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WO2024105104A1 - Microbiocidal tetrahydroisoquinoline derivatives - Google Patents

Microbiocidal tetrahydroisoquinoline derivatives Download PDF

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Publication number
WO2024105104A1
WO2024105104A1 PCT/EP2023/081908 EP2023081908W WO2024105104A1 WO 2024105104 A1 WO2024105104 A1 WO 2024105104A1 EP 2023081908 W EP2023081908 W EP 2023081908W WO 2024105104 A1 WO2024105104 A1 WO 2024105104A1
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Prior art keywords
formula
methyl
hydrogen
compounds
compound
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PCT/EP2023/081908
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French (fr)
Inventor
Andrew Edmunds
Christopher Charles SCARBOROUGH
Atul Mahajan
Guillaume BRUNOT
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Syngenta Crop Protection AG Switzerland
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Syngenta Crop Protection AG Switzerland
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Priority to KR1020257019054A priority Critical patent/KR20250095743A/en
Priority to CR20250206A priority patent/CR20250206A/en
Priority to EP23805614.7A priority patent/EP4619396A1/en
Priority to AU2023381091A priority patent/AU2023381091A1/en
Priority to JP2025528472A priority patent/JP2025537818A/en
Priority to CN202380079234.7A priority patent/CN120225510A/en
Application filed by Syngenta Crop Protection AG Switzerland filed Critical Syngenta Crop Protection AG Switzerland
Publication of WO2024105104A1 publication Critical patent/WO2024105104A1/en
Priority to IL320722A priority patent/IL320722A/en
Priority to CONC2025/0006132A priority patent/CO2025006132A2/en
Priority to MX2025005559A priority patent/MX2025005559A/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • A01N43/80—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 1,2
    • 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
    • A01N43/82—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 three ring hetero atoms
    • 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
    • A01P3/00—Fungicides
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms 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 present invention relates to microbiocidal tetrahydroisoquinoline derivatives, e.g., as active ingredients, which have microbiocidal activity, in particular fungicidal activity.
  • the invention also relates to preparation of these tetrahydroisoquinoline derivatives, to intermediates useful in the preparation of these tetrahydroisoquinoline derivatives, to the preparation of these intermediates, to agrochemical compositions which comprise at least one of the tetrahydroisoquinoline derivatives, to preparation of these compositions and to the use of the tetrahydroisoquinoline derivatives or compositions in agriculture or horticulture for controlling or preventing infestation of plants, harvested food crops, seeds or non-living materials by phytopathogenic microorganisms, in particular fungi.
  • R 1 is selected from hydrogen, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, or Cs-Cecycloalkyl;
  • R 2 is selected from hydrogen, halogen, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl, C3- Cecycloalkyl, Ci-C4-alkylcarbonyl, N-Ci-C4-alkoxy-C-Ci-C4-alkyl-carbonimidoyl, N-hydroxy-C-Ci-C4-alkyl- carbonimidoyl, or Ci-C4-alkoxycarbonyl;
  • R 3 is selected from hydrogen, halogen, C1-C4 haloalkyl, or C1-C4 alkyl;
  • R 4 is selected from hydrogen, halogen, C1-C4 haloalkyl, C3-C6 cycloalkyl, or C1-C4 alkyl;
  • R 5 and R 6 are independently selected from hydrogen, or Ci-C4-alkyl
  • R 7 is selected from hydrogen, Ci-C4-lkyl, Ci-C4-alkylcarbonyl, N-Ci-C4-alkoxy-C-Ci-C4-alkyl-carbonimidoyl, N- hydroxy-C-Ci-C4-alkyl-carbonimidoyl, Ci-C4-alkoxycarbonyl, N-methoxy-N-methyl-carbonyl, C1-C4 alkylaminocarbonyl, di (Ci-C4-alkyl)aminocarbonyl, phenyl, a 5- or 6-membered heteroaryl, or Cs-Ce-cycloalkyl; wherein any of said 5- or 6-membered heteroaryl contains 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S, with the proviso that no more than one is O or S; and wherein any of said phenyl and 5- or 6- membered heteroaryl are unsubstituted or substituted with 1
  • B 1 is selected from CR 10 , or N;
  • B 2 is selected from CR 11 , or N;
  • R 8 , R 9 , R 10 and R 11 are independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, Ci-C4-haloalkoxy, C2-C4-alkenyloxy, C2-C4-alkynyloxy, Ci-C4-alkylsulfanyl, Ci-C4-alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 alkoxy-Ci-C4 alkyl, N-Ci-C4-alkylamino, N,N-di(Ci-C4 alkyl)amino, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl, Ci-C4-alkylaminocarbonyl, di(Ci-C4-alkyl)aminocarbonyl, cyano-Ci-C4alkyl, N
  • a 1 , A 2 and A 3 are independently selected from CR 12 , N, NR 13 , O or S, with the proviso that at least one of A 1 , A 2 and A 3 is selected from N, O or S, and that no more than one of A 1 , A 2 and A 3 is O or S;
  • R 12 , R 13 are independently selected from hydrogen, halogen, C1-C4 alkyl, Ci-C4haloalkyl, C2-C4 alkenyl, or C2- C4 alkynyl; and
  • Z 1 is selected from 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N; wherein any of said 6-membered heteroaryl is unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from halogen, C1-C4 haloalkyl, cyano, C1-C4 alkyl, C2-C4 alkynyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylsulfanyl, C1-C4 alkylsulfinyl, or Ci-C4 alkylsulfonyl; or an agrochemically acceptable salt, stereoisomer, or N-oxide thereof.
  • an agrochemical composition comprising a fungicidally effective amount of a compound of formula (I) according to the invention.
  • Such an agricultural composition may further comprise at least one additional active ingredient and/or an agrochemically- acceptable diluent or carrier.
  • a method of controlling or preventing infestation of useful plants by phytopathogenic microorganisms wherein a fungicidally effective amount of a compound of formula (I) according to the invention, or a composition comprising the compound of formula (I), is applied to the plants, to parts thereof or the locus thereof.
  • a compound of formula (I) according to the invention as a fungicide.
  • the use may exclude methods for treatment of the human or animal body by surgery or therapy and diagnostic methods practised on the human or animal body.
  • 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 Ci- 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 Ci- 04 alkane- or arylsulfonic acids which are unsubstituted or substituted, for example
  • 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 morpholine, 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
  • salts with ammonia or an organic amine such as morpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower-alkylamine, for example ethyl-, die
  • 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.
  • Ci-Cealkyl substituted by 1 , 2 or 3 halogens may include, but not be limited to, -CH2CI, -CHCI2, -CCh, -CH2F, -CHF2, - CF3, -CH2CF3 or -CF2CH3 groups.
  • Ci-Cealkoxy substituted by 1 , 2 or 3 halogens may include, but not be limited to, CH2CIO-, CHCI2O-, CCI3O-, CH2FO-, CHF2O-, CF3O-, CF3CH2O- or CH3CF2O- groups.
  • optionally substituted as used herein, can be used interchangeably with the term “unsubstituted or substituted”.
  • halogen refers to fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo), preferably fluorine, chlorine, or bromine. This also applies, correspondingly, to halogen in combination with other meanings, such as haloalkyl, haloalkenyl, haloalkynyl, haloalkoxy, and halocycloalkyl.
  • amino means a -NH2 group.
  • cyano means a -CN group.
  • hydroxyl or “hydroxy” means an -OH group.
  • carboxylic acid means a -COOH group.
  • Ci-C n -alkyl 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,
  • C2-C n -alkenyl refers to a straight or branched alkenyl chain moiety having from two to n carbon atoms and one or two double bonds, for example, ethenyl, prop-1 -enyl, but-2-enyl.
  • C2-C n -alkynyl refers to a straight or branched alkynyl chain moiety having from two to n carbon atoms and one triple bond, for example, ethynyl, prop-2-ynyl, but-3-ynyl,
  • Cs-Cn-cycloalkyl refers to three (3) to n membered cycloalkyl radical such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Ci-C n -alkoxy refers to a straight-chain or branched saturated alkyl radical having one (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 and 1 ,1 -dimethylethoxy.
  • C2-Cn-alkenyloxy refers to a straight-chain or branched alkenyl chain having two (2) to n carbon atoms (as mentioned above) which is attached via an oxygen atom.
  • C2-Cn alkynyloxy refers to a radical of the formula -OR a where R a is a C2-Cn alkynyl radical as generally defined above.
  • Ci-C n -alkoxy-Ci-C n -alkyl refers to an alkyl radical (as mentioned above) substituted with a Ci-Cn-alkoxy group. Examples are methoxymethyl, methoxyethyl, ethoxymethyl and propoxymethyl.
  • C3-C n -cycloalkyl-Ci-C n -alkyl refers to an alkyl radical (as mentioned above) substituted with a Cs-Cn-cycloalkyl group. Examples are cyclopropylmethyl, cyclopropylethyl.
  • C3-C n -halocycloalkyl-Ci-C n -alkyl refers to an alkyl radical substituted with cycloalkyl group, wherein the cycloalkyl group is substituted by one or more of the same or different halogen atoms. Examples are 3,3- difluorobutylmethyl and 1 -chlorocyclopropylmethyl.
  • Ci-C n -haloalkyl 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-difluoroe
  • Ci-C2fluoroalkyl would refer to a Ci-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.
  • C2-C n -haloalkenyl or “C2-C n -haloalkynyl” as used herein refers to a C2-C n -alkenyl or C2- Cn-alkynyl radical respectively substituted with one or more halogen atoms which may be the same or different.
  • Cs-Cn-halocycloalkyl or “Ci-C n -haloalkoxy” as used herein refers to a Cs-Cn-cycloalkyl radical or Ci-C n -alkoxyl radical respectively substituted with one or more halo atoms which may be the same or different.
  • cyano-Ci-C n -alkyl refers to Ci-C n -alkyl radical having 1 to n carbon atoms (as mentioned above), where one of the hydrogen atoms in the radical is be replaced by a cyano group: for example, cyano-methyl, 2-cyano-ethyl, 2-cyano-propyl, 3-cyano-propyl, 1-(cyano-methyl)-2-ethyl, 1-(methyl)- 2-cyano-ethyl, 4-cyanobutyl, and the like.
  • cyano-Cs-Cn-cycloalkyl refers to a C3-C n - cycloalkyl radical substituted with one of the hydrogen atoms by a cyano group
  • cyano-Cs-Cn- cycloalkyl-Ci-C n -alkyl refers to an Ci-C n -alkyl radical having a cyano-Cs-Cn-cycloalkyl group.
  • Ci-Cn-alkylthio“ or “Ci-Cn-alkylsulfanyl“ refers to a Ci-Cn-alkyl group linked through a sulfur atom.
  • Ci-C n -haloalkylthio“ or “Ci-C n -haloalkylsulfanyl“ refers to a Ci-C n haloalkyl group linked through a sulfur atom.
  • Ci-C n -alkylsulfonyl-Ci-C n -alkyl refers to an a Ci-C n alkyl radical substituted with a Ci-C n alkylsulfonyl group.
  • Ci-C n -alkoxycarbonyl-Ci-C n -alkyl refers to a Ci-C n -alkyl radical substituted by a “C1- Cn-alkoxycarbonyl group.
  • N-Ci-C n alkylamino refers to a radical of the formula -NH-R a where R a is a Ci-C n alkyl radical as defined above.
  • N,N-di(Ci-C n alkyl)amino refers to a radical of the formula -N(R a )R a where each R a is a Ci-C n alkyl radical, which may be the same or different, as defined above.
  • the Ci-C n -alkoxy group linked to the nitrogen may be substituted.
  • heteroaryl refers to a 5- or 6-membered aromatic monocyclic ring radical which comprises 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S.
  • heteroaryl include, but are not limited to, furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidyl or pyridyl.
  • heteroaryl-Ci-C n -alkyl or “heteroaryl- Cs-Cn-cycloalkyl” refers to an Ci-C n -alkyl or Cs-Cn-cycloalkyl radical respectively substituted by a heteroaryl group.
  • the heteroaryl-Ci-C n -alkyl or heteroaryl-Cs-Cn-cycloalkyl radical may be substituted on heteroaryl, alkyl and/or cycloalkyl group as appropriate.
  • 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, using 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 and its lifecycle; the particular compound applied; the type of application; and other relevant circumstances.
  • room temperature or “RT” or “rt” or “ambient temperature” refer to a temperature of about 15° C to about 35° C.
  • rt can refer to a temperature of about 20° C to about 30° C.
  • R 1 is selected from hydrogen, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, or Cs-Cecycloalkyl.
  • R 1 is Ci-C4alkyl.
  • R 1 is methyl, ethyl or isopropyl. More preferably, R 1 is methyl.
  • R 2 is selected from hydrogen, halogen, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4- alkynyl, Ci-C4-haloalkyl, Cs-Cecycloalkyl, Ci-C4-alkylcarbonyl, N-C1-C4 alkoxy-C-Ci-C4 alkyl-carbonimidoyl, N- hydroxy-C-Ci-C4 alkyl-carbonimidoyl, or Ci-C4-alkoxycarbonyl.
  • R 2 is hydrogen, halogen, Ci-C4-alkyl, Cs-Cecycloalkyl, Ci-C4alkylcarbonyl, N-Ci-C4alkoxy-Ci-C4 alkyl-carbonimidoyl, or N-hydroxy-Ci-C4 alkyl-carbonimidoyl.
  • R 2 is hydrogen, halogen, methyl, ethyl, cyclopropyl, C1-C2 alkylcarbonyl, N-C1-C2 alkoxy-C-Ci-C2 alkyl-carbonimidoyl, or N-hydroxy-C-Ci-C2 alkyl-carbonimidoyl.
  • R 2 is hydrogen, halogen, or C1-C4 alkyl. Most preferably R 2 is hydrogen, chlorine, or methyl. In one preferred embodiment R 2 is hydrogen. In another preferred embodiment R 2 is methyl. In still another preferred embodiment R 2 is chlorine.
  • R 3 is selected from hydrogen, halogen, C1-C4 haloalkyl, or C1-C4 alkyl.
  • R 3 is hydrogen or C1-C4 alkyl. More preferably R 3 is hydrogen or methyl. Most preferably R 3 is hydrogen.
  • R 4 is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, or Cs- Ce-cycloalkyl.
  • R 4 is hydrogen, chlorine, bromine, fluorine, methyl, ethyl, trifluoromethyl, difluoromethyl, or cyclopropyl. More preferably R 4 is hydrogen, chlorine, bromine, or methyl. Still more preferably R 4 is hydrogen or methyl. Most preferably R 4 is hydrogen. In one embodiment of the invention R 4 is hydrogen. In another embodiment of the invention R 4 is methyl.
  • R 5 and R 6 are independently selected from hydrogen or Ci-C4-alkyl.
  • R 5 and R 6 are independently selected from hydrogen, methyl, or ethyl. More preferably, R 5 and R 6 are independently selected from hydrogen or methyl. Even more preferably, R 5 and R 6 are hydrogen.
  • R 7 is selected from hydrogen, Ci-C4alkyl, Ci-C4-alkylcarbonyl, N-C1-C4 alkoxy-C-Ci-C4 alkyl-carbonimidoyl, N-hydroxy-C-Ci-C4-alkyl-carbonimidoyl, Ci-C4-alkoxycarbonyl, N-methoxy-N-methyl- carbonyl, Ci-C4alkylaminocarbonyl, di(Ci-C4alkyl)aminocarbonyl, phenyl, a 5- or 6-membered heteroaryl, or Cs-Ce-cycloalkyl; wherein any of said 5- or 6-membered heteroaryl conatins 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S, with the proviso that no more than one is O or S; and wherein any of said phenyl and 5- or 6-membered heteroaryl are unsubstituted or substituted with 1 ,
  • R 7 is selected from hydrogen, Ci-C4alkyl, C3- Ci-C4alkylcarbonyl, Ci- 04 alkoxycarbonyl, N-C1-C4 alkoxy-C-Ci-C4alkyl-carbonimidoyl, N-hydroxy-C-Ci-C4 alkyl-carbonimidoyl, N- methoxy-N-methyl-carbonyl, C1-C4 alkylaminocarbonyl, di(Ci-C4alkyl)aminocarbonyl, phenyl, a 5- or 6- membered heteroaryl, or Cs-Ce-cycloalkyl; wherein any of said 5- or 6-membered heteroaryl contains 1 heteroatom selected from N; and wherein any of said phenyl and 5- or 6-membered heteroaryl are unsubstituted or substituted with 1 or 2 substituents independently selected from halogen, Ci-C4haloalkyl, cyano, or Ci-
  • R 7 is selected from hydrogen, C1-C4 alkyl, or Cs-Ce-cycloalkyl.
  • R 7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl. Even more preferably R 7 is hydrogen, methyl, or cyclopropyl.
  • R 7 is C1-C4 alkyl.
  • R 7 is methyl or ethyl. More preferably R 7 is methyl.
  • R 8 , R 9 , R 10 and R 11 are independently selected hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C2-C4alkenyloxy, C2-C4 alkynyloxy, C1-C4 alkylsulfanyl, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, Ci-C4 alkoxy-Ci-C4 alkyl, N- C1-C4 alkylamino, N,N-di C1-C4 alkylamino, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl, C1-C4 alkylamin
  • R 8 and R 9 are independently selected from hydrogen, halogen, cyano, Ci- 04 alkyl, or C1-C4 alkoxy.
  • R 8 and R 9 are independently selected from hydrogen, halogen, methyl, methoxy, or cyano. More preferably, R 8 and R 9 are independently selected from hydrogen, methyl, chlorine, fluorine, bromine, or methoxy. Even more preferably, R 8 and R 9 are independently selected from hydrogen or methoxy.
  • R 8 is hydrogen, halogen, or cyano.
  • R8 is hydrogen, bromine, chlorine, or cyano. More preferably, R 8 is hydrogen, cyano or bromine. Even more preferably, R 8 is hydrogen.
  • R 9 is selected from hydrogen, halogen, C1-C3 alkyl, C1-C2 haloalkyl, C1-C3 haloalkoxy, Ci- 04 alkoxy, Ci-Csalkenyloxy, Ci-Csalkynyloxy, Ci-C2alkylsulfanyl, C1-C2 alkylsulfinyl, C1-C2 alkylsulfonyl, C1-C2 alkoxy-Ci-C2 alkyl, Ci-Csalkoxycarbonyl, Ci-C2alkylcarbonyl, Ci-C2alkylaminocarbonyl, di(Ci- C2alkyl)aminocarbonyl, cyano-Ci-C2alkyl, N-C1-C2 alkoxy-C-Ci-C2 alkyl-carbonimidoyl, N-hydroxy-C-Ci- C2alkyl-carbonimidoyl, hydroxy
  • R 9 is hydrogen, chloro, bromo, fluoro, cano, methyl, methoxy, propoxy, allyloxy, methoxymethyl, 2- methoxyethoxymethyl, phenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, [4-(trifluoromethyl)pyrazol-1- yl], [3-(trifluoromethyl)pyrazol-1-yl], 3-cyanopyrazol-1-yl, 4-cyanopyrazol-1-yl, 5-chloropyrazol-1-yl, 4- chloropyrazol-1-yl, 3-chloropyrazol-1-yl, 5-fluoropyrazol-1-yl, 4-fluoropyrazol-1-yl, 3-fluoropyrazol-1-yl, 3,5- dimethylpyrazol-1-yl, 5-methylpyrazol-1-yl, 4-methylpyrazol-1-yl, 3-methylpyrazol-1-yl, pyrazol-1-yl
  • B 1 is CR 10 and B 2 is CR 11 or B 1 is N and B 2 is CR 11 or B 1 is CR 10 and B 2 is N.
  • B 1 is CR 10 and B 2 is CR 11 .
  • R 10 and R 11 are independently selected from hydrogen, halogen, hydroxy, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C2-C4alkenyloxy, C2-C4 alkynyloxy, C1-C4 alkylsulfanyl, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, Ci-C4 alkoxy-Ci-C4 alkyl, N- C1-C4 alkylamino, N,N- di C1-C4 alkylamino, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl, Ci-C2alkylaminocarbonyl, di(Ci- C2alkyl)aminocarbonyl, cyano-Ci-C4alkyl, N-C1
  • R 10 and R 11 are independently selected from hydrogen, chloro, bromo, fluoro, cyano, methyl, methoxy, propoxy, allyloxy, methoxymethyl, 2-methoxyethoxymethyl, phenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, [4- (trifluoromethyl)pyrazol-l-yl], [3-(trifluoromethyl)pyrazol-1-yl], 3-cyanopyrazol-1-yl, 4-cyanopyrazol-1-yl, 5- chloropyrazol-1-yl, 4-chloropyrazol-1-yl, 3-chloropyrazol-1-yl, 5-fluoropyrazol-1-yl, 4-fluoropyrazol-1-yl, 3- fluoropyrazol-1-yl, 3,5-dimethylpyrazol-1-yl, 5-methylpyrazol-1-yl, 4-methylpyrazol-1-yl, 3-methylpyrazol-1-yl,
  • R 10 and R 11 are independently selected from hydrogen, chlorine, bromine, or cyano.
  • R 10 and R 11 are independently selected from hydrogen, halogen, C1-C3 alkyl, or Ci-Cs alkoxy.
  • R 10 and R 11 are independently selected from hydrogen or halogen. More preferably R 10 and R 11 are hydrogen, bromine, or chlorine. Even more preferably R 10 and R 11 are hydrogen.
  • a 1 , A 2 and A 3 are independently selected from CR 12 , N, NR 13 , O or S, with the proviso that at least one of A 1 , A 2 and A 3 is selected from N, O or S, and that no more than one of A 1 , A 2 and A 3 is O or S.
  • a 1 and A 2 are independently selected from CR 12 , N or O
  • a 3 is CR 12 , N, O or S, with the proviso that at least one of A 1 , A 2 and A 3 is selected from N, O or S, and that no more than one of A 1 , A 2 and A 3 is O or S.
  • a 1 and A 2 are independently selected from N or O; and A 3 is CR 12 , O or S, with the proviso that at least one of A 1 , A 2 and A 3 is N or O, and that no more than one of A 1 , A 2 and A 3 is O.
  • R 12 is hydrogen or C1-C4 alkyl.
  • R 12 is hydrogen or methyl. More preferably R 12 is hydrogen.
  • R 13 is hydrogen or C1-C4 alkyl.
  • R 13 is hydrogen or methyl. More preferably R 13 is hydrogen.
  • Z 1 is selected from a 6-membered heteroaryl; wherein any of said 6- membered heteroaryl contains 1 or 2 heteroatoms selected from N; and wherein any of said 6-membered heteroaryl is unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from halogen, cyano, C1-C4 alkyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylsulfanyl, C1-C4 alkylsulfinyl, or C1-C4 alkylsulfonyl.
  • Z 1 is selected from a 6-membered heteroaryl, wherein any of said 6-membered heteroaryl contains 1 or 2 heteroatoms selected from N; and wherein any of said 6-membered heteroaryl is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, or C1-C4 alkoxy.
  • Z 1 is selected from a 6-membered heteroaryl, wherein any of said 6-membered heteroaryl contains 1 or 2 heteroatoms selected from N; and wherein any of said 6-membered heteroaryl is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen or C1-C4 haloalkyl. More preferably Z 1 is selected from a 6-membered heteroaryl, wherein any of said 6-membered heteroaryl contains 1 or 2 heteroatoms selected from N; and wherein any of said 6-membered heteroaryl is unsubstituted or substituted with 1 or 2 substituents selected from fluorine.
  • Z 1 is selected from a 6-membered heteroaryl; wherein any of said 6- membered heteroaryl contains 1 heteroatom selected from N; and wherein any of said 6-membered heteroaryl is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, or C1-C4 alkoxy.
  • Z 1 is selected from a 6-membered heteroaryl, wherein any of said 6-membered heteroaryl contains 1 heteroatom selected from N; and wherein any of said 6-membered heteroaryl is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen or C1-C4 haloalkyl. More preferably Z 1 is selected from a 6-membered heteroaryl; wherein any of said heteroaryl contains 1 heteroatom selected from N; and wherein any of said 6-membered heteroaryl is unsubstituted or substituted with 1 or 2 substituents selected from fluorine.
  • Z 1 is selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazin-2-yl, pyridazin-3-yl, pyridazin- 4-yl, pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-yl; wherein any of said pyridyl-, pyrazin- pyridazine, or pyrimidin-moities are unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from halogen, C1-C4 haloalkyl, cyano, C1-C4 alkyl, C2-C4 alkynyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylsulfanyl, C1-C4 alkylsulfinyl, or Ci-C4 alkylsulfonyl.
  • Z 1 is selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazin- 2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-yl; wherein any of said pyridyl-, pyrazin- pyridazine or pyrimidin-moities are unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from halogen, C1-C4 haloalkyl, or C1-C4 alkyl.
  • Z 1 is selected from 2- pyridyl, 3-pyridyl, 4-pyridyl, pyrazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-yl; wherein any of said pyridyl-, pyrazin- pyridazine or pyrimidin-moities are unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from fluorine, trifluoromethyl, difluoromethyl, or methyl.
  • Z 1 is selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazin-2-yl, pyridazin-3-yl, pyridazin- 4-yl, pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-yl; wherein any of said pyridyl-, pyrazin- pyridazine or pyrimidin-moities are unsubstituted or substituted with 1 or 2 substituents selected from fluorine.
  • Z 1 is selected from 5-fluoropyrimidin-4-yl, 3,6-difluoro- 2-pyridyl, 4,6-difluoro-2-pyridyl, 4,5-difluoro-2-pyridyl, 5,6-difluoro-2-pyridyl, 3-fluoro-4-pyridyl, 2-fluoro-4- pyridyl, 2,3-difluoro-4-pyridyl, 2,5-difluoro-4-pyridyl, 2,6-difluoro-4-pyridyl, 3,5-difluoro-4-pyridyl, 2,5-difluoro-4- pyridyl, 2-fluoro-3-pyridyl, 6-fluoro-3-pyridyl, 5-fluoro-3-pyridyl, 4-fluoro-3-pyridyl, 2,6-difluoro-3-pyridyl,
  • Z 1 is selected from 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 6-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, 3,5-difluoro-2-pyridyl, 2-fluoro-4-pyridyl, 5-fluoropyrimidin-4-yl, 5-fluoropyrimidin-2-yl, 4-fluoropyridazin-3-yl, 5- fluoropyridazin-3-yl, 4,5-difluoropyridazin-3-yl, or 5-fluoropyridazin-4-yl.
  • Z 1 is selected from 3- fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, 3,5-difluoro-2-pyridyl, 4-fluoropyridazin-3-yl, 4,5- difluoropyridazin-3-yl or 5-fluoropyridazin-4-yl. Most preferably Z 1 is selected from 3-fluoro-2-pyridyl, 5-fluoro- 2-pyridyl, 3,4-difluoro-2-pyridyl, or 3,5-difluoro-2-pyridyl.
  • the present invention accordingly, makes available a compound of formula (I) having R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , B 1 , B 2 , A 1 , A 2 , A 3 and Z 1 as defined above in all combinations / each permutation.
  • Embodiments according to the invention are provided as set out below.
  • R 1 is methyl, R 2 is hydrogen, chlorine, or methyl;
  • R 3 is hydrogen
  • R 4 is hydrogen, or methyl
  • R 5 and R 6 are hydrogen
  • R 7 is hydrogen, C1-C4 alkyl, or Cs-Ce-cycloalkyl
  • R 8 is hydrogen, bromine, chlorine, or cyano
  • R 9 is hydrogen, bromine, chlorine, cyano, methyl, or methoxy
  • B 1 is N or CR 10 , wherein R 10 is hydrogen, bromine, chlorine, or cyano;
  • B 2 is N or CR 11 , wherein R 11 is hydrogen, bromine, chlorine, or cyano;
  • a 1 , A 2 , A 3 and Z 1 are as defined for the compounds of formula (I) according to the present invention.
  • R 1 is methyl
  • R 2 is hydrogen, chlorine, or methyl
  • R 3 is hydrogen
  • R 4 is hydrogen, or methyl
  • R 5 and R 6 are hydrogen
  • R 7 is hydrogen, C1-C4 alkyl, or Cs-Ce-cycloalkyl
  • R 8 is hydrogen, bromine, chlorine, or cyano
  • R 9 is hydrogen, bromine, chlorine, cyano, methyl, or methoxy
  • B 1 is N or CR 10 , wherein R 10 is hydrogen, bromine, chlorine, or cyano;
  • B 2 is N or CR 11 , wherein R 11 is hydrogen, bromine, chlorine, or cyano;
  • Z 1 is 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-yl; wherein any of said pyridyl-, pyrazin- pyridazine or pyrimidin-moities are unsubstituted or substituted with 1 or 2 substituents selected from fluorine; and
  • a 1 , A 2 and A 3 are as defined for the compounds of formula (I) according to the present invention.
  • the compound of formula (I) may be a compound of formula (l-A) wherein
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , B 1 and B 2 and Z 1 are as defined for the compounds of formula (I) according to the present invention, and A is selected from A1 to A36:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , B 1 , B 2 and Z 1 are as defined for the compounds of formula (I) according to the present invention, and R 12a , R 13a , R 14a , R 12b , R 13b and R 14b are independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl.
  • R 12a , R 13a and R 14a are hydrogen.
  • R 12a , R 13a and R 14a are hydrogen.
  • R 14a is selected from hydrogen or C1-C4 alkyl.
  • R 14a is hydrogen.
  • R 14a is hydrogen.
  • R 12a , R 13a , R 14a , R 12b , R 13b and R 14b are independently selected from hydrogen or methyl.
  • R 12a , R 13a , R 14a , R 12b , R 13b and R 14b are hydrogen.
  • R 12a , R 13a , R 14a , R 12b , R 13b and R 14b are methyl.
  • the compound of formula (l-A) is selected from A4, A7 or A9, and R 14a is hydrogen.
  • the compound of formula (l-A) may be a compound of formula (I-A1) wherein R 1 is methyl, B 1 is CH, and A is defined as for compound (l-A), wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , B 2 and Z 1 are as defined for the compounds of formula (I) according to the present invention.
  • a compound of formula (I-A1) wherein B 2 is N, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and Z 1 are as defined for the compounds of formula (I) according to the present invention.
  • a compound of formula (I-A1) wherein B 2 is CR 11 , and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 11 and Z 1 are as defined for the compounds of formula (I) according to the present invention.
