bis(trimethylsilyl)amide LiHMDS or lithium tetramethylpiperidide LiTMP or other organolithium species such as n-butyllithium or tert-butyllithium
  • anhydrous aprotic solvent such as tetrahydrofuran or 2-methyltetrahydrofuran
  • the formed lithiated intermediate is preferably quenched in situ with for instance ethyl formate or N,N-dimethyl formamide to generate the compounds of the formula (XL- 2). Similar reactions are reported in literature for example in WO 2011/141756, WO 2012/162407, WO 2020/229968, or WO 2022/117475.
  • Hydrazine compounds of the formula R2aNHNH2, or a salt thereof, wherein R2a is as described in formula (I) are either known, or they can be prepared by methods known to a person skilled in the art.
  • compounds of the formula (IIIa) and (IIIb), or a salt thereof as defined above wherein R 1 , R 3 , R 4a , R 5a and R 5b are as described in formula (I), particularly those compounds of the formula (IIIa) and (IIIb), or a salt thereof as defined above, wherein R 3 and R 4a are as described in formula (I) and in which R 1 , R 5a and R 5b are hydrogen, can be prepared in analogy to descriptions found for example in WO 2021/083936, WO 2021/069575, and WO 2022/258481.
  • compounds of the formula (IIIe) and (IIIf), or a salt thereof as defined above wherein R1, R 3 , R 4 and R 5 are as described in formula (I), particularly those compounds of the formula (IIIe) and (IIIf), or a salt thereof as defined above, wherein R 3 and R 4 are as described in formula (I) and in which R 1 is hydrogen or methyl and R 5 is hydrogen, methyl or cyclopropyl, can be prepared in analogy to descriptions found for example in WO 2021/083936, WO 2021/099303, WO 2021/105091, WO 2021/165195, WO 2021/224323, WO 2022/268648, WO 2023/104714 and WO 2023/247360.
  • compounds of the formula (IIIg), wherein R1, R3, R5, R10 and R11 are as described in formula (I) can be prepared according to reactions outlined in Scheme 18.
  • Scheme 18 [0159] As shown in Scheme 18, compounds of the formula (IIIg), wherein R1, R3, R5, R10 and R11 are as described in formula (I), can be prepared from compounds of formula (IIIg-1), wherein R1, R3, R5, R10 and R11 are as described in formula (I), and X- is an anion, by treatment with a base, such as for example a hydroxide base or a carbonate base, for example sodium hydroxide or potassium carbonate, or an ion exchange resin.
  • a base such as for example a hydroxide base or a carbonate base, for example sodium hydroxide or potassium carbonate, or an ion exchange resin.
  • the anion X- is the conjugate base of an acid, such as an inorganic acid, for instance hydrochloric acid, hydrobromic acid, hydrogen fluoride, hydrogen iodide, sulfuric acid, or the like, or of an organic acid, such as a carboxylic acid or a sulfonic acid, for instance trifluoroacetic acid, or methane sulfonic acid, or para-toluene sulfonic acid.
  • an acid such as an inorganic acid, for instance hydrochloric acid, hydrobromic acid, hydrogen fluoride, hydrogen iodide, sulfuric acid, or the like
  • an organic acid such as a carboxylic acid or a sulfonic acid, for instance trifluoroacetic acid, or methane sulfonic acid, or para-toluene sulfonic acid.
  • a great number of such acids are known to a person skilled in the art.
  • Compounds of formula (IIIg-1), wherein R1, R3, R5, R10 and R11 are as described in formula (I), and X- is an anion can be made from compounds of the formula (IIIg-2), wherein R1, R3, R5, R10 and R11 are as described in formula (I), by treatment with an acid, such as the acids listed above.
  • the reaction can be done neat or in a solvent, for instance an organic solvent, such as in methanol, tetrahydrofuran, dichloromethane, trifluoromethylbenzene or in dioxane, or in an inorganic solvent, such as in water, or in a mixture of such solvents.
  • trans-cyclohexyldiamine) or 1,10-phenanthroline optionally in the presence of a base, such as sodium, potassium or cesium carbonate, or potassium phosphate, in inert solvents such as alcohols, amides, esters, ethers, nitriles and water, particularly preferred are methanol, ethanol, 2,2,2- trifluoroethanol, propanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, acetonitrile, ethyl acetate, water or mixtures thereof, at temperatures between 0-150°C, preferably at temperatures ranging from room temperature to the boiling point of the reaction mixture, optionally under microwave irradiation or pressurized conditions using an autoclave.
  • a base such as sodium, potassium or cesium carbonate, or potassium phosphate
  • H2NR11 is ammonia
  • ammonium hydroxide solution of ammonia in water
  • inert organic solvents such as ethyl acetate, dioxane or methanol
  • ammonia surrogates such as ammonium salts (for instance ammonium chloride).
  • compounds of the formula (IIIg-2), wherein R1, R3, R5, R10 and R11 are as described in formula (I), may be prepared by reacting compounds of the formula (IIIg-4), wherein R1, R3 and R5 are as defined for compounds of the formula (I), and in which Xa is a halogen, preferably Br or Cl (even more 109921
  • the anion X- is the conjugate base of an acid, such as an inorganic acid, for instance hydrochloric acid, hydrobromic acid, hydrogen fluoride, hydrogen iodide, sulfuric acid, or the like, or of an organic acid, such as a carboxylic acid or a sulfonic acid, for instance trifluoroacetic acid, or methane sulfonic acid, or para-toluene sulfonic acid.
  • an acid such as an inorganic acid, for instance hydrochloric acid, hydrobromic acid, hydrogen fluoride, hydrogen iodide, sulfuric acid, or the like
  • an organic acid such as a carboxylic acid or a sulfonic acid, for instance trifluoroacetic acid, or methane sulfonic acid, or para-toluene sulfonic acid.
  • a great number of such acids are known to a person skilled in the art.
  • Compounds of formula (IIIh-1), wherein R1, R3 and R5 are as described in formula (I) and X5 is a halogen, preferably Br, Cl or I (even more preferably Br or Cl), and X- is an anion, can be made from compounds of the formula (IIIh-2), wherein R1, R3 and R5 are as described in formula (I) and X5 is a halogen, preferably Br, Cl or I (even more preferably Br or Cl), by treatment with an acid, such as the acids listed above.
  • the reaction can be done neat or in a solvent, for instance an organic solvent, such as in methanol, tetrahydrofuran, dichloromethane, trifluoromethylbenzene or in dioxane, or in an inorganic solvent, such as in water, or in a mixture of such solvents.
  • a solvent for instance an organic solvent, such as in methanol, tetrahydrofuran, dichloromethane, trifluoromethylbenzene or in dioxane, or in an inorganic solvent, such as in water, or in a mixture of such solvents.
  • the reaction can be done in a temperature range between -100 °C and 200 °C, more commonly between 0 °C and 150 °C, such as, for example, at ambient temperature.
  • the reaction can be done neat, or in a solvent, for instance an organic solvent, such as dioxane or acetic acid, or a mixture thereof.
  • the reaction can be performed in the presence or in the absence of a drying agent, such as for example in the presence of molecular sieves, at a temperature between -100 °C and 200 °C, more commonly between 0 °C and 150 °C, such as, for example, at 80 °C.
  • a drying agent such as for example in the presence of molecular sieves
  • compounds of the formula (IIIf-1), wherein R1, R4 and R5 are as defined for compounds of the formula (I), or a salt thereof (IIIf-2), in which X- is an anion as defined above in Scheme 19 (compounds of the formula (IIIf-1) are representatives of compounds of the formula (IIIf) in which R 3 is CH3), can be made (Scheme 20) from compounds of the formula (IIIf-3), wherein R1, R4 and R5 are as defined for compounds of the formula (I), following the chemistry and conditions described above in Scheme 19 (transformation IIIh-2 into IIIh via IIIh-1).
  • compounds of the formula (IIIf-3), wherein R1 and R4 are as defined for compounds of the formula (I), and in which R 5 is C1-C3alkyl or C3-C4cycloalkyl can be prepared by reacting compounds of the formula (IIIf-4), wherein R1 is as defined for compounds of the formula (I) and R5 is C1-C3alkyl or C3- C4cycloalkyl, and RL is -NH2 or -OC1-C4alkyl, with hydrazine compounds of the formula (XII) or a tautomer thereof, or a salt thereof, wherein R4 is as defined for compounds of the formula (I), under analogous conditions 109921
  • Compounds of the formula (IIIf-4), wherein R1 is as defined for compounds of the formula (I) and R5 is C1-C3alkyl or C3-C4cycloalkyl, and R L is -NH2 or -OC1-C4alkyl, can be prepared by reacting compounds of the formula (IIIf-5), wherein R1 is as defined for compounds of the formula (I), with compounds of the formula (IIIf-6) or a tautomer thereof, or a salt thereof (such as a hydrohalide salt, preferably a hydrochloride or a hydrobromide salt, or a trifluoroacetic acid salt, or any other equivalent salt), wherein R 5 is C1-C3alkyl or C3- C4cycloalkyl, and R L is -NH2 or -OC1-C4alkyl, in the presence of a coupling reagent, such as, for example, HATU (1-[bis(dimethylamino)-methylene]
  • Such reactions can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, N,N-dimethylacetamide or N,N- dimethylformamide, in a temperature range of -100 to +300 °C, preferably between ambient temperature and 200 °C, and with or without the addition of a base, such as an inorganic base, for instance sodium, potassium or cesium carbonate, or an organic base, such as, for example, triethylamine, diisopropylethylamine or pyridine.
  • a solvent such as an organic solvent, for instance acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, N,N-dimethylacetamide or N,N- dimethylformamide, in a temperature range of -100 to +300 °
  • Such compounds of the formula (IIa-2-3) can be prepared (Scheme 21) by reacting compounds of the formula (IIa-2-2), wherein A and R2a are as described in formula (I), and in which Ra is C1-C6alkyl or benzyl, with fluorinating reagents such as diethylaminosulfur trifluoride (DAST), bis-(2-methoxy- ethyl)aminosulfur trifluoride (trade name: Deoxo-Fluor), difluoro(morpholino)sulfonium tetrafluoroborate (trade name: XtalFluor-M) or the combination of sulfuryl fluoride and tetramethylammonium fluoride (see Org.
  • DAST diethylaminosulfur trifluoride
  • bis-(2-methoxy- ethyl)aminosulfur trifluoride trade name: Deoxo-Fluor
  • Compounds of the formula (IIa-2-2), wherein A and R2a are as described in formula (I), and in which Ra is C1-C6alkyl or benzyl may be prepared by ozonolysis of alkene compounds of the formula (IIa-2-1), wherein A and R2a are as described in formula (I), and in which Ra is C1-C6alkyl or benzyl, using conditions (reaction with ozone, followed by reductive workup in the presence of dimethyl sulfide, zinc or triphenylphosphine) described for example in WO2012/035039.
  • compounds of the formula (IIa- 2-2) can be obtained by reacting compounds of the formula (IIa-2-1) with for example osmium tetroxide or potassium osmate(VI) dihydrate, preferably in catalytic amounts, and in presence of an oxidant like N- methylmorpholine N-oxide (NMO) or sodium periodate (NaIO4), in solvents such as tetrahydrofuran, 2- methyltetrahydrofuran, dioxane or water, or mixtures thereof, under conditions described for example in Chem. Rev.1980, 80: 187-213 or Adv. Synth. Catal.2002, 344: 421-433.
  • NMO N- methylmorpholine N-oxide
  • NaIO4 sodium periodate
  • compounds of the formula (IIa-2-5) are reacted with a :CF2 carbene species, generated from difluoromethylating agents such a difluoroacetate X c CF2COONa or a difluoromethyl(phosphonate) X c CF2P(O)(OEt)2 reagent, wherein X c can be chloro or bromo, in the presence of a base such as for example sodium or potassium carbonate, or sodium or potassium hydroxide, in an appropriate solvent like for example acetonitrile, ⁇ , ⁇ -dimethylformamide or N- methyl-2-pyrrolidone (NMP), optionally in a mixture with water, optionally in the presence of an additive (such 109921
  • difluoromethylating agents such as a difluoroacetate X c CF2COONa or a difluoro
  • compounds of the formula (IIa-2-5), wherein A and R2a are as described in formula (I), and in which Ra is C1-C6alkyl or benzyl can be prepared from compounds of the formula (IIa-2), wherein A and R2a are as described in formula (I) and R2b is a halogen, preferably Cl, Br or I (even more preferably Br or I), and in which Ra is C1-C6alkyl or benzyl, by a borylation (typically involving 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane; also known as bis(pinacolato)diborane)/oxidation (typically involving H2O2) sequence, under conditions known to a person skilled in the art, and detailed for example in Organic Letter
  • suitable bases are alkali metal or alkaline earth metal hydroxides, alkali metal or alkaline earth metal hydrides, alkali metal or alkaline earth metal amides, alkali metal or alkaline earth metal alkoxides, alkali metal or alkaline earth metal acetates, alkali metal or alkaline earth metal carbonates, alkali metal or alkaline earth metal dialkylamides or alkali metal or alkaline earth metal alkylsilylamides, alkylamines, alkylenediamines, free or N-alkylated saturated or unsaturated cycloalkylamines, basic heterocycles, ammonium hydroxides and carbocyclic amines.
  • Examples which may be mentioned are sodium hydroxide, sodium hydride, sodium amide, sodium methoxide, sodium acetate, sodium carbonate, potassium tert- butoxide, potassium hydroxide, potassium carbonate, potassium hydride, lithium diisopropylamide, potassium bis(trimethylsilyl)amide, calcium hydride, triethylamine, diisopropylethylamine, triethylenediamine, cyclohexylamine, N-cyclohexyl-N,N-dimethylamine, N,N-diethylaniline, pyridine, 4-(N,N- 109921
  • DBU 1,8- diazabicyclo[5.4.0]undec-7-ene
  • the reactants can be reacted with each other as such, i.e. without adding a solvent or diluent. In most cases, however, it is advantageous to add an inert solvent or diluent or a mixture of these. If the reaction is carried out in the presence of a base, bases which are employed in excess, such as triethylamine, pyridine, N- methylmorpholine or N,N-diethylaniline, may also act as solvents or diluents. [0188] The reactions are advantageously carried out in a temperature range from approximately -80°C to approximately +140°C, preferably from approximately -30°C to approximately +100°C, in many cases in the range between ambient temperature and approximately +80°C.
  • Salts of compounds of formula (I) can be prepared in a manner known per se. Thus, for example, acid addition salts of compounds of formula (I) are obtained by treatment with a suitable acid or a suitable ion exchanger reagent and salts with bases are obtained by treatment with a suitable base or with a suitable ion exchanger reagent.
  • Salts of compounds of formula (I) can be converted in the customary manner into the free compounds I, acid addition salts, for example, by treatment with a suitable basic compound or with a suitable ion exchanger reagent and salts with bases, for example, by treatment with a suitable acid or with a suitable ion exchanger reagent.
  • Salts of compounds of formula (I) can be converted in a manner known per se into other salts of compounds of formula (I), acid addition salts, for example, into other acid addition salts, for example by treatment of a salt of inorganic acid such as hydrochloride with a suitable metal salt such as a sodium, barium or silver salt, of an acid, for example with silver acetate, in a suitable solvent in which an inorganic salt which forms, for example silver chloride, is insoluble and thus precipitates from the reaction mixture.
  • a salt of inorganic acid such as hydrochloride
  • a suitable metal salt such as a sodium, barium or silver salt
  • an acid for example with silver acetate
  • an inorganic salt which forms, for example silver chloride is insoluble and thus precipitates from the reaction mixture.
  • the compounds of formula (I) which have salt-forming properties can be obtained in free form or in the form of salts.
  • the compounds of formula (I) and, where appropriate, the tautomers thereof, in each case in free form or in salt form, can be present in the form of one of the isomers which are possible or as a mixture of these, for example in the form of pure isomers, such as antipodes and/or diastereomers, or as isomer mixtures, such as enantiomer mixtures, for example racemates, diastereomer mixtures or racemate mixtures, depending on the number, absolute and relative configuration of asymmetric carbon atoms which occur in the molecule and/or depending on the configuration of non-aromatic double bonds which occur in the molecule; the invention relates to the pure isomers and also to all isomer mixtures which are possible and is to be understood in each case in this sense hereinabove and hereinbelow, even when stereochemical details are not mentioned specifically in each case.