  • the compound of formula (l-A) may be a compound of formula (I-A2) wherein B 1 is CH; R 1 is methyl, R 3 , R 5 and R 6 are hydrogen; and A is defined as for compound (l-A); and wherein R 2 , R 4 , R 7 , R 8 , R 9 , B 2 and Z 1 are as defined for the compounds of formula (I) according to the present invention.
  • R 2 is hydrogen, methyl or chlorine
  • R 4 is hydrogen or methyl
  • R 7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl
  • R 8 is hydrogen, cyano, or bromine
  • R 9 is hydrogen or methoxy
  • B 2 is CR 11 , wherein R 11 is hydrogen
  • a and Z 1 are as defined for the compounds of formula (I) according to the present invention.
  • R 2 is hydrogen, methyl, or chlorine
  • R 4 is hydrogen or methyl
  • R 7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl
  • R 8 is hydrogen, cyano, or bromine
  • R 9 is hydrogen or methoxy
  • B 2 is CR 11 , wherein R 11 is hydrogen
  • A is A4, A7 or A9;
  • Z 1 is as defined for the compounds of formula (I) according to the present invention.
  • R 2 is hydrogen, methyl, or chlorine
  • R 4 is hydrogen or methyl
  • R 7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl
  • R 8 is hydrogen, cyano, or bromine
  • R 9 is hydrogen or methoxy
  • B 2 is CR 11 , wherein R 11 is hydrogen
  • A is A4, A7 or A9;
  • Z 1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, 3,5-difluoro-2-pyridyl, 4-fluoropyridazin-3-yl, 4,5-difluoropyridazin-3-yl, or 5-fluoropyridazin-4-yl.
  • the compound of formula (l-A) may be a compound of formula (I-A3) wherein R 1 is methyl; B 1 and B 2 are CH; and A is defined as for compound (l-A), and wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and Z 1 are as defined for the compounds of formula (I) according to the present invention.
  • the compound of formula (l-A) may be a compound of formula (I-A4) wherein B 1 and B 2 are CH; R 1 is methyl; R 3 , R 4 , R 5 and R 6 are hydrogen and A is defined as for compound
  • R 2 is hydrogen, methyl or chlorine
  • R 7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl
  • R 8 is hydrogen, cyano, or bromine
  • R 9 is hydrogen, or methoxy
  • a and Z 1 are as defined for the compounds of formula (I) according to the present invention.
  • R 2 is hydrogen, methyl, or chlorine
  • R 7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl
  • R 8 is hydrogen, cyano, or bromine
  • R 9 is hydrogen, or methoxy
  • A is A4, A7, or A9;
  • Z 1 is as defined for the compounds of formula (I) according to the present invention.
  • R 2 is hydrogen, methyl, or chlorine
  • R 7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl
  • R 8 is hydrogen, cyano, or bromine
  • R 9 is hydrogen, or methoxy
  • A is A4, A7, or A9;
  • Z 1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, 3,5-difluoro-2-pyridyl, 4-fluoropyridazin-3-yl, 4,5-difluoropyridazin-3-yl, or 5-fluoropyridazin-4-yl.
  • R 2 is hydrogen, methyl, or chlorine
  • R 7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl
  • R 8 is hydrogen, cyano, or bromine
  • R 9 is hydrogen, or methoxy
  • A is A4, A7, or A9;
  • Z 1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, or 3,5-difluoro-2-pyridyl.
  • the compound of formula (l-A) may be a compound of formula (I-A5) wherein R 1 is methyl; R 4 is methyl; R 3 , R 4 , R 5 and R 6 are hydrogen; B 1 and B 2 are CH; and A is defined as for compound (l-A), racemic syn-(l-A5) and wherein R 2 , R 7 , R 8 , R 9 and Z 1 are as defined for the compounds of formula (I) according to the present invention, and wherein when R 7 is not hydrogen the stereochemistry of the pyrazole-derivative-substituent and R 7 at the carbons with the “*” have a syn-relationship to each other.
  • R 2 is hydrogen, methyl, or chlorine
  • R 7 is methyl, cyclopropyl, or 1 -cyanocyclopropyl
  • R 8 is hydrogen, cyano, or bromine
  • R 9 is hydrogen, or methoxy
  • a and Z 1 are as defined for the compounds of formula (I) according to the present invention.
  • R 2 is hydrogen, methyl, or chlorine
  • R 7 is methyl, cyclopropyl, or 1 -cyanocyclopropyl
  • R 8 is hydrogen, cyano, or bromine
  • R 9 is hydrogen, or methoxy
  • A is A4, A7, or A9;
  • Z 1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, 3,5-difluoro-2-pyridyl, 4-fluoropyridazin-3-yl, 4,5-difluoropyridazin-3-yl, or 5-fluoropyridazin-4-yl.
  • R 2 is hydrogen, methyl, or chlorine
  • R 7 is methyl, cyclopropyl, or 1 -cyanocyclopropyl
  • R 8 is hydrogen, cyano, or bromine
  • R 9 is hydrogen, or methoxy
  • A is A4, A7, or A9;
  • Z 1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, or 3,5-difluoro-2-pyridyl.
  • the compound of formula (l-A) may be a compound of formula (l-B) wherein R 1 is methyl; R 3 , R 5 , R 6 are hydrogen; B 1 and B 2 are CH; and A is A4 and wherein R 2 , R 4 , R 7 , R 8 , R 9 and Z 1 are as defined for the compounds of formula (I) according to the present invention.
  • R 2 is hydrogen, methyl, or chlorine
  • R 4 is hydrogen, or methyl
  • R 7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl
  • R 8 is hydrogen, cyano, or bromine
  • R 9 is hydrogen, or methoxy
  • Z 1 is as defined for the compounds of formula (I) according to the present invention.
  • R 2 is hydrogen, methyl, or chlorine
  • R 4 is hydrogen, or methyl
  • R 7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl
  • R 8 is hydrogen, cyano, or bromine
  • R 9 is hydrogen, or methoxy
  • Z 1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, 3,5-difluoro-2-pyridyl, 4-fluoropyridazin-3-yl, 4,5-difluoropyridazin-3-yl, or 5-fluoropyridazin-4-yl.
  • R 2 is hydrogen, methyl, or chlorine
  • R 4 is hydrogen, or methyl
  • R 7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl
  • R 8 is hydrogen, cyano or bromine
  • R 9 is hydrogen or methoxy
  • Z 1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl or 3,5-difluoro-2-pyridyl.
  • R 2 is hydrogen, methyl or chlorine
  • R 4 is hydrogen
  • R 7 is methyl, cyclopropyl, or 1 -cyanocyclopropyl
  • R 8 is hydrogen, cyano, or bromine
  • R 9 is hydrogen or methoxy
  • Z 1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, or 3,5-difluoro-2-pyridyl.
  • the compound of formula (l-A) may be a compound of formula (l-C) wherein R 1 is methyl; R 3 , R 5 , R 6 are hydrogen; B 1 and B 2 are CH; and A is A7 and wherein R 2 , R 4 , R 7 , R 8 , R 9 and Z 1 are as defined for the compounds of formula (I) according to the present invention.
  • R 2 is hydrogen, methyl, or chlorine
  • R 4 is hydrogen or methyl
  • R 7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl
  • R 8 is hydrogen, cyano, or bromine
  • R 9 is hydrogen or methoxy
  • Z 1 is as defined for the compounds of formula (I) according to the present invention.
  • R 2 is hydrogen, methyl, or chlorine
  • R 4 is hydrogen or methyl
  • R 7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl
  • R 8 is hydrogen, cyano, or bromine
  • R 9 is hydrogen or methoxy
  • Z 1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, 3,5-difluoro-2-pyridyl, 4-fluoropyridazin-3-yl, 4,5-difluoropyridazin-3-yl, or 5-fluoropyridazin-4-yl.
  • R 2 is hydrogen, methyl, or chlorine
  • R 4 is hydrogen or methyl
  • R 7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl
  • R 8 is hydrogen, cyano, or bromine
  • R 9 is hydrogen or methoxy
  • Z 1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, or 3,5-difluoro-2-pyridyl.
  • the compound of formula (l-A) may be a compound of formula (l-D) wherein R 1 is methyl; R 3 , R 5 , R 6 are hydrogen; B 1 and B 2 are CH; and A is A9 and wherein R 2 , R 4 , R 7 , R 8 , R 9 and Z 1 are as defined for the compounds of formula (I) according to the present invention.
  • R 2 is hydrogen, methyl, or chlorine
  • R 4 is hydrogen or methyl
  • R 7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl
  • R 8 is hydrogen, cyano, or bromine
  • R 9 is hydrogen or methoxy
  • Z 1 is as defined for the compounds of formula (I) according to the present invention.
  • R 2 is hydrogen, methyl, or chlorine
  • R 4 is hydrogen or methyl
  • R 7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl
  • R 8 is hydrogen, cyano, or bromine
  • R 9 is hydrogen or methoxy
  • Z 1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, 3,5-difluoro-2-pyridyl, 4-fluoropyridazin-3-yl, 4,5-difluoropyridazin-3-yl, or 5-fluoropyridazin-4-yl.
  • R 2 is hydrogen, methyl, or chlorine
  • R 4 is hydrogen or methyl
  • R 7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl
  • R 8 is hydrogen, cyano or bromine
  • R 9 is hydrogen or methoxy
  • Z 1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, or 3,5-difluoro-2-pyridyl.
  • the intermediate compounds of formula (lib) possess the same definitions for A 1 , A 2 , A 3 and Z 1 as for the compounds of formula (I) according to the invention and their corresponding preferences.
  • R° is C1-C4 alkyl
  • a 1 , A 2 , A 3 and Z 1 are as defined forthe compounds of formula (I) according to the present invention.
  • the compound of formula (lib) may be a compound of formula (llb-1): wherein
  • Z 1 is as defined for the compounds of formula (I) according to the present invention; R° is as defined for compounds of formula (lib); and A is selected from A1 to A36 as defined above for compounds of formula (I- A).
  • R 14a is selected from hydrogen or C1-C4 alkyl, wherein Z 1 is as defined for the compounds of formula (I) according to the present invention, and R° is as defined for compounds of formula (lib).
  • R 14a is hydrogen.
  • R 14a is selected from hydrogen or C1-C4 alkyl, wherein Z 1 is as defined for the compounds of formula (I) according to the present invention, and R° is as defined for compounds of formula (lib).
  • R 14a is hydrogen.
  • A is A4;
  • Z 1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4- difluoro-2-pyridyl, or 3,5-difluoro-2-pyridyl; and R° is as defined for compounds of formula (lib).
  • A is A7;
  • Z 1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4- difluoro-2-pyridyl, or 3,5-difluoro-2-pyridyl; and R° is as defined for compounds of formula (lib).
  • A is A9;
  • Z 1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4- difluoro-2-pyridyl or 3,5-difluoro-2-pyridyl;
  • R 14a is hydrogen, and R° is as defined for compounds of formula (Hb).
  • the presence of one or more possible asymmetric carbon atoms in any of the compounds selected from compounds of formula (I), (l-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (l-B), (l-C), or (l-D), or compounds selected from compounds listed in Tables A-1 to A-26, or compounds listed in Table P (below), according to the invention means that the compounds may occur in chiral isomeric forms, i.e., enantiomeric or diastereomeric forms.
  • the compound of formula (I) according to the invention is selected from compounds listed in any one of Tables A-1 to A-26.
  • the compound of formula (I) according to the invention is selected from [4-(1-methylpyrazol-4-yl)-3,4-dihydro-1 H-isoquinolin-2-yl]-[5-(4-pyridyl)isoxazol-3-yl]methanone (P-1), [4-(1-methylpyrazol-4-yl)-3,4-dihydro-1 H-isoquinolin-2-yl]-[5-(3-pyridyl)isoxazol-3-yl]methanone (P-2), [4-(1-methylpyrazol-4-yl)-3,4-dihydro-1 H-isoquinolin-2-yl]-[5-(2-pyridyl)isoxazol-3-yl]methanone (P-3), [5-(6-methoxy-3-pyridyl)isoxazol-3-yl]-[4-(1-methylpyrazol-4-yl]
  • compounds of formula (I) may be prepared by a person skilled in the art following known methods. More specifically, compounds of formula (I) may be prepared from compounds of formula (III) or a salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , B 1 and B 2 are as defined for the compounds of formula (I) by reaction with a compound of formula (II), wherein A 1 , A 2 , A 3 and Z 1 are as defined for the compounds of formula (I). This reaction is shown in Scheme 1.
  • compounds of formula (Ila), where X° is halogen are formed by treatment of compounds of formula (II) with, for example, oxalyl chloride or thionyl chloride in the presence of catalytic quantities of N,N-dimethylformamide (DMF) in inert solvents such as methylene dichloride or tetrahydrofuran (THF) at temperatures between 20°C to 100°C, preferably 25°C.
  • DMF N,N-dimethylformamide
  • inert solvents such as methylene dichloride or tetrahydrofuran (THF)
  • compounds of formula (I) may be prepared by treatment of compounds of formula (II) with dicyclohexyl carbodiimide (DCC), 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC) or 1-[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate (HATU) to give the activated compound of formula (Ila), wherein X° is G 1 , G 2 or G 3 as set forth in Scheme 1 a, in an inert solvent, e.g.
  • DCC dicyclohexyl carbodiimide
  • EDC 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide
  • HATU 1-[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium
  • Compounds of formula (II) can be prepared from compounds of formula (lib), wherein A 1 , A 2 , A 3 are N and Z 1 are as described in formula (I), and R° is Ci-C4alkyl, by ester hydrolysis.
  • a variety of conditions can be used, as for example aqueous sodium hydroxide or lithium hydroxide, and an organic water miscible solvent like THF, dimethoxyethane, methanol, or ethanol.
  • ester hydrolyses are well known to those skilled in the art.
  • compounds of formula (Illa), wherein R 4 and R 6 are hydrogen, R 5 is hydrogen or methyl and R 1 , R 2 , R 3 , R 7 , R 8 , R 9 , R 10 , R 11 , B 1 and B 2 are as defined for the compounds of formula (I), may be prepared from compounds of formula (IVa), wherein R 4 and R 6 are hydrogen, R 5 is hydrogen or methyl and R 1 , R 2 , R 3 , R 7 , R 8 , R 9 , R 10 , R 11 , B 1 and B 2 are as defined for the compounds of formula (I), by treatment with a reducing agent such as NaBHsCN and an acid, for example hydrochloric acid, or acetic acid in a protic solvent such as methanol or ethanol and the like.
  • a reducing agent such as NaBHsCN
  • an acid for example hydrochloric acid, or acetic acid in a protic solvent such as methanol or ethanol and the like.
  • compounds of formula (Illa) may be prepared from compounds of formula (IVa) by reduction with hydrogen in the presence of a suitable metal catalyst, such as Pd, Ir, Rh with a suitable ligand, e.g. diphosphine [1 ,2-bis(diphenylphosphino)ethane (dppe), 1 ,3-bis(diphenylphosphino)propane (dppp) or 1 ,4- bis(diphenylphosphino)butane (dppb)]. Similar reactions have been reported for example in React. Kinet. Cat. Lett. 2007, 92, 99-104. This reaction is shown in Scheme 2.
  • compounds of formula (lllb), wherein R 4 , R 6 and R 7 are hydrogen, R 5 is hydrogen or methyl and R 1 , R 2 , R 3 , R 8 , R 9 , R 10 , R 11 , B 1 and B 2 are as defined for the compounds of formula (I), can be converted to compounds of formula (V), wherein R 4 , R 6 and R 7 are hydrogen, R 5 is hydrogen or methyl and R 1 , R 2 , R 3 , R 8 , R 9 , R 10 , R 11 , B 1 and B 2 are as defined for the compounds of formula (I), by treatment of compounds of formula (lllb) with a compound of formula (VI), wherein X° is a leaving group, such as halogen, and R° is Ci-Cealkyl, by methods known to a person skilled in the art and by those described in Scheme 1 .
  • compounds of formula (V) may be prepared by treatment with an anhydride of formula (R°CO)2O, wherein R° is Ci-Cealkyl, in an inert solvent such as methylene chloride, THF or 2-methyl-THF, optionally in the presence of a base, such as triethylamine or dimethylaminopyridine, at temperatures between 0°C and 60°C.
  • R°CO anhydride of formula (R°CO)2O, wherein R° is Ci-Cealkyl
  • an inert solvent such as methylene chloride, THF or 2-methyl-THF
  • a base such as triethylamine or dimethylaminopyridine
  • a base for example an alkyl metal base, such as tert-butyl lithium, and an additive such as /V,/V,/V,/V'-tetramethylethylendiamine (TMEDA) at low temperature, for example -78°C to room temperature, in an inert polar solvent such as THF or 2-methyl-THF.
  • a base for example an alkyl metal base, such as tert-butyl lithium
  • TEDA /V,/V,/V,/V'-tetramethylethylendiamine
  • Compounds of formula (Va) may be converted to compounds of formula (Illa), wherein R 4 and R 6 are hydrogen, R 5 is hydrogen or methyl and R 1 , R 2 , R 3 , R 7 , R 8 , R 9 , R 10 , R 11 , B 1 and B 2 are as defined for the compounds of formula (I), by methods known to a person skilled in the art.
  • compounds of formula (Va), wherein R° is tert-butyl may be treated with an organic or inorganic acid such as trifluoroacetic acid or HCI to give compounds of formula (Illa). This reaction is shown in Scheme 4.
  • Suzuki-Miyaura cross-coupling reactions between compounds of formula (VIII) and compound of formula (VII) are well known to a person skilled in the art and are usually carried out in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)-palladium(0) or [1 ,1 '-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride dichloromethane complex, and a base, such as sodium or potassium carbonate, in a solvent, such as N,N-dimethylformamide, dioxane or dioxane-water mixtures, at temperatures between room temperature and 160°C, optionally under microwave heating conditions, and preferably under inert atmosphere.
  • a palladium catalyst such as tetrakis(triphenylphosphine)-palladium(0) or [1 ,1 '-bis(diphenylphosphino)ferrocene]palladium(ll) dich
  • a further cross-coupling chemistry namely C-H activation, can also be used to prepare compounds of formula (IVa), wherein R 4 and R 6 are hydrogen, R 5 is hydrogen or methyl and R 1 , R 2 , R 3 , R 7 , R 8 , R 9 , B 1 and B 2 are as defined for the compounds of formula (I) (Scheme 7).
  • compounds of formula (III) may be prepared from compounds of formula (XVI) (Scheme 8).
  • compounds of formula (III) may be prepared by a person skilled in the art by a carbamate deprotection reaction of compounds of formula (XVI), wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , B 1 and B 2 are as defined for the compounds of formula (I) and R 01 may be a member of a common carbamate protecting group substituent, for example methyl, te/Y-butyl, allyl, 2,2,2-trichloroethyl or benzyl.
  • R 01 is methyl
  • a suitable solvent such as dichloromethane and a suitable reagent such as iodotrimethylsilane may be employed to afford the product upon heating at temperatures between room temperature and 200°C, preferably between 20°C and the boiling point of the reaction mixture as described, for example, in J. Am. Chem. Soc. 1992, 114, 5959.
  • the compounds of formula (III) thus obtained are converted to compounds of formula (I) (Scheme 1).
  • Grignard reagents R 5 MgBr or R 6 MgBr, wherein R 5 and R 6 are as defined for the compounds of formula (I) may be added as nucleophiles to compounds of formula (XII), sequentially or simultaneously, to allow more highly substituted amines of formula (XIII) to be prepared.
  • Such Grignard additions to nitriles are carried out in an inert solvent such as diethyl ether, tert-butylmethyl ether, and cyclopentyl methyl ether in the presence of a Lewis acid such as Ti(O-'Pr)4 (see Synlett 2007, (4), 652-654). This reaction is shown in Scheme 11.
  • compounds of formula (XII), wherein R 1 , R 2 , R 3 , R 8 , R 9 , B 1 and B 2 are as defined for the compounds of formula (I) and R 4 is different from hydrogen may be prepared by a person skilled in the art by deprotonation of compound of formula (Xlla) wherein R 1 , R 2 , R 3 , R 8 , R 9 , B 1 and B 2 are as defined for the compounds of formula (I), using a strong base such as n-butyl lithium or sodium hydride at cryogenic temperatures in an inert solvent such as tetrahydrofuran, followed by addition of a suitable alkylating agent R 4 - X, wherein R 4 is Ci-C4alkyl and X is halogen, for example iodomethane.
  • a strong base such as n-butyl lithium or sodium hydride
  • an inert solvent such as tetrahydrofuran
  • Compounds of formula (Xlla), wherein R 1 , R 2 , R 3 , R 8 , R 9 , B 1 and B 2 are as defined for the compounds of formula (I), may be prepared from alcohols of formula (XVII) by treatment with cyanotrimethylsilane (TMSCN) in the presence of a base such as lithium carbonate in a nonpolar solvent such as dichloromethane at temperatures between 0°C and the boiling point of the reaction mixture.
  • TMSCN cyanotrimethylsilane
  • a base such as lithium carbonate
  • a nonpolar solvent such as dichloromethane
  • R 1 is Ci-C4alkyl
  • R 2 is hydrogen, halogen, or Ci-C4alkyl
  • R 3 is hydrogen
  • R 4 is hydrogen or Ci-C4alkyl
  • R 5 , R 6 , R 7 are hydrogen or Ci-C4alkyl
  • R 8 , R 9 , R 10 , and R 11 are as previously defined, with strong acids, for example sulphuric, hydrochloric, hydrobromic, trifluoroacetic, trifllic, or methane sulphonic acids and the like, or Lewis acids, such as aluminium trichloride, or bismuth (I I l)triflate , in an inert solvent such as chlorobenzene, nitrobenzene at temperature between 0°C to 180°C to yield compounds of formula (lllc).
  • strong acids for example sulphuric, hydrochloric, hydrobromic, trifluoroacetic, trifllic, or methane sulphonic acids and the like
  • a benzyl amine of formula (XXI) is used to alkylate a compound of formula (XXII), in the presence of a base, such as EtsN in an inert solvent, such as DMF.
  • a base such as EtsN
  • an inert solvent such as DMF.
  • the compound (XXIII) so obtained may be isolated, or treated directly with BOC-anhydride in situ, to give a compound of formula (XXIV).
  • Compound of formula (XXIV) can be reduced with a hydride source (e.g., NaBH4 in MeOH/THF) to give the target molecule (XVI 11 b) , which can then be cyclized with, for example with camphor sulphonic acid in EtOAc, to give compounds of formula (XlXb).
  • a hydride source e.g., NaBH4 in MeOH/THF
  • compounds of formula (XXIV) can be reacted with a Grignard reagent R 4 MgBr in an inert ethereal solvent (e.g., THF) to give compounds of formula (XVI Ila), which can the cyclized with camphorsulphonic acid in, e.g. EtOAc, to give compounds of formula (XIXa).
  • R 1a is Ci-C4alkyl
  • R 2a is hydrogen, halogen, or Ci-C4alkyl
  • R 4a is hydrogen or Ci- C4alkyl
  • R 5a , R 6a , and R 7a are hydrogen or C1-C4 alkyl
  • R 8 , R 9 , R 10 , and R 11 are as defined for the compounds of formula (I).
  • a further aspect of this Friedel-Crafts chemistry should be noted. If the chemistry is carried out starting with a chiral amine (XXIa), e.g., R 7 is Ci-C4alkyl, the stereochemistry is retained in the final compounds of formula (I). This is illustrated below in Scheme 16, for when R 7 is methyl:
  • compounds of formula (lie) wherein Z 1 is as defined for the compounds of formula (I), and X 05 is C1-C4 alkyl may be prepared by hydrolysis of compounds of formula (lib) by treatment with, for example, an alkaline earth metal hydroxide in water, or with a water miscible organic solvent, such as THF, methanol, ethanol and the like.
  • a water miscible organic solvent such as THF, methanol, ethanol and the like.
  • Compounds of formula (lib) can be obtained by the treatment of compounds of formula (XXVII) wherein Z 1 is as defined for the compounds of formula (I) and X 05 is C1-C4 alkyl with hydroxylamine hydrochloride in a polar solvent, for example ethanol and optionally in the presence of a base, e.g., triethyl amine, K2CO3 and the like.
  • a polar solvent for example ethanol
  • a base e.g., triethyl amine, K2CO3 and the like.
  • Compounds of formula (XXVIII) wherein Z 1 is as defined for the compounds of formula (I) may be also prepared by “one-pot” synthesis via Pd-catalyzed cyanation and amidoximation of compound of formula (XXX) wherein Z 1 is as defined for the compounds of formula (I), using potassium ferrocyanide trihydrate and hydroxylamine hydrochloride as described in for example Org. Biomol. Chem. 2015, 13(9), 2541-2545.
  • Scheme 19 As shown in Scheme 19, compounds of formula (llg) and (Hi) are obtained by ester hydrolysis of (Ilf) and (llg), respectively. In the latter compounds, X 05 and Z 1 are as previously described.
  • Compounds of formula (Ilf) can be obtained from compounds of formula (Ilf) by dehydration of compounds of formula (XXXI).
  • Compounds of formula (XXXI) are obtained by acylation of hydrazides of formula (XXXII) with compounds of formula (XXVIa).
  • Such sequences of reactions to produce oxadiazoles is well known to those skilled in the art. Similar reactions are described in Bioorg. Med. Chem. Let. 2005, 15, 1423-1428 and W02006/044617.
  • Compounds of formula (XXXI) can also be prepared by reaction of activated carboxylic acids of formula (XXXIIIa), wherein Z 1 is as defined for the compounds of formula (I), and X° are as described in Scheme 1 /Scheme 1 a respectively, with compounds of formula (XXXIV).
  • Compounds of formula (XXXIIIa) can be prepared from the corresponding acids of formula (XXXIII) as described in scheme 1 .
  • Such reactions are described for example in, for example, J. Prakt. Chem. 1985, 327, 109-116.
  • compounds of formula (Ilk) are readily obtained by hydrolysis of esters of formula (llj) by methods known to those skilled in the art and described vide supra.
  • Compounds of formula (llj) can be obtained by reaction of compounds of formula (XXXV) with compounds of formula (XXXVI) in the presence of an oxidizing agent, for example (diacetoxyiodo)benzene or N-chlorosuccinimide, in an inert solvent such as methanol or DMF respectively.
  • an oxidizing agent for example (diacetoxyiodo)benzene or N-chlorosuccinimide
  • an inert solvent such as methanol or DMF respectively.
  • Such reaction sequences have been described, for example, in J. Het. Chem. 2013, 50(4), 774-780 and J. Chin. Chem. Soc. 2007, 54(3), 643-652.
  • Compounds of formula (XXXV) are readily prepared from compounds of formula (XXXVII
  • Salts of compounds of formula (I) may be prepared in a manner known perse.
  • 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 tautomer’s 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, or diastereomer 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 herein below, even when stereochemical details are not mentioned specifically in each case.
  • Diastereomeric mixtures or racemic 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.
  • Enantiomeric 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, to give the di
  • Pure diastereomers or enantiomers can be obtained according to the invention not only by separating suitable isomer mixtures, but also by generally known methods of diastereoselective or enantioselective synthesis, for example by carrying out the process according to the invention with starting materials of a suitable stereochemistry.
  • compounds with more than one asymmetric carbon atoms may exist in diastereomeric forms which can be optionally separated using for example supercritical fluid chromatography (SFC) chromatography with chiral columns.
  • SFC supercritical fluid chromatography
  • Such diastereomers can show a different fungicidal activity profile, but all isomers and diastereomers form part of this invention.
  • the compounds of formula (I) have three chiral carbon atoms, (three stereocenters, wherein the star (*) indicates the chiral carbon atom), such there are eight stereoisomers available. These eight stereoisomers consist of four sets of enantiomers.
  • the compounds of formula (I), wherein R 1 is methyl, R 3 , R 4 , R 5 , R 6 are hydrogen and R 2 , R 7 , R 8 , R 9 , B 1 , B 2 , A (A 1 , A 2 , A 3 ) and Z 1 are as defined for the compounds of formula (I), and wherein R 7 is not hydrogen the pyrazole-moiety and R 7 have a syn-relationship to each other.
  • the compounds of formula (I) and, where appropriate, the tautomers thereof, in each case in free form or in salt form, can, if appropriate, also be obtained in the form of hydrates and/or include other solvents, for example those which may have been used for the crystallization of compounds which are present in solid form.
  • the compounds of formula (I) of the present invention have, for practical purposes, a very advantageous level of biological activity for protecting plants against diseases that are caused by fungi.
  • the compounds of formula (I) according to the invention can be used in the agricultural sector and related fields of use, e.g., as active ingredients for controlling plant pests or on non-living materials for the control of spoilage microorganisms or organisms potentially harmful to man.
  • the novel compounds are distinguished by excellent activity at low rates of application, by being well tolerated by plants and by being environmentally safe. They have very useful curative, preventive and systemic properties and can be used for protecting numerous cultivated plants.
  • the compounds of formula (I) can be used to inhibit or destroy the pests that occur on plants or parts of plants (fruit, blossoms, leaves, stems, tubers, roots) of different crops of useful plants, while at the same time protecting also those parts of the plants that grow later, e.g., from phytopathogenic microorganisms.
  • the present invention further relates to a method for controlling or preventing infestation of plants or plant propagation material and/or harvested food crops susceptible to microbial attack by treating plants or plant propagation material and/or harvested food crops wherein an effective amount a compound of formula (I) according to the invention is applied to the plants, to parts thereof or the locus thereof.
  • fungicide as used herein means a compound that controls, modifies, or prevents the growth of fungi.
  • fungicidally effective amount where used means the quantity of such a compound or combination of such compounds that is capable of producing an effect on the growth of fungi. Controlling or modifying effects include all deviation from natural development, such as killing, retardation and the like, and prevention includes barrier or other defensive formation in or on a plant to prevent fungal infection.
  • compounds of formula (I) may also be possible to use compounds of formula (I) according to the invention as dressing agents for the treatment of plant propagation material, e.g., seed, such as fruits, tubers or grains, or plant cuttings, for the protection against fungal infections as well as against phytopathogenic fungi occurring in the soil.
  • the propagation material can be treated with a composition comprising a compound of formula (I) before planting: seed, for example, can be dressed before being sown.
  • the active compounds of formula (I) can also be applied to grains (coating), either by impregnating the seeds in a liquid formulation or by coating them with a solid formulation.
  • the composition can also be applied to the planting site when the propagation material is being planted, for example, to the seed furrow during sowing.
  • the invention relates also to such methods of treating plant propagation material and to the plant propagation material so treated.
  • the compounds of formula (I) according to the invention can be used for controlling fungi in related areas, for example in the protection of technical materials, including wood and wood related technical products, in food storage, in hygiene management.
  • the invention could be used to protect non-living materials from fungal attack, e.g., lumber, wall boards, and paint.
  • the compounds of formula (I) according to the invention are for example, effective against fungi and fungal vectors of disease as well as phytopathogenic bacteria and viruses.
  • These fungi and fungal vectors of disease as well as phytopathogenic bacteria and viruses are for example: Absidia corymbifera, Alternaria spp., Aphanomyces spp., Ascochyta spp., Aspergillus spp. including A. flavus, A. fumigatus, A. nidulans, A. niger, A. terrus, Aureobasidium spp. including A.
  • Botryosphaeria spp. including B. dothidea, B. obtusa, Botrytis spp. including B. cinerea, Candida spp. including C. albicans, C. glabrata, C. krusei, C. lusitaniae, C. parapsilosis, C. tropicalis, Cephaloascus fragrans, Ceratocystis spp., Cercospora spp. including C.
  • capsulatum Laetisaria fuciformis, Leptographium lindbergi, Leveillula taurica, Lophodermium seditiosum, Microdochium nivale, Microsporum spp., Monilinia spp., Mucor spp., Mycosphaerella spp. including M. graminicola, M. pomi, Oncobasidium theobromaeon, Ophiostoma piceae, Paracoccidioides spp., Penicillium spp. including P. digitatum, P. italicum, Petriellidium spp., Peronosclerospora spp. Including P. maydis, P.
  • leucotricha Polymyxa graminis, Polymyxa betae, Pseudocercosporella herpotrichoides, Pseudomonas spp., Pseudoperonospora spp. including P. cubensis, P. humuli, Pseudopeziza tracheiphila, Puccinia spp. including P. hordei, P. recondita, P. striiformis, P. triticina, Pyrenopeziza spp., Pyrenophora spp., Pyricularia spp. including P. oryzae, Pythium spp. including P.
  • the compounds of formula (I) according to the invention may be used for example on turf, ornamentals, such as flowers, shrubs, broad-leaved trees, or evergreens, for example conifers, as well as for tree injection, pest management and the like.
  • target crops and/or useful plants to be protected typically comprise perennial and annual crops, such as berry plants for example blackberries, blueberries, cranberries, raspberries and strawberries; cereals for example barley, maize (corn), millet, oats, rice, rye, sorghum triticale and wheat; fibre plants for example cotton, flax, hemp, jute and sisal; field crops for example sugar and fodder beet, coffee, hops, mustard, oilseed rape (canola), poppy, sugar cane, sunflower, tea and tobacco; fruit trees for example apple, apricot, avocado, banana, cherry, citrus, nectarine, peach, pear and plum; grasses for example Bermuda grass, bluegrass, bentgrass, centipede grass, fescue, ryegrass, St.
  • perennial and annual crops such as berry plants for example blackberries, blueberries, cranberries, raspberries and strawberries
  • cereals for example barley, maize (corn), millet, oats
  • Augustine grass and Zoysia grass herbs such as basil, borage, chives, coriander, lavender, lovage, mint, oregano, parsley, rosemary, sage and thyme; legumes for example beans, lentils, peas and soya beans; nuts for example almond, cashew, ground nut, hazelnut, peanut, pecan, pistachio and walnut; palms for example oil palm; ornamentals for example flowers, shrubs and trees; other trees, for example cacao, coconut, olive and rubber; vegetables for example asparagus, aubergine, broccoli, cabbage, carrot, cucumber, garlic, lettuce, marrow, melon, okra, onion, pepper, potato, pumpkin, rhubarb, spinach and tomato; and vines for example grapes.
  • herbs such as basil, borage, chives, coriander, lavender, lovage, mint, oregano, parsley, rosemary, sage and thyme
  • legumes for example beans, lentils, peas and soya beans
  • useful plants is to be understood as also including useful plants that have been rendered tolerant to herbicides like bromoxynil or classes of herbicides (such as, for example, HPPD inhibitors, ALS inhibitors, for example primisulfuron, prosulfuron and trifloxysulfuron, EPSPS (5-enol-pyrovyl-shikimate-3-phosphate- synthase) inhibitors, GS (glutamine synthetase) inhibitors or PPO (protoporphyrinogen-oxidase) inhibitors) as a result of conventional methods of breeding or genetic engineering.
  • herbicides like bromoxynil or classes of herbicides
  • ALS inhibitors for example primisulfuron, prosulfuron and trifloxysulfuron
  • EPSPS (5-enol-pyrovyl-shikimate-3-phosphate- synthase) inhibitors
  • GS glutamine synthetase
  • PPO protoporphyrinogen-oxida
  • An example of a crop that has been rendered tolerant to imidazolinones, e.g., imazamox, by conventional methods of breeding (mutagenesis) is Clearfield® summer rape (Canola).
  • crops that have been rendered tolerant to herbicides or classes of herbicides by genetic engineering methods include glyphosate- and glufosinate-resistant maize varieties commercially available under the trade names RoundupReady®, Herculex I® and LibertyLink®.
  • useful plants is to be understood as also including useful plants which have been so transformed by the use of recombinant DNA techniques that they are capable of synthesising one or more selectively acting toxins, such as are known, for example, from toxin-producing bacteria, especially those of the genus Bacillus.
  • YieldGard® (maize variety that expresses a CrylA(b) toxin); YieldGard Rootworm® (maize variety that expresses a Cry II IB(b1 ) toxin); YieldGard Plus® (maize variety that expresses a CrylA(b) and a CrylllB(bl) toxin); Starlink® (maize variety that expresses a Cry9(c) toxin); Herculex I® (maize variety that expresses a CrylF(a2) toxin and the enzyme phosphinothricine N-acetyltransferase (PAT) to achieve tolerance to the herbicide glufosinate ammonium); NuCOTN 33B® (cotton variety that expresses a CrylA(c) toxin); Bollgard I® (cotton variety that expresses a CrylA(c) toxin); Bollgard II® (cotton variety that
  • crops is to be understood as including also crop plants which have been so transformed using recombinant DNA techniques that they are capable of synthesising one or more selectively acting toxins, such as are known, for example, from toxin-producing bacteria, especially those of the genus Bacillus.
  • Toxins that can be expressed by such transgenic plants include, for example, insecticidal proteins from Bacillus cereus or Bacillus popilliae; or insecticidal proteins from Bacillus thuringiensis, such as delta-endotoxins, e.g. CrylAb, CrylAc, Cry1 F, Cry1 Fa2, Cry2Ab, Cry3A, Cry3Bb1 or Cry9C, or vegetative insecticidal proteins (Vip), e.g. Vip1 , Vip2, Vip3 or Vip3A; or insecticidal proteins of bacteria colonising nematodes, for example Photorhabdus spp.
  • insecticidal proteins from Bacillus cereus or Bacillus popilliae such as delta-endotoxins, e.g. CrylAb, CrylAc, Cry1 F, Cry1 Fa2, Cry2Ab, Cry3A, Cry3Bb1 or Cry9C, or vegetative insecticidal proteins
  • 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
  • delta-endotoxins for example CrylAb, CrylAc, Cry1 F, Cry1 Fa2, Cry2Ab, Cry3A, Cry3Bb1 or Cry9C, or vegetative insecticidal proteins (Vip), for example Vip1 , Vip2, Vip3 or Vip3A, expressly also hybrid toxins, truncated toxins and modified toxins.
  • Hybrid toxins are produced recombinantly by a new combination of different domains of those proteins (see, for example, W002/15701).
  • Truncated toxins for example a truncated CrylAb, are known.
  • modified toxins one or more amino acids of the naturally occurring toxin are replaced.
  • amino acid replacements 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 W02003/018810).
  • Examples of such toxins or transgenic plants capable of synthesising such toxins are disclosed, for example, in EP-0374753, WO93/07278, WO95/34656, EP0427529, EP0451878 and W003/052073.
  • the toxin contained in the transgenic plants imparts to the plants tolerance to harmful insects.
  • insects can occur in any taxonomic group of insects but are especially commonly found in the beetles (Coleoptera), two-winged insects (Diptera) and butterflies (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 Cry1 Ab toxin); YieldGard Rootworm® (maize variety that expresses a Cry3Bb1 toxin); YieldGard Plus® (maize variety that expresses a CrylAb and a Cry3Bb1 toxin); Starlink® (maize variety that expresses a Cry9C toxin); Herculex I® (maize variety that expresses a Cry1 Fa2 toxin and the enzyme phosphinothricine N-acetyltransferase (PAT) to achieve tolerance to the herbicide glufosinate ammonium); NuCOTN 33B® (cotton variety that expresses a CrylAc toxin); Bollgard I® (cotton variety that expresses
  • transgenic crops are:
  • Bt1 1 Maize from Syngenta Seeds SAS, Chemin de I'Hobit 27, F-31 790 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 CrylAb toxin. Bt11 maize also transgenically expresses the enzyme PAT to achieve tolerance to the herbicide glufosinate ammonium.
  • MIR604 Maize from Syngenta Seeds SAS, Chemin de I'Hobit 27, F-31 790 St. Sauveur, France, registration number C/FR/96/05/10. Maize which has been rendered insect-resistant by transgenic expression of a modified Cry3A toxin. This toxin is Cry3A055 modified by insertion of a cathepsin-G-protease recognition sequence. The preparation of such transgenic maize plants is described in W02003/018810. 4.
  • MON 863 Maize from Monsanto Europe S.A. 270-272 Avenue de Tervuren, B-1150 Brussels, Belgium, registration number C/DE/02/9. MON 863 expresses a Cry3Bb1 toxin and has resistance to certain Coleoptera insects.
  • NK603 x MON 810 Maize from Monsanto Europe S.A. 270-272 Avenue de Tervuren, B 1150 Brussels, Belgium, registration number C/GB/02/M3/03. Consists of conventionally bred hybrid maize varieties by crossing the genetically modified varieties NK603 and MON 810.
  • NK603 x MON 810 Maize transgenically expresses the protein CP4 EPSPS, obtained from Agrobacterium sp. strain CP4, which imparts tolerance to the herbicide Roundup® (contains glyphosate), and also a CrylAb toxin obtained from Bacillus thuringiensis subsp. kurstaki which brings about tolerance to certain Lepidoptera, include the European corn borer.
  • the compounds of formula (I) according to the invention may be used in controlling or preventing phytopathogenic diseases, especially phytopathogenic fungi such as Alternaria species in fruits, vegetables and potatoes; Botrytis cinerea in strawberries, tomatoes, sunflower, pulse crops, vegetables and grapes; Rhizoctonia solani in potatoes and vegetables; Uncinula necator in grapes; Cladosporium cucumerinum, Didymella bryoniae, Sphaerotheca fuliginea and Glomerella lagenarium in cucurbits; Leveillula taurica in cucurbits and solanacious crops; Fusarium spp. in cereals; Leptosphaeria spp. in cereals; and Zymospetoria spp. in cereals.
  • phytopathogenic diseases especially phytopathogenic fungi such as Alternaria species in fruits, vegetables and potatoes; Botrytis cinerea in strawberries, tomatoes, sunflower, pulse crops, vegetables and grapes; Rhizoctonia solani in potatoes and vegetables; Uncinul
  • locus means fields in or on which plants are growing, or where seeds of cultivated plants are sown, or where seed will be placed into the soil. It includes soil, seeds, and seedlings, as well as established vegetation.
  • plants refers to all physical parts of a plant, including seeds, seedlings, saplings, roots, tubers, stems, stalks, foliage, and fruits.
  • plant propagation material is understood to denote generative parts of the plant, such as seeds, which can be used for the multiplication of the latter, and vegetative material, such as cuttings or tubers, for example potatoes.
  • vegetative material such as cuttings or tubers, for example potatoes.
  • seeds in the strict sense
  • roots in the strict sense
  • fruits in the tubers
  • bulbs rhizomes
  • parts of plants may also be mentioned.
  • Germinated plants and young plants which are to be transplanted after germination or after emergence from the soil, may also be mentioned. These young plants can be protected before transplantation by a total or partial treatment by immersion.
  • plant propagation material is understood to denote seeds.
  • the compounds of formula (I) according to the invention may be used in unmodified form or, preferably, together with the adjuvants conventionally employed in the art of formulation. To this end they may be conveniently formulated in known manner to emulsifiable concentrates, coatable pastes, directly sprayable or dilutable solutions or suspensions, dilute emulsions, wettable powders, soluble powders, dusts, granulates, and also encapsulations e.g., in polymeric substances. As with the type of the compositions, the methods of application, such as spraying, atomising, dusting, scattering, coating or pouring, are chosen in accordance with the intended objectives and the prevailing circumstances. The compositions may also contain further adjuvants such as stabilizers, antifoams, viscosity regulators, binders or tackifiers as well as fertilizers, micronutrient donors or other formulations for obtaining special effects.
  • Suitable carriers and adjuvants can be solid or liquid and are substances useful in formulation technology, e.g. natural or regenerated mineral substances, solvents, dispersants, wetting agents, tackifiers, thickeners, binders or fertilizers.
  • Such carriers are for example described in WO1997/33890.
  • Suspension concentrates are aqueous formulations in which finely divided solid particles of the active compound are suspended. Such formulations include anti-settling agents and dispersing agents and may further include a wetting agent to enhance activity as well an anti-foam and a crystal growth inhibitor. In use, these concentrates are diluted in water and normally applied as a spray to the area to be treated. The amount of active ingredient may range from 0.5% to 95% of the concentrate.
  • Wettable powders are in the form of finely divided particles which disperse readily in water or other liquid carriers.
  • the particles contain the active ingredient retained in a solid matrix.
  • Typical solid matrices include fuller’s earth, kaolin clays, silicas and other readily wet organic or inorganic solids. Wettable powders normally contain from 5% to 95% of the active ingredient plus a small amount of wetting, dispersing or emulsifying agent.
  • Emulsifiable concentrates are homogeneous liquid compositions dispersible in water or other liquid and may consist entirely of the active compound with a liquid or solid emulsifying agent, or may also contain a liquid carrier, such as xylene, heavy aromatic naphthas, isophorone and other non-volatile organic solvents. In use, these concentrates are dispersed in water or other liquid and normally applied as a spray to the area to be treated. The amount of active ingredient may range from 0.5% to 95% of the concentrate.
  • Granular formulations include both extrudates and relatively coarse particles and are usually applied without dilution to the area in which treatment is required.
  • Typical carriers for granular formulations include sand, fuller’s earth, attapulgite clay, bentonite clays, montmorillonite clay, vermiculite, perlite, calcium carbonate, brick, pumice, pyrophyllite, kaolin, dolomite, plaster, wood flour, ground corn cobs, ground peanut hulls, sugars, sodium chloride, sodium sulphate, sodium silicate, sodium borate, magnesia, mica, iron oxide, zinc oxide, titanium oxide, antimony oxide, cryolite, gypsum, diatomaceous earth, calcium sulphate and other organic or inorganic materials which absorb or which can be coated with the active compound.
  • Granular formulations normally contain 5% to 25% of active ingredients which may include surface-active agents such as heavy aromatic naphthas, kerosene and other petroleum fractions, or vegetable oils
  • Dusts are free-flowing admixtures of the active ingredient with finely divided solids such as talc, clays, flours, and other organic and inorganic solids which act as dispersants and carriers.
  • Microcapsules are typically droplets or granules of the active ingredient enclosed in an inert porous shell which allows escape of the enclosed material to the surroundings at controlled rates. Encapsulated droplets are typically 1 to 50 microns in diameter.
  • the enclosed liquid typically constitutes 50 to 95% of the weight of the capsule and may include solvent in addition to the active compound.
  • Encapsulated granules are generally porous granules with porous membranes sealing the granule pore openings, retaining the active species in liquid form inside the granule pores.
  • Granules typically range from 1 millimetre to 1 centimetre and preferably 1 to 2 millimetres in diameter. Granules are formed by extrusion, agglomeration or prilling, or are naturally occurring. Examples of such materials are vermiculite, sintered clay, kaolin, attapulgite clay, sawdust, and granular carbon.
  • Shell or membrane materials include natural and synthetic rubbers, cellulosic materials, styrene-butadiene copolymers, polyacrylonitriles, polyacrylates, polyesters, polyamides, polyureas, polyurethanes and starch xanthates.
  • compositions for agrochemical applications include simple solutions of the active ingredient in a solvent in which it is completely soluble at the desired concentration, such as acetone, alkylated naphthalenes, xylene and other organic solvents.
  • Pressurised sprayers wherein the active ingredient is dispersed in finely divided form as a result of vaporisation of a low boiling dispersant solvent carrier, may also be used.
  • Suitable agricultural adjuvants and carriers that are useful in formulating the compositions of the invention in the formulation types described above are well known to a person skilled in the art.
  • Liquid carriers that can be employed include, for example, water, toluene, xylene, petroleum naphtha, crop oil, acetone, methyl ethyl ketone, cyclohexanone, acetic anhydride, acetonitrile, acetophenone, amyl acetate, 2- butanone, chlorobenzene, cyclohexane, cyclohexanol, alkyl acetates, diacetonalcohol, 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, dipropylene glycol, dipropylene glycol methyl ether, dipropylene glycol dibenz
  • Water is generally the carrier of choice for the dilution of concentrates.
  • suitable solid carriers include, for example, talc, titanium dioxide, pyrophyllite clay, silica, attapulgite clay, kieselguhr, chalk, diatomaxeous earth, lime, calcium carbonate, bentonite clay, fuller’s earth, cotton seed hulls, wheat flour, soybean flour, pumice, wood flour, walnut shell flour and lignin.
  • a broad range of surface-active agents are advantageously employed in both said liquid and solid compositions, especially those designed to be diluted with carrier before application.
  • These agents when used, normally comprise from 0.1 % to 15% by weight of the formulation. They can be anionic, cationic, non-ionic or polymeric in character and can be employed as emulsifying agents, wetting agents, suspending agents or for other purposes.
  • Typical surface-active agents include salts of alkyl sulfates, such as diethanolammonium lauryl sulphate; alkylarylsulfonate salts, such as calcium dodecylbenzenesulfonate; alkylphenol-alkylene oxide addition products, such as nonylphenol-C.sub.
  • alcohol-alkylene oxide addition products such as tridecyl alcohol-C.sub. 16 ethoxylate
  • soaps such as sodium stearate
  • alkylnaphthalenesulfonate salts such as sodium dibutylnaphthalenesulfonate
  • dialkyl esters of sulfosuccinate salts such as sodium di(2 ethylhexyl) sulfosuccinate
  • sorbitol esters such as sorbitol oleate
  • quaternary amines such as lauryl trimethylammonium chloride
  • polyethylene glycol esters of fatty acids such as polyethylene glycol stearate
  • salts of mono and dialkyl phosphate esters such as mono and dialkyl phosphate esters.
  • adjuvants commonly utilized in agricultural compositions include crystallisation inhibitors, viscosity modifiers, suspending agents, spray droplet modifiers, pigments, antioxidants, foaming agents, anti-foaming agents, light-blocking agents, compatibilizing agents, antifoam agents, sequestering agents, neutralising agents and buffers, corrosion inhibitors, dyes, odorants, spreading agents, penetration aids, micronutrients, emollients, lubricants and sticking agents.
  • biocidal active ingredients or compositions may be combined with the compositions of the invention and used in the methods of the invention and applied simultaneously or sequentially with the compositions of the invention. When applied simultaneously, these further active ingredients may be formulated together with the compositions of the invention or mixed in, for example, the spray tank. These further biocidal active ingredients may be fungicides, herbicides, insecticides, bactericides, acaricides, nematicides and/or plant growth regulators.
  • Pesticidal agents are referred to herein using their common name are known, for example, from “The Pesticide Manual”, 15th Ed., British Crop Protection Council 2009.
  • compositions of the invention may also be applied with one or more systemically acquired resistance inducers (“SAR” inducer).
  • SAR inducers are known and described in, for example, United States Patent No. US 6,919,298 and include, for example, salicylates and the commercial SAR inducer acibenzolar- S-methyl.
  • the compounds of formula (I) according to the invention are normally used in the form of agrochemical compositions and can be applied to the crop area or plant to be treated, simultaneously or in succession with further compounds.
  • further compounds can be e.g., fertilizers or micronutrient donors or other preparations, which influence the growth of plants. They can also be selective herbicides or non-selective herbicides as well as insecticides, fungicides, bactericides, nematicides, molluscicides or mixtures of several of these preparations, if desired together with further carriers, surfactants or application promoting adjuvants customarily employed in the art of formulation.
  • the compounds of formula (I) according to the invention may be used in the form of (fungicidal) compositions for controlling or protecting against phytopathogenic microorganisms, comprising as active ingredient at least one compound of formula (I) or of at least one preferred individual compound as defined herein, in free form or in agrochemical usable salt form, and at least one of the above-mentioned adjuvants.
  • the invention therefore provides a composition, preferably a fungicidal composition, comprising at least one compound of formula (I) according to the invention, an agriculturally acceptable carrier and optionally an adjuvant.
  • An agricultural acceptable carrier is for example a carrier that is suitable for agricultural use.
  • Agricultural carriers are well known in the art.
  • said composition may comprise at least one or more pesticidal-active compounds, for example an additional fungicidal active ingredient in addition to the compound of formula (I).
  • the compound of formula (I) according to the invention may be the sole active ingredient of a composition or it may be admixed with one or more additional active ingredients such as a pesticide, fungicide, synergist, herbicide or plant growth regulator where appropriate.
  • An additional active ingredient may, in some cases, result in unexpected synergistic activities.
  • Suitable additional active ingredients include the following: acycloamino acid fungicides, aliphatic nitrogen fungicides, amide fungicides, anilide fungicides, antibiotic fungicides, aromatic fungicides, arsenical fungicides, aryl phenyl ketone fungicides, benzamide fungicides, benzanilide fungicides, benzimidazole fungicides, benzothiazole fungicides, botanical fungicides, bridged diphenyl fungicides, carbamate fungicides, carbanilate fungicides, conazole fungicides, copper fungicides, dicarboximide fungicides, dinitrophenol fungicides, dithiocarbamate fungicides, dithiolane fungicides, furamide fungicides, furanilide fungicides, hydrazide fungicides, imidazole fungicides, mercury fungicides, morpholine fung
  • Suitable additional active ingredients include the following: petroleum oils, 1 ,1 -bis(4-chlorophenyl)- 2-ethoxyethanol, 2,4-dichlorophenyl benzenesulfonate, 2-fluoro-N-methyl-N-1 -naphthylacetamide, 4- chlorophenyl phenyl sulfone, acetoprole, aldoxycarb, amidithion, amidothioate, amiton, amiton hydrogen oxalate, amitraz, aramite, arsenous oxide, azobenzene, azothoate, benomyl, benoxa-fos, benzyl benzoate, bixafen, brofenvalerate, bromocyclen, bromophos, bromopropylate, buprofezin, butocarboxim, butoxycarboxim, butylpyridaben, calcium polysulfide, camphechlor, carban
  • Adoxophyes orana GV Agrobacterium radiobacter, Amblyseius spp., Anagrapha falcifera NPV, Anagrus atomus, Aphelinus abdominalis, Aphidius colemani, Aphidoletes aphidimyza, Autographa californica NPV, Bacillus sphaericus Neide, Beauveria brongniartii, Chrysoperla carnea, Cryptolaemus montrouzieri, Cydia pomonella GV, Dacnusa sibirica, Diglyphus isaea, Encarsia formosa, Eretmocerus eremicus, Heterorhabditis bacteriophora and H.
  • lecontei NPV, Orius spp. Paecilomyces fumosoroseus, Phytoseiulus persimilis, Steinernema bibionis, Steinernema carpocapsae, Steinernema feltiae, Steinernema glaseri, Steinernema riobrave, Steinernema riobravis, Steinernema scapterisci, Steinernema spp., Trichogramma spp., Typhlodromus occidentalis, Verticillium lecanii, apholate, bisazir, busulfan, dimatif, hemel, hempa, metepa, methiotepa, methyl apholate, morzid, penfluron, tepa, thiohempa, thiotepa, tretamine, uredepa, (E)-dec-5-en-1-yl acetate
  • this compound may be prepared from the methods described in WO2016/156290); 3-[2-(1-chlorocyclopropyl)- 3-(3-chloro-2-fluoro-phenyl)-2-hydroxy-propyl]imidazole-4-carbonitrile (this compound may be prepared from the methods described in WO2016/156290); (4-phenoxyphenyl)methyl 2-amino-6-methyl-pyridine-3- carboxylate (this compound may be prepared from the methods described in WO2014/006945); 2,6-Dimethyl- 1 H,5H-[1 ,4]dithiino[2,3-c:5,6-c']dipyrrole-1 ,3,5,7(2H,6H)-tetrone (this compound may be prepared from the methods described in WO2011/138281) N-methyl-4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl]benzenecarbothioamide; N-methyl-4-[5-(
  • the compounds of the invention may also be used in combination with anthelmintic agents.
  • anthelmintic agents include, compounds selected from the macrocyclic lactone class of compounds such as ivermectin, avermectin, abamectin, emamectin, eprinomectin, doramectin, selamectin, moxidectin, nemadectin and milbemycin derivatives as described in EP0357460, EP0444964 and EP0594291 .
  • Additional anthelmintic agents include semisynthetic and biosynthetic avermectin/milbemycin derivatives such as those described in US5, 015,630, WO9415944 and WO9522552. Additional anthelmintic agents include the benzimidazoles such as albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, and other members of the class. Additional anthelmintic agents include imidazothiazoles and tetrahydropyrimidines such as tetramisole, levamisole, pyrantel pamoate, oxantel or morantel. Additional anthelmintic agents include flukicides, such as triclabendazole and clorsulon and the cestocides, such as praziquantel and epsiprantel.
  • the compounds of the invention may be used in combination with derivatives and analogues of the paraherquamide/marcfortine class of anthelmintic agents, as well as the antiparasitic oxazolines such as those disclosed in US5478855, US4639771 and DE-19520936.
  • the compounds of the invention may be used in combination with derivatives and analogues of the general class of dioxomorpholine antiparasitic agents as described in WO9615121 and also with anthelmintic active cyclic depsipeptides such as those described in WO961 1945, WO9319053, WO9325543, EP0626375, EP0382173, WO9419334, EP0382173, and EP0503538.
  • the compounds of the invention may be used in combination with other ectoparasiticides; for example, fipronil; pyrethroids; organophosphates; insect growth regulators such as lufenuron; ecdysone agonists such as tebufenozide and the like; neonicotinoids such as imidacloprid and the like.
  • ectoparasiticides for example, fipronil; pyrethroids; organophosphates; insect growth regulators such as lufenuron; ecdysone agonists such as tebufenozide and the like; neonicotinoids such as imidacloprid and the like.
  • the compounds of the invention may be used in combination with terpene alkaloids, for example those described in WO95/19363 or W004/72086, particularly the compounds disclosed therein.
  • Organophosphates acephate, azamethiphos, azinphos-ethyl, azinphos- methyl, bromophos, bromophos- ethyl, cadusafos, chlorethoxyphos, chlorpyrifos, chlorfenvinphos, chlormephos, demeton, demeton-S-methyl, demeton-S-methyl sulphone, dialifos, diazinon, dichlorvos, dicrotophos, dimethoate, disulfoton, ethion, ethoprophos, etrimfos, famphur, fenamiphos, fenitrothion, fensulfothion, fenthion, flupyrazofos, fonofos, formothion, fosthiazate, heptenophos, isazophos, isothioate, isoxathion, malathion,
  • Carbamates alanycarb, aldicarb, 2-sec-butylphenyl methylcarbamate, benfuracarb, carbaryl, carbofuran, carbosulfan, cloethocarb, ethiofencarb, fenoxycarb, fenthiocarb, furathiocarb, HCN-801 , isoprocarb, indoxacarb, methiocarb, methomyl, 5-methyl-m-cumenylbutyryl(methyl)carbamate, oxamyl, pirimicarb, propoxur, thiodicarb, thiofanox, triazamate, UC-51717.
  • Pyrethroids acrinathin, allethrin, alphametrin, 5-benzyl-3-furylmethyl (E)-(1 R)-cis-2,2-dimethyl-3-(2- oxothiolan-3-ylidenemethyl)cyclopropanecarboxylate, bifenthrin, beta-cyfluthrin, cyfluthrin, a-cypermethrin, beta-cypermethrin, bioallethrin, bioallethrin((S)-cyclopentylisomer), bioresmethrin, bifenthrin, NCI-85193, cycloprothrin, cyhalothrin, cythithrin, cyphenothrin, deltamethrin, empenthrin, esfenvalerate, ethofenprox, fenfluthrin, fenpropathrin, fenvaler
  • Arthropod growth regulators a) chitin synthesis inhibitors: benzoylureas: chlorfluazuron, diflubenzuron, fluazuron, flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, novaluron, teflubenzuron, triflumuron, buprofezin, diofenolan, hexythiazox, etoxazole, chlorfentazine; b) ecdysone antagonists: halofenozide, methoxyfenozide, tebufenozide; c) juvenoids: pyriproxyfen, methoprene (including S-methoprene), fenoxycarb; d) lipid biosynthesis inhibitors: spirodiclofen.
  • antiparasitics acequinocyl, amitraz, AKD-1022, ANS-118, azadirachtin, Bacillus thuringiensis, bensultap, bifenazate, binapacryl, bromopropylate, BTG-504, BTG-505, camphechlor, cartap, chlorobenzilate, chlordimeform, chlorfenapyr, chromafenozide, clothianidine, cyromazine, diacloden, diafenthiuron, DBI-3204, dinactin, dihydroxymethyldihydroxypyrrolidine, dinobuton, dinocap, endosulfan, ethiprole, ethofenprox, fenazaquin, flumite, MTI-800, fenpyroximate, fluacrypyrim, flubenzimine, flubrocythrinate, flufenzine, flufenprox, fluproxyfen, halofenprox, hydr
  • Biological agents Bacillus thuringiensis ssp. aizawai, kurstaki, Bacillus thuringiensis delta endotoxin, baculovirus, entomopathogenic bacteria, virus, and fungi.
  • Bactericides chlortetracycline, oxytetracycline, streptomycin.