  • Diastereomer mixtures or racemate mixtures of compounds of formula (I), in free form or in salt form, which can be obtained depending on which starting materials and procedures have been chosen can be separated in a known manner into the pure diastereomers or racemates on the basis of the physicochemical differences of the components, for example by fractional crystallization, distillation and/or chromatography.
  • Enantiomer mixtures such as racemates, which can be obtained in a similar manner can be resolved into the optical antipodes by known methods, for example by recrystallization from an optically active solvent, by chromatography on chiral adsorbents, for example high-performance liquid chromatography (HPLC) on acetyl cellulose, with the aid of suitable microorganisms, by cleavage with specific, immobilized enzymes, via the formation of inclusion compounds, for example using chiral crown ethers, where only one enantiomer is complexed, or by conversion into diastereomeric salts, for example by reacting a basic end-product racemate with an optically active acid, such as a carboxylic acid, for example camphor, tartaric or malic acid, or sulfonic acid, for example camphorsulfonic acid, and separating the diastereomer mixture which can be obtained in this manner, for example by fractional crystallization based on their differing solubilities,
  • N-oxides can be prepared by reacting a compound of the formula (I) with a suitable oxidizing agent, for example the H2O2/urea adduct in the presence of an acid anhydride, e.g. trifluoroacetic anhydride.
  • a suitable oxidizing agent for example the H2O2/urea adduct
  • an acid anhydride e.g. trifluoroacetic anhydride.
  • Tables A-1 to A-30 and Tables B-1 to B-5 can be prepared according to the methods described above.
  • the examples which follow are intended to illustrate the invention and show preferred compounds of formula (I), in the form of a compound of formula (I- A) and (I-B). 109921
  • Table A-1 provides 20 compounds A-1.001 to A-1.020 of formula I-A wherein R2a is CH3, A is CH, R2b is Cl, R1 is H and Q are as defined in table Z.
  • compound A-4.011 is [0203]
  • Table A-2 provides 20 compounds A-2.001 to A-2.020 of formula I-A wherein R2a is CH3, A is CH, R2b is Cl, R1 is CH3 and Q are as defined in table Z.
  • Table A-3 provides 20 compounds A-3.001 to A-3.020 of formula I-A wherein R2a is CH3, A is CH, R2b is Br, R1 is H and Q are as defined in table Z.
  • Table A-4 provides 20 compounds A-4.001 to A-4.020 of formula I-A wherein R2a is CH3, A is CH, R2b is Br, R1 is CH3 and Q are as defined in table Z.
  • Table A-5 provides 20 compounds A-5.001 to A-5.020 of formula I-A wherein R2a is CH3, A is CH, R2b is CF3, R1 is H and Q are as defined in table Z.
  • Table A-6 provides 20 compounds A-6.001 to A-6.020 of formula I-A wherein R2a is CH3, A is CH, R2b is CF3, R1 is CH3 and Q are as defined in table Z.
  • Table A-7 provides 20 compounds A-7.001 to A-7.020 of formula I-A wherein R2a is CH3, A is CH, R2b is CHF2, R1 is H and Q are as defined in table Z.
  • Table A-8 provides 20 compounds A-8.001 to A-8.020 of formula I-A wherein R2a is CH3, A is CH, R2b is CHF2, R1 is CH3 and Q are as defined in table Z.
  • Table A-9 provides 20 compounds A-9.001 to A-9.020 of formula I-A wherein R2a is CH3, A is CH, R2b is Cyp, R1 is H and Q are as defined in table Z.
  • Table A-10 provides 20 compounds A-10.001 to A-10.020 of formula I-A wherein R2a is CH3, A is CH, R 2b is Cyp, R 1 is CH 3 and Q are as defined in table Z.
  • Table A-11 provides 20 compounds A-11.001 to A-11.020 of formula I-A wherein R2a is CH2CH3, A is CH, R 2b is Cl, R1 is H and Q are as defined in table Z.
  • Table A-12 provides 20 compounds A-12.001 to A-12.020 of formula I-A wherein R2a is CH2CH3, A is CH, R 2b is Cl, R1 is CH3 and Q are as defined in table Z.
  • Table A-13 provides 20 compounds A-13.001 to A-13.020 of formula I-A wherein R2a is CH2CH3, A is CH, R 2b is Br, R1 is H and Q are as defined in table Z.
  • Table A-14 provides 20 compounds A-14.001 to A-14.020 of formula I-A wherein R2a is CH2CH3, A is CH, R 2b is Br, R1 is CH3 and Q are as defined in table Z. 109921
  • Table A-15 provides 20 compounds A-15.001 to A-15.020 of formula I-A wherein R2a is CH2CH3, A is CH, R 2b is CF3, R1 is H and Q are as defined in table Z.
  • Table A-16 provides 20 compounds A-16.001 to A-16.020 of formula I-A wherein R2a is CH2CH3, A is CH, R 2b is CF3, R1 is CH3 and Q are as defined in table Z.
  • Table A-17 provides 20 compounds A-17.001 to A-17.020 of formula I-A wherein R2a is CH2CH3, A is CH, R 2b is CHF2, R1 is H and Q are as defined in table Z.
  • Table A-18 provides 20 compounds A-18.001 to A-18.020 of formula I-A wherein R2a is CH2CH3, A is CH, R 2b is CHF2, R1 is CH3 and Q are as defined in table Z.
  • Table A-19 provides 20 compounds A-19.001 to A-19.020 of formula I-A wherein R2a is CH2CH3, A is CH, R 2b is Cyp, R1 is H and Q are as defined in table Z.
  • Table A-20 provides 20 compounds A-20.001 to A-20.020 of formula I-A wherein R2a is CH2CH3, A is CH, R 2b is Cyp, R1 is CH3 and Q are as defined in table Z.
  • Table A-21 provides 20 compounds A-21.001 to A-21.020 of formula I-A wherein R2a is Cyp, A is CH, R 2b is Cl, R1 is H and Q are as defined in table Z.
  • Table A-22 provides 20 compounds A-22.001 to A-22.020 of formula I-A wherein R2a is Cyp, A is CH, R 2b is Cl, R 1 is CH 3 and Q are as defined in table Z.
  • Table A-23 provides 20 compounds A-23.001 to A-23.020 of formula I-A wherein R2a is Cyp, A is CH, R 2b is Br, R1 is H and Q are as defined in table Z.
  • Table A-24 provides 20 compounds A-24.001 to A-24.020 of formula I-A wherein R2a is Cyp, A is CH, R 2b is Br, R1 is CH3 and Q are as defined in table Z.
  • Table A-25 provides 20 compounds A-25.001 to A-25.020 of formula I-A wherein R2a is Cyp, A is CH, R 2b is CF3, R1 is H and Q are as defined in table Z.
  • Table A-26 provides 20 compounds A-26.001 to A-26.020 of formula I-A wherein R2a is Cyp, A is CH, R 2b is CF3, R1 is CH3 and Q are as defined in table Z.
  • Table A-27 provides 20 compounds A-27.001 to A-27.020 of formula I-A wherein R2a is Cyp, A is CH, R 2b is CHF 2 , R 1 is H and Q are as defined in table Z.
  • Table A-28 provides 20 compounds A-28.001 to A-28.020 of formula I-A wherein R2a is Cyp, A is CH, R 2b is CHF2, R1 is CH3 and Q are as defined in table Z.
  • Table A-29 provides 20 compounds A-29.001 to A-29.020 of formula I-A wherein R2a is Cyp, A is CH, R 2b is Cyp, R1 is H and Q are as defined in table Z.
  • Table A-30 provides 20 compounds A-30.001 to A-30.020 of formula I-A wherein R2a is Cyp, A is CH, R 2b is Cyp, R1 is CH3 and Q are as defined in table Z.
  • Table Z Substituent definitions of Q 109921
  • Table B-1 provides 19 compounds B-1.001 to B-1.019 of formula I-B wherein R2a is Cyp, A is CH, R2b is CF3, R 1 is H, R 5 is CH3 and R 4x are as defined in table Z1.
  • Table B-2 provides 19 compounds B-2.001 to B-2.019 of formula I-B wherein R2a is Cyp, A is CH, R2b is CF3, R 1 is H, R 5 is CH2CH3 and R 4x are as defined in table Z1.
  • Table B-3 provides 19 compounds B-3.001 to B-3.019 of formula I-B wherein R2a is Cyp, A is CH, R2b is CF 3 , R 1 is H, R 5 is cyclopropyl and R 4x are as defined in table Z1.
  • Table B-4 provides 19 compounds B-4.001 to B-4.019 of formula I-B wherein R2a is Cyp, A is CH, R2b is CF3, R 1 is H, R 5 is OCH3 and R 4x are as defined in table Z1.
  • Table B-5 provides 19 compounds B-5.001 to B-5.019 of formula I-B wherein R2a is Cyp, A is CH, R2b is CF3, R 1 is H, R 5 is Br and R 4x are as defined in table Z1.
  • Table Z1 Substituent definitions of R 4x I ndex R4x Index R4x Index R4x 109921
  • a compound of formula IIa-1 as shown below, where A, R2a and R2b are as defined for compounds of formula (I); for instance where A, R2a and R2b are as described in Tables A-1 to A-30 and Tables B-1 to B-5; in particular where A is CH, R2a is cyclopropyl, and R2b is chloro, bromo, difluoromethyl, difluoromethoxy or trifluoromethyl, preferably difluoromethyl, difluoromethoxy or trifluoromethyl; more particularly where A is CH, R2a is cyclopropyl, and R2b is difluoromethyl, difluoromethoxy, or trifluoromethyl, such as R 2b is trifluoromethyl; ⁇ A compound of formula IIa-2, as shown below, where A, R2a and R2b are as defined for compounds of formula (I), and Ra is C1-C6alkyl or benzyl, preferably Ra is methyl, eth
  • the compounds of formula (I) according to the invention are preventively and/or curatively valuable ac-tive ingredients in the field of pest control, even at low rates of application, which have a very favorable biocidal spectrum and are well tolerated by warm-blooded species, fish and plants.
  • 83176 FF according to the invention act against all or individual developmental stages of normally sensitive, but also resistant, animal pests, such as insects or representatives of the order Acarina.
  • the insecticidal or acaricidal activity of the active ingredients according to the invention can manifest itself directly, i.e.
  • Examples of the above mentioned animal pests are: ⁇ from the order Acarina, for example, Acalitus spp., Aculus spp., Acaricalus spp., Aceria spp., Acarus siro, Amblyomma spp., Argas spp., Boophilus spp., Brevipalpus spp., Bryobia spp., Calipitrimerus spp., Chorioptes spp., Dermanyssus gallinae, Dermatophagoides spp., Eotetranychus spp., Eriophyes spp., Hemitarsonemus spp., Hyalomma spp., Ixodes spp.
  • Acarina for example, Acalitus spp., Aculus spp., Acaricalus spp., Aceria spp., Acarus siro, Amblyomma
  • ⁇ from the order Anoplura for example, Haematopinus spp., Linognathus spp., Pediculus spp., Pemphigus spp. and Phylloxera spp.
  • ⁇ from the order Coleoptera for example, Agriotes spp., Amphimallon majale, Anomala orientalis, Anthonomus spp., Aphodius spp., Astylus atromaculatus, Ataenius spp., Atomaria linearis, Chaetocnema tibialis, Cerotoma spp., Conoderus spp., Cosmopolites spp., Cotinis nitida, Curculio spp., Cyclocephala spp., Dermestes spp., Diabrotica spp., Diloboderus abderus, Epilachna s
  • Trogoderma spp. ⁇ from the order Diptera, for example, Aedes spp., Anopheles spp., Antherigona soccata, Bactrocea oleae, Bibio hortulanus, Bradysia spp., Calliphora erythrocephala, Ceratitis spp., Chrysomyia spp., Culex spp., Cuterebra spp., Dacus spp., Delia spp., Drosophila melanogaster, Fannia spp., Gastrophilus spp., Geomyza tripunctata, Glossina spp., Hypoderma spp., Hyppobosca spp., Liriomyza spp., Lucilia spp., Melanagromyza spp., Musca spp., Oestrus spp., Orseolia spp., O
  • ⁇ from the order Hemiptera for example, Acanthocoris scabrator, Acrosternum spp., Adelphocoris lineolatus, Aleurodes spp., Amblypelta nitida, Bathycoelia thalassina, Blissus spp., Cimex spp., Clavigralla tomentosicollis, Creontiades spp., Distantiella theobroma, Dichelops furcatus, Dysdercus spp., Edessa spp., Euchistus spp., Eurydema pulchrum, Eurygaster spp., Halyomorpha halys, Horcias nobilellus, Leptocorisa spp., Lygus spp., Margarodes spp., Murgantia histrionic, Neomegalotomus spp., Nesidiocor
  • Thyanta spp Triatoma spp., Vatiga illudens, Acyrthosium pisum, Adalges spp., Agalliana ensigera, Agonoscena targionii, Aleurodicus spp., Aleurocanthus spp., Aleurolobus barodensis, Aleurothrixus floccosus, Aleyrodes brassicae, Amarasca biguttula, Amritodus atkinsoni, Aonidiella spp., Aphididae, Aphis spp., Aspidiotus spp., Aulacorthum solani, Bactericera cockerelli, Bemisia spp., Brachycaudus spp., Brevicoryne brassicae, Cacopsylla spp., Cavariella aegopodii Scop., Ceroplaster spp., Chrysom
  • Vespa spp. ⁇ from the order Isoptera, for example, Coptotermes spp., Corniternes cumulans, Incisitermes spp., Macrotermes spp., Mastotermes spp., Microtermes spp., Reticulitermes spp.; Solenopsis geminata; ⁇ from the order Lepidoptera, for example, Acleris spp., Adoxophyes spp., Aegeria spp., Agrotis spp., Alabama argillaceae, Amylois spp., Anticarsia gemmatalis, Archips spp., Argyresthia spp., Argyrotaenia spp., Autographa spp., Bucculatrix thurberiella, Busseola fusca, Cadra cautella, Carposina nipponensis, Chilo spp., Choristoneura spp., Chry
  • ⁇ from the order Orthoptera for example, Blatta spp., Blattella spp., Gryllotalpa spp., Leucophaea maderae, Locusta spp., Neocurtilla hexadactyla, Periplaneta spp. , Scapteriscus spp., and Schistocerca spp.
  • ⁇ from the order Psocoptera for example, Liposcelis spp.
  • Siphonaptera for example, Ceratophyllus spp., Ctenocephalides spp.
  • Thysanoptera for example, Calliothrips phaseoli, Frankliniella spp., Heliothrips spp., Hercinothrips spp., Parthenothrips spp., Scirtothrips aurantii, Sericothrips variabilis, Taeniothrips spp., Thrips spp; ⁇ from the order Thysanura, for example, Lepisma saccharina.
  • the invention may also relate to a method of controlling damage to plant and parts thereof by plant parasitic nematodes (Endoparasitic-, Semiendoparasitic- and Ectoparasitic nematodes), especially plant parasitic nematodes such as root knot nematodes, Meloidogyne hapla, Meloidogyne incognita, Meloidogyne javanica, Meloidogyne arenaria and other Meloidogyne species; cyst-forming nematodes, Globodera rostochiensis and other Globodera species; Heterodera avenae, Heterodera glycines, Heterodera schachtii, Heterodera trifolii, and other Heterodera species; Seed gall nematodes, Anguina species; Stem and foliar nematodes, Aphelenchoides species; Sting nematodes, Bel
  • the compounds of the invention may also have activity against the molluscs.
  • Examples of which include, for example, Ampullariidae; Arion (A. ater, A. circumscriptus, A. hortensis, A. rufus); Bradybaenidae (Bradybaena fruticum); Cepaea (C. hortensis, C. nemoralis); Ochlodina; Deroceras (D. agrestis, D. empiricorum, D. laeve, D. reticulatum); Discus (D. rotundatus); Euomphalia; Galba (G.
  • the active ingredients according to the invention can be used for controlling, i.e.
  • pests of the abovementioned type which occur in particular on plants, especially on useful plants and ornamentals in agriculture, in horticulture and in forests, or on organs, such as fruits, flowers, foliage, stalks, tubers or roots, of such plants, and in some cases even plant organs which are formed at a later point in time remain protected against these pests.