  • TX means one compound selected from compounds of formula (I), (l-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (l-B), (l-C), or (l-D), or compounds selected from compounds listed in Tables A-1 to A-26, or compounds listed in Table P (below), and a compound selected from the group of substances consisting of petroleum oils + TX, 1 ,1-bis(4-chlorophenyl)-2-ethoxyethanol + TX, 2,4-dichlorophenyl benzenesulfonate + TX, 2-fluoro-N-methyl- N-1 -naphthylacetamide + TX, 4-chlorophenyl phenyl sulfone + TX, acetoprole + TX, aldoxycarb + TX, amidithion + TX,
  • TX Paecilomyces fumosoroseus + TX, Phytoseiulus persimilis + TX, Steinernema bibionis + TX, Steinernema carpocapsae + TX, Steinernema feltiae + TX, Steinernema glaseri + TX, Steinernema riobrave + TX, Steinernema riobravis + TX, Steinernema scapterisci + TX, Steinernema spp. + TX, Trichogramma spp.
  • the compounds in this paragraph may be prepared from the methods described in WO2017/055473, WO2017/055469, WO2017/093348 and WO2017/118689; 2-[6-(4- chlorophenoxy)-2-(trifluoromethyl)-3-pyridyl]-1-(1 ,2,4-triazol-1-yl)propan-2-ol + TX (this compound may be prepared from the methods described in WO2017/029179); 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)-3- pyridyl]-1-(1 ,2,4-triazol-1-yl)propan-2-ol + TX (this compound may be prepared from the methods described in WO2017/029179); 3-[2-(1-chlorocyclopropyl)-3-(2-fluorophenyl)-2-hydroxy-propyl]imidazole-4-carbonitrile + TX (this compound may be prepared from the methods described in WO2016
  • the active ingredient mixture of the compound selected from compounds of (I), (l-A), (I-A1), (I-A2), (I-A3), (I- A4), (I-A5), (l-B), (l-C), or (l-D), or compounds selected from compounds listed in Tables A-1 to A-26, or compounds listed in Table P (below), is preferably in a mixing ratio of from 100:1 to 1 :100, 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, and still more especially from 5:1 to 1 :5 Those mixing ratios are by weight.
  • the mixtures as described above can be used in a method for controlling pests, which comprises applying a composition comprising a mixture 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 practised on the human or animal body.
  • the mixtures comprising a compound selected from compounds of formula (I), (l-A), (I-A1), (I-A2), (I-A3), (I- A4), (I-A5), (l-B), (l-C), or (l-D), or compounds selected from compounds listed in Tables A-1 to A-26, or compounds listed in Table P (below), 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 composed 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 sequential manner, i.e. one after the other with a reasonably short period, such as a few hours or days.
  • 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).
  • Another aspect of the invention is related to the use of a compound of formula (I) according to the invention or of a preferred individual compound as defined herein, of a composition comprising at least one compound of formula (I) or at least one preferred individual compound as defined herein, or of a fungicidal or insecticidal mixture comprising at least one compound of formula (I) or at least one preferred individual compound as defined herein, in admixture with other fungicides or insecticides as described above, for controlling or preventing infestation of plants, e.g. useful plants such as crop plants, propagation material thereof, e.g. seeds, harvested crops, e.g. harvested food crops, or non-living materials by insects or by phytopathogenic microorganisms, preferably fungal organisms.
  • useful plants such as crop plants, propagation material thereof, e.g. seeds, harvested crops, e.g. harvested food crops, or non-living materials by insects or by phytopathogenic microorganisms, preferably fungal organisms.
  • a further aspect of invention is related to a method of controlling or preventing an infestation of plants, e.g. useful plants such as crop plants, propagation material thereof, e.g. seeds, harvested crops, e.g. harvested food crops, or of non-living materials by phytopathogenic or spoilage microorganisms or organisms potentially harmful to man, especially fungal organisms, which comprises the application of a compound of formula (I) according to the invention or of a preferred individual compound as defined herein as active ingredient to the plants, to parts of the plants or to the locus thereof, to the propagation material thereof, or to any part of the non-living materials.
  • plants e.g. useful plants such as crop plants, propagation material thereof, e.g. seeds, harvested crops, e.g. harvested food crops, or of non-living materials by phytopathogenic or spoilage microorganisms or organisms potentially harmful to man, especially fungal organisms
  • a compound of formula (I) according to the invention or of a preferred individual compound as defined herein as active ingredient to the
  • Controlling or preventing means reducing infestation by insects or by phytopathogenic or spoilage microorganisms or organisms potentially harmful to man, especially fungal organisms, to such a level that an improvement is demonstrated.
  • a preferred method of controlling or preventing an infestation of crop plants by phytopathogenic microorganisms, especially fungal organisms, or insects which comprises the application of a compound of formula (I) according to the invention, or an agrochemical composition which contains at least one compound of formula (I), is foliar application.
  • the frequency of application and the rate of application will depend on the risk of infestation by the corresponding pathogen or insect.
  • the compounds of formula (I) according to the invention can also penetrate the plant through the roots via the soil (systemic action) by drenching the locus of the plant with a liquid formulation, or by applying the compounds in solid form to the soil, e.g. in granular form (soil application). In crops of water rice such granulates can be applied to the flooded rice field.
  • the compounds of formula (I) may also be applied to seeds (coating) by impregnating the seeds or tubers either with a liquid formulation of the fungicide or coating them with a solid formulation.
  • a formulation e.g. a composition containing the compound of formula (I) according to the invention and, if desired, a solid or liquid adjuvant or monomers for encapsulating the compound of formula (I), may be prepared in a known manner, typically by intimately mixing and/or grinding the compound with extenders, for example solvents, solid carriers and, optionally, surface active compounds (surfactants).
  • Advantageous rates of application are normally from 5g to 2kg of active ingredient (a.i.) per hectare (ha), preferably from 10g to I kg a.i./ha, most preferably from 20g to 600g a.i./ha.
  • convenient dosages are from 10mg to 1 g of active substance per kg of seeds.
  • g a.i./ha refers to the application rate given in gram [g] of active ingredient [a.i.] per unit of surface [ha].
  • the unit hectare symbol ha is the metric unit of area that equals a square with 100 m side (1 hm 2 ) or 10,000 square meters. Hectare is a commonly used unit of area in the metric system.
  • rates of 0.001 to 50 g of a compound of formula (I) per kg of seed preferably from 0.01 to 10g per kg of seed are generally sufficient.
  • composition comprising a compound of formula (I) according to the present invention is applied either preventative, meaning prior to disease development or curative, meaning after disease development.
  • compositions of the invention may be employed in any conventional form, for example in the form of a twin pack, a powder for dry seed treatment (DS), an emulsion for seed treatment (ES), a flowable concentrate for seed treatment (FS), a solution for seed treatment (LS), a water dispersible powder for seed treatment (WS), a capsule suspension for seed treatment (CF), a gel for seed treatment (GF), an emulsion concentrate (EC), a suspension concentrate (SC), a suspo-emulsion (SE), a capsule suspension (CS), a water dispersible granule (WG), an emulsifiable granule (EG), an emulsion, water in oil (EG), an emulsion, oil in water (EW), a micro-emulsion (ME), an oil dispersion (OD), an oil miscible flowable (OF), an oil miscible liquid (OL), a soluble concentrate (SL), an ultra-low volume suspension (SU), an ultra-low volume liquid (UL), a technical concentrate (TK
  • compositions may be produced in conventional manner, e.g. by mixing the active ingredients with appropriate formulation inerts (diluents, solvents, fillers and optionally other formulating ingredients such as surfactants, biocides, anti-freeze, stickers, thickeners and compounds that provide adjuvancy effects).
  • appropriate formulation inerts diiluents, solvents, fillers and optionally other formulating ingredients such as surfactants, biocides, anti-freeze, stickers, thickeners and compounds that provide adjuvancy effects.
  • conventional slow release formulations may be employed where long lasting efficacy is intended.
  • Particularly formulations to be applied in spraying forms such as water dispersible concentrates (e.g. EC, SC, DC, OD, SE, EW, EO and the like), wettable powders and granules, may contain surfactants such as wetting and dispersing agents and other compounds that provide adjuvancy effects, e.g.
  • a seed dressing formulation is applied in a manner known per se to the seeds employing the combination of the invention and a diluent in suitable seed dressing formulation form, e.g. as an aqueous suspension or in a dry powder form having good adherence to the seeds.
  • suitable seed dressing formulation form e.g. as an aqueous suspension or in a dry powder form having good adherence to the seeds.
  • seed dressing formulations are known in the art.
  • Seed dressing formulations may contain the single active ingredients or the combination of active ingredients in encapsulated form, e.g., as slow release capsules or microcapsules.
  • the formulations include from 0.01 to 90% by weight of active agent, from 0 to 20% agriculturally acceptable surfactant and 10 to 99.99% solid or liquid formulation inerts and adjuvant(s), the active agent consisting of at least the compound of formula (I) according to the invention optionally together with other active agents, particularly microbiocides or conservatives or the like.
  • Concentrated forms of compositions generally contain in between about 2 and 80%, preferably between about 5 and 70% by weight of active agent.
  • Application forms of formulation may for example contain from 0.01 to 20% by weight, preferably from 0.01 to 5% by weight of active agent. Whereas commercial products will preferably be formulated as concentrates, the end user will normally employ diluted 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.
  • 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 %, preferably 15 to 90 %
  • Granules active ingredient: 0.1 to 30 %, preferably 0.1 to 15 % solid carrier: 99.5 to 70 %, preferably 97 to 85 %
  • active ingredient 0.1 to 30 %, preferably 0.1 to 15 % solid carrier: 99.5 to 70 %, preferably 97 to 85 %
  • Table A This table discloses 75 compounds of formula (la) according to the invention wherein: w as defined below:
  • the following compounds represent specific compounds of formula (la) as described in Tables A-1 to A-26 wherein G is as defined in Table A.
  • the compound A-1.G1 represents a compound of formula (la) wherein R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and B 2 are as defined in Table A-1 and G is G1 as defined in Table A.
  • Table A-1 This table provides 75 compounds A-1.G1 to A-1.G75 of formula (la) wherein R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are H, B 2 is CH, and G is as defined in Table A.
  • compound A-1 ,G3 has the following structure:
  • Table A-2 This table provides 75 compounds A-2.G1 to A-2.G75 of formula (la) wherein R 2 is CH3, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are H, B 2 is CH, and G is as defined in Table A.
  • compound A-2.G2 has the following structure:
  • Table A-3 This table provides 75 compounds A-3.G1 to A-3.G75 of formula (la) wherein R 2 is F, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are H, B 2 is CH, and G is as defined in Table A.
  • Table A-4 This table provides 75 compounds A-4.G1 to A-4.G75 of formula (la) wherein R 2 is Cl, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are H, B 2 is CH, and G is as defined in Table A.
  • Table A-5 This table provides 75 compounds A-5.G1 to A-5.G75 of formula (la) wherein R 2 is cyclopropyl, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are H, B 2 is CH, and G is as defined in Table A.
  • Table A-6 This table provides 75 compounds A-6.G1 to A-6.G75 of formula (la) wherein R 2 is COCH3, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are H, B 2 is CH, and G is as defined in Table A.
  • Table A-8 This table provides 75 compounds A-8.G1 to A-8.G75 of formula (la) wherein R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are H, R 4 is CH3, B 2 is CH, and G is as defined in Table A.
  • compound A-8.G32 has the following structure:
  • Table A-10 This table provides 75 compounds A-10.G1 to A-10.G75 of formula (la) wherein R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are H, R 2 and R 4 are CH3, B 2 is N, and G is as defined in Table A.
  • Table A-11 This table provides 75 racem/c-compounds A-11 ,G1 to A-11 .G75 of formula (la) wherein R 5 , R 6 , R 8 , R 9 , R 10 are H, R 2 and R 7 are CH3, B 2 is CH, and G is as defined in Table A.
  • the pyrazole substituent and the R 7 CH3 substituent have a syn-relationship to each other.
  • compound rac-A- 11 ,G2 has the following structure
  • Table A-12 This table provides 75 racem/c-compounds A-12.G1 to A-12.G75 of formula (la) wherein R 5 , R 6 , R 8 , R 9 , R 10 are H, R 2 is Cl, R 7 is CH3, B 2 is CH and G is as defined in Table A.
  • the pyrazole substituent and the R 7 CH3 substituent have a syn-relationship to each other.
  • compound rac-A- 12.G67 has the following structure;
  • Table A-13 This table provides 75 compounds A-13.G1 to A-13.G75 of formula (la) wherein R 5 , R 6 , R 8 , R 9 , R 10 are H, R 2 , R 7 , and R 4 are CH3, B 2 is CH, and G is as defined in Table A.
  • Table A-14 This table provides 75 racem/c-compounds A-14.G1 to A-14.G75 of formula (la) wherein R 5 , R 6 , R 8 , R 9 , R 10 are H, R 2 and R 7 are CH3, B 2 is C-Br, and G is as defined in Table A.
  • the pyrazole substituent and the R 7 CH3 substituent have a syn-relationship to each other.
  • Table A-15 This table provides 75 racem/c-compounds A-15.G1 to A-15.G75 of formula (la) wherein R 5 , R 6 , R 8 , R 9 , R 10 are H, R 2 and R 7 are CH3, B 2 is C-CN, and G is as defined in Table A.
  • the pyrazole substituent and the R 7 CH3 substituent have a syn-relationship to each other.
  • Table A-16 This table provides 75 /'acem/c-compounds A-16.G1 to A-16.G75 of formula (la) wherein R 5 , R 6 , R 8 , R 9 , R 10 are H, R 2 is Cl, R 7 is CH3, B 2 is C-CI, and G is as defined in Table A.
  • the pyrazole substituent and the R 7 CH3 substituent have a syn-relationship to each other.
  • Table A-17 This table provides 75 /'acem/c-compounds A-17.G1 to A-17.G75 of formula (la) wherein R 5 , R 6 , R 8 , R 9 , R 10 are H, R 2 is Cl, R 7 is CH3, B 2 is C-CN, and G is as defined in Table A.
  • the pyrazole substituent and the R 7 CH3 substituent have a syn-relationship to each other.
  • compound rac-A- 17.G53 has the following structure;
  • Table A-18 This table provides 15 compounds A-18.G1 to A-18.G15 of formula (la) wherein R 4 , R 5 , R 6 , R 8 , R 9 , and R 10 are H, R 2 and R 7 are CH3, B 2 is N and G is as defined in Table A.
  • Table A-19 This table provides 15 racem/c-compounds A-19.G1 to A-19.G15 of formula (la) wherein R 4 , R 5 , R 6 , R 8 , and R 10 are H, R 9 is OCH3, R 2 and R 7 are CH3, B 2 is C-CI, and G is as defined in Table A.
  • the pyrazole substituent and the R 7 CH3 substituent have a syn-relationship to each other.
  • compound rac-A-19.G15 has the following structure compound rac-A-19.G15
  • Table A-20 This table provides 15 /'acem/c-compounds A-20.G1 to A-20.G15 of formula (la) wherein R 4 , R 5 , R 6 , R 8 , and R 10 are H, R 9 is OCH3, R 2 and R 7 are CH3, B 2 is C-H, and G is as defined in Table A.
  • the pyrazole substituent and the R 7 CH3 substituent have a syn-relationship to each other.
  • Table A-21 This table provides 15 /'acem/c-compounds A-21 ,G1 to A-21 ,G15 of formula (la) wherein R 4 , R 5 , R 6 , R 8 , and R 10 are H, R 9 is Br, R 2 and R 7 are CH3, B 2 is C-H, and G is as defined in Table A.
  • the pyrazole substituent and the R 7 CH3 substituent have a syn-relationship to each other.
  • Table A-22 This table provides 15 /'acem/c-compounds A-22.G1 to A-22.G15 of formula (la) wherein R 4 , R 5 , R 6 , R 8 , and R 10 are H, R 9 is Cl, R 2 and R 7 are CH3, B 2 is C-H, and G is as defined in Table A.
  • the pyrazole substituent and the R 7 CH3 substituent have a syn-relationship to each other.
  • Table A-23 This table provides 15 racem/c-compounds A-23.G1 to A-23.G15 of formula (la) wherein R 4 , R 5 , R 6 , R 8 , and R 10 are H, R 9 is CN, R 2 and R 7 are CH3, B 2 is C-H, and G is as defined in Table A.
  • the pyrazole substituent and the R 7 CH3 substituent have a syn-relationship to each other.
  • Table A-24 This table provides 15 /'acem/c-compounds A-24.G1 to A-24.G15 of formula (la) wherein R 4 , R 5 , R 6 , R 8 , and R 9 are H, R 10 is Br, R 2 and R 7 are CH3, B 2 is C-H, and G is as defined in Table A.
  • the pyrazole substituent and the R 7 CH3 substituent have a syn-relationship to each other.
  • Table A-25 This table provides 15 /'acem/c-compounds A-25.G1 to A-25.G15 of formula (la) wherein R 4 , R 5 , R 6 , R 8 , and R 9 are H, R 10 is Cl, R 2 and R 7 are CH3, B 2 is C-H, and G is as defined in Table A.
  • the pyrazole substituent and the R 7 CH3 substituent have a syn-relationship to each other.
  • Table A-26 This table provides 15 /'acem/c-compounds A-26.G1 to A-26.G15 of formula (la) wherein R 4 , R 5 , R 6 , R 8 , and R 9 are H, R 10 is CN, R 2 and R 7 are CH3, B 2 is C-H, and G is as defined in Table A.
  • the pyrazole substituent and the R 7 CH3 substituent have a syn-relationship to each other.
  • compound A-26.G6 has the following structure: compound rac-/ ⁇ -2Q.GQ
  • the compounds of the invention can be distinguished from known compounds by virtue of greater efficacy at low application rates, which can be verified by a person skilled in the art using the experimental procedures outlined in the Examples, using lower application rates if necessary, for example 60 ppm, 20 ppm or 2 ppm.
  • Compounds of formula (I) may possess any number of benefits including, inter alia, advantageous levels of biological activity for protecting plants against diseases that are caused by fungi or superior properties for use as agrochemical active ingredients (for example, greater biological activity, an advantageous spectrum of activity, an increased safety profile (including improved crop tolerance), improved physico-chemical properties, or increased biodegradability).
  • advantageous levels of biological activity for protecting plants against diseases that are caused by fungi or superior properties for use as agrochemical active ingredients (for example, greater biological activity, an advantageous spectrum of activity, an increased safety profile (including improved crop tolerance), improved physico-chemical properties, or increased biodegradability).
  • temperatures are given in degrees Celsius and “m.p.” means melting point.
  • LC/MS means Liquid Chromatography Mass Spectroscopy and the description of the apparatus, and the methods is as follows.
  • LC-MS Method A Spectra were recorded on a mass spectrometer from Waters (SQD, SQDII Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive and negative ions, Capillary: 3.00 kV, Cone range: 30 V, Extractor: 2.00 V, Source Temperature: 150°C, Desolvation Temperature: 350°C, Cone Gas Flow: 50 l/h, Desolvation Gas Flow: 650 l/h, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: binary pump, heated column compartment, diode-array detector and ELSD detector.
  • LC-MS Method B Spectra were recorded on a ACQUITY Mass Spectrometer from Waters Corporations (SQD or SQDII Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive or negative ions, Capillary: 3.0 kV, Cone: 30V, Extractor: 3.00 V, Source Temperature: 150°C, Desolvation Temperature: 400°C, Cone Gas Flow: 60 L/hr, Desolvation Gas Flow: 700 L/hr, Mass range: 140 to 800 Da) and an ACQUITY UPLC from Waters Corporations with solvent degasser, binary pump, heated column compartment and diode-array detector.
  • an electrospray source Polyity: positive or negative ions, Capillary: 3.0 kV, Cone: 30V, Extractor: 3.00 V, Source Temperature: 150°C, Desolvation Temperature: 400°C, Cone Gas Flow: 60 L/hr, Desolvation Gas Flow:
  • LC-MS Method C Spectra were recorded on a Mass Spectrometer from Waters (Acquity QDa Mass Spectrometer) equipped with an electrospray source (Polarity: Positive and Negative Polarity Switch), Capillary: 0.8 kV, Cone range: 25 V, Extractor: V (No extractor voltage for Qda detector) Source Temperature: 120°C, Desolvation Temperature: 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.
  • LC-MS Method D 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.
  • LC-MS Method E Spectra were recorded on a Mass Spectrometer from Agilent Technologies (6410 Triple Quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive or negative ions, MS2 Scan, Capillary: 4.00 kV, Fragmentor: 100 V, Desolvation Temperature: 350°C, Gas Flow: 11 L/min, Nebulizer Gas: 45 psi, Mass range: 110 to 1000 Da) and a 1200 Series HPLC from Agilent: quaternary pump, heated column compartment and VWD detector.
  • Wettable powders a) b) c) active ingredients 25 % 50 % 75 % sodium lignosulfonate 5 % 5 % - sodium lauryl sulfate 3 % - 5 % sodium diisobutylnaphthalenesulfonate 6 % 10 % phenol polyethylene glycol ether (7-8 mol ethylene oxide) - 2 % - highly dispersed silicic acid 5 % 10 % 10 % Kaolin 62 % 27 % -
  • the combination is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording wettable powders that can be diluted with water to give suspensions of the desired concentration.
  • 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 % -
  • 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 dodecylbenzene sulfonate 3 % castor oil polyglycol ether (35 mol of ethylene oxide) 4 %
  • Emulsions of any required dilution which can be used in plant protection, can be obtained from this concentrate by dilution with water.
  • Ready-for-use dusts are obtained by mixing the combination with the carrier and grinding the mixture in a suitable mill. Such dusts can also be used for dry dressings for seed.
  • the combination is mixed and ground with the adjuvants, and the mixture is moistened with water.
  • the mixture is extruded and then dried in a stream of air.
  • 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.
  • 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.
  • a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water.
  • living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or immersion.
  • Flowable concentrate for seed treatment active ingredients 40 % propylene glycol 5 % copolymer butanol PO/EO 2 %
  • Silicone oil (in the form of a 75 % emulsion in water) 0.2 %
  • the finely ground combination is intimately mixed with the adjuvants, giving a flowable concentrate from which solutions of any desired dilution can be obtained by dilution with water, that can be used directly for seed treatment.
  • solutions of any desired dilution can be obtained by dilution with water, that can be used directly for seed treatment.
  • dilutions living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or immersion.
  • 28 parts of the combination are mixed with 2 parts of an aromatic solvent and 7 parts of toluene diisocyanate/polymethylene-polyphenylisocyanate-mixture (8:1).
  • This mixture is emulsified in a mixture of 1.2 parts of polyvinylalcohol, 0.05 parts of a defoamer and 51 .6 parts of water until the desired particle size is achieved.
  • a mixture of 2.8 parts 1 ,6-diaminohexane in 5.3 parts of water is added.
  • the mixture is agitated until the polymerization reaction is completed.
  • the obtained capsule suspension is stabilized by adding 0.25 parts of a thickener and 3 parts of a dispersing agent.
  • the capsule suspension formulation contains 28% of the active ingredients.
  • the medium capsule diameter is 8-15 microns.
  • the resulting formulation is applied to seeds as an aqueous suspension in an apparatus suitable for that purpose.
  • Formulation types include an emulsion concentrate (EC), a suspension concentrate (SC), a suspo-emulsion (SE), a capsule suspension (CS), a water dispersible granule (WG), an emulsifiable granule (EG), an emulsion, water in oil (EO), an emulsion, oil in water (EW), a micro-emulsion (ME), an oil dispersion (OD), an oil miscible flowable (OF), an oil miscible liquid (OL), a soluble concentrate (SL), an ultra-low volume suspension (SU), an ultra-low volume liquid (UL), a technical concentrate (TK), a dispersible concentrate (DC), a wettable powder (WP), a soluble granule (SG) or any technically feasible formulation in combination with agriculturally acceptable adjuvants.
  • EC emulsion concentrate
  • SC suspension concentrate
  • SE suspo-emulsion
  • CS capsule suspension
  • WG water dispersible granule
  • EG
  • DABCO 1 ,4-diazabicyclo[2.2.2]octane also known as triethylenediamine or TEDA
  • T3P propanephosphonic acid anhydride also called 2,4,6-tripropyl-1 , 3, 5, 2,4,6- trioxatriphosphorinane-2,4,6-trioxide
  • the compounds of formula (I) according to the invention may be prepared using the synthetic techniques described both above and below.
  • Mp means melting point in °C. Free radicals represent methyl groups.
  • 1 H NMR and 19 F NMR measurements were recorded on a Bruker 400MHz spectrometer (or 600MHz as indicated), chemical shifts are given in ppm relevant to a TMS ( 1 H) and CFCI3 ( 19 F) standard. Spectra measured in deuterated solvents as indicated. Either one of the LC-MS methods below was used to characterize the compounds. 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)’.
  • Example P1 Synthesis of [5-(3,5-difluoro-2-pyridyl)isoxazol-3-yl1-[rac-(1 S,4S)-4-(1 ,5-dimethylpyrazol-4-yl)-1- methyl-3,4-dihydro-1 H-isoquinolin-2-yl1methanone (Compound P-6, Table P)
  • Step 1 Preparation of 3,5-difluoro-N-methoxy-N-methyl-pyridine-2-carboxamide
  • Methyl magnesium bromide solution (7.9 mL, 23.59 mmol) was added dropwise to a cooled pale brown solution (0-5°C) of 3,5-difluoro-N-methoxy-N-methyl-pyridine-2-carboxamide (2.38 g, 11 .79 mmol) in THF (35 mL) under argon.
  • the resulting suspension was allowed to reach rt and stirred for 30 minutes under an argon atmosphere.
  • the reaction mixture was slowly quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the title compound.
  • Step 3 Preparation of ethyl 4-(3,5-difluoro-2-pyridyl)-2,4-dioxo-butanoate
  • Step 4 Preparation of ethyl 5-(3,5-difluoro-2-pyridyl)isoxazole-3-carboxylate
  • Step 6 Preparation of (1 ,5-dimethylpyrazol-4-yD-phenyl-methanol
  • Step 7 Preparation of 2-(1 ,5-dimethylpyrazol-4-yl)-2-phenyl-acetonitrile
  • Step 8 Preparation of 2-(1 ,5-dimethylpyrazol-4-yl)-2-phenyl-ethanamine (Option A)
  • reaction mixture was cooled to 0°C before adding hydrochloric acid (23 g, 34.71 mL, 208.2 mmol) dropwise (strong gas evolution) and the reaction mixture was stirred at 65°C for 1 hour and allowed to stand overnight at rt.
  • the mixture was diluted with water and treated with NaOH 6M (to pH 12).
  • the mixture extracted twice with EtOAc and the combined organic layers were washed with brine, dried over Na2SC>4, and concentrated in vacuo to give the title compound as a yellow oil which was used without further purification in the next step.
  • Step 9 Preparation of methyl N-[2-(1 ,5-dimethylpyrazol-4-yl)-2-phenyl-ethyl1carbamate
  • Step 11 Preparation of rac-(1 S,4S)-4-(1 ,5-dimethylpyrazol-4-yl)-1-methyl-1 ,2,3,4-tetrahydroisoquinoline
  • Step 12 Synthesis of [5-(3,5-difluoro-2-pyridyl)isoxazol-3-yl]-[rac-(1 S,4S)-4-(1 ,5-dimethylpyrazol-4-yl)-1- methyl-3,4-dihydro-1 H-isoquinolin-2-yl]methanone (Compound P-6, Table P)
  • the reaction mixture was stirred for 1 hr at rt under argon diluted with EtOAc and quenched with aqueous NaHCOs.
  • the organic phase was separated, and the aqueous phase back extracted with EtOAc.
  • the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo.
  • the crude product was purified by flash chromatography eluting with EtOAc/cyclohexane to afford the title compound.
  • Example P2 Preparation of [5-(3,5-difluoro-2-pyridyl)-1 ,3,4-thiadiazol-2-yl]-[4-(1 ,5-dimethylpyrazol-4-yl)-3,4- dihydro-1 H-isoquinolin-2-yl1methanone (Compound P-7, Table P)
  • Step 2 Preparation of tert-butyl N-[(3,5-difluoropyridine-2-carbonyl)amino]carbamate
  • Step 4 Preparation of methyl 2-[2-(3,5-difluoropyridine-2-carbonyl)hydrazino1-2-oxo-acetate
  • Step 5 Preparation of methyl 5-(3,5-difluoro-2-pyridyl)-1 ,3,4-thiadiazole-2-carboxylate
  • reaction mixture was heated at 100°C and stirred for 1 hour under microwave irradiation. After cooling down to rt, the reaction mixture was partitioned between water and EtOAc and the organic layer separated, dried over Na2SO4, filtered and concentrated in vacuo. Purification of the crude material by flash chromatography over silica gel (eluting with EtOAc acetate/30% methanol) afforded the title compound.
  • hydrochloride salt of the title product (4-(1 ,5-dimethylpyrazol-4-yl)-1 ,2,3,4-tetrahydroisoquinoline; hydrochloride) could be obtained by treating the yellow oil with 2 M HCI in diethyl ether and then concentration in vacuo.
  • Step 8 Preparation of [5-(3,5-difluoro-2-pyridyl)-1 ,3,4-thiadiazol-2-yl1-[4-(1 ,5-dimethylpyrazol-4-yl)-3,4- dihydro-1 H-isoquinolin-2-yl]methanone (Compound P-7, Table P)
  • Example P3 Preparation of [5-(2,6-difluoro-3-pyridyl)-1 ,3,4-thiadiazol-2-yl1-[4-(1 ,5-dimethylpyrazol-4-yl)-3,4- dihydro-1 H-isoquinolin-2-yl1methanone (Compound P-8, Table P)
  • the desired compound was prepared from 2,6-difluoropyridine-3-carboxylic acid and oxalyl chloride, analogously to the example described in example 2, step 1 , to afford 2,6-difluoropyridine-3-carbonyl chloride.
  • Step 2 Preparation of tert-butyl N-[(2,6-difluoropyridine-3-carbonyl)amino]carbamate
  • Step 4 Preparation of methyl 2-[2-(2,6-difluoropyridine-3-carbonyl)hydrazino]-2-oxo-acetate
  • Step 5 Preparation of methyl 5-(2,6-difluoro-3-pyridyl)-1 ,3,4-thiadiazole-2-carboxylate
  • Step 6 Preparation of [5-(2,6-difluoro-3-pyridyl)-1 ,3,4-thiadiazol-2-yl1-[4-(1 ,5-dimethylpyrazol-4-yl)-3,4- dihydro-1 H-isoquinolin-2-yl1methanone (Compound P-8, Table P)
  • Example P4 Preparation of [5-(2,6-difluoro-3-pyridyl)-1 ,3,4-thiadiazol-2-yl]-[rac-(1 S,4S)-4-(1 ,5- dimethylpyrazol-4-yl)-1-methyl-3,4-dihydro-1 H-isoquinolin-2-yl]methanone (Compound P-9, Table P)
  • reaction mixture was heated and stirred at 90°C. After ⁇ 90', the mixture was allowed to cool to rt and was then added to 10ml NaOH 2M aqueous solution. After dilution with water (30ml) the mixture was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo to afford crude product. The crude was purified by chromatography over silica gel to afford the title compound.
  • Example B1 Altemaria solani / tomato / leaf disc (early blight)
  • Tomato leaf disks cv. Baby are placed on agar in multiwell plates (24-well format) and sprayed with the formulated test compound diluted in water.
  • the leaf disks are inoculated with a spore suspension of the fungus 2 days after application.
  • the inoculated leaf disks are incubated at 23°C / 21 °C (day/night) and 80% rh under a light regime of 12 h light / 12 h darkness in a climate cabinet and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears on untreated check disk leaf disks (5 to 7 days after application).
  • Example B2 Botryotinia fuckeliana (Botrytis cinerea) / liquid culture (Gray mould)
  • Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (Vogels broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24°C and the inhibition of growth is determined photometrically 3 to 4 days after application.
  • DMSO fetal sulfate
  • Example B3 Glomerella laqenarium (Colletotrichum laqenarium) / liquid culture (Anthracnose)
  • Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24°C and the inhibition of growth is measured photometrically 3 to 4 days after application.
  • nutrient broth PDB potato dextrose broth
  • Example B4 Blumeria graminis f. sp. tritici (Erysiphe graminis f. sp. tritici) / wheat / leaf disc preventative (Powdery mildew on wheat)
  • Wheat leaf segments cv. Kanzler are placed on agar in a multiwell plate (24-well format) and sprayed with the formulated test compound diluted in water.
  • the leaf disks are inoculated by shaking powdery mildew infected plants above the test plates 1 day after application.
  • the inoculated leaf disks are incubated at 20°C and 60% rh under a light regime of 24 h darkness followed by 12 h light / 12 h darkness in a climate chamber and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears on untreated check leaf segments (6 to 8 days after application).
  • Example B5 Fusarium culmorum / liquid culture (Head blight)
  • Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24°C and the inhibition of growth is determined photometrically 3 to 4 days after application.
  • nutrient broth PDB potato dextrose broth
  • Example B6 Fusarium cu/morum / wheat / spikelet preventative (Head blight)
  • Wheat spikelets cv. Monsun are placed on agar in multiwell plates (24-well format) and sprayed with the formulated test compound diluted in water.
  • the spikelets are inoculated with a spore suspension of the fungus 1 day after application.
  • the inoculated spikelets are incubated at 20°C and 60% rh under a light regime of 72 h semi darkness followed by 12 h light / 12 h darkness in a climate chamber and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears on untreated check spikelets (6 to 8 days after application).
  • Example B7 Gibberella zeae (Fusarium graminearum) / wheat / spikelet preventative (Head blight) Wheat spikelets cv. Monsun are placed on agar in multiwell plates (24-well format) and sprayed with the formulated test compound diluted in water. One day after application, the spikelets are inoculated with a spore suspension of the fungus.
  • the inoculated test leaf disks are incubated at 20°C and 60% rh under a light regime of 72 h semi darkness followed by 12 h light / 12 h darkness in a climate chamber, the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears on untreated check spikelets (6 to 8 days after application).
  • Example B8 Phaeosphaeria nodorum (Septoria nodorum) / wheat / leaf disc preventative (Glume blotch)
  • Wheat leaf segments cv. Kanzler are placed on agar in a multiwell plate (24-well format) and sprayed with the formulated test compound diluted in water.
  • the leaf disks are inoculated with a spore suspension of the fungus 2 days after application.
  • the inoculated test leaf disks are incubated at 20°C and 75% rh under a light regime of 12 h light / 12 h darkness in a climate cabinet and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf disks (5 to 7 days after application).
  • Example B9 Monoqraphella nivalis (Microdochium nivale) / liquid culture (foot rot cereals)
  • Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24°C and the inhibition of growth is determined photometrically 4 to 5 days after application.
  • nutrient broth PDB potato dextrose broth
  • Example B10 Mycosphaerella arachidis (Cercospora arachidicola) / liquid culture (early leaf spot)
  • Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24°C and the inhibition of growth is determined photometrically 4 to 5 days after application. The following compounds gave at least 80% control of Mycosphaerella arachidis at 20 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
  • Example B11 Pyrenophora teres / barley / leaf disc preventative (Net blotch)
  • Barley leaf segments cv. Hasso are placed on agar in a multiwell plate (24-well format) and sprayed with the formulated test compound diluted in water.
  • the leaf segments are inoculated with a spore suspension of the fungus 2 days after application.
  • the inoculated leaf segments are incubated at 20°C and 65% rh under a light regime of 12 h light / 12 h darkness in a climate cabinet and the activity of a compound is assessed as disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf segments (5 to 7 days after application).
  • Example B12 Sclerotinia sclerotiorum / liquid culture (cottony rot)
  • Mycelia fragments of a newly grown liquid culture of the fungus are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format) the nutrient broth containing the fungal material is added. The test plates are incubated at 24°C and the inhibition of growth is determined photometrically 3 to 4 days after application.
  • nutrient broth PDB potato dextrose broth
  • Example B13 Mycosphaerella qraminicola (Septoria tritici) / liquid culture (Septoria blotch)
  • Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24°C and the inhibition of growth is determined photometrically 4 to 5 days after application.
  • nutrient broth PDB potato dextrose broth
  • Example B14 Puccinia recondita f. sp. tritici / wheat / leaf disc curative (Brown rust) Wheat leaf segments cv. Kanzler are placed on agar in multiwell plates (24-well format). The leaf segments are inoculated with a spore suspension of the fungus. Plates are stored in darkness at 19 °C and 75% rh. The formulated test compound diluted in water is applied 1 day after inoculation.
  • the leaf segments are incubated at 19°C and 75% rh under a light regime of 12 h light / 12 h darkness in a climate cabinet and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf segments (6 to 8 days after application).
  • Example B15 Puccinia recondita f. sp. tritici / wheat / leaf disc preventative (Brown rust)
  • Wheat leaf segments cv. Kanzler are placed on agar in multiwell plates (24-well format) and sprayed with the formulated test compound diluted in water.
  • the leaf disks are inoculated with a spore suspension of the fungus 1 day after application.
  • the inoculated leaf segments are incubated at 19°C and 75% rh under a light regime of 12 h light / 12 h darkness in a climate cabinet and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf segments (7 to 9 days after application).
  • Example B16 Maqnaporthe qrisea (Pyricularia oryzae) / liquid culture (Rice Blast)
  • Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24°C and the inhibition of growth is determined photometrically 3 to 4 days after application.
  • nutrient broth PDB potato dextrose broth
  • Example B17 Maqnaporthe qrisea (Pyricularia oryzae) / rice / leaf disc preventative (Rice Blast)
  • Rice leaf segments cv. Ballila are placed on agar in a multiwell plate (24-well format) and sprayed with the formulated test compound diluted in water.
  • the leaf segments are inoculated with a spore suspension of the fungus 2 days after application.
  • the inoculated leaf segments are incubated at 22°C and 80% rh under a light regime of 24 h darkness followed by 12 h light / 12 h darkness in a climate cabinet and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf segments (5 to 7 days after application).
  • the following compounds gave at least 80% control of Magnaporthe grisea at 200 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
  • Example B18 Thanatephorus cucumeris (Rhizoctonia solani) / liquid culture (foot rot, damping-off)
  • Mycelia fragments of a newly grown liquid culture of the fungus are directly mixed into nutrient broth (PDB potato dextrose broth).
  • nutrient broth PDB potato dextrose broth
  • DMSO DMSO

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Abstract

A compound of formula (I) (I) wherein the substituents are as defined in claim 1, and the agrochemically acceptable salts, stereoisomers, enantiomers, tautomers and N-oxides of those compounds, which can be used as fungicides.

Description

MICROBIOCIDAL TETRAHYDROISOQUINOLINE DERIVATIVES
The present invention relates to microbiocidal tetrahydroisoquinoline derivatives, e.g., as active ingredients, which have microbiocidal activity, in particular fungicidal activity. The invention also relates to preparation of these tetrahydroisoquinoline derivatives, to intermediates useful in the preparation of these tetrahydroisoquinoline derivatives, to the preparation of these intermediates, to agrochemical compositions which comprise at least one of the tetrahydroisoquinoline derivatives, to preparation of these compositions and to the use of the tetrahydroisoquinoline derivatives or compositions in agriculture or horticulture for controlling or preventing infestation of plants, harvested food crops, seeds or non-living materials by phytopathogenic microorganisms, in particular fungi.
According to a first aspect of the present invention, there is provided a compound of formula (I)
Figure imgf000002_0001
wherein
R1 is selected from hydrogen, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, or Cs-Cecycloalkyl;
R2 is selected from hydrogen, halogen, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl, C3- Cecycloalkyl, Ci-C4-alkylcarbonyl, N-Ci-C4-alkoxy-C-Ci-C4-alkyl-carbonimidoyl, N-hydroxy-C-Ci-C4-alkyl- carbonimidoyl, or Ci-C4-alkoxycarbonyl;
R3 is selected from hydrogen, halogen, C1-C4 haloalkyl, or C1-C4 alkyl;
R4 is selected from hydrogen, halogen, C1-C4 haloalkyl, C3-C6 cycloalkyl, or C1-C4 alkyl;
R5 and R6 are independently selected from hydrogen, or Ci-C4-alkyl;
R7 is selected from hydrogen, Ci-C4-lkyl, Ci-C4-alkylcarbonyl, N-Ci-C4-alkoxy-C-Ci-C4-alkyl-carbonimidoyl, N- hydroxy-C-Ci-C4-alkyl-carbonimidoyl, Ci-C4-alkoxycarbonyl, N-methoxy-N-methyl-carbonyl, C1-C4 alkylaminocarbonyl, di (Ci-C4-alkyl)aminocarbonyl, phenyl, a 5- or 6-membered heteroaryl, or Cs-Ce-cycloalkyl; wherein any of said 5- or 6-membered heteroaryl contains 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S, with the proviso that no more than one is O or S; and wherein any of said phenyl and 5- or 6- membered heteroaryl are unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from halogen, Ci-C4haloalkyl, cyano, carboxy, Ci-C4alkyl, or Ci-C4alkoxy; and wherein said Cs-Ce-cycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from halogen, Ci-C4haloalkyl, cyano, Ci-C4alkyl, or Ci-C4alkoxy;
B1 is selected from CR10, or N;
B2 is selected from CR11, or N;
R8, R9, R10 and R11 are independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, Ci-C4-haloalkoxy, C2-C4-alkenyloxy, C2-C4-alkynyloxy, Ci-C4-alkylsulfanyl, Ci-C4-alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 alkoxy-Ci-C4 alkyl, N-Ci-C4-alkylamino, N,N-di(Ci-C4 alkyl)amino, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl, Ci-C4-alkylaminocarbonyl, di(Ci-C4-alkyl)aminocarbonyl, cyano-Ci-C4alkyl, N-C1-C4 alkoxy-Ci-C4-alkyl-carbonimidoyl, N-hydroxy-Ci-C4 alkyl-carbonimidoyl, hydroxy, trifluoromethylsulfonyloxy, cyano, carboxy, amino, phenyl, 5- or 6-membered heteroaryl, or C3-C6 cycloalkyl; wherein any of said 5- or e- membered heteroaryl contains 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S, with the proviso that no more than one is O or S; and wherein any of said phenyl, 5- or 6-membered heteroaryl and C3-C6- cycloalkyl are unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, or Ci-C4alkoxy;
A1, A2 and A3 are independently selected from CR12, N, NR13, O or S, with the proviso that at least one of A1, A2 and A3 is selected from N, O or S, and that no more than one of A1, A2 and A3 is O or S;
R12, R13 are independently selected from hydrogen, halogen, C1-C4 alkyl, Ci-C4haloalkyl, C2-C4 alkenyl, or C2- C4 alkynyl; and
Z1 is selected from 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N; wherein any of said 6-membered heteroaryl is unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from halogen, C1-C4 haloalkyl, cyano, C1-C4 alkyl, C2-C4 alkynyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylsulfanyl, C1-C4 alkylsulfinyl, or Ci-C4 alkylsulfonyl; or an agrochemically acceptable salt, stereoisomer, or N-oxide thereof.
Surprisingly, it has been found that the compounds of formula (I) have, for practical purposes, a very advantageous level of biological activity for protecting plants against diseases that are caused by fungi.
According to a second aspect of the invention, there is provided an agrochemical composition comprising a fungicidally effective amount of a compound of formula (I) according to the invention. Such an agricultural composition may further comprise at least one additional active ingredient and/or an agrochemically- acceptable diluent or carrier.
According to a third aspect of the invention, there is provided a method of controlling or preventing infestation of useful plants by phytopathogenic microorganisms, wherein a fungicidally effective amount of a compound of formula (I) according to the invention, or a composition comprising the compound of formula (I), is applied to the plants, to parts thereof or the locus thereof.
According to a fourth aspect of the invention, there is provided the use of a compound of formula (I) according to the invention as a fungicide. According to this particular aspect of the invention, the use may exclude methods for treatment of the human or animal body by surgery or therapy and diagnostic methods practised on the human or animal body.
According to a fifth aspect of the invention, there is provided a compound of formula (llb-1) as respectively described in the invention.
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 Ci- 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 Ci- 04 alkane- or arylsulfonic acids which are unsubstituted or substituted, for example by halogen, for example methane- or p-toluenesulfonic acid. 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 morpholine, 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.
In each case, 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.
Where substituents are indicated as being “optionally substituted”, this means that they may or may not carry one or more identical or different substituents, e.g., one, two or three Rx substituents. For example, Ci-Cealkyl substituted by 1 , 2 or 3 halogens, may include, but not be limited to, -CH2CI, -CHCI2, -CCh, -CH2F, -CHF2, - CF3, -CH2CF3 or -CF2CH3 groups. As another example, Ci-Cealkoxy substituted by 1 , 2 or 3 halogens, may include, but not be limited to, CH2CIO-, CHCI2O-, CCI3O-, CH2FO-, CHF2O-, CF3O-, CF3CH2O- or CH3CF2O- groups. Further the term “optionally substituted”, as used herein, can be used interchangeably with the term “unsubstituted or substituted”.
As used herein, the term "halogen" or “halo” refers to fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo), preferably fluorine, chlorine, or bromine. This also applies, correspondingly, to halogen in combination with other meanings, such as haloalkyl, haloalkenyl, haloalkynyl, haloalkoxy, and halocycloalkyl.
As used herein, amino means a -NH2 group. As used herein, cyano means a -CN group.
As used herein, the term “hydroxyl” or “hydroxy” means an -OH group.
As used herein, the term “carboxylic acid” means a -COOH group.
As used herein, the term "Ci-Cn-alkyl” 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, 1 ,1 ,2-trimethylpropyl, 1 ,2,2-trimethylpropyl, 1 -ethyl-1 -methylpropyl, or 1-ethyl-2- methylpropyl.
As used herein, the term “C2-Cn-alkenyl” refers to a straight or branched alkenyl chain moiety having from two to n carbon atoms and one or two double bonds, for example, ethenyl, prop-1 -enyl, but-2-enyl.
As used herein, the term “C2-Cn-alkynyl” refers to a straight or branched alkynyl chain moiety having from two to n carbon atoms and one triple bond, for example, ethynyl, prop-2-ynyl, but-3-ynyl,
As used herein, the term “Cs-Cn-cycloalkyl” refers to three (3) to n membered cycloalkyl radical such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
As used herein, the term "Ci-Cn-alkoxy" refers to a straight-chain or branched saturated alkyl radical having one (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 and 1 ,1 -dimethylethoxy. The term “C2-Cn-alkenyloxy” as used herein refers to a straight-chain or branched alkenyl chain having two (2) to n carbon atoms (as mentioned above) which is attached via an oxygen atom.
As used herein, the term "C2-Cn alkynyloxy" refers to a radical of the formula -ORa where Ra is a C2-Cn alkynyl radical as generally defined above.
As used herein, the term “Ci-Cn-alkoxy-Ci-Cn-alkyl” refers to an alkyl radical (as mentioned above) substituted with a Ci-Cn-alkoxy group. Examples are methoxymethyl, methoxyethyl, ethoxymethyl and propoxymethyl.
As used herein, the term “C3-Cn-cycloalkyl-Ci-Cn-alkyl” refers to an alkyl radical (as mentioned above) substituted with a Cs-Cn-cycloalkyl group. Examples are cyclopropylmethyl, cyclopropylethyl. Similarly, the term “C3-Cn-halocycloalkyl-Ci-Cn-alkyl” refers to an alkyl radical substituted with cycloalkyl group, wherein the cycloalkyl group is substituted by one or more of the same or different halogen atoms. Examples are 3,3- difluorobutylmethyl and 1 -chlorocyclopropylmethyl.
As used herein, the term "Ci-Cn-haloalkyl" 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-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 2-fluoropropyl, 3-fluoropropyl, 2,2- difluoropropyl, 2,3-difluoropropyl, 2-chloropropyl, 3-chloropropyl, 2,3-dichloropropyl, 2-bromopropyl, 3- bromopropyl, 3,3,3-trifluoropropyl, 3,3,3-trichloropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 1- (fluoromethyl)-2-fluoroethyl, 1-(chloromethyl)-2-chloroethyl, 1 -(bromomethyl)-2-bromoethyl, 4-fluorobutyl, 4- chlorobutyl, 4-bromobutyl or nonafluorobutyl. Accordingly, a term "Ci-C2fluoroalkyl" would refer to a Ci-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. Similarly, the term “C2-Cn-haloalkenyl” or “C2-Cn-haloalkynyl” as used herein refers to a C2-Cn-alkenyl or C2- Cn-alkynyl radical respectively substituted with one or more halogen atoms which may be the same or different. Similarly, the term “Cs-Cn-halocycloalkyl” or “Ci-Cn-haloalkoxy” as used herein refers to a Cs-Cn-cycloalkyl radical or Ci-Cn-alkoxyl radical respectively substituted with one or more halo atoms which may be the same or different.
As used herein, the term “cyano-Ci-Cn-alkyl” refers to Ci-Cn-alkyl radical having 1 to n carbon atoms (as mentioned above), where one of the hydrogen atoms in the radical is be replaced by a cyano group: for example, cyano-methyl, 2-cyano-ethyl, 2-cyano-propyl, 3-cyano-propyl, 1-(cyano-methyl)-2-ethyl, 1-(methyl)- 2-cyano-ethyl, 4-cyanobutyl, and the like. Similarly, the term “cyano-Cs-Cn-cycloalkyl” refers to a C3-Cn- cycloalkyl radical substituted with one of the hydrogen atoms by a cyano group; and the term “cyano-Cs-Cn- cycloalkyl-Ci-Cn-alkyl” refers to an Ci-Cn-alkyl radical having a cyano-Cs-Cn-cycloalkyl group.
As used herein, the term “Ci-Cn-alkylthio“ or “Ci-Cn-alkylsulfanyl“refers to a Ci-Cn-alkyl group linked through a sulfur atom.
As used herein, the term “Ci-Cn-haloalkylthio“ or “Ci-Cn-haloalkylsulfanyl“refers to a Ci-Cnhaloalkyl group linked through a sulfur atom.
As used herein, the term “Ci-Cn-alkylsulfinyl“ refers to a Ci-Cnalkyl group linked through the sulfur atom of a sulfinyl (or S(=O)-) group.
As used herein, the term “Ci-Cn-alkylsulfonyl“ refers to a Ci-Cnalkyl group linked through the sulfur atom of a sulfonyl (or S(=O)2-) group.
As used herein, the term “Ci-Cn-alkylsulfonyl-Ci-Cn-alkyl” refers to an a Ci-Cnalkyl radical substituted with a Ci-Cnalkylsulfonyl group.
As used herein, the term “Ci-Cn-alkylcarbonyl” refers to a Ci-Cn-alkyl group linked through the carbon atom of a carbonyl (C=O) group.
As used herein, the term “Ci-Cn-alkoxycarbonyl” refers to a Ci-Cn-alkoxy moiety linked through a carbon atom of a carbonyl (or C=O) group.
As used herein, the term “Ci-Cn-alkoxycarbonyl-Ci-Cn-alkyl” refers to a Ci-Cn-alkyl radical substituted by a “C1- Cn-alkoxycarbonyl group. As used herein, the term “benzoyl” refers to a phenyl group linked through the carbon atom of a carbonyl (C=O) group.
As used herein, the term “Ci-Cn-haloalkoxycarbonyl” refers to a Ci-Cn-haloalkoxy group linked through the carbon atom of a carbonyl (C=O) group.
As used herein, the term “C2-Cn-alkenyloxycarbonyl” refers to a C2-Cn-alkenyloxy group linked through the carbon atom of a carbonyl (C=O) group.
As used herein, the term “Ci-Cn-alkylaminocarbonyl” refers to a group of the formula RaNHC(=O)-, wherein Ra is a Ci-Cn-alkyl group, as generally defined above, linked through the carbon atom of a carbonyl (C=O) group.
As used herein, the term “di(Ci-Cnalkyl)aminocarbonyl” refers to a radical of the formula RaNRbC(=O), where Ra is a Ci Cn alkyl radical as generally defined above, and Rb is a Ci-Cn alkyl radical as generally defined above, linked through the carbon atom of a carbonyl (C=O) group.
As used herein, the term “N-Ci-Cn alkylamino” refers to a radical of the formula -NH-Ra where Ra is a Ci-Cn alkyl radical as defined above.
As used herein, the term "N,N-di(Ci-Cn alkyl)amino" refers to a radical of the formula -N(Ra)Ra where each Ra is a Ci-Cn alkyl radical, which may be the same or different, as defined above.
As used herein, the term “Ci-Cn-alkylcarbonyloxy-Ci-Cn-alkyl” refers to a Ci-Cn-alkyl radical substituted by a Ci-Cn-alkylcarbonyloxy (or RaC(=O)O-) group, wherein Ra is a Ci-Cn-haloalkyl group.
As used herein, the term “Ci-Cn-alkoxycarbonyloxy-Ci-Cn-alkyl” refers to a Ci-Cn-alkyl radical substituted by a Ci-Cn-alkoxycarbonyloxy (or RcC(=O)O-) group, wherein Rc is a Ci-Cn-alkoxy group. The Ci-Cn-alkoxy group linked to the nitrogen may be substituted.
As used herein, the term “N-C1-C4 alkoxy-C-Ci-C4 alkyl-carbonimidoyl” refers to a radical of the formula - C(Ra)=NO(Rb) where Ra is a C1-C4 alkyl radical as generally defined above, and Rb is a C1-C4 alkyl radical as generally defined above.
As used herein the term “N-hydroxy-C-Ci-C4alkyl-carbonimidoyl” refers to a radical of the formula -C(Ra)=NOH where Ra is a C1-C4 alkyl radical as generally defined above.
As used herein, the term “heteroaryl" refers to a 5- or 6-membered aromatic monocyclic ring radical which comprises 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S. Examples of heteroaryl include, but are not limited to, furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidyl or pyridyl. The term “heteroaryl-Ci-Cn-alkyl” or “heteroaryl- Cs-Cn-cycloalkyl” refers to an Ci-Cn-alkyl or Cs-Cn-cycloalkyl radical respectively substituted by a heteroaryl group. The heteroaryl-Ci-Cn-alkyl or heteroaryl-Cs-Cn-cycloalkyl radical may be substituted on heteroaryl, alkyl and/or cycloalkyl group as appropriate.
As used herein, the term "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. As used herein, the term "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.
As used herein, 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, using 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 and its lifecycle; the particular compound applied; the type of application; and other relevant circumstances.
As used herein, the term “room temperature” or “RT” or “rt” or “ambient temperature” refer to a temperature of about 15° C to about 35° C. For example, rt can refer to a temperature of about 20° C to about 30° C.
The following list provides definitions, including preferred definitions, for substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, B1, B2, A1, A2, A3 and Z1 with reference to the compounds of formula (I) of the present invention. For any one of these substituents, any of the definitions given below may be combined with any definition of any other substituent given below or elsewhere in this document.
In one embodiment of the invention R1 is selected from hydrogen, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, or Cs-Cecycloalkyl. In another embodiment of the invention, R1 is Ci-C4alkyl. Preferably, R1 is methyl, ethyl or isopropyl. More preferably, R1 is methyl.
In one embodiment of the invention, R2 is selected from hydrogen, halogen, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4- alkynyl, Ci-C4-haloalkyl, Cs-Cecycloalkyl, Ci-C4-alkylcarbonyl, N-C1-C4 alkoxy-C-Ci-C4 alkyl-carbonimidoyl, N- hydroxy-C-Ci-C4 alkyl-carbonimidoyl, or Ci-C4-alkoxycarbonyl. In another embodiment of the invention, R2 is hydrogen, halogen, Ci-C4-alkyl, Cs-Cecycloalkyl, Ci-C4alkylcarbonyl, N-Ci-C4alkoxy-Ci-C4 alkyl-carbonimidoyl, or N-hydroxy-Ci-C4 alkyl-carbonimidoyl. Preferably R2 is hydrogen, halogen, methyl, ethyl, cyclopropyl, C1-C2 alkylcarbonyl, N-C1-C2 alkoxy-C-Ci-C2 alkyl-carbonimidoyl, or N-hydroxy-C-Ci-C2 alkyl-carbonimidoyl. More preferably R2 is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, cyclopropyl, acetyl, -C(CH3)=NOCH3, - C(CH3)=NOCH2CH3, or -C(CH3)=NOH. In a preferred embodiment of the invention R2 is hydrogen, halogen, or C1-C4 alkyl. Most preferably R2 is hydrogen, chlorine, or methyl. In one preferred embodiment R2 is hydrogen. In another preferred embodiment R2 is methyl. In still another preferred embodiment R2 is chlorine.
In one embodiment R3 is selected from hydrogen, halogen, C1-C4 haloalkyl, or C1-C4 alkyl. Preferably R3 is hydrogen or C1-C4 alkyl. More preferably R3 is hydrogen or methyl. Most preferably R3 is hydrogen.
In one embodiment of the invention R4 is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, or Cs- Ce-cycloalkyl. Preferably R4 is hydrogen, chlorine, bromine, fluorine, methyl, ethyl, trifluoromethyl, difluoromethyl, or cyclopropyl. More preferably R4 is hydrogen, chlorine, bromine, or methyl. Still more preferably R4 is hydrogen or methyl. Most preferably R4 is hydrogen. In one embodiment of the invention R4 is hydrogen. In another embodiment of the invention R4 is methyl.
In one embodiment of the invention R5 and R6 are independently selected from hydrogen or Ci-C4-alkyl. Preferably R5 and R6 are independently selected from hydrogen, methyl, or ethyl. More preferably, R5 and R6 are independently selected from hydrogen or methyl. Even more preferably, R5 and R6 are hydrogen.
In one embodiment R7 is selected from hydrogen, Ci-C4alkyl, Ci-C4-alkylcarbonyl, N-C1-C4 alkoxy-C-Ci-C4 alkyl-carbonimidoyl, N-hydroxy-C-Ci-C4-alkyl-carbonimidoyl, Ci-C4-alkoxycarbonyl, N-methoxy-N-methyl- carbonyl, Ci-C4alkylaminocarbonyl, di(Ci-C4alkyl)aminocarbonyl, phenyl, a 5- or 6-membered heteroaryl, or Cs-Ce-cycloalkyl; wherein any of said 5- or 6-membered heteroaryl conatins 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S, with the proviso that no more than one is O or S; and wherein any of said phenyl and 5- or 6-membered heteroaryl are unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from halogen, Ci-C4haloalkyl, cyano, carboxy, Ci-C4alkyl, or Ci-C4-alkoxy; and wherein said Cs-Ce-cycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from halogen, Ci-C4-haloalkyl, cyano, Ci-C4alkyl, or Ci-C4alkoxy.
In another embodiment of the invention R7 is selected from hydrogen, Ci-C4alkyl, C3- Ci-C4alkylcarbonyl, Ci- 04 alkoxycarbonyl, N-C1-C4 alkoxy-C-Ci-C4alkyl-carbonimidoyl, N-hydroxy-C-Ci-C4 alkyl-carbonimidoyl, N- methoxy-N-methyl-carbonyl, C1-C4 alkylaminocarbonyl, di(Ci-C4alkyl)aminocarbonyl, phenyl, a 5- or 6- membered heteroaryl, or Cs-Ce-cycloalkyl; wherein any of said 5- or 6-membered heteroaryl contains 1 heteroatom selected from N; and wherein any of said phenyl and 5- or 6-membered heteroaryl are unsubstituted or substituted with 1 or 2 substituents independently selected from halogen, Ci-C4haloalkyl, cyano, or Ci-C4alkyl; and wherein said Cs-Ce-cycloalkyl is unsubstituted or substituted with 1 substituent selected from cyano. Preferably R7 is selected from hydrogen, methyl, acetyl, C(CHs)=NOCHs, - C(CHS)=NOCH2CHS, -C(CHS)=NOH, methoxycarbonyl, ethoxycarbonyl, N-methoxy-N-methyl-carbonyl, methylaminocarbonyl, dimethylaminocarbonyl, phenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, [4- (trifluoromethyl)pyrazol-l-yl], [3-(trifluoromethyl)pyrazol-1-yl], 3-cyanopyrazol-1-yl, 4-cyanopyrazol-1-yl, 5- chloropyrazol-1-yl, 5-fluoropyrazol-1-yl, 3,5-dimethylpyrazol-1-yl, 5-methylpyrazol-1-yl, pyrazol-1-yl, cyclopropyl, or 1 -cyanocyclopropyl. More preferably R7 is selected from hydrogen, methyl, acetyl, C(CHs)=NOCHs, -C(CHS)=NOCH2CHS, -C(CHS)=NOH, phenyl, 4-cyanophenyl, pyrazol-1-yl, cyclopropyl, or 1- cyanocyclopropyl. Even more preferably R7 is selected from hydrogen, methyl, cyclopropyl, or 1- cyanocyclopropyl.