  • Suitable target crops are, in particular, cereals, such as wheat, barley, rye, oats, rice, maize or sorghum; beet, such as sugar or fodder beet; fruit, for example pomaceous fruit, stone fruit or soft fruit, such as apples, pears, plums, peaches, almonds, cherries or berries, for example strawberries, raspberries or blackberries; leguminous crops, such as beans, lentils, peas or soya; oil crops, such as oilseed rape, mustard, poppies, olives, sunflowers, coco-nut, castor, cocoa or ground nuts; cucurbits, such as pumpkins, cucumbers or melons; fibre plants, such as cotton, flax, hemp or jute; citrus fruit, such as oranges, lemons, grapefruit or tangerines; vegetables, such as spinach, lettuce, asparagus, cabbages, carrots, onions, tomatoes, potatoes or bell peppers; Lauraceae, such as avocado, Cinnamonium or camphor; and
  • compositions and/or methods of the present invention may be also used on any ornamental and/or vegetable crops, including flowers, shrubs, broad-leaved trees and evergreens.
  • the invention may be used on any of the following ornamental species: Ageratum spp., Alonsoa spp., Anemone spp., Anisodontea capsenisis, Anthemis spp., Antirrhinum spp., Aster spp., Begonia spp. (e.g. B. elatior, B. semperflorens, B. tubéreux), Bougainvillea spp., Brachycome spp., Brassica spp.
  • Coreopsis spp. Crassula coccinea, Cuphea ignea, Dahlia spp., Delphinium spp., Dicentra spectabilis, Dorotheantus spp., Eustoma grandiflorum, Forsythia spp., Fuchsia spp., Geranium gnaphalium, Gerbera spp., Gomphrena globosa, Heliotropium spp., Helianthus spp., Hibiscus spp., Hortensia spp., Hydrangea spp., Hypoestes phyllostachya, Impatiens spp. (I.
  • Iresines spp. Kalanchoe spp., Lantana camara, Lavatera trimestris, Leonotis leonurus, Lilium spp., Mesembryanthemum spp., Mimulus spp., Monarda spp., Nemesia spp., Tagetes spp., Dianthus spp. (carnation), Canna spp., Oxalis spp., Bellis spp., Pelargonium spp. (P. peltatum, P. Zonale), Viola spp.
  • the invention may be used on any of the following vegetable species: Allium spp. (A. sativum, A.. cepa, A. oschaninii, A. Porrum, A. ascalonicum, A.
  • Daucus carota Foeniculum vulgare, Hypericum spp., Lactuca sativa, Lycopersicon spp. (L. esculentum, L. lycopersicum), Mentha spp., Ocimum basilicum, Petroselinum crispum, Phaseolus spp. (P. vulgaris, P. coccineus), Pisum sativum, Raphanus sativus, Rheum rhaponticum, Rosemarinus spp., Salvia spp., Scorzonera hispanica, Solanum melongena, Spinacea oleracea, Valerianella spp. (V. locusta, V.
  • Preferred ornamental species include African violet, Begonia, Dahlia, Gerbera, Hydrangea, Verbena, Rosa, Kalanchoe, Poinsettia, Aster, Centaurea, Coreopsis, Delphinium, Monarda, Phlox, Rudbeckia, Sedum, Petunia, Viola, Impatiens, Geranium, Chrysanthemum, Ranunculus, Fuchsia, Salvia, Hortensia, rosemary, sage, St. Johnswort, mint, sweet pepper, tomato and cucumber.
  • the active ingredients according to the invention are especially suitable for controlling Aphis craccivora, Diabrotica balteata, Heliothis virescens, Myzus persicae, Plutella xylostella and Spodoptera littoralis in cotton, vegetable, maize, rice and soya crops.
  • the active ingredients according to the invention are further especially suitable for controlling Mamestra (preferably in vegetables), Cydia pomonella (preferably in apples), Empoasca (preferably in vegetables, vineyards), Leptinotarsa (preferably in potatos) and Chilo supressalis (preferably in rice).
  • the compounds of formula (I) are particularly suitable for control of ⁇ a pest of the order Hemiptera, for example, one or more of the species Bemisia tabaci, Aphis craccivora, Myzus persicae, Rhopalosiphum padi, Nilaparvata lugens, and Euschistus heros (preferably in sunflower, vegetables, soybeans, and sugarcane);
  • ⁇ a pest of the order Lepidoptera for example, one or more of the species Spodoptera littoralis, Spodoptera frugiperda, Plutella xylostella, Cnaphalocrocis medinalis, Cydia pomonella, Chrysodeixis includes, Chilo suppressalis, Elasmopalpus lignosellus, Pseudoplusia includens, and Tuta a bsoluta (preferably in vegetables and corn);
  • Toxins that can be expressed by such transgenic plants include, for example, insecticidal proteins, for example insecticidal proteins from Bacillus cereus or Bacillus popilliae; or insecticidal proteins from Bacillus thuringiensis, such as ⁇ -endotoxins, e.g.
  • Vip vegetative insecticidal proteins
  • Vip1 Vip1, Vip2, Vip3 or Vip3A
  • insecticidal proteins of bacteria colonising nematodes for example Photorhabdus spp.
  • Xenorhabdus spp. such as Photorhabdus luminescens, Xenorhabdus nematophilus
  • toxins produced by animals such as scorpion toxins, arachnid toxins, wasp toxins and other insect-specific neurotoxins
  • toxins produced by fungi such as Streptomycetes toxins, plant lectins, such as pea lectins, barley lectins or snowdrop lectins
  • agglutinins proteinase inhibitors, such as trypsin inhibitors, serine protease inhibitors, patatin, cystatin, papain inhibitors
  • steroid metabolism enzymes such as 3-hydroxysteroidoxidase, ecdysteroid-UDP-glycosyl-transferase, cholesterol oxidases, ecd
  • ⁇ -endotoxins for example Cry1Ab, Cry1Ac, Cry1F, Cry1FA 2 , Cry2Ab, Cry3A, Cry3Bb1 or Cry9C, or vegetative insecticidal proteins (Vip), for example Vip1, Vip2, Vip3 or Vip3A
  • Vip vegetative insecticidal proteins
  • Hybrid toxins are produced recombinantly by a new combination of different domains of those proteins (see, for example, WO 02/15701).
  • Truncated toxins for example a truncated Cry1Ab, are known.
  • modified toxins one or more amino acids of the naturally occurring toxin are replaced.
  • preferably non-naturally present protease recognition sequences are inserted into the toxin, such as, for example, in the case of Cry3A055, a cathepsin-G-recognition sequence is inserted into a Cry3A toxin (see WO 03/018810).
  • Examples of such toxins or transgenic plants capable of synthesising such toxins are disclosed, for example, in EP-A-0 374 753, WO 93/07278, WO 95/34656, EP-A-0 427 529, EP-A-451 878 and WO 03/052073.
  • transgenic plants are generally known to the person skilled in the art and are described, for example, in the publications mentioned above.
  • CryI-type deoxyribonucleic acids and their preparation are known, for example, from WO 95/34656, EP-A-0367474, EP-A-0401979 and WO 90/13651.
  • the toxin contained in the transgenic plants imparts to the plants tolerance to harmful insects.
  • Such insects can occur in any taxonomic group of insects, but are especially commonly found in the beetles (Coleoptera), two-winged insects (Diptera) and moths (Lepidoptera).
  • Transgenic plants containing one or more genes that code for an insecticidal resistance and express one or more toxins are known and some of them are commercially available. Examples of such plants are: YieldGard® (maize variety that expresses a Cry1Ab toxin); YieldGard Rootworm® (maize variety that expresses a Cry3Bb1 toxin); YieldGard Plus® (maize variety that expresses a Cry1Ab and a Cry3Bb1 toxin); Starlink® (maize variety that expresses a Cry9C toxin); Herculex I® (maize variety that expresses a Cry1FA 2 toxin and the enzyme phosphinothricine N-acetyltransferase (PAT) to achieve tolerance to the herbicide glufosinate ammonium); NuCOTN 33B® (cotton variety that expresses a Cry1Ac toxin); Bollgard I® (cotton variety
  • transgenic crops are: 1. Bt11 Maize from Syngenta Seeds SAS, Chemin de l'Hobit 27, F-31790 St. Sauveur, France, registration number C/FR/96/05/10. Genetically modified Zea mays which has been rendered resistant to attack by the European corn borer (Ostrinia nubilalis and Sesamia nonagrioides) by transgenic expression of a truncated Cry1Ab toxin. Bt11 maize also transgenically expresses the enzyme PAT to achieve tolerance to the herbicide glufosinate ammonium. 2 . Bt176 Maize from Syngenta Seeds SAS, Chemin de l'Hobit 27, F-31790 St.
  • This toxin is Cry3A055 modified by insertion of a cathepsin-G- protease recognition sequence.
  • the preparation of such transgenic maize plants is described in WO 03/018810.
  • MON 863 expresses a Cry3Bb1 toxin and has resistance to certain Coleoptera insects.
  • NK603 ⁇ MON 810 Maize t ransgenically expresses the protein CP4 EPSPS, obtained from Agrobacterium sp. strain CP4, which imparts tolerance to the herbicide Roundup® (contains glyphosate), and also a Cry1Ab toxin obtained f rom Bacillus thuringiensis subsp. kurstaki which brings about tolerance to certain Lepidoptera, include the European corn borer. [0260] Transgenic crops of insect-resistant plants are also described in BATS (Zentrum für Bioschreib und Nachhaltmaschine, Zentrum BATS, Clarastrasse 13, 4058 Basel, Switzerland) Report 2003, (http://bats.ch).
  • crops is to be understood as including also crop plants which have been so transformed by the use of recombinant DNA techniques that they are capable of synthesising antipathogenic substances 109921
  • PRPs pathogenesis-related proteins
  • Examples of such antipathogenic substances and transgenic plants capable of synthesising such antipathogenic substances are known, for example, from EP-A-0392225, WO 95/33818 and EP-A-0353 191.
  • the methods of producing such transgenic plants are generally known to the person skilled in the art and are described, for example, in the publications mentioned above.
  • Crops may also be modified for enhanced resistance to fungal (for example Fusarium, Anthracnose, or Phytophthora), bacterial (for example Pseudomonas) or viral (for example potato leafroll virus, tomato spotted wilt virus, cucumber mosaic virus) pathogens.
  • Crops also include those that have enhanced resistance to nematodes, such as the soybean cyst nematode.
  • Crops that are tolerant to abiotic stress include those that have enhanced tolerance to drought, high salt, high temperature, chill, frost, or light radiation, for example through expression of NF-YB or other proteins known in the art.
  • Antipathogenic substances which can be expressed by such transgenic plants include, for example, ion channel blockers, such as blockers for sodium and calcium channels, for example the viral KP1, KP4 or KP6 toxins; stilbene synthases; bibenzyl synthases; chitinases; glucanases; the so-called "pathogenesis- related proteins" (PRPs; see e.g. EP-A-0392225); antipathogenic substances produced by microorganisms, for example peptide antibiotics or heterocyclic antibiotics (see e.g. WO 95/33818) or protein or polypeptide factors involved in plant pathogen defence (so-called "plant disease resistance genes", as described in WO 03/000906).
  • ion channel blockers such as blockers for sodium and calcium channels
  • the viral KP1, KP4 or KP6 toxins stilbene synthases; bibenzyl synthases; chitinases; glucanases; the so-called "pathogenesis- related
  • compositions according to the invention are the protection of stored goods and store rooms and the protection of raw materials, such as wood, textiles, floor coverings or buildings, and also in the hygiene sector, especially the protection of humans, domestic animals and productive livestock against pests of the mentioned type.
  • the present invention provides a compound of the first aspect for use in therapy.
  • the present invention provides a compound of the first aspect, for use in controlling parasites in or on an animal.
  • the present invention further provides a compound of the first aspect, for use in controlling ectoparasites on an animal.
  • present invention further provides a compound of the first aspect, for use in preventing and/or treating diseases transmitted by ectoparasites.
  • the present invention provides the use of a compound of the first aspect, for the manufacture of a medicament for controlling parasites in or on an animal.
  • the present invention further provides the use of a compound of the first aspect, for the manufacture of a medicament for controlling ectoparasites on an animal.
  • the present invention further provides the use of a compound of the first aspect, for the manufacture of a medicament for preventing and/or treating diseases transmitted by ectoparasites.
  • the present invention provides the use of a compound of the first aspect, in controlling parasites in or on an animal.
  • the present invention further provides the use of a compound of the first aspect , in controlling ectoparasites on an animal.
  • controlling when used in context of parasites in or on an animal refers to reducing the number of pests or parasites, eliminating pests or parasites and/or preventing further pest or parasite infestation.
  • treating when used in context of parasites in or on an animal refers to restraining, slowing, stopping or reversing the progression or severity of an existing symptom or disease.
  • preventing when used in context of parasites in or on an animal refers to the avoidance of a symptom or disease developing in the animal.
  • animal when used in context of parasites in or on an animal may refer to a mammal and a non-mammal, such as a bird or fish. In the case of a mammal, it may be a human or non-human mammal.
  • Non-human mammals include, but are not limited to, livestock animals and companion animals.
  • Livestock animals include, but are not limited to, cattle, camelids, pigs, sheep, goats and horses.
  • Companion animals include, but are not limited to, dogs, cats and rabbits.
  • a "parasite” is a pest which lives in or on the host animal and benefits by deriving nutrients at the host animal's expense.
  • An "endoparasite” is a parasite which lives in the host animal.
  • Ectoparasite is a parasite which lives on the host animal. Ectoparasites include, but are not limited to, acari, insects and crustaceans (e.g. sea lice).
  • the Acari (or Acarina) sub-class comprises ticks and mites.
  • Ticks include, but are not limited to, members of the following genera: Rhipicaphalus, for example, Rhipicaphalus (Boophilus) microplus and Rhipicephalus sanguineus; Amblyomrna; Dermacentor; Haemaphysalis; Hyalomma; Ixodes; Rhipicentor; Margaropus; Argas; Otobius; and Ornithodoros.
  • Mites include, but are not limited to, members of the following genera: Chorioptes, for example Chorioptes bovis; Psoroptes, for example Psoroptesovis; Cheyletiella; Dermanyssus; for example Dermanyssusgallinae; Ortnithonyssus; Demodex, for example Demodexcanis; Sarcoptes, for example Sarcoptes scabiei; and Psorergates.
  • Insects include, but are not limited to, members of the orders: Siphonaptera, Diptera, Phthiraptera, Lepidoptera, Coleoptera and Homoptera.
  • Members of the Siphonaptera order include, but are not limited to, Ctenocephalides felis and Ctenocephatides canis.
  • Members of the Diptera order include, but are not limited to, Musca spp.; bot fly, for example Gasterophilus intestinalis and Oestrus ovis; biting flies; horse flies, for example Haematopota spp. and Tabunus spp.; haematobia, for example haematobia irritans; Stomoxys; Lucilia; midges; and mosquitoes.
  • Members of the Phthiraptera class include, but are not limited to, blood sucking lice and chewing lice, for example Bovicola ovis and Bovicola bovis.
  • the term "effective amount" when used in context of parasites in or on an animal refers to the amount or dose of the compound of the invention, or a salt thereof, which, upon single or multiple dose administration to the animal, provides the desired effect in or on the animal.
  • the effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances.
  • the compounds of the invention may be administered to the animal by any route which has the desired effect including, but not limited to topically, orally, parenterally ' and subcutaneously. Topical administration is preferred.
  • Formulations suitable for topical administration include, for example, solutions, emulsions and suspensions and may take the form of a pour-on, spot-on, spray-on, spray race or dip.
  • the compounds of the invention may be administered by means of an ear tag or collar.
  • Salt forms of the compounds of the invention include both pharmaceutically acceptable salts and veterinary acceptable salts, which can be different to agrochemically acceptable salts.
  • Pharmaceutically and veterinary acceptable salts and common methodology for preparing them are well known in the art. See, for example, Gould, P.L., "Salt selection for basic drugs", International Journal of Pharmaceutics, 33: 201 -217 (1986); Bastin, R.J., et al.