In another embodiment R7 is selected from hydrogen, C1-C4 alkyl, or Cs-Ce-cycloalkyl. Preferably R7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl. Even more preferably R7 is hydrogen, methyl, or cyclopropyl.
In another preferred embodiment R7 is C1-C4 alkyl. Preferably R7 is methyl or ethyl. More preferably R7 is methyl. In one embodiment of the invention R8, R9, R10 and R11 are independently selected hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C2-C4alkenyloxy, C2-C4 alkynyloxy, C1-C4 alkylsulfanyl, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, Ci-C4 alkoxy-Ci-C4 alkyl, N- C1-C4 alkylamino, N,N-di C1-C4 alkylamino, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl, C1-C4 alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl, cyano-Ci- C4alkyl, N-C1-C4 alkoxy-Ci-C4 alkyl-carbonimidoyl, N-hydroxy-Ci-C4 alkyl-carbonimidoyl, hydroxy, trifluoromethylsulfonyloxy, cyano, carboxy, amino, phenyl, 5- or 6-membered heteroaryl, or C3-C6 cycloalkyl; wherein any of said 5- or 6-membered heteroaryl contains 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S, with the proviso that no more than one is O or S; and wherein any of said phenyl, 5- or 6- membered heteroaryl, and Cs-Ce-cycloalkyl are unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, or Ci-C4alkoxy;
In one embodiment of the invention, R8 and R9 are independently selected from hydrogen, halogen, cyano, Ci- 04 alkyl, or C1-C4 alkoxy. Preferably, R8 and R9 are independently selected from hydrogen, halogen, methyl, methoxy, or cyano. More preferably, R8 and R9 are independently selected from hydrogen, methyl, chlorine, fluorine, bromine, or methoxy. Even more preferably, R8 and R9 are independently selected from hydrogen or methoxy.
In another embodiment of the invention, R8 is hydrogen, halogen, or cyano. Preferably R8 is hydrogen, bromine, chlorine, or cyano. More preferably, R8 is hydrogen, cyano or bromine. Even more preferably, R8 is hydrogen.
In one embodiment R9 is selected from hydrogen, halogen, C1-C3 alkyl, C1-C2 haloalkyl, C1-C3 haloalkoxy, Ci- 04 alkoxy, Ci-Csalkenyloxy, Ci-Csalkynyloxy, Ci-C2alkylsulfanyl, C1-C2 alkylsulfinyl, C1-C2 alkylsulfonyl, C1-C2 alkoxy-Ci-C2 alkyl, Ci-Csalkoxycarbonyl, Ci-C2alkylcarbonyl, Ci-C2alkylaminocarbonyl, di(Ci- C2alkyl)aminocarbonyl, cyano-Ci-C2alkyl, N-C1-C2 alkoxy-C-Ci-C2 alkyl-carbonimidoyl, N-hydroxy-C-Ci- C2alkyl-carbonimidoyl, hydroxy, trifluoromethylsulfonyloxy, cyano, carboxy, phenyl, 2-cyanophenyl, 3- cyanophenyl, 4-cyanophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, [4-(trifluoromethyl)pyrazol-1- yl], [3-(trifluoromethyl)pyrazol-1-yl], 3-cyanopyrazol-1-yl, 4-cyanopyrazol-1-yl, 5-chloropyrazol-1-yl, 4- chloropyrazol-1-yl, 3-chloropyrazol-1-yl, 5-fluoropyrazol-1-yl, 4-fluoropyrazol-1-yl, 3-fluoropyrazol-1-yl, 3,5- dimethylpyrazol-1-yl, 5-methylpyrazol-1-yl, 4-methylpyrazol-1-yl, 3-methylpyrazol-1-yl, pyrazol-1-yl, cyclopropyl, or 1 -cyanocyclopropyl. Preferably R9 is hydrogen, chloro, fluoro, bromo, methyl, ethyl, trifluoromethyl, difluoromethyl, difluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, methoxy, ethoxy, propoxy, allyloxy, prop-2-ynoxy, methylsulfanyl, methylsulfinyl, methylsulfonyl, methoxymethyl, ethoxymethyl, 2-methoxyethoxymethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, acetyl, propanoyl, - C(CH3)=NOCH3, -C(CH3)=NOCH2CH3, -C(CH3)=NOH, methylaminocarbonyl, di(methylamino)carbonyl, trifluoromethylsulfonyloxy, cyano, carboxy, phenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2- methylphenyl, 3-methylphenyl, 4-methylphenyl, [4-(trifluoromethyl)pyrazol-1-yl], [3-(trifluoromethyl)pyrazol-1- yl], 3-cyanopyrazol-1-yl, 4-cyanopyrazol-1-yl, 5-chloropyrazol-1-yl, 4-chloropyrazol-1-yl, 3-chloropyrazol-1-yl, 5-fluoropyrazol-1-yl, 4-fluoropyrazol-1-yl, 3-fluoropyrazol-1-yl, 3,5-dimethylpyrazol-1-yl, 5-methylpyrazol-1-yl, 4-methylpyrazol-1-yl, 3-methylpyrazol-1-yl, pyrazol-1 -yl, cyclopropyl, or 1 -cyanocyclopropyl. More preferably R9 is hydrogen, chloro, bromo, fluoro, cano, methyl, methoxy, propoxy, allyloxy, methoxymethyl, 2- methoxyethoxymethyl, phenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, [4-(trifluoromethyl)pyrazol-1- yl], [3-(trifluoromethyl)pyrazol-1-yl], 3-cyanopyrazol-1-yl, 4-cyanopyrazol-1-yl, 5-chloropyrazol-1-yl, 4- chloropyrazol-1-yl, 3-chloropyrazol-1-yl, 5-fluoropyrazol-1-yl, 4-fluoropyrazol-1-yl, 3-fluoropyrazol-1-yl, 3,5- dimethylpyrazol-1-yl, 5-methylpyrazol-1-yl, 4-methylpyrazol-1-yl, 3-methylpyrazol-1-yl, pyrazol-1-yl, cyclopropyl, or 1 -cyanocyclopropyl. Even more preferably R9 is hydrogen, chloro, bromo, cyano, methyl, or methoxy. Most preferably R9 is hydrogen or methoxy.
In an embodiment of the invention, B1 is CR10 and B2 is CR11 or B1 is N and B2 is CR11 or B1 is CR10 and B2 is N. Preferably, B1 is CR10 and B2 is CR11.
In one embodiment of the invention R10 and R11 are independently selected from hydrogen, halogen, hydroxy, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C2-C4alkenyloxy, C2-C4 alkynyloxy, C1-C4 alkylsulfanyl, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, Ci-C4 alkoxy-Ci-C4 alkyl, N- C1-C4 alkylamino, N,N- di C1-C4 alkylamino, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl, Ci-C2alkylaminocarbonyl, di(Ci- C2alkyl)aminocarbonyl, cyano-Ci-C4alkyl, N-C1-C4 alkoxy-Ci-C4 alkyl-carbonimidoyl, N-hydroxy-Ci-C4 alkylcarbonimidoyl, alkyl-C=N-ORx (X = (CH2)n-CN, hydroxy, trifluoromethylsulfonyloxy, carboxy, phenyl, 5- or 6- membered heteroaryl, or C3-C6 cycloalkyl; wherein any of said 5- or 6-membered heteroaryl contains 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S; and wherein any of said phenyl, 5- or 6-membered heteroaryl and Cs-Ce-cycloalkyl are unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from halogen, cyano, C1-C4 alkyl, C1-C 4haloalkyl, or C1-C4 alkoxy. Preferably R10 and R11 are independently selected from hydrogen, chloro, fluoro, bromo, methyl, ethyl, trifluoromethyl, difluoromethyl, difluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, methoxy, ethoxy, propoxy, allyloxy, prop-2-ynoxy, methylsulfanyl, methylsulfinyl, methylsulfonyl, methoxymethyl, ethoxymethyl, 2-methoxyethoxymethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, acetyl, propanoyl, -C(CH3)=NOCH3, C(CH3)=NOCH2CH3, -C(CH3)=NOH, methylaminocarbonyl, di(methylamino)carbonyl, trifluoromethylsulfonyloxy, cyano, carboxy, phenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2- methylphenyl, 3-methylphenyl, 4-methylphenyl, [4-(trifluoromethyl)pyrazol-1-yl], [3-(trifluoromethyl)pyrazol-1- yl], 3-cyanopyrazol-1-yl, 4-cyanopyrazol-1-yl, 5-chloropyrazol-1-yl, 4-chloropyrazol-1-yl, 3-chloropyrazol-1-yl, 5-fluoropyrazol-1-yl, 4-fluoropyrazol-1-yl, 3-fluoropyrazol-1-yl, 3,5-dimethylpyrazol-1-yl, 5-methylpyrazol-1-yl, 4-methylpyrazol-1-yl, 3-methylpyrazol-1-yl, pyrazol-1 -yl, cyclopropyl, or 1 -cyanocyclopropyl. More preferably R10 and R11 are independently selected from hydrogen, chloro, bromo, fluoro, cyano, methyl, methoxy, propoxy, allyloxy, methoxymethyl, 2-methoxyethoxymethyl, phenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, [4- (trifluoromethyl)pyrazol-l-yl], [3-(trifluoromethyl)pyrazol-1-yl], 3-cyanopyrazol-1-yl, 4-cyanopyrazol-1-yl, 5- chloropyrazol-1-yl, 4-chloropyrazol-1-yl, 3-chloropyrazol-1-yl, 5-fluoropyrazol-1-yl, 4-fluoropyrazol-1-yl, 3- fluoropyrazol-1-yl, 3,5-dimethylpyrazol-1-yl, 5-methylpyrazol-1-yl, 4-methylpyrazol-1-yl, 3-methylpyrazol-1-yl, pyrazol-1-yl, C(CH3)=NOCH3, -C(CH3)=NOCH2CH3, -C(CH3)=NOH, cyclopropyl, or 1 -cyanocyclopropyl. Still more preferably R10 and R11 are independently selected from hydrogen, chlorine, bromine, or cyano. In another embodiment R10 and R11 are independently selected from hydrogen, halogen, C1-C3 alkyl, or Ci-Cs alkoxy. Preferably R10 and R11 are independently selected from hydrogen or halogen. More preferably R10 and R11 are hydrogen, bromine, or chlorine. Even more preferably R10 and R11 are hydrogen.
In one embodiment of the invention A1, A2 and A3 are independently selected from CR12, N, NR13, O or S, with the proviso that at least one of A1, A2 and A3 is selected from N, O or S, and that no more than one of A1, A2 and A3 is O or S. In another embodiment of the invention, A1 and A2 are independently selected from CR12, N or O, and A3 is CR12, N, O or S, with the proviso that at least one of A1, A2 and A3 is selected from N, O or S, and that no more than one of A1, A2 and A3 is O or S. Preferably, A1 and A2 are independently selected from N or O; and A3 is CR12, O or S, with the proviso that at least one of A1, A2 and A3 is N or O, and that no more than one of A1, A2 and A3 is O.
In an embodiment of the invention, R12 is hydrogen or C1-C4 alkyl. Preferably, R12 is hydrogen or methyl. More preferably R12 is hydrogen.
In an embodiment of the invention, R13 is hydrogen or C1-C4 alkyl. Preferably, R13 is hydrogen or methyl. More preferably R13 is hydrogen.
In one embodiment of the invention, Z1 is selected from a 6-membered heteroaryl; wherein any of said 6- membered heteroaryl contains 1 or 2 heteroatoms selected from N; and wherein any of said 6-membered heteroaryl is unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from halogen, cyano, C1-C4 alkyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylsulfanyl, C1-C4 alkylsulfinyl, or C1-C4 alkylsulfonyl. In one embodiment of the invention, Z1 is selected from a 6-membered heteroaryl, wherein any of said 6-membered heteroaryl contains 1 or 2 heteroatoms selected from N; and wherein any of said 6-membered heteroaryl is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, or C1-C4 alkoxy. Preferably Z1 is selected from a 6-membered heteroaryl, wherein any of said 6-membered heteroaryl contains 1 or 2 heteroatoms selected from N; and wherein any of said 6-membered heteroaryl is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen or C1-C4 haloalkyl. More preferably Z1 is selected from a 6-membered heteroaryl, wherein any of said 6-membered heteroaryl contains 1 or 2 heteroatoms selected from N; and wherein any of said 6-membered heteroaryl is unsubstituted or substituted with 1 or 2 substituents selected from fluorine.
In another embodiment of the invention, Z1 is selected from a 6-membered heteroaryl; wherein any of said 6- membered heteroaryl contains 1 heteroatom selected from N; and wherein any of said 6-membered heteroaryl is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, or C1-C4 alkoxy. Preferably Z1 is selected from a 6-membered heteroaryl, wherein any of said 6-membered heteroaryl contains 1 heteroatom selected from N; and wherein any of said 6-membered heteroaryl is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen or C1-C4 haloalkyl. More preferably Z1 is selected from a 6-membered heteroaryl; wherein any of said heteroaryl contains 1 heteroatom selected from N; and wherein any of said 6-membered heteroaryl is unsubstituted or substituted with 1 or 2 substituents selected from fluorine. In another embodiment Z1 is selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazin-2-yl, pyridazin-3-yl, pyridazin- 4-yl, pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-yl; wherein any of said pyridyl-, pyrazin- pyridazine, or pyrimidin-moities are unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from halogen, C1-C4 haloalkyl, cyano, C1-C4 alkyl, C2-C4 alkynyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylsulfanyl, C1-C4 alkylsulfinyl, or Ci-C4 alkylsulfonyl. Preferably Z1 is selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazin- 2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-yl; wherein any of said pyridyl-, pyrazin- pyridazine or pyrimidin-moities are unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from halogen, C1-C4 haloalkyl, or C1-C4 alkyl. More preferably Z1 is selected from 2- pyridyl, 3-pyridyl, 4-pyridyl, pyrazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-yl; wherein any of said pyridyl-, pyrazin- pyridazine or pyrimidin-moities are unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from fluorine, trifluoromethyl, difluoromethyl, or methyl. More preferably Z1 is selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazin-2-yl, pyridazin-3-yl, pyridazin- 4-yl, pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-yl; wherein any of said pyridyl-, pyrazin- pyridazine or pyrimidin-moities are unsubstituted or substituted with 1 or 2 substituents selected from fluorine.
In another more preferred embodiment of the invention Z1 is selected from 5-fluoropyrimidin-4-yl, 3,6-difluoro- 2-pyridyl, 4,6-difluoro-2-pyridyl, 4,5-difluoro-2-pyridyl, 5,6-difluoro-2-pyridyl, 3-fluoro-4-pyridyl, 2-fluoro-4- pyridyl, 2,3-difluoro-4-pyridyl, 2,5-difluoro-4-pyridyl, 2,6-difluoro-4-pyridyl, 3,5-difluoro-4-pyridyl, 2,5-difluoro-4- pyridyl, 2-fluoro-3-pyridyl, 6-fluoro-3-pyridyl, 5-fluoro-3-pyridyl, 4-fluoro-3-pyridyl, 2,6-difluoro-3-pyridyl, 2,5- difluoro-3-pyridyl, 2,4-difluoro-3-pyridyl, 4,6-difluoro-3-pyridyl, 5,6-difluoro-3-pyridyl, 6-fluoropyrimidin-4-yl, 2- fluoropyrimidin-4-yl, 2,5-difluoropyrimidin-4-yl, 2,6-difluoropyrimidin-4-yl, 5,6-difluoropyrimidin-4-yl, 4- fluoropyrimidin-5-yl, 2-fluoropyrimidin-5-yl, 2,4-difluoropyrimidin-5-yl, 4-fluoropyrimidin-2-yl, 5-fluoropyrimidin- 2-yl, 4,5-difluoropyrimidin-2-yl, 4,6-difluoropyrimidin-2-yl, 4-fluoropyridazin-3-yl, 5-fluoropyridazin-3-yl, 6- fluoropyridazin-3-yl, 4,5-difluoropyridazin-3-yl, 4,6-difluoropyridazin-3-yl, 5,6-difluoropyridazin-3-yl, 3- fluoropyridazin-4-yl, 6-fluoropyridazin-4-yl, 5-fluoropyridazin-4-yl, 3,6-difluoropyridazin-4-yl, 5,6- difluoropyridazin-4-yl, 3,5-difluoropyridazin-4-yl, 3,5-difluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, 6-fluoro-2-pyridyl, 4-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3-fluoro-2-pyridyl, 4,5-difluoro-3-pyridyl, or 4-fluoropyrimidin-5-yl. Preferably Z1 is selected from 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 6-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, 3,5-difluoro-2-pyridyl, 2-fluoro-4-pyridyl, 5-fluoropyrimidin-4-yl, 5-fluoropyrimidin-2-yl, 4-fluoropyridazin-3-yl, 5- fluoropyridazin-3-yl, 4,5-difluoropyridazin-3-yl, or 5-fluoropyridazin-4-yl. More preferably Z1 is selected from 3- fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, 3,5-difluoro-2-pyridyl, 4-fluoropyridazin-3-yl, 4,5- difluoropyridazin-3-yl or 5-fluoropyridazin-4-yl. Most preferably Z1 is selected from 3-fluoro-2-pyridyl, 5-fluoro- 2-pyridyl, 3,4-difluoro-2-pyridyl, or 3,5-difluoro-2-pyridyl.
The present invention, accordingly, makes available a compound of formula (I) having R1, R2, R3, R4, R5, R6, R7, R8, R9, B1, B2, A1, A2, A3 and Z1 as defined above in all combinations / each permutation.
Embodiments according to the invention are provided as set out below.
Preferably in a compound of formula (I)
R1 is methyl, R2 is hydrogen, chlorine, or methyl;
R3 is hydrogen;
R4 is hydrogen, or methyl;
R5 and R6 are hydrogen;
R7 is hydrogen, C1-C4 alkyl, or Cs-Ce-cycloalkyl;
R8 is hydrogen, bromine, chlorine, or cyano;
R9 is hydrogen, bromine, chlorine, cyano, methyl, or methoxy;
B1 is N or CR10, wherein R10 is hydrogen, bromine, chlorine, or cyano;
B2 is N or CR11, wherein R11 is hydrogen, bromine, chlorine, or cyano; and
A1, A2, A3 and Z1 are as defined for the compounds of formula (I) according to the present invention.
Preferably in a compound of formula (I)
R1 is methyl,
R2 is hydrogen, chlorine, or methyl;
R3 is hydrogen;
R4 is hydrogen, or methyl;
R5 and R6 are hydrogen;
R7 is hydrogen, C1-C4 alkyl, or Cs-Ce-cycloalkyl;
R8 is hydrogen, bromine, chlorine, or cyano;
R9 is hydrogen, bromine, chlorine, cyano, methyl, or methoxy;
B1 is N or CR10, wherein R10 is hydrogen, bromine, chlorine, or cyano;
B2 is N or CR11, wherein R11 is hydrogen, bromine, chlorine, or cyano;
Z1 is 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-yl; wherein any of said pyridyl-, pyrazin- pyridazine or pyrimidin-moities are unsubstituted or substituted with 1 or 2 substituents selected from fluorine; and
A1, A2 and A3 are as defined for the compounds of formula (I) according to the present invention.
In one embodiment of the invention, the compound of formula (I) may be a compound of formula (l-A)
Figure imgf000014_0001
wherein
R1, R2, R3, R4, R5, R6, R7, R8, R9, B1 and B2 and Z1 are as defined for the compounds of formula (I) according to the present invention, and A is selected from A1 to A36:
Figure imgf000015_0001
wherein indicates the bond to the C(=O) group and the arrow the bond to the Z1 group, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, B1, B2 and Z1 are as defined for the compounds of formula (I) according to the present invention, and R12a, R13a, R14a, R12b, R13b and R14b are independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl.
In an embodiment of the invention, in the compound of formula (l-A), wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, B1 and B2 and Z1 are as defined for the compounds of formula (I) according to the present invention, and A is selected from
Figure imgf000015_0002
Figure imgf000016_0001
wherein indicates the bond to the C(=O) group and the arrow the bond to the Z1 group, and R12a, R13a and R14a are independently selected from hydrogen or C1-C4 alkyl. Preferably R12a, R13a and R14a are hydrogen. In another embodiment of the invention, in the compound of formula (l-A), wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, B1 and B2 and Z1 are as defined for the compounds of formula (I) according to the present invention, and A is selected from
Figure imgf000016_0002
wherein indicates the bond to the C(=O) group and the arrow the bond to the Z1 group, and R12a, R13a and R14a are independently selected from hydrogen or C1-C4 alkyl. Preferably R12a, R13a and R14a are hydrogen.
In another embodiment of the invention, in the compound of formula (l-A), wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, B1 and B2 and Z1 are as defined for the compounds of formula (I) according to the present invention, and A is selected from
Figure imgf000017_0001
A4 A6 A7 A9, or A10 wherein indicates the bond to the C(=O) group and the arrow the bond to the Z1 group, and R14a is selected from hydrogen or C1-C4 alkyl. Preferably R14a is hydrogen.
In another embodiment of the invention, in the compound of formula (l-A), wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, B1 and B2 and Z1 are as defined for the compounds of formula (I) according to the present invention, and A is selected from
Figure imgf000017_0002
wherein indicates the bond to the C(=O) group and the arrow the bond to the Z1 group, and R14a is selected from hydrogen or C1-C4 alkyl. Preferably R14a is hydrogen. In an embodiment of the invention, R12a, R13a, R14a, R12b, R13b and R14b are independently selected from hydrogen or methyl.
In another embodiment of the invention, R12a, R13a, R14a, R12b, R13b and R14b are hydrogen.
In another embodiment of the invention, R12a, R13a, R14a, R12b, R13b and R14b are methyl.
Preferably in the compound of formula (l-A) A is selected from A4, A7 or A9, and R14a is hydrogen. In one embodiment of the invention, the compound of formula (l-A) may be a compound of formula (I-A1) wherein R1 is methyl, B1 is CH, and A is defined as for compound (l-A),
Figure imgf000017_0003
wherein R2, R3, R4, R5, R6, R7, R8, R9, B2 and Z1 are as defined for the compounds of formula (I) according to the present invention.
Preferably a compound of formula (I-A1), wherein B2 is N, and R2, R3, R4, R5, R6, R7, R8, R9, and Z1 are as defined for the compounds of formula (I) according to the present invention.
Preferably a compound of formula (I-A1), wherein B2 is CR11, and R2, R3, R4, R5, R6, R7, R8, R9, R11 and Z1 are as defined for the compounds of formula (I) according to the present invention.
In a variant of this embodiment of the invention, the compound of formula (l-A) may be a compound of formula (I-A2) wherein B1 is CH; R1 is methyl, R3, R5 and R6 are hydrogen; and A is defined as for compound (l-A); and
Figure imgf000018_0001
wherein R2, R4, R7, R8, R9, B2 and Z1 are as defined for the compounds of formula (I) according to the present invention.
Preferably in a compound of formula (I-A2)
R2 is hydrogen, methyl or chlorine;
R4 is hydrogen or methyl;
R7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl;
R8 is hydrogen, cyano, or bromine;
R9 is hydrogen or methoxy;
B2 is CR11, wherein R11 is hydrogen; and
A and Z1 are as defined for the compounds of formula (I) according to the present invention.
Preferably in a compound of formula (I-A2)
R2 is hydrogen, methyl, or chlorine;
R4 is hydrogen or methyl;
R7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl;
R8 is hydrogen, cyano, or bromine;
R9 is hydrogen or methoxy;
B2 is CR11, wherein R11 is hydrogen
A is A4, A7 or A9; and
Z1 is as defined for the compounds of formula (I) according to the present invention.
Preferably in a compound of formula (I-A2) R2 is hydrogen, methyl, or chlorine;
R4 is hydrogen or methyl;
R7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl;
R8 is hydrogen, cyano, or bromine;
R9 is hydrogen or methoxy;
B2 is CR11, wherein R11 is hydrogen
A is A4, A7 or A9; and
Z1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, 3,5-difluoro-2-pyridyl, 4-fluoropyridazin-3-yl, 4,5-difluoropyridazin-3-yl, or 5-fluoropyridazin-4-yl.
In one embodiment of the invention, the compound of formula (l-A) may be a compound of formula (I-A3) wherein R1 is methyl; B1 and B2 are CH; and A is defined as for compound (l-A), and
Figure imgf000019_0001
wherein R2, R3, R4, R5, R6, R7, R8, R9 and Z1 are as defined for the compounds of formula (I) according to the present invention.
In a variant of this embodiment of the invention, the compound of formula (l-A) may be a compound of formula (I-A4) wherein B1 and B2 are CH; R1 is methyl; R3, R4, R5 and R6 are hydrogen and A is defined as for compound
Figure imgf000019_0002
(I-A4) wherein R2, R7, R8, R9 and Z1 are as defined forthe compounds of formula (I) according to the present invention.
Preferably in a compound of formula (I-A4)
R2 is hydrogen, methyl or chlorine;
R7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl; R8 is hydrogen, cyano, or bromine;
R9 is hydrogen, or methoxy; and
A and Z1 are as defined for the compounds of formula (I) according to the present invention.
Preferably in a compound of formula (I-A4)
R2 is hydrogen, methyl, or chlorine;
R7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl;
R8 is hydrogen, cyano, or bromine;
R9 is hydrogen, or methoxy;
A is A4, A7, or A9; and
Z1 is as defined for the compounds of formula (I) according to the present invention.
More preferably in a compound of formula (I-A4)
R2 is hydrogen, methyl, or chlorine;
R7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl;
R8 is hydrogen, cyano, or bromine;
R9 is hydrogen, or methoxy;
A is A4, A7, or A9; and
Z1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, 3,5-difluoro-2-pyridyl, 4-fluoropyridazin-3-yl, 4,5-difluoropyridazin-3-yl, or 5-fluoropyridazin-4-yl.
Even more preferably in a compound of formula (I-A4)
R2 is hydrogen, methyl, or chlorine;
R7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl;
R8 is hydrogen, cyano, or bromine;
R9 is hydrogen, or methoxy;
A is A4, A7, or A9; and
Z1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, or 3,5-difluoro-2-pyridyl.
In one embodiment of the invention, the compound of formula (l-A) may be a compound of formula (I-A5) wherein R1 is methyl; R4 is methyl; R3, R4, R5 and R6 are hydrogen; B1 and B2 are CH; and A is defined as for compound (l-A),
Figure imgf000020_0001
racemic syn-(l-A5) and wherein R2, R7, R8, R9 and Z1 are as defined for the compounds of formula (I) according to the present invention, and wherein when R7 is not hydrogen the stereochemistry of the pyrazole-derivative-substituent and R7 at the carbons with the “*” have a syn-relationship to each other.
Preferably in a compound of formula (I-A5)
R2 is hydrogen, methyl, or chlorine;
R7 is methyl, cyclopropyl, or 1 -cyanocyclopropyl;
R8 is hydrogen, cyano, or bromine;
R9 is hydrogen, or methoxy; and
A and Z1 are as defined for the compounds of formula (I) according to the present invention.
More preferably in a compound of formula (I-A5)
R2 is hydrogen, methyl, or chlorine;
R7 is methyl, cyclopropyl, or 1 -cyanocyclopropyl;
R8 is hydrogen, cyano, or bromine;
R9 is hydrogen, or methoxy;
A is A4, A7, or A9; and
Z1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, 3,5-difluoro-2-pyridyl, 4-fluoropyridazin-3-yl, 4,5-difluoropyridazin-3-yl, or 5-fluoropyridazin-4-yl.
Even more preferably in a compound of formula (I-A5)
R2 is hydrogen, methyl, or chlorine;
R7 is methyl, cyclopropyl, or 1 -cyanocyclopropyl;
R8 is hydrogen, cyano, or bromine;
R9 is hydrogen, or methoxy;
A is A4, A7, or A9; and
Z1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, or 3,5-difluoro-2-pyridyl.
In another embodiment of the invention, the compound of formula (l-A) may be a compound of formula (l-B) wherein R1 is methyl; R3, R5, R6 are hydrogen; B1 and B2 are CH; and A is A4
Figure imgf000021_0001
and wherein R2, R4, R7, R8, R9 and Z1 are as defined for the compounds of formula (I) according to the present invention.
Preferably in a compound of formula (l-B) R2 is hydrogen, methyl, or chlorine; R4 is hydrogen, or methyl;
R7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl;
R8 is hydrogen, cyano, or bromine;
R9 is hydrogen, or methoxy; and
Z1 is as defined for the compounds of formula (I) according to the present invention.
More preferably in a compound of formula (l-B)
R2 is hydrogen, methyl, or chlorine;
R4 is hydrogen, or methyl;
R7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl;
R8 is hydrogen, cyano, or bromine;
R9 is hydrogen, or methoxy; and
Z1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, 3,5-difluoro-2-pyridyl, 4-fluoropyridazin-3-yl, 4,5-difluoropyridazin-3-yl, or 5-fluoropyridazin-4-yl.
Even more preferably in a compound of formula (l-B)
R2 is hydrogen, methyl, or chlorine;
R4 is hydrogen, or methyl;
R7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl;
R8 is hydrogen, cyano or bromine;
R9 is hydrogen or methoxy; and
Z1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl or 3,5-difluoro-2-pyridyl.
Even more preferably in a compound of formula (l-B)
R2 is hydrogen, methyl or chlorine;
R4 is hydrogen;
R7 is methyl, cyclopropyl, or 1 -cyanocyclopropyl;
R8 is hydrogen, cyano, or bromine;
R9 is hydrogen or methoxy; and
Z1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, or 3,5-difluoro-2-pyridyl.
In another embodiment of the invention, the compound of formula (l-A) may be a compound of formula (l-C) wherein R1 is methyl; R3, R5, R6 are hydrogen; B1 and B2 are CH; and A is A7
Figure imgf000022_0001
and wherein R2, R4, R7, R8, R9 and Z1 are as defined for the compounds of formula (I) according to the present invention.
Preferably in a compound of formula (l-C)
R2 is hydrogen, methyl, or chlorine;
R4 is hydrogen or methyl;
R7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl;
R8 is hydrogen, cyano, or bromine;
R9 is hydrogen or methoxy; and
Z1 is as defined for the compounds of formula (I) according to the present invention.