  • the present invention also provides a method for controlling pests (such as mosquitoes and other disease vectors; see also http://www.who.int/malaria/vector_control/irs/en/).
  • the method for controlling pests comprises applying the compositions of the invention to the target pests, to their locus or to a surface or substrate by brushing, rolling, spraying, spreading or dipping.
  • an IRS indoor residual spraying
  • a surface such as a wall, ceiling or floor surface is contemplated by the method of the invention.
  • the method for controlling such pests comprises applying a pesticidally effective amount of the compositions of the invention to the target pests, to their locus, or to a surface or substrate so as to provide effective residual pesticidal activity on the surface or substrate.
  • a pesticidally effective amount of the compositions of the invention to the target pests, to their locus, or to a surface or substrate so as to provide effective residual pesticidal activity on the surface or substrate.
  • Such application may be made by brushing, rolling, spraying, spreading or dipping the pesticidal composition of the invention.
  • an IRS application of a surface such as a wall, ceiling or floor surface is contemplated by the method of the invention so as to provide effective residual pesticidal activity on the surface.
  • a substrate such as a fabric material in the form of (or which can be used in the manufacture of) netting, clothing, bedding, curtains and tents.
  • Substrates including non-woven, fabrics or netting to be treated may be made of natural fibres such as cotton, raffia, jute, flax, sisal, hessian, or wool, or synthetic fibres such as polyamide, polyester, polypropylene, polyacrylonitrile or the like.
  • the polyesters are particularly suitable.
  • 83176 FF treatment are known, e.g. WO 2008/151984, WO 2003/034823, US 5631072, WO 2005/64072, WO 2006/128870, EP 1724392, WO 2005/113886 or WO 2007/090739.
  • Further areas of use of the compositions according to the invention are the field of tree injection/trunk treatment for all ornamental trees as well all sort of fruit and nut trees.
  • the compounds according to the present invention are especially suitable against wood-boring insects from the order Lepidoptera as mentioned above and from the order Coleoptera, especially against woodborers listed in the following tables A and B: Table A.
  • the present invention may be used to control insect pests at various stages of their life cycle, including eggs, larvae, nymphs and adults.
  • the present invention may be used to control insect pests that feed on the roots of turfgrass including white grubs (such as Cyclocephala spp. (e.g. masked chafer, C. lurida), Rhizotrogus spp. (e.g. European chafer, R. majalis), Cotinus spp. (e.g. Green June beetle, C. nitida), Popillia spp. (e.g. Japanese beetle, P. japonica), Phyllophaga spp. (e.g.
  • Ataenius spp. e.g. Black turfgrass ataenius, A. spretulus
  • Maladera spp. e.g. Asiatic garden beetle, M. castanea
  • Tomarus spp. ground pearls (Margarodes spp.)
  • mole crickets tawny, southern, and short-winged; Scapteriscus spp., Gryllotalpa africana) and leatherjackets (European crane fly, Tipula spp.).
  • the present invention may also be used to control insect pests of turfgrass that are thatch dwelling, including armyworms (such as fall armyworm Spodoptera frugiperda, and common armyworm Pseudaletia unipuncta), cutworms, billbugs (Sphenophorus spp., such as S. venatus verstitus and S. parvulus), and sod webworms (such as Crambus spp. and the tropical sod webworm, Herpetogramma phaeopteralis).
  • armyworms such as fall armyworm Spodoptera frugiperda, and common armyworm Pseudaletia unipuncta
  • cutworms such as S. venatus verstitus and S. parvulus
  • sod webworms such as Crambus spp. and the tropical sod webworm, Herpetogramma phaeopteralis.
  • the present invention may also be used to control insect pests of turfgrass that live above the ground and feed on the turfgrass leaves, including chinch bugs (such as southern chinch bugs, Blissus insularis), Bermudagrass mite (Eriophyes cynodoniensis), rhodesgrass mealybug (Antonina graminis), two- lined spittlebug (Propsapia bicincta), leafhoppers, cutworms (Noctuidae family), and greenbugs.
  • the present invention may also be used to control other pests of turfgrass such as red imported fire ants (Solenopsis invicta) that create ant mounds in turf.
  • compositions according to the invention are active against ectoparasites such as hard ticks, soft ticks, mange mites, harvest mites, flies (biting and licking), parasitic fly larvae, lice, hair lice, bird lice and fleas.
  • ectoparasites such as hard ticks, soft ticks, mange mites, harvest mites, flies (biting and licking), parasitic fly larvae, lice, hair lice, bird lice and fleas.
  • Examples of such parasites are: ⁇ Of the order Anoplurida: Haematopinus spp., Linognathus spp., Pediculus spp., Phtirus spp., Solenopotes spp..
  • Nematocerina and Brachycerina for example Aedes spp., Anopheles spp., Culex spp., Simulium spp., Eusimulium spp., Phlebotomus spp., Lutzomyia spp., Culicoides spp., Chrysops spp., Hybomitra spp., Atylotus spp., Tabanus spp., Haematopota spp., Philipomyia spp., Braula spp., Musca spp., Hydrotaea spp., Stomoxys spp., Haematobia spp., Morellia spp., Fannia spp., Glossina spp., Calliphora spp., Glossina spp., Chrysomyia spppp
  • Siphonapta for example Pulex spp., Ctenocephalides spp., Xenopsylla spp., Ceratophyllus spp.. ⁇
  • Heteropterida for example Cimex spp., Triatoma spp., Rhodnius spp., Panstrongylus spp.. 109921
  • Blattarida for example Blatta orientalis, Periplaneta americana, Blattela germanica and Supella spp..
  • Actinedida Prostigmata
  • Acaridida Acaridida
  • Acarapis spp. Cheyletiella spp., Ornitrocheyletia spp., Myobia spp., Psorergatesspp., Demodex spp., Trombicula spp., Listrophorus spp., Acarus spp., Tyrophagus spp., Caloglyphus spp., Hypodectes spp., Pterolichus spp., Psoroptes spp., Chorioptes spp., Otodectes spp., Sarcoptes spp., Notoedres spp., Knemidocoptes spp., Cytodites spp.
  • compositions according to the invention are also suitable for protecting against insect infestation in the case of materials such as wood, textiles, plastics, adhesives, glues, paints, paper and card, leather, floor coverings and buildings.
  • compositions according to the invention can be used, for example, against the following pests : beetles such as Hylotrupes bajulus, Chlorophorus pilosis, Anobium punctatum, Xestobium rufovillosum, Ptilinuspecticornis, Dendrobium pertinex, Ernobius mollis, Priobium carpini, Lyctus brunneus, Lyctus africanus, Lyctus planicollis, Lyctus linearis, Lyctus pubescens, Trogoxylon aequale, Minthesrugicollis, Xyleborus spp., Tryptodendron spp., Apate monachus, Bostrychus capucins, Heterobostrychus brunneus, Sinoxylon spp., and Dinoderus minutus, and also hymenopterans such as Sirex juvencus, Urocerus gigas, Urocer
  • the compounds of formulae I, and I’a, or salts thereof, are especially suitable for controlling one or more pests selected from the family: Noctuidae, Plutellidae, Chrysomelidae, Thripidae, Pentatomidae, Tortricidae, Delphacidae, Aphididae, Noctuidae, Crambidae, Meloidogynidae, and Heteroderidae.
  • a compound TX controls one or more of pests selected from the family: Noctuidae, Plutellidae, Chrysomelidae, Thripidae, Pentatomidae, Tortricidae, Delphacidae, Aphididae, Noctuidae, Crambidae, Meloidogynidae, and Heteroderidae.
  • the compounds of formulae I, and I’a, or salts thereof, are especially suitable for controlling one or more pests selected from the genus: Spodoptera spp., Plutella spp., Frankliniella spp., Thrips spp., Euschistus spp., Cydia spp., Nilaparvata spp., Myzus spp., Aphis spp., Diabrotica spp., Rhopalosiphum spp., Pseudoplusia spp and Chilo spp.
  • a compound TX controls one or more of pests selected from the genus: Spodoptera spp., Plutella spp., Frankliniella spp., Thrips 109921
  • the compounds of formulae I, and I’a, or salts thereof, are especially suitable for controlling one or more of Spodoptera littoralis, Plutella xylostella, Frankliniella occidentalis, Thrips tabaci, Euschistus heros, Cydia pomonella, Nilaparvata lugens, Myzus persicae, Chrysodeixis incIudens, Aphis craccivora, Diabrotica balteata, Rhopalosiphum padi, and Chilo suppressalis.
  • a compound TX controls one or more of Spodoptera littoralis, Plutella xylostella, Frankliniella occidentalis, Thrips tabaci, Euschistus heros, Cydia pomonella, Nilaparvata lugens, Myzus persicae, Chrysodeixis incIudens, Aphis craccivora, Diabrotica balteata, Rhopalosiphum Padia, and Chilo Suppressalis, such as Spodoptera littoralis + TX, Plutella xylostella + TX; Frankliniella occidentalis + TX, Thrips tabaci + TX, Euschistus heros + TX, Cydia pomonella + TX, Nilaparvat
  • a compound selected from the compounds defined in Tables A-1 to A-30, Tables B-1 to B-5, and Table P is suitable for controlling Spodoptera littoralis, Plutella xylostella, Frankliniella occidentalis, Thrips tabaci, Euschistus heros, Cydia pomonella, Nilaparvata lugens, Myzus persicae, Chrysodeixis incIudens, Aphis craccivora, Diabrotica balteata, Rhopalosiphum Padia, and Chilo Suppressalis in cotton, vegetable, maize, cereal, rice and soya crops.
  • a compound selected from the compounds defined in Tables A-1 to A-30, Tables B-1 to B-5, and Table P is suitable for controlling Mamestra (preferably in vegetables), Cydia pomonella (preferably in apples), Empoasca (preferably in vegetables, vineyards), Leptinotarsa (preferably in potatos) and Chilo supressalis (preferably in rice).
  • Compounds according to the invention may possess any number of benefits including, inter alia, advantageous levels of biological activity for protecting plants against insects or superior properties for use as agrochemical active ingredients (for example, greater biological activity, an advantageous spectrum of activity, an increased safety profile (against non-target organisms above and below ground (such as fish, birds and bees), improved physico-chemical properties, or increased biodegradability).
  • advantageous levels of biological activity for protecting plants against insects or superior properties for use as agrochemical active ingredients for example, greater biological activity, an advantageous spectrum of activity, an increased safety profile (against non-target organisms above and below ground (such as fish, birds and bees), improved physico-chemical properties, or increased biodegradability).
  • certain compounds of formula (I) may show an advantageous safety profile with respect to non-target arthropods, in particular pollinators such as honey bees, solitary bees, and bumble bees, most particularly, Apis mellifera.
  • Israelensis + TX Bacillus thuringiensis subsp. Japonensis + TX, Bacillus thuringiensis subsp. Kurstaki + TX, Bacillus thurin-giensis subsp. Tenebrionis + TX, Bacillus thuringiensis subspec.
  • TX Muscodor roseus A3-5 (NRRL Accession No. 30548) + TX, Myrothecium verrucaria composition + TX, nabam + TX, NC-184 + TX, Neem tree based products + TX, Neodiprion sertifer NPV and N.
  • lecontei NPV + TX nickel bis(dimethyldithiocarbamate) + TX, niclosamide + TX, niclosamide-olamine + TX, nicofluprole + TX, nitenpyram + TX, nithiazine + TX, nitrapyrin + TX, octadeca- 2,13-dien-1-yl acetate + TX, octadeca-3,13-dien-1-yl acetate + TX, octhilinone + TX, omethoate + TX, orfralure + TX, Orius spp.
  • TX trifenmorph + TX, trifluenfuronate + TX, triflumezopyrim + TX, trimedlure + TX, trimedlure A + TX, trimedlure B1 + TX, trimedlure B2 + TX, trimedlure C + TX, trimethacarb + TX, triphenyltin acetate + TX, triphenyltin hydroxide + TX, trunc-call + TX, tyclopyrazoflor + TX, Typhlodromus occidentalis + TX, uredepa + TX, Verticillium lecanii + TX, Verticillium spp.
  • acridum + TX Metarhizium anisopliae var. anisopliae + TX, metarylpicoxamid + TX, metconazole + TX, metepa + TX, methacrifos + TX, methanesulfonyl fluoride + TX, methasulfocarb + TX, methiotepa + TX, methocrotophos + TX, methoprene + TX, methoquin-butyl + TX, methothrin + TX, methoxychlor + TX, methyl (Z)-2-(5-cyclohexyl-2-methyl-phenoxy)-3-methoxy-prop-2-enoate + TX, methyl (Z)-2-(5-cyclopentyl-2-methyl- phenoxy)-3-methoxy-prop-2-enoate (these compounds may be prepared from the methods described in WO2020/193387) + TX, methyl
  • Bacillus subtilis strain AQ178 + TX Bacillus subtilis strain AQ153 + TX, Bacillus subtilis strain AQ743 + TX, Bacillus subtilis strain QST 713 (CEASE®, Serenade®, Rhapsody®) + TX, Bacillus subtilis strain QST 714 (JAZZ®) + TX, Bacillus subtilis strain QST3002 + TX, Bacillus subtilis strain QST3004 + TX, Bacillus subtilis var.
  • amyloliquefaciens strain FZB24 (Taegro®, Rhizopro®) + TX, Bacillus thuringiensis aizawai GC 91 (Agree®) + TX, Bacillus thuringiensis Cry 2Ae + TX, Bacillus thuringiensis Cry1Ab + TX, Bacillus thuringiensis israelensis (BMP123®, Aquabac®, VectoBac®) + TX, Bacillus thuringiensis kurstaki (Javelin®, Deliver®, CryMax®, Bonide®, Scutella WP®, Turilav WP ®, Astuto®, Dipel WP®, Biobit®, Foray®) + TX, Bacillus thuringiensis kurstaki BMP 123 (Baritone®) + TX, Bacillus thuringiensis kurstaki HD-1 (Bioprotec-CAF / 3P®) + TX
  • TX Botrytis cineria + TX, Bradyrhizobium japonicum (TerraMax®) + TX, Brevibacillus brevis + TX, Burkholderia cepacia (Deny®, Intercept®, Blue Circle®) + TX, Burkholderia gladii + TX, Burkholderia gladioli + TX, Burkholderia spp.
  • TX Canadian thistle fungus (CBH Canadian Bioherbicide®) + TX, Candida butyri + TX, Candida famata + TX, Candida fructus + TX, Candida glabrata + TX, Candida guilliermondii + TX, Candida melibiosica + TX, Candida oleophila strain O + TX, Candida parapsilosis + TX, Candida pelliculosa + TX, Candida pulcherrima + TX, Candida reuêtii + TX, Candida saitoana (Bio-Coat®, Biocure®) + TX, Candida sake + TX, Candida spp.
  • TX Cladosporium tenuissimum + TX, Clonostachys rosea (EndoFine®) + TX, Colletotrichum acutatum + TX, Coniothyrium minitans (Cotans WG®) + TX, Coniothyrium spp.
  • TX Filobasidium floriforme + 109921
  • TX Lagenidium giganteum (Laginex®) + TX, Lecanicillium lecanii (formerly known as Verticillium lecanii (Mycotal®) conidia of strain KV01 (e.g. Vertalec® by Koppert/Arysta) + TX, Lecanicillium longisporum (Vertiblast®) + TX, Lecanicillium muscarium (Vertikil®) + TX, Lymantria Dispar nucleopolyhedrosis virus (Disparvirus®) + TX, Marinococcus halophilus + TX, Meira geulakonigii + TX, Metarhizium anisopliae (Destruxin WP®) + TX, Metarhizium anisopliae (Met52®) + TX, Metschnikowia fruticola (Shemer®) + TX, Metschnikowia pulcherrima + TX, Microdochium dimerum (Antibot®) + TX
  • NRRL 305408 + TX, Mycorrhizae spp. (AMykor®, Root Maximizer®) + TX, Myrothecium verrucaria strain AARC-0255 (DiTera®, BROS PLUS®) + TX, Ophiostoma piliferum strain D97 (Sylvanex®) + TX, Paecilomyces farinosus + TX, Paecilomyces lilacinus strain 251 (MeloCon WG®) + TX, Paecilomyces linacinus (Biostat WP®) + TX, Paenibacillus polymyxa + TX, Pantoea agglomerans (BlightBan C9-1®) + TX, Pantoea spp.