More preferably in a compound of formula (l-C)
R2 is hydrogen, methyl, or chlorine;
R4 is hydrogen or methyl;
R7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl;
R8 is hydrogen, cyano, or bromine;
R9 is hydrogen or methoxy; and
Z1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, 3,5-difluoro-2-pyridyl, 4-fluoropyridazin-3-yl, 4,5-difluoropyridazin-3-yl, or 5-fluoropyridazin-4-yl.
Even more preferably in a compound of formula (l-C)
R2 is hydrogen, methyl, or chlorine;
R4 is hydrogen or methyl;
R7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl;
R8 is hydrogen, cyano, or bromine;
R9 is hydrogen or methoxy; and
Z1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, or 3,5-difluoro-2-pyridyl.
In another embodiment of the invention, the compound of formula (l-A) may be a compound of formula (l-D) wherein R1 is methyl; R3, R5, R6 are hydrogen; B1 and B2 are CH; and A is A9
Figure imgf000023_0001
and wherein R2, R4, R7, R8, R9 and Z1 are as defined for the compounds of formula (I) according to the present invention.
Preferably in a compound of formula (l-D)
R2 is hydrogen, methyl, or chlorine; R4 is hydrogen or methyl;
R7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl;
R8 is hydrogen, cyano, or bromine;
R9 is hydrogen or methoxy; and
Z1 is as defined for the compounds of formula (I) according to the present invention.
More preferably in a compound of formula (l-D)
R2 is hydrogen, methyl, or chlorine;
R4 is hydrogen or methyl;
R7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl;
R8 is hydrogen, cyano, or bromine;
R9 is hydrogen or methoxy; and
Z1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, 3,5-difluoro-2-pyridyl, 4-fluoropyridazin-3-yl, 4,5-difluoropyridazin-3-yl, or 5-fluoropyridazin-4-yl.
Even more preferably in a compound of formula (l-D)
R2 is hydrogen, methyl, or chlorine;
R4 is hydrogen or methyl;
R7 is hydrogen, methyl, cyclopropyl, or 1 -cyanocyclopropyl;
R8 is hydrogen, cyano or bromine;
R9 is hydrogen or methoxy; and
Z1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, or 3,5-difluoro-2-pyridyl.
The below intermediates are novel and as such form a further aspect of the invention.
A compound of formula (lib) or a salt thereof:
Figure imgf000024_0001
wherein R° is Ci-Cealkyl, and wherein A1, A2, A3 and Z1 are defined as for the compounds of formula (I) according to the present invention.
The intermediate compounds of formula (lib) possess the same definitions for A1, A2, A3 and Z1 as for the compounds of formula (I) according to the invention and their corresponding preferences.
In one embodiment R° is C1-C4 alkyl; A1, A2, A3 and Z1 are as defined forthe compounds of formula (I) according to the present invention.
In one embodiment, the compound of formula (lib) may be a compound of formula (llb-1):
Figure imgf000025_0001
wherein
Z1 is as defined for the compounds of formula (I) according to the present invention; R° is as defined for compounds of formula (lib); and A is selected from A1 to A36 as defined above for compounds of formula (I- A).
Preferably in the compound of formula (llb-1) A is selected from
Figure imgf000025_0002
wherein indicates the bond to the C(=O) group and the arrow the bond to the Z1 group, and R14a is selected from hydrogen or C1-C4 alkyl, wherein Z1 is as defined for the compounds of formula (I) according to the present invention, and R° is as defined for compounds of formula (lib). Preferably R14a is hydrogen.
In another embodiment of the invention, in the compound of formula (llb-1) A is selected from
Figure imgf000025_0003
wherein indicates the bond to the C(=O) group and the arrow the bond to the Z1 group, and R14a is selected from hydrogen or C1-C4 alkyl, wherein Z1 is as defined for the compounds of formula (I) according to the present invention, and R° is as defined for compounds of formula (lib). Preferably R14a is hydrogen.
In one embodiment in the compound of formula (llb-1) A is A4; Z1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4- difluoro-2-pyridyl, or 3,5-difluoro-2-pyridyl; and R° is as defined for compounds of formula (lib).
In one embodiment in the compound of formula (llb-1) A is A7; Z1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4- difluoro-2-pyridyl, or 3,5-difluoro-2-pyridyl; and R° is as defined for compounds of formula (lib).
In one embodiment in the compound of formula (llb-1) A is A9; Z1 is 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 3,4- difluoro-2-pyridyl or 3,5-difluoro-2-pyridyl; R14a is hydrogen, and R° is as defined for compounds of formula (Hb). The presence of one or more possible asymmetric carbon atoms in any of the compounds selected from compounds of formula (I), (l-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (l-B), (l-C), or (l-D), or compounds selected from compounds listed in Tables A-1 to A-26, or compounds listed in Table P (below), according to the invention means that the compounds may occur in chiral isomeric forms, i.e., enantiomeric or diastereomeric forms.
More preferably, the compound of formula (I) according to the invention is selected from compounds listed in any one of Tables A-1 to A-26.
Even more preferably the compound of formula (I) according to the invention is selected from compounds as listed in Table P (below).
In one embodiment the compound of formula (I) according to the invention is selected from [4-(1-methylpyrazol-4-yl)-3,4-dihydro-1 H-isoquinolin-2-yl]-[5-(4-pyridyl)isoxazol-3-yl]methanone (P-1), [4-(1-methylpyrazol-4-yl)-3,4-dihydro-1 H-isoquinolin-2-yl]-[5-(3-pyridyl)isoxazol-3-yl]methanone (P-2), [4-(1-methylpyrazol-4-yl)-3,4-dihydro-1 H-isoquinolin-2-yl]-[5-(2-pyridyl)isoxazol-3-yl]methanone (P-3), [5-(6-methoxy-3-pyridyl)isoxazol-3-yl]-[4-(1-methylpyrazol-4-yl)-3,4-dihydro-1 H-isoquinolin-2-yl]methanone (P-
4), [5-(2-methoxy-3-pyridyl)isoxazol-3-yl]-[4-(1-methylpyrazol-4-yl)-3,4-dihydro-1 H-isoquinolin-2-yl]methanone (P-
5),
[5-(3,5-difluoro-2-pyridyl)isoxazol-3-yl]-[rac-(1 S,4S)-4-(1 ,5-dimethylpyrazol-4-yl)-1 -methyl-3,4-dihydro-1 H- isoquinolin-2-yl]methanone (P-6), [5-(3,5-difluoro-2-pyridyl)-1 ,3,4-thiadiazol-2-yl]-[4-(1 ,5-dimethylpyrazol-4-yl)-3,4-dihydro-1 H-isoquinolin-2- yl]methanone (P-7), [5-(2,6-difluoro-3-pyridyl)-1 ,3,4-thiadiazol-2-yl]-[4-(1 ,5-dimethylpyrazol-4-yl)-3,4-dihydro-1 H-isoquinolin-2- yl]methanone (P-8), or [[5-(2,6-difluoro-3-pyridyl)-1 ,3,4-thiadiazol-2-yl]-[rac-(1 S,4S)-4-(1 ,5-dimethylpyrazol-4-yl)-1-methyl-3,4- dihydro-1 H-isoquinolin-2-yl]methanone (P-9), as listed in Table P (below).
The compounds of formula (I) according to the present invention can be made as shown in the following Schemes below, in which, unless otherwise stated, the definition of each variable is as defined above for a compound of formula (I).
The compounds of formula (I) according to the present invention can be made as shown in the following Schemes 1 to 20, in which, unless otherwise stated, the definition of each variable is as defined above for a compound of formula (I).
In particular, compounds of formula (I), wherein R4 and R6 are hydrogen, and R5 is hydrogen or methyl, can be made as shown in the following Schemes 1 to 7, in which, unless otherwise stated, the definition of each variable is as defined above for a compound of formula (I). In any of the Schemes below, the presence of one or more possible asymmetric carbon atoms in a compound of formula (I) according to the invention means that the compounds may occur in chiral isomeric forms, i.e., enantiomeric or diastereomeric forms.
Compounds of formula (I) may be prepared by a person skilled in the art following known methods. More specifically, compounds of formula (I) may be prepared from compounds of formula (III) or a salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 , B1 and B2 are as defined for the compounds of formula (I) by reaction with a compound of formula (II), wherein A1 , A2, A3 and Z1 are as defined for the compounds of formula (I). This reaction is shown in Scheme 1.
Figure imgf000027_0001
Scheme 1
In Scheme 1 , compounds of formula (II), wherein A1, A2, A3 and Z1 are as defined forthe compounds of formula (I), are activated to compounds of formula (Ila) by methods known to a person skilled in the art and described, for example, in Tetrahedron 2005, 61 (46), 10827-10852. For example, compounds of formula (Ila), where X° is halogen, are formed by treatment of compounds of formula (II) with, for example, oxalyl chloride or thionyl chloride in the presence of catalytic quantities of N,N-dimethylformamide (DMF) in inert solvents such as methylene dichloride or tetrahydrofuran (THF) at temperatures between 20°C to 100°C, preferably 25°C. Treatment of compounds of formula (Ila) with compounds of formula (III), wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, B1 and B2 are as defined for the compounds of formula (I), optionally in the presence of a base, e.g. triethylamine or pyridine, leads to compounds of formula (I). Alternatively, compounds of formula (I) may be prepared by treatment of compounds of formula (II) with dicyclohexyl carbodiimide (DCC), 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC) or 1-[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate (HATU) to give the activated compound of formula (Ila), wherein X° is G1, G2 or G3 as set forth in Scheme 1 a, in an inert solvent, e.g. pyridine, DMF, acetonitrile, CH2CI2 or THF, optionally in the presence of a base, e.g. triethylamine, at temperatures between 30°C and 180°C. Finally, a compound of formula (II) can also be activated by reaction with a coupling reagent such as propanephosphonic acid anhydride (T3P) to provide compounds of formula (Ila), wherein X° is G4 as set forth in Scheme 1 a, as described for example in Synthesis 2013, 45, 1569. Further reaction with an amine (or a salt thereof) of the compound of formula (III) leads to compounds of formula (I).
Figure imgf000028_0001
Figure imgf000028_0002
indicates the bond to the C(=O) group
Scheme 1 a
Compounds of formula (II) can be prepared from compounds of formula (lib), wherein A1, A2, A3 are N and Z1 are as described in formula (I), and R° is Ci-C4alkyl, by ester hydrolysis. A variety of conditions can be used, as for example aqueous sodium hydroxide or lithium hydroxide, and an organic water miscible solvent like THF, dimethoxyethane, methanol, or ethanol. Such ester hydrolyses are well known to those skilled in the art. Compounds of formula (lib) can also be directly converted to compounds of formula (I) by reacting compounds of formula (lib) with compounds of formula (III) in the presence of trimethyl aluminium, or trimethyl aluminium- DABCO complex in an inert solvent such as toluene or methylene chloride. Such reactions have been reported in the literature (see Tetrahedron Lett. 1977, 4171 -4174, Tetrahedron Lett. 2006, 5767-5769, and references cited therein). Compounds of formula (II) and (lib) are commercially available or can be synthesized as described vide infra.
For example, compounds of formula (Illa), wherein R4 and R6 are hydrogen, R5 is hydrogen or methyl and R1, R2, R3, R7, R8, R9, R10, R11, B1 and B2 are as defined for the compounds of formula (I), may be prepared from compounds of formula (IVa), wherein R4 and R6 are hydrogen, R5 is hydrogen or methyl and R1, R2, R3, R7, R8, R9, R10, R11, B1 and B2 are as defined for the compounds of formula (I), by treatment with a reducing agent such as NaBHsCN and an acid, for example hydrochloric acid, or acetic acid in a protic solvent such as methanol or ethanol and the like. Such reactions are well known in the literature and analogous reactions have been described for example in Deng, Zeping et al, CN103772278, and Synthesis 1979, 4, 281-283. Alternatively, compounds of formula (Illa) may be prepared from compounds of formula (IVa) by reduction with hydrogen in the presence of a suitable metal catalyst, such as Pd, Ir, Rh with a suitable ligand, e.g. diphosphine [1 ,2-bis(diphenylphosphino)ethane (dppe), 1 ,3-bis(diphenylphosphino)propane (dppp) or 1 ,4- bis(diphenylphosphino)butane (dppb)]. Similar reactions have been reported for example in React. Kinet. Cat. Lett. 2007, 92, 99-104. This reaction is shown in Scheme 2.
Figure imgf000029_0001
Scheme 2
As shown in Scheme 3, compounds of formula (lllb), wherein R4, R6 and R7 are hydrogen, R5 is hydrogen or methyl and R1, R2, R3, R8, R9, R10, R11, B1 and B2 are as defined for the compounds of formula (I), can be converted to compounds of formula (V), wherein R4, R6 and R7 are hydrogen, R5 is hydrogen or methyl and R1, R2, R3, R8, R9, R10, R11, B1 and B2 are as defined for the compounds of formula (I), by treatment of compounds of formula (lllb) with a compound of formula (VI), wherein X° is a leaving group, such as halogen, and R° is Ci-Cealkyl, by methods known to a person skilled in the art and by those described in Scheme 1 . Alternatively, compounds of formula (V) may be prepared by treatment with an anhydride of formula (R°CO)2O, wherein R° is Ci-Cealkyl, in an inert solvent such as methylene chloride, THF or 2-methyl-THF, optionally in the presence of a base, such as triethylamine or dimethylaminopyridine, at temperatures between 0°C and 60°C. Compounds of formula (V) are then metalated with a base, for example an alkyl metal base, such as tert-butyl lithium, and an additive such as /V,/V,/V,/V'-tetramethylethylendiamine (TMEDA) at low temperature, for example -78°C to room temperature, in an inert polar solvent such as THF or 2-methyl-THF. Subsequent treatment of the anion of formula (V) formed under such conditions with an electrophile of formula R7-X°, wherein X° is as previously defined and R7 is Ci-C4alkyl, Ci-C4alkylcarbonyl, Ci-C4alkoxycarbonyl, N-methoxy- N-methyl-carbonyl, C1-C4 alkylaminocarbonyl, di(Ci-C4alkyl)aminocarbonyl, or Cs-Cecycloalkyl, wherein said Cs-Ce-cycloalkyl is unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy, yields compounds of formula (Va), wherein R4 and R6 are hydrogen, R5 is hydrogen or methyl, R° is Ci-Ce alkyl and R1, R2, R3, R7, R8, R9, R10, R11, B1 and B2 are as defined for the compounds of formula (I). This reaction is shown in Scheme 3.
Figure imgf000030_0001
Scheme 3
Compounds of formula (Va) may be converted to compounds of formula (Illa), wherein R4 and R6 are hydrogen, R5 is hydrogen or methyl and R1, R2, R3, R7, R8, R9, R10, R11, B1 and B2 are as defined for the compounds of formula (I), by methods known to a person skilled in the art. For example, compounds of formula (Va), wherein R° is tert-butyl, may be treated with an organic or inorganic acid such as trifluoroacetic acid or HCI to give compounds of formula (Illa). This reaction is shown in Scheme 4.
Figure imgf000030_0002
Scheme 4 Compounds of formula (IVa), wherein R4 and R6 are hydrogen, R5 is hydrogen or methyl and R1, R2, R3, R7, R8, R9, B1 and B2 are as defined for the compounds of formula (I), may be prepared by reacting compounds of formula (VIII), wherein R1, R2 and R3 are as defined for the compounds of formula (I) and X° is halogen, preferably chlorine, bromine or iodine, with compounds of formula (VII), wherein R5 is hydrogen or methyl and R7, R8, R9, R10, R11, B1 and B2 are as defined for the compounds of formula (I), by means of a C-C bond formation reaction typically under palladium-catalyzed (alternatively nickel-catalyzed) cross-coupling conditions. This reaction is shown in Scheme 5.
Figure imgf000031_0001
Scheme 5
Suzuki-Miyaura cross-coupling reactions between compounds of formula (VIII) and compound of formula (VII) are well known to a person skilled in the art and are usually carried out in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)-palladium(0) or [1 ,1 '-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride dichloromethane complex, and a base, such as sodium or potassium carbonate, in a solvent, such as N,N-dimethylformamide, dioxane or dioxane-water mixtures, at temperatures between room temperature and 160°C, optionally under microwave heating conditions, and preferably under inert atmosphere. Such reactions have been reviewed for example in J. Organomet. Chem. 1999, 576, 147-168. A person skilled in the art will also recognize that the reaction can be reversed, i.e. by reacting a compound of formula (X), wherein R1, R2 and R3 are as defined for the compounds of formula (I), with a compound of formula (IX), wherein R5 is hydrogen or methyl, R7, R8, R9, B1 and B2 are as defined for the compounds of formula (I) and X° is halogen, preferably chlorine, bromine or iodine, to provide a compound of formula (IVa), wherein R4 and R6 are hydrogen, R5 is hydrogen or methyl and R1, R2, R3, R7, R8, R9, B1 and B2 are as defined for the compounds of formula (I). This reaction is shown in Scheme 6.
Figure imgf000031_0002
Scheme 6
A further cross-coupling chemistry, namely C-H activation, can also be used to prepare compounds of formula (IVa), wherein R4 and R6 are hydrogen, R5 is hydrogen or methyl and R1, R2, R3, R7, R8, R9, B1 and B2 are as defined for the compounds of formula (I) (Scheme 7).
Figure imgf000032_0001
Scheme 7
As shown in Scheme 7, compounds of formula (IX), wherein R5 is hydrogen or methyl, R7, R8, R9, B1 and B2 are as defined for the compounds of formula (I) and X° is halogen, preferably chlorine, bromine or iodine, are reacted with compounds of formula (XI), wherein R1, R2 and R3 are as defined for the compounds of formula (I), in the presence of a palladium catalyst, typically palladium acetate Pd(OAc)2, a suitable ligand, for example 1 ,10-phenanthroline, in the presence of a base such as cesium carbonate or potassium carbonate, in inert solvents such as chlorobenzene, toluene or xylene at temperatures between room temperature and 180°C, optionally under microwave heating conditions, preferably under inert atmosphere. Similar reactions have been reported in the literature for example in Chem. Sci. 2013, 4, 2374-2379.
Also, compounds of formula (III) may be prepared from compounds of formula (XVI) (Scheme 8).
Figure imgf000032_0002
Scheme 8
As shown in Scheme 8, compounds of formula (III) may be prepared by a person skilled in the art by a carbamate deprotection reaction of compounds of formula (XVI), wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, B1 and B2 are as defined for the compounds of formula (I) and R01 may be a member of a common carbamate protecting group substituent, for example methyl, te/Y-butyl, allyl, 2,2,2-trichloroethyl or benzyl. For example, when R01 is methyl, a suitable solvent such as dichloromethane and a suitable reagent such as iodotrimethylsilane may be employed to afford the product upon heating at temperatures between room temperature and 200°C, preferably between 20°C and the boiling point of the reaction mixture as described, for example, in J. Am. Chem. Soc. 1992, 114, 5959. The compounds of formula (III) thus obtained are converted to compounds of formula (I) (Scheme 1).
Compounds of formula (XVI), wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, B1 and B2 are as defined for the compounds of formula (I) and wherein R01 is as described above, may be formed by a Pictet-Spengler reaction between an aldehyde (including formaldehyde in its various forms) of formula (XV), wherein R7 is as defined for the compounds of formula (I), and a compound of formula (XIV), wherein R1, R2, R3, R4, R5, R6, R8, R9, B1 and B2 are as defined for the compounds of formula (I) and wherein R01 is as described above, by combination with an acid in a suitable solvent, for example as described in Tetrahedron 1987, 43, 439 (Scheme 9).
Figure imgf000033_0001
Scheme 9
Compounds of formula (XIV), wherein R1, R2, R3, R4, R5, R6, R8, R9, B1 and B2 are as defined forthe compounds of formula (I) and wherein R01 is as described above, may be prepared by a reaction between amines of formula (XIII), wherein R1, R2, R3, R4, R5, R6, R8, R9, B1 and B2 are as defined for the compounds of formula (I), and a suitable protecting reagent such as methyl chloroformate, optionally in the presence of a base such as triethylamine or pyridine, in a suitable solvent such as dichloromethane at temperatures between -20°C and the boiling point of the mixture, as for example described in Org. Biomol. Chem. 2016, 14, 6853. This reaction is shown in Scheme 10.
Figure imgf000033_0002
Scheme 10
Compounds of formula (XIII), or salts thereof, wherein R1, R2, R3, R4, R5, R6, R8, R9, B1 and B2 are as defined for the compounds of formula (I), may be prepared by a person skilled in the art by a reaction between nitriles of formula (XII), wherein R1, R2, R3, R4, R8, R9, B1 and B2 are as defined for the compounds of formula (I), and a suitable nucleophile such as (dimethyl sulfide)dihydroboron (BMS) in a suitable aprotic solvent such as tetrahydrofuran, for example as described in J. Org Chem. 1981 , 47, 3153. Alternatively, Grignard reagents R5MgBr or R6MgBr, wherein R5 and R6 are as defined for the compounds of formula (I), may be added as nucleophiles to compounds of formula (XII), sequentially or simultaneously, to allow more highly substituted amines of formula (XIII) to be prepared. Such Grignard additions to nitriles are carried out in an inert solvent such as diethyl ether, tert-butylmethyl ether, and cyclopentyl methyl ether in the presence of a Lewis acid such as Ti(O-'Pr)4 (see Synlett 2007, (4), 652-654). This reaction is shown in Scheme 11.
Figure imgf000034_0001
Alternatively compounds of formula (XIII), wherein R1, R2, R3, R4, R5, R6, R8, R9, B1 and B2 are as defined for the compounds of formula (I), and wherein R5, R6 are hydrogen, namely compounds of formula (Xllla) may be prepared by a person skilled in the art by a reaction between unsaturated nitro compounds of formula (Xlllb), wherein R1, R2, R3, R4, R8, R9, B1 and B2 are as defined for the compounds of formula (I), and compounds of formula (VIII), wherein R1, R2 and R3 are as defined for the compounds of formula (I) and X° is halogen, preferably iodine, followed by subsequent reduction of compounds of formula (Xlllb), wherein R1, R2, R3, R4, R8, R9, B1 and B2 are as defined for the compounds of formula (I), to compounds formula (Xllla). Such a reaction is described in the preparatory section under Example P1 , Step 8 (Option B - Step A and Step B). This reaction is shown in Scheme 12.
Figure imgf000034_0002
Scheme 12 Compounds of formula (XII), wherein R1, R2, R3, R4, R8, R9, B1 and B2 are as defined for the compounds of formula (I), may be prepared by a person skilled in the art following known methods. More specifically, compounds of formula (XI I), and intermediates thereof, may be prepared from compounds of formula (XVII) as shown in Scheme 13.
Figure imgf000035_0001
(XVII) (Xlla) (XII)
Scheme 13
For example, compounds of formula (XII), wherein R1, R2, R3, R8, R9, B1 and B2 are as defined for the compounds of formula (I) and R4 is different from hydrogen, may be prepared by a person skilled in the art by deprotonation of compound of formula (Xlla) wherein R1, R2, R3, R8, R9, B1 and B2 are as defined for the compounds of formula (I), using a strong base such as n-butyl lithium or sodium hydride at cryogenic temperatures in an inert solvent such as tetrahydrofuran, followed by addition of a suitable alkylating agent R4- X, wherein R4 is Ci-C4alkyl and X is halogen, for example iodomethane.
Compounds of formula (Xlla), wherein R1, R2, R3, R8, R9, B1 and B2 are as defined for the compounds of formula (I), may be prepared from alcohols of formula (XVII) by treatment with cyanotrimethylsilane (TMSCN) in the presence of a base such as lithium carbonate in a nonpolar solvent such as dichloromethane at temperatures between 0°C and the boiling point of the reaction mixture. Such transformations are well known in the literature under a variety of conditions, for example as described in Org. Lett. 2008, 10, 4570 and references therein. This reaction is shown in Scheme 13.
A further synthesis of compounds of formula (III) wherein B1 is CR10, B2 is CR11, R1a is Ci-C4alkyl, R2a is hydrogen, halogen, or Ci-C4alkyl, R3 is hydrogen, R4a, R5a, R6a R7a are hydrogen or C1-C4 alkyl, and R8, R9, R10, and R11 are as defined for the compounds of formula (I), namely compounds of formula (lllc) is described below.
Figure imgf000035_0002
Compounds of formula (lllc) also be prepared by treating compounds of formula (XVIII)
Figure imgf000036_0001
(XVIII) wherein R1 is Ci-C4alkyl, R2 is hydrogen, halogen, or Ci-C4alkyl, R3 is hydrogen, R4 is hydrogen or Ci-C4alkyl, R5, R6, R7 are hydrogen or Ci-C4alkyl, and R8, R9, R10, and R11 are as previously defined, with strong acids, for example sulphuric, hydrochloric, hydrobromic, trifluoroacetic, trifllic, or methane sulphonic acids and the like, or Lewis acids, such as aluminium trichloride, or bismuth (I I l)triflate , in an inert solvent such as chlorobenzene, nitrobenzene at temperature between 0°C to 180°C to yield compounds of formula (lllc). These are converted to compounds of formula (I) as previously described vide supra. Those skilled in the art will realize that such cyclisation’s can proceed through intermediates such as compounds of formula (XIX),
Figure imgf000036_0002
and (when R4 is methyl), compound of formula (XX)
Figure imgf000036_0003
and wherein the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 in these compounds are as defined for the compounds of formula (I). Depending on the conditions of the reaction these intermediates can be isolated and/or converted further directly to compounds of formula (lllc). Those skilled in the art will also realize that when R7 is Ci-C4alkyl, mixtures of diastereoisomers racemic-(syn-\ lie) and racemic-(anti-\\\c) can be obtained in ratios that can be controlled to direct preferential formation of one isomer over the other (Scheme 14).
Figure imgf000037_0001
Scheme 14
The intermediates (XVIII), (XIX), and (XX) are novel and as such form part of the current invention.
Compounds (XVIII), (XIX), and (XX) can be prepared as shown in the following Scheme 15, and as described in the experimental section.
Figure imgf000038_0001
Scheme 15
As shown in Scheme 15, a benzyl amine of formula (XXI) is used to alkylate a compound of formula (XXII), in the presence of a base, such as EtsN in an inert solvent, such as DMF. The compound (XXIII) so obtained, may be isolated, or treated directly with BOC-anhydride in situ, to give a compound of formula (XXIV).
Compound of formula (XXIV) can be reduced with a hydride source (e.g., NaBH4 in MeOH/THF) to give the target molecule (XVI 11 b) , which can then be cyclized with, for example with camphor sulphonic acid in EtOAc, to give compounds of formula (XlXb). Alternatively, compounds of formula (XXIV) can be reacted with a Grignard reagent R4MgBr in an inert ethereal solvent (e.g., THF) to give compounds of formula (XVI Ila), which can the cyclized with camphorsulphonic acid in, e.g. EtOAc, to give compounds of formula (XIXa). In compounds (XIX) and (XVIII) R1a is Ci-C4alkyl, R2a is hydrogen, halogen, or Ci-C4alkyl, R4a is hydrogen or Ci- C4alkyl, R5a, R6a, and R7a are hydrogen or C1-C4 alkyl, and R8, R9, R10, and R11 are as defined for the compounds of formula (I). A further aspect of this Friedel-Crafts chemistry should be noted. If the chemistry is carried out starting with a chiral amine (XXIa), e.g., R7 is Ci-C4alkyl, the stereochemistry is retained in the final compounds of formula (I). This is illustrated below in Scheme 16, for when R7 is methyl:
Figure imgf000039_0001
Scheme 16
Compounds of formula (XVII) may be prepared by methods known to a person skilled in the art. Compounds of formula (XXI) and (XXII) are easily prepared by those skilled in the art or can be purchased.
Compounds of formula II, wherein A1 is N, A2 is O, A3 is CH, and Z1 is as defined for the compounds of formula (I), namely compounds of formula (He) can be prepared as shown in Scheme 17.
Figure imgf000039_0002
Scheme 17
As shown in Scheme 17, compounds of formula (lie) wherein Z1 is as defined for the compounds of formula (I), and X05 is C1-C4 alkyl may be prepared by hydrolysis of compounds of formula (lib) by treatment with, for example, an alkaline earth metal hydroxide in water, or with a water miscible organic solvent, such as THF, methanol, ethanol and the like. Such ester hydrolyses are well known to those skilled in the art. Compounds of formula (lib) can be obtained by the treatment of compounds of formula (XXVII) wherein Z1 is as defined for the compounds of formula (I) and X05 is C1-C4 alkyl with hydroxylamine hydrochloride in a polar solvent, for example ethanol and optionally in the presence of a base, e.g., triethyl amine, K2CO3 and the like.
Compounds of formula (XXVII) are prepared by reaction of compounds of formula (XXV), wherein Z1 is as defined for the compounds of formula (I), with compounds of formula (XXVI) or compounds of formula (XXVIa), wherein X05 is C1-C4 alkyl in presence of base, e.g., potassium tert-butoxide, sodium hydride or lithium bis(trimethylsilyl)amid in a solvent such THF or toluene. Similar reaction sequences to those described in Scheme 17 to prepare compounds of formula (lib) and (He) have been described in for example CN111072582 and WO2019/195810, and WO2018/019929. Further reaction conditions for preparation of compounds of formula (XXVII) are described in for example Bioorg. Med. Chem. 2016, 109, 350-359.
Compounds of formula (II) wherein A1 is O, A2 and A3 are N, and Z1 is as defined for the compounds of formula (I), namely compounds of formula (lie) can be prepared as shown in Scheme 18.