  • TX Pasteuria nishizawae in particular strain Pn1 (CLARIVA from Syngenta/ChemChina); + TX, Pasteuria spp. (Econem®) + TX, Penicillium aurantiogriseum + TX, Penicillium billai (Jumpstart®, TagTeam®) + TX, Penicillium brevicompactum + TX, Penicillium frequentans + TX, Penicillium griseofulvum + TX, Penicillium purpurogenum + TX, Penicillium spp.
  • TX Penicillium viridicatum + TX, Phlebiopsis gigantean (Rotstop®) + TX, phosphate solubilizing bacteria (Phosphomeal®) + TX, Phytophthora cryptogea + TX, Phytophthora palmivora (Devine®) + TX, Pichia anomala + TX, Pichia guilliermondii + TX, Pichia membranaefaciens + TX, Pichia onychis + TX, Pichia stipites + TX, Pseudomonas aeruginosa + TX, Pseudomonas aureofasciens (Spot-Less Biofungicide®) + TX, Pseudomonas cepacia + TX, Pseudomonas chlororaphis (AtEze®) + TX, Pseudomonas corrugate + TX, P
  • TX Pseudomonas syringae (Bio-Save®) + TX, Pseudomonas viridiflava + TX, Pseudozyma flocculosa strain PF-A22 UL (Sporodex L®) + TX, Puccinia canaliculata + TX, Puccinia thlaspeos (Wood Warrior®) + TX, Pythium paroecandrum + TX, Pythium oligandrum (Polygandron®, Polyversum®) + TX, Pythium periplocum + TX, Rhanella aquatilis + TX, Rhanella spp.
  • Rhizobia Distal®, Vault®
  • Rhizoctonia + TX Rhodococcus globerulus strain AQ719 + TX, Rhodosporidium diobovatum + TX, Rhodosporidium toruloides + TX, Rhodotorula glutinis + TX, Rhodotorula graminis + TX, Rhodotorula mucilagnosa + TX, Rhodotorula rubra + TX, Rhodotorula spp.
  • Trichoderma asperellum T34 Biocontrol®
  • TX Trichoderma atroviride
  • Trichoderma gamsii TX
  • Trichoderma hamatum TH 382 + TX Trichoderma harzianum rifai (Mycostar®) + TX
  • Trichoderma harzianum T-22 Trianum-P®, PlantShield HC®, RootShield®, Trianum-G® + TX, Trichoderma harzianum T-39 (Trichodex®) + TX, Trichoderma inhamatum + TX, Trichoderma koningii + TX, Trichoderma lignorum + TX, Trichoderma longibrachiatum + TX, Trichoderma polysporum (Binab T®) + TX, Trichoderma spp.
  • LC 52 (Sentinel®) + TX, Trichoderma taxi + TX, Trichoderma virens (formerly Gliocladium virens GL-21) (SoilGuard®) + TX, Trichoderma virens + TX, Trichoderma viride + TX, Trichoderma viride strain ICC 080 (Remedier®) + TX, Trichosporon pullulans + TX, Trichosporon spp. + TX, Trichothecium roseum + TX, Trichothecium spp.
  • TX maydis + TX, various bacteria and supplementary micronutrients (Natural II®) + TX, various fungi (Millennium Microbes®) + TX, Verticillium chlamydosporium + TX, Vip3Aa20 (VIPtera®) + TX, Virgibaclillus marismortui + TX, Xanthomonas campestris pv.
  • TX Bombus terrestris (Beeline®, Tripol®) + TX, Bombus terrestris (Natupol Beehive®) + TX, Cephalonomia stephanoderis + TX, Chilocorus nigritus + TX, Chrysoperla carnea (Chrysoline®, Chrysopa®) + TX, Chrysoperla rufilabris + TX, Cirrospilus ingenuus + TX, Cirrospilus quadristriatus + TX, Citrostichus phyllocnistoides + TX, Closterocerus chamaeleon + TX, Closterocerus spp.
  • TX Coccidoxenoides perminutus (Planopar®) + TX, Coccophagus cowperi + TX, Coccophagus lycimnia + TX, Cotesia flavipes + TX, Cotesia plutellae + TX, Cryptolaemus montrouzieri (Cryptobug®, Cryptoline®) + TX, Cybocephalus nipponicus + TX, Dacnusa sibirica (Minusa®, DacDigline®, Minex®) + TX, Delphastus catalinae (Delphastus®) + TX, Delphastus pusillus + TX, Diachasmimorpha krausii + TX, Diachasmimorpha longicaudata + TX, Diaparsis jucunda + TX, Diaphorencyrtus aligarhensis + TX, Diglyphus isaea (Diminex®, Miglyphus,
  • TX Steinernematid spp. (Guardian Nematodes®) + TX, Stethorus punctillum (Stethorus®) + TX, Tamarixia radiate + TX, Tetrastichus setifer + TX, Thripobius semiluteus + TX, Torymus sinensis + TX, Trichogramma brassicae (Tricholine b®) + TX, Trichogramma brassicae (Tricho-Strip®) + TX, Trichogramma evanescens + TX, Trichogramma minutum + TX, Trichogramma ostriniae + TX, Trichogramma platneri + TX, Trichogramma pretiosum + TX, Xanthopimpla stemmator + TX; abscisic acid + TX, Aminomite® + TX, BioGain® + TX, bioSea® + TX, Chondrostereum purpureum (Chontrol Paste®)
  • NCAIM (P) B001389) (WO 2013/034938) from Certis USA LLC + TX
  • Bacillus pumilus in particular strain BU F-33, having NRRL Accession No.50185 (CARTISSA® from BASF, EPA Reg. No.71840-19) + TX
  • Bacillus subtilis CX-9060 from Certis USA LLC
  • Bacillus sp. in particular strain D747 (available as DOUBLE NICKEL® from Kumiai Chemical Industry Co., Ltd.), having 109921
  • Patent No.7,094,592 + TX Bacillus subtilis strain BU1814, (VELONDIS® PLUS, VELONDIS® FLEX and VELONDIS® EXTRA from BASF SE) + TX, Bacillus subtilis var. amyloliquefaciens strain FZB24 having Accession No. DSM 10271 (available from Novozymes as TAEGRO® or TAEGRO® ECO (EPA Registration No.70127-5)) + TX, Bacillus subtilis, in particular strain QST713/AQ713 (having NRRL Accession No. B-21661 and described in U.S.
  • Patent No.6,060,051 available as SERENADE® OPTI or SERENADE® ASO from Bayer CropScience LP, US
  • TX Paenibacillus polymyxa
  • strain AC-1 e.g. TOPSEED® from Green Biotech Company Ltd.
  • TX Paenibacillus sp. strain having Accession No. NRRL B-50972 or Accession No. NRRL B-67129, WO 2016/154297 + TX, Pantoea agglomerans, in particular strain E325 (Accession No.
  • NRRL B-21856 (available as BLOOMTIME BIOLOGICALTM FD BIOPESTICIDE from Northwest Agri Products) + TX, Pseudomonas proradix (e.g. PRORADIX® from Sourcon Padena) + TX; Aureobasidium pullulans, in particular blastospores of strain DSM14940, blastospores of strain DSM 14941 or mixtures of blastospores of strains DSM14940 and DSM14941 (e.g., BOTECTOR® and BLOSSOM PROTECT® from bio-ferm, CH) + TX, Pseudozyma aphidis (as disclosed in WO2011/151819 by Yissum Research Development Company of the Hebrew University of Jerusalem) + TX, Saccharomyces cerevisiae, in particular strains CNCM No.
  • CNCM No. 1-3936, CNCM No. 1-3937, CNCM No. 1-3938 or CNCM No. 1-3939 (WO 2010/086790) from Lesaffre et Compagnie, FR + TX; Agrobacterium radiobacter strain K84 (e.g. GALLTROL-A® from AgBioChem, CA) + TX, Bacillus amyloliquefaciens isolate B246 (e.g. AVOGREENTM from University of Pretoria) + TX, Bacillus amyloliquefaciens strain F727 (also known as strain MBI110) (NRRL Accession No.
  • Agrobacterium radiobacter strain K84 e.g. GALLTROL-A® from AgBioChem, CA
  • Bacillus amyloliquefaciens isolate B246 e.g. AVOGREENTM from University of Pretoria
  • Bacillus amyloliquefaciens strain F727 also known as strain MBI110
  • Patent No. 5,061,495 + TX Bacillus subtilis strain Y1336 (available as BIOBAC® WP from Bion-Tech, Taiwan, registered 109921
  • NRRL B-50897, WO 2017/019448 e.g., HOWLERTM and ZIO® from AgBiome Innovations, US
  • TX Pseudomonas chlororaphis
  • strain MA342 e.g. CEDOMON®, CERALL®, and CEDRESS® by Bioagri and Koppert
  • TX Pseudomonas fluorescens strain A506 (e.g. BLIGHTBAN® A506 by NuFarm) + TX
  • Pseudomonas proradix e.g.
  • PRORADIX® from Sourcon Padena + TX
  • Streptomyces griseoviridis strain K61 also known as Streptomyces galbus strain K61
  • DSM 7206 Streptomyces galbus strain K61
  • MYCOSTOP® from Verdera, PREFENCE® from BioWorks, cf.
  • BIOKUPRUMTM by AgriLife + TX
  • Chaetomium globosum available as RIVADIOM® by Rivale
  • TX Cladosporium cladosporioides
  • strain H39 having Accession No. CBS122244, US 2010/0291039 (by Stichting Moowgrass Onderzoek) + TX
  • Coniothyrium minitans in particular strain CON/M/91-8 (Accession No. DSM9660, e.g.
  • strain ICC 080 having Accession No. IMI 392151 (e.g., BIO-TAMTM from Isagro USA, Inc. or BIODERMA® by Agrobiosol de Mexico, S.A. de C.V.) + TX, Penicillium vermiculatum + TX, Phlebiopsis gigantea strain VRA 1992 (ROTSTOP® C from danstar Ferment) + TX, Pseudozyma flocculosa, strain PF-A22 UL (available as SPORODEX® L by Plant Products Co., CA) + TX, Saccharomyces cerevisiae strain LAS117 cell walls (CEREVISANE® from Lesaffre, ROMEO® from BASF SE) + TX, Saccharomyces cerevisiae strains CNCM No.1-3936, CNCM No.1-3937, CNCM No.1-3938, CNCM No.1- 3939 (WO 2010/086790) from Lesaffre et Com
  • T-Gro from Andermatt Biocontrol + TX
  • Trichoderma atroviride strain 77B T77 from Andermatt Biocontrol
  • Trichoderma atroviride strain ATCC 20476 IMI 206040
  • Trichoderma atroviride strain LC52 e.g. Tenet by Agrimm Technologies Limited
  • Trichoderma atroviride strain LU132 e.g. Sentinel from Agrimm Technologies Limited
  • TX Trichoderma atroviride strain NMI no. V08/002388 + TX
  • Trichoderma atroviride strain NMI no. V08/002389 + TX Trichoderma atroviride strain NMI no.
  • Trichoderma atroviride Trichoderma atroviride,strain CNCM 1-1237 (e.g. Esquive® WP from Agrauxine, FR) + TX, Trichoderma fertile (e.g. product TrichoPlus from BASF) + TX, Trichoderma gamsii (formerly T. viride) + TX, Trichoderma gamsii (formerly T. viride) strain ICC 080 (IMI CC 392151 CABI) (available as BIODERMA® by AGROBIOSOL DE MEXICO, S.A. DE C.V.), + TX, Trichoderma gamsii strain ICC080 (IMI CC 392151 CABI, e.g.
  • Trianum-P from Koppert TX
  • Trichoderma harzianum strain T-22 e.g. Trianum-P from Andermatt Biocontrol or Koppert
  • Trichoderma harzianum strain TH35 e.g. Root-Pro by Mycontrol
  • Trichoderma polysporum strain IMI 206039 e.g. Binab TF WP by BINAB Bio-Innovation AB, Sweden
  • Trichoderma stromaticum having Accession No. Ts3550 (e.g. Tricovab by CEPLAC, Brazil) + TX
  • Trichoderma virens also known as Gliocladium virens
  • strain GL-21 e.g.
  • Trichoderma virens strain G-41 formerly known as Gliocladium virens (Accession No. ATCC 20906) (e.g., ROOTSHIELD® PLUS WP and TURFSHIELD® PLUS WP from BioWorks, US) + TX, Trichoderma viride in particular strain B35 (Pietr et al., 109921
  • WCS850 deposited at the Central Bureau for Fungi Cultures (e.g., DUTCH TRIG® by Tree Care Innovations) + TX, Verticillium chlamydosporium + TX; a mixture of Azotobacter vinelandii and Clostridium pasteurianum (available as INVIGORATE® from Agrinos) + TX, a mixture of Bacillus licheniformis FMCH001 and Bacillus subtilis FMCH002 (available as QUARTZO® (WG), PRESENCE® (WP) from FMC Corporation) + TX, Azorhizobium caulinodans, in particular strain ZB-SK-5 + TX, Azospirillum brasilense (e.g., VIGOR® from KALO, Inc.) + TX, Azospirillum lipoferum (e.g., VERTEX-IFTM from TerraMax, Inc.) + TX, Azotobacter chroococcum, in particular strain H
  • NRRL B-5015 + TX
  • Bacillus amyloliquefaciens in particular strain FZB42 e.g. RHIZOVITAL® from ABiTEP, DE
  • Bacillus amyloliquefaciens in particular strain IN937a + TX Bacillus amyloliquefaciens pm414 (LOLI- PEPTA® from Biofilm Crop Protection) + TX
  • Bacillus amyloliquefaciens SB3281 ATCC # PTA-7542, WO 2017/205258
  • Bacillus amyloliquefaciens TJ1000 available as QUIKROOTS® from Novozymes
  • Bacillus cereus family member EE128 NRRL No.
  • YIELD SHIELD® from Bayer Crop Science, DE
  • + TX Bacillus pumilus in particular strain QST2808 (Accession No. NRRL No. B-30087) + TX
  • Bacillus siamensis in particular strain KCTC 13613T + TX Bacillus subtilis in particular strain AQ30002 (Accession No. NRRL No. B-50421 and described in U.S. Patent Application No. 13/330,576) + TX
  • Bacillus subtilis in particular strain AQ30004 (NRRL No. B-50455 and described in U.S. Patent Application No. 13/330,576) + TX, Bacillus subtilis in particular strain MBI 600 (e.g.
  • BIOBOOST® from Brett Young Seeds + TX, Lactobacillus sp. (e.g. LACTOPLANT® from LactoPAFI) + TX, Mesorhizobium cicer (e.g., NODULATOR from BASF SE) + TX, Paenibacillus polymyxa in particular strain AC-1 (e.g. TOPSEED® from Green Biotech Company Ltd.) + TX, Pseudomonas aeruginosa in particular strain PN1 + TX, Pseudomonas proradix (e.g.
  • PRORADIX® from Sourcon Padena + TX, Rhizobium leguminosarium biovar viciae (e.g., NODULATOR from BASF SE) + TX, Rhizobium leguminosarum in particular bv. viceae strain Z25 (Accession No. CECT 4585) + TX, Serratia marcescens in particular strain SRM (Accession No. MTCC 8708), + TX, Sinorhizobium meliloti strain NRG-185-1 (NITRAGIN® GOLD from Bayer CropScience) + TX, Thiobacillus sp. (e.g.
  • Trichoderma atroviride strain SC1 (described in WO2009/116106) + TX, Trichoderma harzianum strain 1295-22 + TX, Trichoderma harzianum strain ITEM 908 + TX, Trichoderma harzianum strain T-22 (e.g. Trianum-P from Andermatt Biocontrol or Koppert) + TX, Trichoderma harzianum strain TSTh20, + TX, Trichoderma virens strain GI-3 + TX, Trichoderma virens strain GL-21 (e.g.
  • aizawai in particular serotype H-7 (e.g. FLORBAC® WG from Valent BioSciences, US) + TX, Bacillus thuringiensis subsp. aizawai, in particular strain ABTS-1857 (SD-1372, e.g. XENTARI® from Valent BioSciences) + TX, Bacillus thuringiensis subsp. israelensis (serotype H-14) strain AM65-52 (Accession No. ATCC 1276) (e.g. VECTOBAC® by Valent BioSciences, US) + TX, Bacillus thuringiensis subsp.
  • serotype H-7 e.g. FLORBAC® WG from Valent BioSciences, US
  • TX Bacillus thuringiensis subsp. aizawai, in particular strain ABTS-1857 (SD-1372, e.g. XENTARI® from Valent BioSciences) + TX
  • israeltaki strain ABTS 351 + TX Bacillus thuringiensis subsp. kurstaki strain BMP 123 (from Becker Microbial Products, IL, BARITONE from Bayer CropScience) + TX, Bacillus thuringiensis subsp. kurstaki strain EG 2348 (LEPINOX from Certis, US) + TX, Bacillus thuringiensis subsp. kurstaki strain EG 7841 (CRYMAX from Certis, US) + TX, Bacillus thuringiensis subsp. kurstaki strain HD-1 (e.g. DIPEL® ES from Valent BioSciences, US) + TX, Bacillus thuringiensis subsp.
  • BMP 123 from Becker Microbial Products, IL, BARITONE from Bayer CropScience
  • TX Bacillus thuringiensis subsp. kurstaki strain EG 2348 (LEPINOX from Certis, US) + TX
  • israeltaki strain PB 54 + TX Bacillus thuringiensis subsp. kurstaki strain SA 11 (JAVELIN from Certis, US) + TX, Bacillus thuringiensis subsp. kurstaki strain SA 12 (THURICIDE from Certis, US) + TX, Bacillus thuringiensis subsp. tenebrionis strain NB 176 (SD-5428, e.g. NOVODOR® FC from BioFa DE) + TX, Bacillus thuringiensis var. Colmeri (e.g. TIANBAOBTC by Changzhou Jianghai Chemical Factory) + TX, Bacillus thuringiensis var.
  • SD-5428 e.g. NOVODOR® FC from BioFa DE
  • Bacillus thuringiensis var. Colmeri e.g. TIANBAOBTC by Changzhou Jianghai Chemical Factory
  • MBI206 TGAI and ZELTO® from Marrone Bio Innovations + TX
  • Chromobacterium subtsugae in particular strain PRAA4-1T e.g. MBI-203, e.g. GRANDEVO® from Marrone Bio Innovations
  • TX Chromobacterium subtsugae in particular strain PRAA4-1T
  • MBI-203 e.g. GRANDEVO® from Marrone Bio Innovations
  • TX Lecanicillium muscarium Ve6 (MYCOTAL from Koppert) + TX
  • Paenibacillus popilliae (formerly Bacillus popilliae, e.g. MILKY SPORE POWDERTM or MILKY SPORE GRANULARTM from St. Gabriel Laboratories) + TX
  • Serratia entomophila e.g.
  • ATCC74250 e.g. BOTANIGUARD® ES and MYCONTROL-O® from Laverlam International Corporation
  • TX Metarhizium anisopliae 3213-1 (deposited under NRRL accession number 67074 disclosed in WO 2017/066094, Pioneer Hi-Bred International) + TX, Metarhizium robertsii 15013-1 (deposited under NRRL accession number 67073) + TX, Metarhizium robertsii 23013-3 (deposited under NRRL accession number 67075) + TX, Paecilomyces lilacinus strain 251 (MELOCON from Certis, US) + TX, Zoophtora radicans + TX; Adoxophyes orana (summer fruit tortrix) granulosis virus (GV) + TX, Cydia pomonella (codling moth) granulosis virus (GV) + TX, Helicoverpa armiger
  • Burkholderia cepacia (formerly known as Pseudomonas cepacia) + TX, Gigaspora spp. + TX, Glomus spp. + TX, Laccaria spp. + TX, LactoBacillus buchneri + TX, Paraglomus spp. + TX, Pisolithus tinctorus + TX, Pseudomonas spp. + TX, Rhizobium spp. in particular Rhizobium trifolii + TX, Rhizopogon spp. + TX, Scleroderma spp. + TX, Streptomyces spp. + TX, Suillus spp.
  • the designation is not a "common name”
  • the nature of the designation used instead is given in round brackets for 109921
  • "CAS Reg. No” means the Chemical Abstracts Registry Number.
  • the active ingredient mixture of the compounds of formula (I) selected from the compounds defined in the Tables A-1 to A-30, Tables B-1 to B-5, and Table P, with active ingredients described above comprises a compound selected from one compound defined in the Tables A-1 to A-30, Tables B-1 to B-5, and Table P, and an active ingredient as described above preferably in a mixing ratio of from 100:1 to 1:6000, especially from 50:1 to 1:50, more especially in a ratio of from 20:1 to 1:20, even more especially from 10:1 to 1:10, very especially from 5:1 to 1:5, special preference being given to a ratio of from 2:1 to 1:2, and a ratio of from 4:1 to 2:1 being likewise preferred, above all in a ratio of 1:1, or 5:1, or 5:2, or 5:3, or 5:4, or 4:1, or 4:2, or 4:3, or 3:1, or 3:2, or 2:1, or 1:5, or 2:5, or 3:5, or 4:5, or 1:4, or 2:4, or 3:4, or 1:
  • the compounds and mixtures as described above can be used in a method for controlling pests, which comprises applying a composition comprising a compound or mixture respectively as described above to the pests or their environment, with the exception of a method for treatment of the human or animal body by surgery or therapy and diagnostic methods practiced on the human or animal body.
  • the mixtures comprising a compound of formula (I) selected from the compounds defined in the Tables A-1 to A-30, Tables B-1 to B-5, and Table P, and one or more active ingredients as described above can be applied, for example, in a single "ready-mix” form, in a combined spray mixture com-posed from separate formulations of the single active ingredient components, such as a "tank-mix", and in a combined use of the single active ingredients when applied in a sequen-tial manner, i.e. one after the other with a reasonably short period, such as a few hours or days.
  • the order of applying the compounds of formula (I) and the active ingredients as described above is not essential for working the present invention.
  • the compounds according to the invention can be used as pesticidal agents in unmodified form, but they are generally formulated into compositions in various ways using formulation adjuvants, such as carriers, solvents and surface-active substances.
  • formulation adjuvants such as carriers, solvents and surface-active substances.
  • the formulations can be in various physical forms, e.g.
  • formulations can either be used directly or diluted prior to use.
  • the dilutions can be made, for example, with water, liquid fertilisers, micronutrients, biological organisms, oil or solvents.
  • the formulations can be prepared e.g. by mixing the active ingredient with the formulation adjuvants in order to obtain compositions in the form of finely divided solids, granules, solutions, dispersions or emulsions.
  • the active ingredients can also be formulated with other adjuvants, such as finely divided solids, mineral oils, oils of vegetable or animal origin, modified oils of vegetable or animal origin, organic solvents, water, surface- active substances or combinations thereof.
  • the active ingredients can also be contained in very fine microcapsules. Microcapsules contain the active ingredients in a porous carrier. This enables the active ingredients to be released into the environment in controlled amounts (e.g. slow-release). Microcapsules usually have a diameter of from 0.1 to 500 microns. They contain active ingredients in an amount of about from 25 to 95 % by weight of the capsule weight.
  • the active ingredients can be in the form of a monolithic solid, in the form of fine particles in solid or liquid dispersion or in the form of a suitable solution.
  • the encapsulating membranes can comprise, for example, natural or synthetic rubbers, cellulose, styrene/butadiene copolymers, polyacrylonitrile, polyacrylate, polyesters, polyamides, polyureas, polyurethane or chemically modified polymers and starch xanthates or other polymers that are known to the person skilled in the art.
  • very fine microcapsules can be formed in which the active ingredient is contained in the form of finely divided particles in a solid matrix of base substance, but the microcapsules are not themselves encapsulated.
  • liquid carriers there may be used: water, toluene, xylene, petroleum ether, vegetable oils, acetone, methyl ethyl ketone, cyclohexanone, acid anhydrides, acetonitrile, acetophenone, amyl acetate, 2-butanone, butylene carbonate, chlorobenzene, cyclohexane, cyclohexanol, alkyl esters of acetic acid, diacetone alcohol, 1,2-dichloropropane, diethanolamine, p-diethylbenzene, diethylene glycol, diethylene glycol abietate, diethylene glycol butyl ether, diethylene glycol ethyl ether, diethylene glycol methyl ether, N,N- dimethyl-formamide, dimethyl sulfoxide, 1,4-dioxane, diprop
  • Suitable solid carriers are, for example, talc, titanium dioxide, pyrophyllite clay, silica, attapulgite clay, kieselguhr, limestone, calcium carbonate, bentonite, calcium montmorillonite, cottonseed husks, wheat flour, soybean flour, pumice, wood flour, ground walnut shells, lignin and similar substances. 109921
  • 83176 FF A large number of surface-active substances can advantageously be used in both solid and liquid formulations, especially in those formulations which can be diluted with a carrier prior to use.
  • Surface-active substances may be anionic, cationic, non-ionic or polymeric and they can be used as emulsifiers, wetting agents or suspending agents or for other purposes.
  • Typical surface-active substances include, for example, salts of alkyl sulfates, such as diethanolammonium lauryl sulfate; salts of alkylarylsulfonates, such as calcium dodecylbenzenesulfonate; alkylphenol/alkylene oxide addition products, such as nonylphenol ethoxylate; alcohol/alkylene oxide addition products, such as tridecylalcohol ethoxylate; soaps, such as sodium stearate; salts of alkylnaphthalenesulfonates, such as sodium dibutylnaphthalenesulfonate; dialkyl esters of sulfosuccinate salts, such as sodium di(2-ethylhexyl)sulfosuccinate; sorbi
  • Further adjuvants that can be used in pesticidal formulations include crystallisation inhibitors, viscosity modifiers, suspending agents, dyes, anti-oxidants, foaming agents, light absorbers, mixing auxiliaries, antifoams, complexing agents, neutralising or pH-modifying substances and buffers, corrosion inhibitors, fragrances, wetting agents, take-up enhancers, micro-nutrients, plasticisers, glidants, lubricants, dispersants, thickeners, antifreezes, microbicides, and liquid and solid fertilisers.
  • compositions according to the invention can include an additive comprising an oil of vegetable or animal origin, a mineral oil, alkyl esters of such oils or mixtures of such oils and oil derivatives.
  • the amount of oil additive in the composition according to the invention is generally from 0.01 to 10 %, based on the mixture to be applied.
  • the oil additive can be added to a spray tank in the desired concentration after a spray mixture has been prepared.
  • Preferred oil additives comprise mineral oils or an oil of vegetable origin, for example rapeseed oil, olive oil or sunflower oil, emulsified vegetable oil, alkyl esters of oils of vegetable origin, for example the methyl derivatives, or an oil of animal origin, such as fish oil or beef tallow.
  • Preferred oil additives comprise alkyl esters of C8-C22 fatty acids, especially the methyl derivatives of C12-C18 fatty acids, for example the methyl esters of lauric acid, palmitic acid and oleic acid (methyl laurate, methyl palmitate and methyl oleate, respectively).
  • Many oil derivatives are known from the Compendium of Herbicide Adjuvants, 10 th Edition, Southern Illinois University, 2010.
  • the inventive compositions generally comprise from 0.1 to 99 % by weight, especially from 0.1 to 95 % by weight, of compounds of the present invention and from 1 to 99.9 % by weight of a formula-tion adjuvant which preferably includes from 0 to 25 % by weight of a surface-active substance.
  • the end user will normally employ dilute formulations.
  • the rates of application vary within wide limits and depend on the nature of the soil, the method of application, the crop plant, the pest to be controlled, the prevailing climatic conditions, and other factors governed by the method of application, the time of application and the target crop.
  • As a general guideline compounds may be applied at a rate of from 1 to 2000 l/ha, especially from 10 to 1000 l/ha.
  • Preferred formulations can have the following compositions (weight %): Emulsifiable concentrates: ⁇ active ingredient: 1 to 95 %, preferably 60 to 90 % ⁇ surface-active agent: 1 to 30 %, preferably 5 to 20 % ⁇ liquid carrier: 1 to 80 %, preferably 1 to 35 % Dusts: ⁇ active ingredient: 0.1 to 10 %, preferably 0.1 to 5 % ⁇ solid carrier: 99.9 to 90 %, preferably 99.9 to 99 % Suspension concentrates: ⁇ active ingredient: 5 to 75 %, preferably 10 to 50 % ⁇ water: 94 to 24 %, preferably 88 to 30 % ⁇ surface-active agent: 1 to 40 %, preferably 2 to 30 % Wettable powders: ⁇ active ingredient: 0.5 to 90 %, preferably 1 to 80 % ⁇ surface-active agent: 0.5 to 20 %, preferably 1 to 15 % ⁇ solid carrier: 5 to 95
  • compositions according to the invention can be broadened considerably, and adapted to prevailing circumstances, by adding other insecticidally, acaricidally and/or fungicidally active ingredients.
  • the mixtures of the compounds of formula (I) with other insecticidally, acaricidally and/or fungicidally active ingredients may also have further surprising advantages which can also be described, in a wider sense, as synergistic activity.
  • Suitable additions to active ingredients are, for example, representatives of the following classes of active ingredients: organophosphorus compounds, nitrophenol derivatives, thioureas, juvenile hormones, formamidines, benzophenone derivatives, ureas, pyrrole derivatives, carbamates, pyrethroids, chlorinated hydrocarbons, acylureas, pyridylmethyleneamino derivatives, macrolides, neonicotinoids and Bacillus thuringiensis preparations.
  • compositions according to the invention can also comprise further solid or liquid auxiliaries, such as stabilizers, for example unepoxidized or epoxidized vegetable oils (for example epoxidized coconut oil, rapeseed oil or soya oil), antifoams, for example silicone oil, preservatives, viscosity regulators, binders and/or tackifiers, fertilizers or other active ingredients for achieving specific effects, for example bactericides, fungicides, nematocides, plant activators, molluscicides or herbicides.
  • auxiliaries such as stabilizers, for example unepoxidized or epoxidized vegetable oils (for example epoxidized coconut oil, rapeseed oil or soya oil), antifoams, for example silicone oil, preservatives, viscosity regulators, binders and/or tackifiers, fertilizers or other active ingredients for achieving specific effects, for example bactericides, fungicides, nematocides
  • compositions according to the invention are prepared in a manner known per se, in the absence of auxiliaries for example by grinding, screening and/or compressing a solid active ingredient and in the presence of at least one auxiliary for example by intimately mixing and/or grinding the active ingredient with the auxiliary (auxiliaries).
  • auxiliaries for example by grinding, screening and/or compressing a solid active ingredient and in the presence of at least one auxiliary for example by intimately mixing and/or grinding the active ingredient with the auxiliary (auxiliaries).
  • compositions that is the methods of controlling pests of the abovementioned type, such as spraying, atomizing, dusting, brushing on, dressing, scattering or pouring - which are to be selected to suit the intended aims of the prevailing circumstances - and the use of the compositions for controlling pests of the abovementioned type are other subjects of the invention.
  • Typical rates of concentration are between 0.1 and 1000 ppm, preferably between 0.1 and 500 ppm, of active ingredient.
  • the rate of application per hectare is generally 1 to 2000 g of active ingredient per hectare, in particular 10 to 1000 g/ha, preferably 10 to 600 g/ha.
  • a preferred method of application in the field of crop protection is application to the foliage of the plants (foliar application), it being possible to select frequency and rate of application to match the danger of infestation with the pest in question.
  • the active ingredi-ent can reach the plants via the root system (systemic action), by drenching the locus of the plants with a liquid composition or by incorporating the active ingredient in solid form into the locus of the plants, for example into the soil, for example in the form of granules (soil application).
  • systemic action systemic action
  • the active ingredient in solid form into the locus of the plants for example into the soil, for example in the form of granules (soil application).
  • paddy rice crops such granules can be metered into the flooded paddy-field.
  • the compounds of formula (I) of the invention and compositions thereof are also suitable for the protection of plant propagation material, for example seeds, such as fruit, tubers or kernels, or nursery plants, against pests of the abovementioned type.
  • the propagation material can be treated with the compound prior to planting, for example seed can be treated prior to sowing.
  • the compound can be applied to seed kernels (coating), either by soaking the kernels in a liquid composition or by applying a layer of a solid composition. It is also possible to apply the compositions when the propagation material is planted to the site of application, for example into the seed furrow during drilling.
  • 83176 FF rates would depend on the plant and pest/fungi to be controlled and are generally between 1 to 200 grams per 100 kg of seeds, preferably between 5 to 150 grams per 100 kg of seeds, such as between 10 to 100 grams per 100 kg of seeds.
  • seed embraces seeds and plant propagules of all kinds including but not limited to true seeds, seed pieces, suckers, corns, bulbs, fruit, tubers, grains, rhizomes, cuttings, cut shoots and the like and means, in a preferred embodiment, true seeds.
  • the present invention also comprises seeds coated or treated with or containing a compound of formula (I).
  • seed treatment comprises all suitable seed treatment techniques known in the art, such as seed dressing, seed coating, seed dusting, seed soaking and seed pelleting.
  • the seed treatment application of the compound formula (I) can be carried out by any known methods, such as spraying or by dusting the seeds before sowing or during the sowing/planting of the seeds.
  • the compounds of the invention can be distinguished from other similar compounds by virtue of greater efficacy at low application rates and/or different pest control, which can be verified by the person skilled in the art using the experimental procedures, using lower concentrations if necessary, for example 10 ppm, 5 ppm, 2 ppm, 1 ppm or 0.2 ppm; or lower application rates, such as 300, 200 or 100, mg of AI per m 2 .
  • Powders for dry seed treatment a ) b) c) active ingredients 25 % 50 % 75 % light mineral oil 5 % 5 % 5 % highly dispersed silicic acid 5 % 5 % - Kaolin 65 % 40 % - Talcum - 20 % [0335] The combination is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording powders that can be used directly for seed treatment.
  • Emulsifiable concentrate active ingredients 10 % octylphenol polyethylene glycol ether (4-5 mol of ethylene oxide) 3 % calcium dodecylbenzenesulfonate 3 % castor oil polyglycol ether (35 mol of ethylene oxide) 4 % Cyclohexanone 30 % xylene mixture 50 % [0336] Emulsions of any required dilution, which can be used in plant protection, can be obtained from this concentrate by dilution with water.
  • Coated granules Active ingredients 8 % polyethylene glycol (mol. wt.200) 3 % Kaolin 89 % [0339] The finely ground combination is uniformly applied, in a mixer, to the kaolin moistened with polyethylene glycol. Non-dusty coated granules are obtained in this manner.
  • Flowable concentrate for seed treatment active ingredients 40 % propylene glycol 5 % copolymer butanol PO/EO 2 % Tristyrenephenole with 10-20 moles EO 2 % 1,2-benzisothiazolin-3-one (in the form of a 20% solution in water) 0.5 % monoazo-pigment calcium salt 5 % Silicone oil (in the form of a 75 % emulsion in water) 0.2 % Water 45.3 % [0341] The finely ground combination is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water.
  • the characteristic LCMS values obtained for each compound were the retention time (“Rt”, recorded in minutes) and the measured molecular ion [M+H] + or [M-H]-.
  • Method 1 [0344] Spectra were recorded on a Mass Spectrometer from Waters Corporation (SQD, SQDII or QDA Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive and negative ions), Capillary: 0.8-3.00 kV, Cone: 5-30 V, Source Temperature: 120-150°C, Desolvation Temperature: 350- 600°C, Cone Gas Flow: 50-150 l/h, Desolvation Gas Flow: 650-1000 l/h, Mass range: 100 to 900 Da and an Acquity UPLC from Waters Corporation: Binary pump, heated column compartment , diode-array detector and ELSD.
  • Method 3 [0346] Spectra were recorded on a Mass Spectrometer from Waters (SQD2 or QDA Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: Positive and Negative Polarity Switch), Capillary: 0.8-3.00 kV, Cone range: 25 Source Temperature: 120-150°C, Desolvation Temperature: 500-600°C, Cone Gas Flow: 50 L/h, Desolvation Gas Flow: 1000 L/h, Mass range: 110 to 850 Da) and an Acquity UPLC from Waters: Quaternary solvent manager, heated column compartment , diode-array detector.
  • an electrospray source Polarity: Positive and Negative Polarity Switch
  • Method 5 [0348] Spectra were recorded on a Mass Spectrometer from Waters (SQD2 or QDA Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: Positive and Negative Polarity Switch), Capillary: 0.8-3.00 kV, Cone range: 25 Source Temperature: 120-150°C, Desolvation Temperature: 500-600°C, Cone Gas Flow: 50 L/h, Desolvation Gas Flow: 1000 L/h, Mass range: 110 to 850 Da) and an Acquity UPLC from Waters: Quaternary solvent manager, heated column compartment , diode-array detector.
  • an electrospray source Polarity: Positive and Negative Polarity Switch
  • Step 2 Preparation of N-[[2-bromo-6-fluoro-4-(trifluoromethyl)phenyl]methyleneamino]cyclopropanamine (I-2) [0351] To a solution of 2-bromo-6-fluoro-4-(trifluoromethyl)benzaldehyde (I-1) (8.2 g, 30 mmol) in tetrahydrofuran (160 mL) were added cyclopropylhydrazine hydrochloride (4.9 g, 45 mmol) and triethylamine (45 mmol, 6.4 mL) at room temperature.
  • Step 3 Preparation of 4-bromo-1-cyclopropyl-6-(trifluoromethyl)indazole (I-3) (I-3) [0353] To a solution of N-[[2-bromo-6-fluoro-4-(trifluoromethyl)phenyl]methylene-amino]cyclopropanamine (I-2) (8 g, 24.6 mmol) in N,N-dimethylformamide (80 mL) was added potassium carbonate (10.3 g, 73.8 mmol) 109921
  • Step 4 Preparation of methyl 1-cyclopropyl-6-(trifluoromethyl)indazole-4-carboxylate (I-4) (I-4) [0355] A 100 mL autoclave vessel was charged with 4-bromo-1-cyclopropyl-6-(trifluoromethyl)indazole (I-3) (4.2 g, 14 mmol), triethylamine (1.9 mL, 14 mmol), methanol (42 mL), and [1,1'-bis(diphenylphosphino)- ferrocene]dichloropalladium(II) dichloromethane complex (Pd(dppf)Cl2 CH2Cl2, CAS 95464-05-4) (1.4 mmol, 1.1 g).
  • the vessel was flushed three times with nitrogen, then with carbon monoxide.
  • the reaction mixture was heated to 80°C under a 15 bar carbon monoxide pressure for 3 hours. After cooling to room temperature, the pressure was carefully released, and the vessel flushed with nitrogen.
  • the mixture was diluted with water and the product extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • the crude product was purified by combiflash (EtOAc/hexane) to afford methyl 1-cyclopropyl-6-(trifluoromethyl)indazole-4-carboxylate (I-4, 2.35 g).
  • Step 5 Preparation of 1-cyclopropyl-6-(trifluoromethyl)indazole-4-carboxylic acid (I-5) (I-5) [0357] To a solution of methyl 1-cyclopropyl-6-(trifluoromethyl)indazole-4-carboxylate (I-4) (4 g, 14.07 mmol) in methanol (40 mL) and water (40 mL) was added lithium hydroxide (1.37 g, 56.3 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 hours, then concentrated in vacuo. The residue was acidified with aqueous 2N HCl and the product extracted with ethyl acetate.
  • Step 5a Preparation of 1-cyclopropyl-6-(trifluoromethyl)indazole-4-carbonyl chloride (I-5a) (I-5a) [0359] A mixture of 1-cyclopropyl-6-(trifluoromethyl)indazole-4-carboxylic acid (I-5) (150 mg, 0.56 mmol) in EtOAc (2.8 mL) was treated with oxalyl chloride (0.144 g, 2 equiv.). After stirring for 2 minutes, N,N- dimethylformamide (one drop) was added, and stirring continued at RT for 2 hours.
  • Step 6 Preparation of N-[(1S)-1-[2-(5-cyano-2-pyridyl)-1,2,4-triazol-3-yl]ethyl]-1-cyclopropyl-6- (trifluoromethyl)indazole-4-carboxamide (P2) [0361] To a mixture of 1-cyclopropyl-6-(trifluoromethyl)indazole-4-carboxylic acid (I-5) (65 mg, 0.23 mmol) and [(1S)-1-[2-(5-cyano-2-pyridyl)-1,2,4-triazol-3-yl]ethyl]ammonium;chloride (CAS 2378554-38-0) (83 mg, 0.334 mmol) in acetonitrile (1.3 mL) were added N,N-diisopropylethylamine (940 mg, 0.71 mmol), followed by propanephosphonic acid cyclic anhydride (T3P®, 50
  • Example E2 Preparation of N-[(1S)-1-[2-(5-cyanothiazol-2-yl)-1,2,4-triazol-3-yl]ethyl]-1-cyclopropyl-6- (trifluoromethyl)indazole-4-carboxamide (P6) [0363] To a solution of [(1S)-1-[2-(5-cyanothiazol-2-yl)-1,2,4-triazol-3-yl]ethyl]ammonium chloride (CAS 2648588-59-2) (171 mg, 0.67 mmol, 1.2 equiv.) and triethylamine (0.178 mL, 2.3 equiv.) in EtOAc (3.3 mL) was added a solution of 1-cyclopropyl-6-(trifluoromethyl)indazole-4-carbonyl chloride (I-5a) (160 mg, 0.55 mmol, 1.0 equiv.) in EtOAc (2.8 m
  • Example E3 Preparation of N-[(1S)-1-[2-(5-cyanothiazol-2-yl)-5-ethyl-1,2,4-triazol-3-yl]ethyl]-1-cyclopropyl-6- (trifluoromethyl)indazole-4-carboxamide (P23) [0365] A reaction vessel was charged with [(1S)-1-[2-(5-cyanothiazol-2-yl)-5-ethyl-1,2,4-triazol-3- yl]ethyl]ammonium chloride (I-38) (0.198 mmol, 1.1 equiv.), DMA (1.0 mL) and N,N-diisopropylethylamine (0.54 109921
  • N-[(1S)-1-[2-(5-bromopyrimidin-2-yl)-5-methyl-1,2,4-triazol-3-yl]ethyl]-1-cyclopropyl-6- (trifluoromethyl)indazole-4-carboxamide (compound P12) was prepared from 1-cyclopropyl-6- (trifluoromethyl)indazole-4-carboxylic acid (I-5) and [(1S)-1-[2-(5-bromopyrimidin-2-yl)-5-methyl-1,2,4-triazol-3- yl]ethyl]ammonium chloride (I-24, prepared as described below) by following above protocol in analogy.
  • Example PI-1 Preparation of [(1S)-1-[2-[6-(methoxycarbonylamino)pyrimidin-4-yl]-1,2,4-triazol-3- yl]ethyl]ammonium chloride (I-6)
  • Step 1 Preparation of tert-butyl N-[(1S)-1-[2-(6-aminopyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (I-7) 109921
  • reaction mixture was concentrated, the crude adsorbed on celite and purified by reverse phase column chromatography using H2O and ACN as eluent to afford tert-butyl N-[(1S)-1-[2-(6-aminopyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (1.9 g) as a white solid.
  • Step 2 Preparation of methyl N-[6-[5-[(1S)-1-(tert-butoxycarbonylamino)ethyl]-1,2,4-triazol-1-yl]pyrimidin-4- yl]carbamate (I-8) [0376] To a mixture of tert-butyl N-[(1S)-1-[2-(6-aminopyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (I- 7) (1.90 g, 6.22 mmol) and potassium carbonate (2.58 g, 18.67 mmol) in acetonitrile (28.5 mL) was added methyl chloroformate (1.18 g, 0.96 mL, 12.44 mmol) at room temperature.
  • Step 3 Preparation of [(1S)-1-[2-[6-(methoxycarbonylamino)pyrimidin-4-yl]-1,2,4-triazol-3-yl]ethyl]ammonium chloride (I-6) 109921
  • Example PI-2 Preparation of [(1S)-1-[2-(5-bromopyrimidin-2-yl)-1,2,4-triazol-3-yl]ethyl]ammonium chloride (I- 23)
  • Step 1 Preparation of (5-bromopyrimidin-2-yl)hydrazine (I-16)
  • 5-bromo-2-chloro-pyrimidine 15.0 g, 77.55 mmol
  • methanol 150 mL
  • hydrazine hydrate 10.1 mL, 155.1 mmol, 2.0 equiv.
  • Step 2 Preparation of tert-butyl N-[(1S)-2-[(E)-dimethylaminomethyleneamino]-1-methyl-2-oxo- ethyl]carbamate (I-17) (I-17) [0382] tert-Butyl N-[(1S)-2-amino-1-methyl-2-oxo-ethyl]carbamate (CAS 85642-13-3) (70.0 g, 353 mmol, 1 equiv.) was mixed with 2-methyltetrahydrofuran (1.12 L) and N,N-dimethylformamide-dimethylacetal (DMF- DMA, 70 mL, 530 mmol, 1.5 equiv.), and the mixture heated to 40°C for 2 hours.
  • DMF- DMA N,N-dimethylformamide-dimethylacetal
  • tert-butyl N-[(1S)-2-[(E)-1-(dimethylamino)ethylideneamino]-1-methyl-2-oxo- ethyl]carbamate (I-18) was prepared from tert-butyl N-[(1S)-2-amino-1-methyl-2-oxo-ethyl]carbamate (CAS 85642-13-3) and N,N-dimethylacetamide-dimethyl acetal (CAS 18871-66-4) by following above protocol in analogy.
  • Step 3 Preparation of tert-butyl N-[(1S)-1-[2-(5-bromopyrimidin-2-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (I-19) (I-19) [0386] To a mixture of tert-butyl N-[(1S)-2-[(E)-dimethylaminomethyleneamino]-1-methyl-2-oxo- ethyl]carbamate (I-17, prepared as described above) (7.73 g, 30.5 mmol, 1.2 equiv.) in 1,4-dioxane (32 mL) were added (5-bromopyrimidin-2-yl)hydrazine (I-16) (5.0 g, 25.4 mmol, 1.0 equiv.) and acetic acid (32 mL).
  • the reaction mixture was stirred at 75°C for 3 hours, then concentrated under reduced pressure.
  • the solid residue was diluted with EtOAc and water, the layers separated, the aqueous phase extracted with EtOAc, the combined organic layers washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo.
  • the residue was purified with flash column chromatography over silica gel (tert-butyl methyl ether in dichloromethane) to provide the desired product (I-19) as a solid.
  • tert-butyl N-[(1S)-1-[2-(5-bromopyrimidin-2-yl)-5-methyl-1,2,4-triazol-3-yl]ethyl]carbamate (I-20) was prepared from tert-butyl N-[(1S)-2-[(E)-1-(dimethylamino)ethylideneamino]-1-methyl-2-oxo- ethyl]carbamate (I-18) and (5-bromopyrimidin-2-yl)hydrazine (I-16) by applying above protocol in analogy.
  • tert-butyl N-[(1S)-1-[2-(5-fluoropyrimidin-2-yl)-5-methyl-1,2,4-triazol-3-yl]ethyl]carbamate (I-21) was prepared from tert-butyl N-[(1S)-2-[(E)-1-(dimethylamino)ethylideneamino]-1-methyl-2-oxo- ethyl]carbamate (I-18) and (5-fluoropyrimidin-2-yl)hydrazine (CAS 104408-28-8) by applying above protocol in analogy.
  • chloropyrimidin-2-yl)-5-methyl-1,2,4-triazol-3-yl]ethyl]carbamate (I-22) was prepared from tert-butyl N-[(1S)-2-[(E)-1-(dimethylamino)ethylideneamino]-1-methyl-2-oxo- ethyl]carbamate (I-18) and (5-chloropyrimidin-2-yl)hydrazine (CAS 823-90-5) by applying above protocol in analogy.
  • Example PI-3 Preparation of [(1S)-1-[2-(5-bromopyrimidin-2-yl)-5-cyclopropyl-1,2,4-triazol-3- yl]ethyl]ammonium chloride (I-31)
  • Step 1 Preparation of tert-butyl N-[(1S)-2-[[amino(cyclopropyl)methylene]amino]-1-methyl-2-oxo- ethyl]carbamate (I-27)
  • (2S)-2-(tert-butoxycarbonylamino)propanoic acid 5.00 g, 26.4 mmol, 1.0 equiv.
  • cyclopropanecarboximidoylammonium chloride 5.74 g, 47.6 mmol, 1.8 equiv.
  • tert-butyl N-[(1S)-2-(1-aminopropylideneamino)-1-methyl-2-oxo-ethyl]carbamate (I-28) was prepared from (2S)-2-(tert-butoxycarbonylamino)propanoic acid and propanimidoyl-ammonium chloride by applying above protocol in analogy.
  • TLC 50% EtOAc in cyclohexane
  • reaction mixture was heated at 45°C for 90 minutes, then at 60°C for 1 hour. After cooling to room temperature, the mixture was diluted with a saturated aqueous solution of sodium carbonate, and the product extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • tert-butyl N-[(1S)-1-[2-(5-bromopyrimidin-2-yl)-5-ethyl-1,2,4-triazol-3-yl]ethyl]carbamate (I- 30) was prepared from tert-butyl N-[(1S)-2-(1-aminopropylideneamino)-1-methyl-2-oxo-ethyl]carbamate (I-28) and (5-bromopyrimidin-2-yl)hydrazine (I-16) by applying above protocol in analogy.
  • Example PI-4 Preparation of (1S)-1-[2-(5-bromopyrimidin-2-yl)-5-methoxy-1,2,4-triazol-3-yl]ethanamine (I-34) 109921
  • 83176 FF Step 1 Preparation of 2-[(1S)-1-[2-(5-bromopyrimidin-2-yl)-5-methoxy-1,2,4-triazol-3-yl]ethyl]isoindoline-1,3- dione (I-33) [0412] To a solution of O-methyl N-[(2S)-2-(1,3-dioxoisoindolin-2-yl)propanoyl]carbamothioate (CAS 2592405-42-8, prepared as described in WO21/165195) (8.4 g, 90 mass%, 26 mmol) in ethanol (170 mL) was added (5-bromopyrimidin-2-yl)hydrazine (I-16)
  • Example PI-5 Preparation of [(1S)-1-[2-(5-cyanothiazol-2-yl)-5-ethyl-1,2,4-triazol-3-yl]ethyl]ammonium chloride (I-38) (I-38) Step 1: Preparation of ethyl 2-[5-[(1S)-1-(tert-butoxycarbonylamino)ethyl]-3-ethyl-1,2,4-triazol-1-yl]thiazole-5- carboxylate (I-35) (I-35) [0415] Ethyl 2-[5-[(1S)-1-(tert-butoxycarbonylamino)ethyl]-3-ethyl-1,2,4-triazol-1-yl]thiazole-5-carboxylate (I-35) was prepared from tert-butyl N-[(1S)-2-(1-aminopropylideneamino)-1-methyl-2-
  • Step 3 Preparation of tert-butyl N-[(1S)-1-[2-(5-cyanothiazol-2-yl)-5-ethyl-1,2,4-triazol-3-yl]ethyl]carbamate (I- 37) (I-37) [0419] To a solution of tert-butyl N-[1-[2-(5-carbamoylthiazol-2-yl)-5-ethyl-1,2,4-triazol-3-yl]ethyl]carbamate (I-36) (4.0 g, 10.9 mmol) in acetonitrile (40 mL) at 20°C was added triethylamine (4.7 mL, 33.6 mmol).
  • Step 4 Preparation of [(1S)-1-[2-(5-cyanothiazol-2-yl)-5-ethyl-1,2,4-triazol-3-yl]ethyl]ammonium chloride (I- 38) [0421] [(1S)-1-[2-(5-Cyanothiazol-2-yl)-5-ethyl-1,2,4-triazol-3-yl]ethyl]ammonium chloride (I-38) was prepared from tert-butyl N-[(1S)-1-[2-(5-cyanothiazol-2-yl)-5-ethyl-1,2,4-triazol-3-yl]ethyl]carbamate (I-37) by applying above protocol ‘Example PI-3, step 3’ in analogy.
  • Example PI-6 Preparation of [(1S)-1-[2-(5-bromopyrazin-2-yl)-1,2,4-triazol-3-yl]ethyl]ammonium;2,2,2- trifluoroacetate (I-10)
  • Step 1 Preparation of tert-butyl N-[(1S)-1-[2-(5-bromopyrazin-2-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (I-9)
  • tert-butyl N-[(1S)-1-[2-(5-chloropyrazin-2-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (I-43) was prepared from tert-butyl N-[(1S)-2-amino-1-methyl-2-oxo-ethyl]carbamate and 2-chloro-5-hydrazinylpyrazine (prepared as described in WO 2021/126923) by applying above protocol in analogy.
  • LCMS (method 3): retention time 1.09 min, m/z 325/327 [M+H] + .
  • Step 2 Preparation of [(1S)-1-[2-(5-bromopyrazin-2-yl)-1,2,4-triazol-3-yl]ethyl]ammonium;2,2,2- trifluoroacetate (I-10) 109921
  • Example PI-7 Preparation of 6-bromo-1-cyclopropyl-indazole-4-carboxylic acid (I-11) (I-11) [0428] Compound 6-bromo-1-cyclopropyl-indazole-4-carboxylic acid (CAS 1346703-51-2) (I-11) can be prepared as described for example in WO 2011/140325.
  • Example PI-8 Preparation of 1-cyclopropyl-6-(difluoromethyl)indazole-4-carboxylic acid (I-12) (I-12) Step 1: Preparation of methyl 1-cyclopropyl-6-vinyl-indazole-4-carboxylate (I-13) (I-13) 109921
  • Step 2 Preparation of methyl 1-cyclopropyl-6-formyl-indazole-4-carboxylate (I-14) [0432] To methyl 1-cyclopropyl-6-vinyl-indazole-4-carboxylate (I-13) (preparation described hereabove) (3.86 g) in tetrahydrofuran (38.6 mL) were added water (19.3 mL) and potassium osmate (K2OsO4) (0.264 g). The mixture was stirred at 25°C for 2 hours, then sodium periodate (NaIO4) (10.2 g) was added portionwise over 10 minutes. After stirring for 10 more minutes, the reaction mixture was diluted with water and extracted with ethyl acetate.
  • NaIO4 sodium periodate
  • Step 3 Preparation of methyl 1-cyclopropyl-6-(difluoromethyl)indazole-4-carboxylate (I-15) [0434] To methyl 1-cyclopropyl-6-formyl-indazole-4-carboxylate (I-14) (preparation described hereabove) (3.39 g) in dichloromethane (40.7 mL) at 0°C under inert atmosphere was added diethylaminosulfur trifluoride (DAST) (5.23 mL) dropwise over 10 minutes. The reaction mixture was stirred at 25°C for 16 hours, then cooled to 0°C and quenched by careful addition of a saturated aqueous solution of sodium bicarbonate (47 mL).
  • DAST diethylaminosulfur trifluoride
  • Step 4 Preparation of 1-cyclopropyl-6-(difluoromethyl)indazole-4-carboxylic acid (I-12) (I-12) [0436] To a solution of methyl 1-cyclopropyl-6-(difluoromethyl)indazole-4-carboxylate (I-15) (preparation described hereabove) (2.93 g) in methanol (17.6 mL) and tetrahydrofuran (5 mL) were added water (3 mL) and lithium hydroxide monohydrate (0.754 g). The mixture was stirred at 25°C for 3 hours, then diluted with water and acidified by dropwise addition of 4.0 M aqueous HCl until pH 2.
  • Example PI-9 Preparation of 1-cyclopropyl-6-(difluoromethoxy)indazole-4-carboxylic acid (I-39)
  • Step 1 Preparation of methyl 1-cyclopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole-4- carboxylate (I-40)
  • CAS 1346703-50-1 prepared as described in WO 2011/140325
  • 6.91 g in dioxane (70 mL) at 25°C were added 109921
  • Step 2 Preparation of methyl 1-cyclopropyl-6-hydroxy-indazole-4-carboxylate (I-41) [0440] To crude methyl 1-cyclopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole-4-carboxylate (I-40) (preparation described hereabove) (8.01 g) in tetrahydrofuran (80 mL) at 0°C was added aqueous hydrogen peroxide (35% w/w) (8.2 mL) dropwise over 15 minutes.
  • Step 3 Preparation of 1-cyclopropyl-6-(difluoromethoxy)indazole-4-carboxylic acid (I-39) [0442] To a solution of methyl 1-cyclopropyl-6-hydroxy-indazole-4-carboxylate (I-41) (preparation described hereabove) (4.12 g) and potassium hydroxide (23.4 g) in a mixture of water (88.5 mL) and acetonitrile (88.5 mL) at 25°C was added diethyl (bromodifluoromethyl)phosphonate (9.45 mL). The mixture was stirred at 25°C for 16 hours, then diluted with water (45 mL) and washed with ethyl acetate.
  • aqueous phase was acidified with aqueous 4.0 M HCl (34.5 mL) and the product extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified 109921
  • Example PI-10 Preparation of [(1S)-1-[2-(5-carbamoylpyrazin-2-yl)-5-methyl-1,2,4-triazol-3- yl]ethyl]ammonium chloride (I-42) [0444] Compound (I-42) was prepared by following in analogy the synthesis route for [(1S)-1-[2-(5- carbamoylpyrazin-2-yl)-1,2,4-triazol-3-yl]ethyl]ammonium chloride (CAS 3024825-20-2) outlined in WO 23/247360 (Example PI-4 on page 147), but replacing N,N-dimethylformamide dimethyl acetal with N,N- dimethylacetamide-dimethyl acetal (CAS 18871-66-4) in step 1.
  • Example PI-11 Preparation of [(1S)-1-[2-(5-chloropyrazin-2-yl)-1,2,4-triazol-3-yl]ethyl]ammonium chloride (I- 44) [0446] To a solution of tert-butyl N-[(1S)-1-[2-(5-chloropyrazin-2-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (I-43) (preparation described hereabove) (1 g) in 1,4-dioxane (8 mL) was added a 4.0 M solution of HCl in 1,4-dioxane (8.2 mL) at RT.
  • Example B1 Activity against Chilo suppressalis (Striped rice stemborer) [0450] 24-well microtiter plates with artificial diet were treated with aqueous test solutions prepared from 10'000 ppm DMSO stock solutions by pipetting. After drying, the plates were infested with L2 larvae (6-8 per well).
  • the samples were assessed for mortality, anti-feeding effect, and growth inhibition in comparison to untreated samples 6 days after infestation.
  • Control of Chilo suppressalis by a test sample is given when at least one of the categories mortality, anti-feedant effect, and growth inhibition is higher than the untreated sample.
  • Example B2 Activity against Diabrotica balteata (Corn root worm) [0452] Maize sprouts placed onto an agar layer in 24-well microtiter plates were treated with aqueous test solutions prepared from 10'000 ppm DMSO stock solutions by spraying. After drying, the plates were infested with L2 larvae (6 to 10 per well). The samples were assessed for mortality and growth inhibition in comparison to untreated samples 4 days after infestation.
  • Example B3 Activity against Euschistus heros (Neotropical Brown Stink Bug) [0454] Soybean leaves on agar in 24-well microtiter plates were sprayed with aqueous test solutions prepared from 10'000 ppm DMSO stock solutions. After drying the leaves were infested with N2 nymphs. The samples were assessed for mortality and growth inhibition in comparison to untreated samples 5 days after infestation.
  • Test compounds prepared from 10'000 ppm DMSO stock solutions were applied by pipette into 24- well microtiter plates and mixed with a sucrose solution or a nutrient solution. The plates were closed with a stretched Parafilm. A plastic stencil with 24 holes was placed onto the plate and infested pea seedlings were placed directly on the Parafilm. The infested plate was closed with a gel blotting paper and another plastic stencil and then turned upside down. The samples were assessed for mortality 5 days after infestation.
  • Example B6 Activity against Myzus persicae (Green peach aphid). Feeding/Contact activity [0460] Eggplant leaf discs were placed onto agar in a 24-well microtiter plate and sprayed with aqueous test solutions prepared from 10'000 ppm DMSO stock solutions. After drying, the leaf discs were infested with an aphid population of mixed ages. The samples were assessed for mortality 6 days after infestation. [0461] The following compounds resulted in at least 80% mortality at an application rate of 200 ppm: P1, P6, P10, P11, P15, P24, P31, P32, P46, P62, P66, P74, P100.
  • Example B7 Activity against Plutella xylostella (Diamond back moth) [0462] 24-well microtiter plates with artificial diet were treated with aqueous test solutions prepared from 10'000 ppm DMSO stock solutions by pipetting. After drying, Plutella eggs were pipetted through a plastic stencil onto a gel blotting paper and the plate was closed with it. The samples were assessed for mortality and growth inhibition in comparison to untreated samples 8 days after infestation.
  • Example B8 Activity against Spodoptera littoralis (Egyptian cotton leaf worm) [0464] Cotton leaf discs were placed onto agar in 24-well microtiter plates and sprayed with aqueous test solutions prepared from 10'000 ppm DMSO stock solutions. After drying the leaf discs were infested with five L1 larvae. The samples were assessed for mortality, anti-feeding effect, and growth inhibition in comparison to untreated samples 3 days after infestation. Control of Spodoptera littoralis by a test sample is given when at least one of the categories mortality, anti-feedant effect, and growth inhibition is higher than the untreated sample.
  • Table B10 Concentration Mortality Compound Insect (ppm) (%) Present invention – Compound P1 200 Spodoptera littoralis 100 200 Chilo suppressalis 100 200 Diabrotica balteata 100 200 Plutella xylostella 100 200 Euschistus heros 100 Present invention – Compound P32 200 Spodoptera littoralis 100 200 Chilo suppressalis 100 200 Diabrotica balteata 0 200 Plutella xylostella 100 200 Euschistus heros 100 Present invention – Compound P66 200 Spodoptera littoralis 100 200 Chilo suppressalis 100 200 Diabrotica balteata 100 200 Plutella xylostella 100 200 Euschistus heros 100 Present invention – Compound P89 200 Spodoptera littoralis 100 200 Chilo suppressalis 100 200 Diabrotica balteata 100 200 Plutella xylostella 100 200 Euschistus heros 100 109921
  • Example B11 Comparison of the insecticidal activity of compound P15 according to the invention with structurally most closely comparable compounds from the state of the art: [0470] Activity of compound P15 according to the preparatory examples and of compounds from WO 20/094363 against Spodoptera littoralis (Example B8 above), Plutella xylostella (Example B7 above) and Euschistus heros (Example B3 above) is summarized in Table B11.
  • Table B11 Concentration Mortality Compound Insect (ppm) (%) Present invention – Compound P15 12.5 Spodoptera littoralis 100 3 Plutella xylostella 80 50 Euschistus heros 100
  • Example B12 Comparison of the insecticidal activity of compound P8 according to the invention with structurally most closely comparable compounds from the state of the art: [0472] Activity of compound P8 according to the preparatory examples and of compounds from WO 21/069575 against Spodoptera littoralis (Example B8 above), Plutella xylostella (Example B7 above) and Diabrotica balteata (Example B2 above) is summarized in Table B12.
  • Table B12 Concentration Mortality Compound Insect (ppm) (%) Present invention – Compound P8 12.5 Spodoptera littoralis 100 50 Plutella xylostella 50 12.5 Diabrotica balteata 80 D escribed in WO 2021/069575 as compound 12.5 Spodoptera littoralis 0 I -20 (page 151) – State of the art 50 Plutella xylostella 0 12.5 Diabrotica balteata 0 D escribed in WO 2021/069575 as compound 12.5 Spodoptera littoralis 0 I -1 (page 139) – State of the art 50 Plutella xylostella 0 12.5 Diabrotica balteata 0 [0473] Table B12 shows that compound P8 according to the invention exert a substantially better insecticidal action on Spodoptera littoralis, Plutella xylostella and Diabrotica balteata than the compounds

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Abstract

Les composés de formule (I) dans laquelle les substituants sont tels que définis dans la revendication 1, et les sels, stéréoisomères, énantiomères, tautomères et N-oxydes agrochimiquement acceptables de ces composés, peuvent être utilisés en tant qu'insecticides.
PCT/EP2025/064886 2024-05-31 2025-05-28 Composés d'indazole à action pesticide Pending WO2025248032A1 (fr)

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