Figure imgf000040_0001
(XXVIII)
Scheme 18
As shown in Scheme 18, compounds of formula (He) are obtained by ester hydrolysis of compounds of formula (lid) as described previously in Scheme 17. Compounds of formula (lid), wherein Z1 is as defined for the compounds of formula (I) and X05 is C1-C4 alkyl are prepared by reaction of compounds of formula (XXVIa) with compounds of formula (XXVIII), optionally in the presence of base, example.g., pyridine or triethylamine, in a solvent such as acetonitrile, chloroform or THF. Similar reactions have been reported in for example Bioorg. Med. Chem. 2016, 24(22), 5693-5701 and CN114933573. Compounds of formula (XXVIII) wherein Z1 is as defined for the compounds of formula (I), can be obtained by treatment of compounds of formula (XXIX) with hydroxylamine hydrochloride in presence of base such K2CO3 or Na2COs in a polar solvent for example ethanol. The reaction can also be performed without base using a solution of hydroxylamine. Such reactions have been described in, for example, Bioorg. Med. Chem. Lett. 2020, 30(21), 127508 and Bioorg. Med. Chem. Lett. 2016, 26(23), 5679-5684. Compounds of formula (XXVIII) wherein Z1 is as defined for the compounds of formula (I), may be also prepared by “one-pot” synthesis via Pd-catalyzed cyanation and amidoximation of compound of formula (XXX) wherein Z1 is as defined for the compounds of formula (I), using potassium ferrocyanide trihydrate and hydroxylamine hydrochloride as described in for example Org. Biomol. Chem. 2015, 13(9), 2541-2545. Compounds of formula (II) wherein A1 and A2 are N, and A3 is O, and Z1 is as previously described, (namely compounds of formula (llg)), and A1 and A2 are N, and A3 is S, and Z1 is as defined for the compounds of formula (I), (namely compounds of formula (Hi)) can be prepared as shown in Scheme 19.
Figure imgf000041_0001
Scheme 19 As shown in Scheme 19, compounds of formula (llg) and (Hi) are obtained by ester hydrolysis of (Ilf) and (llg), respectively. In the latter compounds, X05 and Z1 are as previously described. Compounds of formula (Ilf) can be obtained from compounds of formula (Ilf) by dehydration of compounds of formula (XXXI). Compounds of formula (XXXI) are obtained by acylation of hydrazides of formula (XXXII) with compounds of formula (XXVIa). Such sequences of reactions to produce oxadiazoles is well known to those skilled in the art. Similar reactions are described in Bioorg. Med. Chem. Let. 2005, 15, 1423-1428 and W02006/044617. Compounds of formula (XXXI) can also be prepared by reaction of activated carboxylic acids of formula (XXXIIIa), wherein Z1 is as defined for the compounds of formula (I), and X° are as described in Scheme 1 /Scheme 1 a respectively, with compounds of formula (XXXIV). Compounds of formula (XXXIIIa) can be prepared from the corresponding acids of formula (XXXIII) as described in scheme 1 . Such reactions are described for example in, for example, J. Prakt. Chem. 1985, 327, 109-116. Compounds of formula (llh) can also be prepared from the common intermediate of formula (XXXI), wherein Z1 is as defined for the compounds of formula (I), and X05 is as previously described, by treatment with Lawesson’s reagent or phosphorous pentasulfide neat, or in inert solvents such as toluene or xylene. Similar reactions are known in the literature (see for example WO2010/006713, W02009/149858 and J. Org Chem. 1961 , 26, 4410-12).
Compounds of formula (II) wherein A1 is O, A2 is N, A3 is methine, and Z1 is as defined for the compounds of formula (I), namely compounds of formula (Ilk), can be prepared, for example, as shown in Scheme 20.
Figure imgf000042_0001
(XXXVII) (XXXV) (llj) (||k)
Scheme 20
As shown in Scheme 20, compounds of formula (Ilk) are readily obtained by hydrolysis of esters of formula (llj) by methods known to those skilled in the art and described vide supra. Compounds of formula (llj) can be obtained by reaction of compounds of formula (XXXV) with compounds of formula (XXXVI) in the presence of an oxidizing agent, for example (diacetoxyiodo)benzene or N-chlorosuccinimide, in an inert solvent such as methanol or DMF respectively. Such reaction sequences have been described, for example, in J. Het. Chem. 2013, 50(4), 774-780 and J. Chin. Chem. Soc. 2007, 54(3), 643-652. Compounds of formula (XXXV) are readily prepared from compounds of formula (XXXVII), wherein Z1 is as defined for the compounds of formula (I), by treatment with hydroxylamine under conditions well known to those skilled in the art.
Salts of compounds of formula (I) may be prepared in a manner known perse. 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. Depending on the procedure or the reaction conditions, 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 tautomer’s 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, or diastereomer 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 herein below, even when stereochemical details are not mentioned specifically in each case.
Diastereomeric mixtures or racemic 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.
Enantiomeric 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, to give the diastereomers, from which the desired enantiomer can be set free by the action of suitable agents, for example basic agents.
Pure diastereomers or enantiomers can be obtained according to the invention not only by separating suitable isomer mixtures, but also by generally known methods of diastereoselective or enantioselective synthesis, for example by carrying out the process according to the invention with starting materials of a suitable stereochemistry.
It is advantageous to isolate or synthesize in each case the biologically more effective isomer, for example enantiomer or diastereomer, or isomer mixture, for example enantiomer mixture or diastereomer mixture, if the individual components have a different biological activity.
As an example, compounds with more than one asymmetric carbon atoms may exist in diastereomeric forms which can be optionally separated using for example supercritical fluid chromatography (SFC) chromatography with chiral columns. Such diastereomers can show a different fungicidal activity profile, but all isomers and diastereomers form part of this invention. The compounds of formula (I) have three chiral carbon atoms, (three stereocenters, wherein the star (*) indicates the chiral carbon atom), such there are eight stereoisomers available. These eight stereoisomers consist of four sets of enantiomers.
Figure imgf000044_0001
For compounds of formula (I), wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, B1, B2, A (A1, A2, A3) and Z1 are as defined forthe compounds of formula (I) and wherein R7 is not hydrogen, the relationship between enantiomers and diastereomers is illustrated in Scheme 21.
Figure imgf000045_0001
Scheme 21 A person skilled in the art is well aware that these diastereomers and enantiomers of formula (I) (as shown in Scheme 21) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, B1, B2, A (A1, A2, A3) and Z1 are as defined for formula (I) and wherein R7 is not hydrogen, are within the scope if the invention.
For compounds of formula (I), wherein R1 is methyl, R3, R4, R5, R6 are hydrogen and R2, R7, R8, R9, B1, B2, A (A1, A2, A3) and Z1 are as defined for the compounds of formula (I), and wherein R7 is not hydrogen, the relationship between enantiomers and diastereomers is illustrated in Scheme 22.
Figure imgf000046_0001
In one embodiment the compounds of formula (I), wherein R1 is methyl, R3, R4, R5, R6 are hydrogen and R2, R7, R8, R9, B1, B2, A (A1, A2, A3) and Z1 are as defined for the compounds of formula (I), and wherein R7 is not hydrogen the pyrazole-moiety and R7 have a syn-relationship to each other.
The syn-lsomers of the compounds of formula (I), wherein R1 is methyl, R3, R4, R5, R6 are hydrogen and R2, R7, R8, R9, B1, B2, A (A1, A2, A3) and Z1 are as defined for the compounds of formula (I), and wherein R7 is not hydrogen are shown in Scheme 23.
Figure imgf000047_0001
Scheme 23
Preferably the compounds of formula (I), wherein R1 is methyl, R3, R4, R5, R6 are hydrogen and R2, R7, R8, R9, B1, B2, A (A1, A2, A3) and Z1 are as defined for the compounds of formula (I), and wherein R7 is not hydrogen the pyrazole-moiety and R7 have a syn-relationship to each other, as shown in Scheme 23.
The compounds of formula (I) and, where appropriate, the tautomers thereof, in each case in free form or in salt form, can, if appropriate, also be obtained in the form of hydrates and/or include other solvents, for example those which may have been used for the crystallization of compounds which are present in solid form.
As already indicated, surprisingly, it has now been found that the compounds of formula (I) of the present invention have, for practical purposes, a very advantageous level of biological activity for protecting plants against diseases that are caused by fungi.
The compounds of formula (I) according to the invention can be used in the agricultural sector and related fields of use, e.g., as active ingredients for controlling plant pests or on non-living materials for the control of spoilage microorganisms or organisms potentially harmful to man. The novel compounds are distinguished by excellent activity at low rates of application, by being well tolerated by plants and by being environmentally safe. They have very useful curative, preventive and systemic properties and can be used for protecting numerous cultivated plants. The compounds of formula (I) can be used to inhibit or destroy the pests that occur on plants or parts of plants (fruit, blossoms, leaves, stems, tubers, roots) of different crops of useful plants, while at the same time protecting also those parts of the plants that grow later, e.g., from phytopathogenic microorganisms.
The present invention further relates to a method for controlling or preventing infestation of plants or plant propagation material and/or harvested food crops susceptible to microbial attack by treating plants or plant propagation material and/or harvested food crops wherein an effective amount a compound of formula (I) according to the invention is applied to the plants, to parts thereof or the locus thereof.
It is also possible to use a compound of formula (I) according to the invention as a fungicide. The term “fungicide” as used herein means a compound that controls, modifies, or prevents the growth of fungi. The term “fungicidally effective amount” where used means the quantity of such a compound or combination of such compounds that is capable of producing an effect on the growth of fungi. Controlling or modifying effects include all deviation from natural development, such as killing, retardation and the like, and prevention includes barrier or other defensive formation in or on a plant to prevent fungal infection.
It may also be possible to use compounds of formula (I) according to the invention as dressing agents for the treatment of plant propagation material, e.g., seed, such as fruits, tubers or grains, or plant cuttings, for the protection against fungal infections as well as against phytopathogenic fungi occurring in the soil. The propagation material can be treated with a composition comprising a compound of formula (I) before planting: seed, for example, can be dressed before being sown. The active compounds of formula (I) can also be applied to grains (coating), either by impregnating the seeds in a liquid formulation or by coating them with a solid formulation. The composition can also be applied to the planting site when the propagation material is being planted, for example, to the seed furrow during sowing. The invention relates also to such methods of treating plant propagation material and to the plant propagation material so treated.
Furthermore, the compounds of formula (I) according to the invention can be used for controlling fungi in related areas, for example in the protection of technical materials, including wood and wood related technical products, in food storage, in hygiene management.
In addition, the invention could be used to protect non-living materials from fungal attack, e.g., lumber, wall boards, and paint.
The compounds of formula (I) according to the invention are for example, effective against fungi and fungal vectors of disease as well as phytopathogenic bacteria and viruses. These fungi and fungal vectors of disease as well as phytopathogenic bacteria and viruses are for example: Absidia corymbifera, Alternaria spp., Aphanomyces spp., Ascochyta spp., Aspergillus spp. including A. flavus, A. fumigatus, A. nidulans, A. niger, A. terrus, Aureobasidium spp. including A. pullulans, Blastomyces dermatitidis, Blumeria graminis, Bremia lactucae, Botryosphaeria spp. including B. dothidea, B. obtusa, Botrytis spp. including B. cinerea, Candida spp. including C. albicans, C. glabrata, C. krusei, C. lusitaniae, C. parapsilosis, C. tropicalis, Cephaloascus fragrans, Ceratocystis spp., Cercospora spp. including C. arachidicola, Cercosporidium personatum, Cladosporium spp., Claviceps purpurea, Coccidioides immitis, Cochliobolus spp., Colletotrichum spp. including C. musae, Cryptococcus neoformans, Diaporthe spp., Didymella spp., Drechslera spp., Elsinoe spp.,Epidermophyton spp., Erwinia amylovora, Erysiphe spp. including E. cichoracearum, Eutypa lata, Fusarium spp. including F. culmorum, F. graminearum, F. langsethiae, F. moniliforme, F. oxysporum, F. proliferatum, F. subglutinans, F. solani, Gaeumannomyces graminis, Gibberella fujikuroi, Gloeodes pomigena, Gloeosporium musarum, Glomerella cingulate, Guignardia bidwellii, Gymnosporangium juniperi-virginianae, Helminthosporium spp., Hemileia spp., Histoplasma spp. including H. capsulatum, Laetisaria fuciformis, Leptographium lindbergi, Leveillula taurica, Lophodermium seditiosum, Microdochium nivale, Microsporum spp., Monilinia spp., Mucor spp., Mycosphaerella spp. including M. graminicola, M. pomi, Oncobasidium theobromaeon, Ophiostoma piceae, Paracoccidioides spp., Penicillium spp. including P. digitatum, P. italicum, Petriellidium spp., Peronosclerospora spp. Including P. maydis, P. philippinensis and P. sorghi, Peronospora spp., Phaeosphaeria nodorum, Phakopsora pachyrhizi, Phellinus igniarus, Phialophora spp., Phoma spp., Phomopsis viticola, Phytophthora spp. including P. infestans, Plasmopara spp. including P. halstedii, P. viticola, Pleospora spp., Podosphaera spp. including P. leucotricha, Polymyxa graminis, Polymyxa betae, Pseudocercosporella herpotrichoides, Pseudomonas spp., Pseudoperonospora spp. including P. cubensis, P. humuli, Pseudopeziza tracheiphila, Puccinia spp. including P. hordei, P. recondita, P. striiformis, P. triticina, Pyrenopeziza spp., Pyrenophora spp., Pyricularia spp. including P. oryzae, Pythium spp. including P. ultimum, Ramularia spp., Rhizoctonia spp., Rhizomucor pusillus, Rhizopus arrhizus, Rhynchosporium spp., Scedosporium spp. including S. apiospermum and S. prolificans, Schizothyrium pomi, Sclerotinia spp., Sclerotium spp., Septoria spp., including S. nodorum, S. tritici, Sphaerotheca macularis, Sphaerotheca fusca (Sphaerotheca fuliginea), Sporothorix spp., Stagonospora nodorum, Stemphylium spp., Stereum hirsutum, Thanatephorus cucumeris, Thielaviopsis basicola, Tilletia spp., Trichoderma spp. including T. harzianum, T. pseudokoningii, T. viride, Trichophyton spp., Typhula spp., Uncinula necator, Urocystis spp., Ustilago spp., Venturia spp. including V. inaequalis, Verticillium spp., and Xanthomonas spp.
The compounds of formula (I) according to the invention may be used for example on turf, ornamentals, such as flowers, shrubs, broad-leaved trees, or evergreens, for example conifers, as well as for tree injection, pest management and the like.
Within the scope of present invention, target crops and/or useful plants to be protected typically comprise perennial and annual crops, such as berry plants for example blackberries, blueberries, cranberries, raspberries and strawberries; cereals for example barley, maize (corn), millet, oats, rice, rye, sorghum triticale and wheat; fibre plants for example cotton, flax, hemp, jute and sisal; field crops for example sugar and fodder beet, coffee, hops, mustard, oilseed rape (canola), poppy, sugar cane, sunflower, tea and tobacco; fruit trees for example apple, apricot, avocado, banana, cherry, citrus, nectarine, peach, pear and plum; grasses for example Bermuda grass, bluegrass, bentgrass, centipede grass, fescue, ryegrass, St. Augustine grass and Zoysia grass; herbs such as basil, borage, chives, coriander, lavender, lovage, mint, oregano, parsley, rosemary, sage and thyme; legumes for example beans, lentils, peas and soya beans; nuts for example almond, cashew, ground nut, hazelnut, peanut, pecan, pistachio and walnut; palms for example oil palm; ornamentals for example flowers, shrubs and trees; other trees, for example cacao, coconut, olive and rubber; vegetables for example asparagus, aubergine, broccoli, cabbage, carrot, cucumber, garlic, lettuce, marrow, melon, okra, onion, pepper, potato, pumpkin, rhubarb, spinach and tomato; and vines for example grapes.
The term "useful plants" is to be understood as also including useful plants that have been rendered tolerant to herbicides like bromoxynil or classes of herbicides (such as, for example, HPPD inhibitors, ALS inhibitors, for example primisulfuron, prosulfuron and trifloxysulfuron, EPSPS (5-enol-pyrovyl-shikimate-3-phosphate- synthase) inhibitors, GS (glutamine synthetase) inhibitors or PPO (protoporphyrinogen-oxidase) inhibitors) as a result of conventional methods of breeding or genetic engineering. An example of a crop that has been rendered tolerant to imidazolinones, e.g., imazamox, by conventional methods of breeding (mutagenesis) is Clearfield® summer rape (Canola). Examples of crops that have been rendered tolerant to herbicides or classes of herbicides by genetic engineering methods include glyphosate- and glufosinate-resistant maize varieties commercially available under the trade names RoundupReady®, Herculex I® and LibertyLink®. The term "useful plants" is to be understood as also including useful plants which have been so transformed by the use of recombinant DNA techniques that they are capable of synthesising one or more selectively acting toxins, such as are known, for example, from toxin-producing bacteria, especially those of the genus Bacillus.
Examples of such plants are: YieldGard® (maize variety that expresses a CrylA(b) toxin); YieldGard Rootworm® (maize variety that expresses a Cry II IB(b1 ) toxin); YieldGard Plus® (maize variety that expresses a CrylA(b) and a CrylllB(bl) toxin); Starlink® (maize variety that expresses a Cry9(c) toxin); Herculex I® (maize variety that expresses a CrylF(a2) toxin and the enzyme phosphinothricine N-acetyltransferase (PAT) to achieve tolerance to the herbicide glufosinate ammonium); NuCOTN 33B® (cotton variety that expresses a CrylA(c) toxin); Bollgard I® (cotton variety that expresses a CrylA(c) toxin); Bollgard II® (cotton variety that expresses a CrylA(c) and a CryllA(b) toxin); VIPCOT® (cotton variety that expresses a VIP toxin); NewLeaf® (potato variety that expresses a CrylllA toxin); Nature-Gard® Agrisure® GT Advantage (GA21 glyphosate- tolerant trait), Agrisure® CB Advantage (Bt11 corn borer (CB) trait), Agrisure® RW (corn rootworm trait) and Protecta®.
The term "crops" is to be understood as including also crop plants which have been so transformed using recombinant DNA techniques that they are capable of synthesising one or more selectively acting toxins, such as are known, for example, from toxin-producing bacteria, especially those of the genus Bacillus.
Toxins that can be expressed by such transgenic plants include, for example, insecticidal proteins from Bacillus cereus or Bacillus popilliae; or insecticidal proteins from Bacillus thuringiensis, such as delta-endotoxins, e.g. CrylAb, CrylAc, Cry1 F, Cry1 Fa2, Cry2Ab, Cry3A, Cry3Bb1 or Cry9C, or vegetative insecticidal proteins (Vip), e.g. Vip1 , Vip2, Vip3 or Vip3A; or insecticidal proteins of bacteria colonising nematodes, for example Photorhabdus spp. or 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; ribosome-inactivating proteins (RIP), such as ricin, maize-RIP, abrin, luffin, saporin or bryodin; steroid metabolism enzymes, such as 3-hydroxysteroidoxidase, ecdysteroid- UDP-glycosyl-transferase, cholesterol oxidases, ecdysone inhibitors, HMG-COA-reductase, ion channel blockers, such as blockers of sodium or calcium channels, juvenile hormone esterase, diuretic hormone receptors, stilbene synthase, bibenzyl synthase, chitinases and glucanases.
Further, in the context of the present invention there are to be understood by delta-endotoxins, for example CrylAb, CrylAc, Cry1 F, Cry1 Fa2, Cry2Ab, Cry3A, Cry3Bb1 or Cry9C, or vegetative insecticidal proteins (Vip), for example Vip1 , Vip2, Vip3 or Vip3A, expressly also hybrid toxins, truncated toxins and modified toxins. Hybrid toxins are produced recombinantly by a new combination of different domains of those proteins (see, for example, W002/15701). Truncated toxins, for example a truncated CrylAb, are known. In the case of modified toxins, one or more amino acids of the naturally occurring toxin are replaced. In such amino acid replacements, 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 W02003/018810).
Examples of such toxins or transgenic plants capable of synthesising such toxins are disclosed, for example, in EP-0374753, WO93/07278, WO95/34656, EP0427529, EP0451878 and W003/052073.
The processes for the preparation of such transgenic plants are generally known to a person skilled in the art and are described, for example, in the publications mentioned above. Cryl-type deoxyribonucleic acids and their preparation are known, for example, from WO95/34656, EP0367474, EP0401979 and WO90/13651.
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 butterflies (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 Cry1 Ab toxin); YieldGard Rootworm® (maize variety that expresses a Cry3Bb1 toxin); YieldGard Plus® (maize variety that expresses a CrylAb and a Cry3Bb1 toxin); Starlink® (maize variety that expresses a Cry9C toxin); Herculex I® (maize variety that expresses a Cry1 Fa2 toxin and the enzyme phosphinothricine N-acetyltransferase (PAT) to achieve tolerance to the herbicide glufosinate ammonium); NuCOTN 33B® (cotton variety that expresses a CrylAc toxin); Bollgard I® (cotton variety that expresses a CrylAc toxin); Bollgard II® (cotton variety that expresses a CrylAc and a Cry2Ab toxin); VipCot® (cotton variety that expresses a Vip3A and a CrylAb toxin); NewLeaf® (potato variety that expresses a Cry3A toxin); NatureGard®, Agrisure® GT Advantage (GA21 glyphosate-tolerant trait), Agrisure® CB Advantage (Bt11 corn borer (CB) trait) and Protecta®.
Further examples of such transgenic crops are:
1. Bt1 1 Maize from Syngenta Seeds SAS, Chemin de I'Hobit 27, F-31 790 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 CrylAb 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 I'Hobit 27, F-31 790 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 CrylAb toxin. Bt176 maize also transgenically expresses the enzyme PAT to achieve tolerance to the herbicide glufosinate ammonium.
3. MIR604 Maize from Syngenta Seeds SAS, Chemin de I'Hobit 27, F-31 790 St. Sauveur, France, registration number C/FR/96/05/10. Maize which has been rendered insect-resistant by transgenic expression of a modified Cry3A toxin. This toxin is Cry3A055 modified by insertion of a cathepsin-G-protease recognition sequence. The preparation of such transgenic maize plants is described in W02003/018810. 4. MON 863 Maize from Monsanto Europe S.A. 270-272 Avenue de Tervuren, B-1150 Brussels, Belgium, registration number C/DE/02/9. MON 863 expresses a Cry3Bb1 toxin and has resistance to certain Coleoptera insects.
5. IPC 531 Cotton from Monsanto Europe S.A. 270-272 Avenue de Tervuren, B-1150 Brussels, Belgium, registration number C/ES/96/02.
6. 1507 Maize from Pioneer Overseas Corporation, Avenue Tedesco, 7 B-1160 Brussels, Belgium, registration number C/NL/00/10. Genetically modified maize for the expression of the protein Cry1 F for achieving resistance to certain Lepidoptera insects and of the PAT protein for achieving tolerance to the herbicide glufosinate ammonium.
7. NK603 x MON 810 Maize from Monsanto Europe S.A. 270-272 Avenue de Tervuren, B 1150 Brussels, Belgium, registration number C/GB/02/M3/03. Consists of conventionally bred hybrid maize varieties by crossing the genetically modified varieties NK603 and MON 810. NK603 x MON 810 Maize transgenically expresses the protein CP4 EPSPS, obtained from Agrobacterium sp. strain CP4, which imparts tolerance to the herbicide Roundup® (contains glyphosate), and also a CrylAb toxin obtained from Bacillus thuringiensis subsp. kurstaki which brings about tolerance to certain Lepidoptera, include the European corn borer.
The compounds of formula (I) according to the invention may be used in controlling or preventing phytopathogenic diseases, especially phytopathogenic fungi such as Alternaria species in fruits, vegetables and potatoes; Botrytis cinerea in strawberries, tomatoes, sunflower, pulse crops, vegetables and grapes; Rhizoctonia solani in potatoes and vegetables; Uncinula necator in grapes; Cladosporium cucumerinum, Didymella bryoniae, Sphaerotheca fuliginea and Glomerella lagenarium in cucurbits; Leveillula taurica in cucurbits and solanacious crops; Fusarium spp. in cereals; Leptosphaeria spp. in cereals; and Zymospetoria spp. in cereals.
The term “locus” as used herein means fields in or on which plants are growing, or where seeds of cultivated plants are sown, or where seed will be placed into the soil. It includes soil, seeds, and seedlings, as well as established vegetation.
The term “plants” refers to all physical parts of a plant, including seeds, seedlings, saplings, roots, tubers, stems, stalks, foliage, and fruits.
The term “plant propagation material” is understood to denote generative parts of the plant, such as seeds, which can be used for the multiplication of the latter, and vegetative material, such as cuttings or tubers, for example potatoes. There can be mentioned for example seeds (in the strict sense), roots, fruits, tubers, bulbs, rhizomes, and parts of plants. Germinated plants and young plants which are to be transplanted after germination or after emergence from the soil, may also be mentioned. These young plants can be protected before transplantation by a total or partial treatment by immersion. Preferably “plant propagation material” is understood to denote seeds.
The compounds of formula (I) according to the invention may be used in unmodified form or, preferably, together with the adjuvants conventionally employed in the art of formulation. To this end they may be conveniently formulated in known manner to emulsifiable concentrates, coatable pastes, directly sprayable or dilutable solutions or suspensions, dilute emulsions, wettable powders, soluble powders, dusts, granulates, and also encapsulations e.g., in polymeric substances. As with the type of the compositions, the methods of application, such as spraying, atomising, dusting, scattering, coating or pouring, are chosen in accordance with the intended objectives and the prevailing circumstances. The compositions may also contain further adjuvants such as stabilizers, antifoams, viscosity regulators, binders or tackifiers as well as fertilizers, micronutrient donors or other formulations for obtaining special effects.
Suitable carriers and adjuvants, e.g. for agricultural use, can be solid or liquid and are substances useful in formulation technology, e.g. natural or regenerated mineral substances, solvents, dispersants, wetting agents, tackifiers, thickeners, binders or fertilizers. Such carriers are for example described in WO1997/33890.
Suspension concentrates are aqueous formulations in which finely divided solid particles of the active compound are suspended. Such formulations include anti-settling agents and dispersing agents and may further include a wetting agent to enhance activity as well an anti-foam and a crystal growth inhibitor. In use, these concentrates are diluted in water and normally applied as a spray to the area to be treated. The amount of active ingredient may range from 0.5% to 95% of the concentrate.
Wettable powders are in the form of finely divided particles which disperse readily in water or other liquid carriers. The particles contain the active ingredient retained in a solid matrix. Typical solid matrices include fuller’s earth, kaolin clays, silicas and other readily wet organic or inorganic solids. Wettable powders normally contain from 5% to 95% of the active ingredient plus a small amount of wetting, dispersing or emulsifying agent.
Emulsifiable concentrates are homogeneous liquid compositions dispersible in water or other liquid and may consist entirely of the active compound with a liquid or solid emulsifying agent, or may also contain a liquid carrier, such as xylene, heavy aromatic naphthas, isophorone and other non-volatile organic solvents. In use, these concentrates are dispersed in water or other liquid and normally applied as a spray to the area to be treated. The amount of active ingredient may range from 0.5% to 95% of the concentrate.
Granular formulations include both extrudates and relatively coarse particles and are usually applied without dilution to the area in which treatment is required. Typical carriers for granular formulations include sand, fuller’s earth, attapulgite clay, bentonite clays, montmorillonite clay, vermiculite, perlite, calcium carbonate, brick, pumice, pyrophyllite, kaolin, dolomite, plaster, wood flour, ground corn cobs, ground peanut hulls, sugars, sodium chloride, sodium sulphate, sodium silicate, sodium borate, magnesia, mica, iron oxide, zinc oxide, titanium oxide, antimony oxide, cryolite, gypsum, diatomaceous earth, calcium sulphate and other organic or inorganic materials which absorb or which can be coated with the active compound. Granular formulations normally contain 5% to 25% of active ingredients which may include surface-active agents such as heavy aromatic naphthas, kerosene and other petroleum fractions, or vegetable oils; and/or stickers such as dextrins, glue or synthetic resins.
Dusts are free-flowing admixtures of the active ingredient with finely divided solids such as talc, clays, flours, and other organic and inorganic solids which act as dispersants and carriers. Microcapsules are typically droplets or granules of the active ingredient enclosed in an inert porous shell which allows escape of the enclosed material to the surroundings at controlled rates. Encapsulated droplets are typically 1 to 50 microns in diameter. The enclosed liquid typically constitutes 50 to 95% of the weight of the capsule and may include solvent in addition to the active compound. Encapsulated granules are generally porous granules with porous membranes sealing the granule pore openings, retaining the active species in liquid form inside the granule pores. Granules typically range from 1 millimetre to 1 centimetre and preferably 1 to 2 millimetres in diameter. Granules are formed by extrusion, agglomeration or prilling, or are naturally occurring. Examples of such materials are vermiculite, sintered clay, kaolin, attapulgite clay, sawdust, and granular carbon. Shell or membrane materials include natural and synthetic rubbers, cellulosic materials, styrene-butadiene copolymers, polyacrylonitriles, polyacrylates, polyesters, polyamides, polyureas, polyurethanes and starch xanthates.
Other useful formulations for agrochemical applications include simple solutions of the active ingredient in a solvent in which it is completely soluble at the desired concentration, such as acetone, alkylated naphthalenes, xylene and other organic solvents. Pressurised sprayers, wherein the active ingredient is dispersed in finely divided form as a result of vaporisation of a low boiling dispersant solvent carrier, may also be used.
Suitable agricultural adjuvants and carriers that are useful in formulating the compositions of the invention in the formulation types described above are well known to a person skilled in the art.
Liquid carriers that can be employed include, for example, water, toluene, xylene, petroleum naphtha, crop oil, acetone, methyl ethyl ketone, cyclohexanone, acetic anhydride, acetonitrile, acetophenone, amyl acetate, 2- butanone, chlorobenzene, cyclohexane, cyclohexanol, alkyl acetates, diacetonalcohol, 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, dipropylene glycol, dipropylene glycol methyl ether, dipropylene glycol dibenzoate, diproxitol, alkyl pyrrolidinone, ethyl acetate, 2-ethyl hexanol, ethylene carbonate, 1 ,1 ,1 -trichloroethane, 2-heptanone, alpha pinene, d-limonene, ethylene glycol, ethylene glycol butyl ether, ethylene glycol methyl ether, gammabutyrolactone, glycerol, glycerol diacetate, glycerol monoacetate, glycerol triacetate, hexadecane, hexylene glycol, isoamyl acetate, isobornyl acetate, isooctane, isophorone, isopropyl benzene, isopropyl myristate, lactic acid, laurylamine, mesityl oxide, methoxy-propanol, methyl isoamyl ketone, methyl isobutyl ketone, methyl laurate, methyl octanoate, methyl oleate, methylene chloride, m-xylene, n-hexane, n-octylamine, octadecanoic acid, octyl amine acetate, oleic acid, oleylamine, o-xylene, phenol, polyethylene glycol (PEG400), propionic acid, propylene glycol, propylene glycol monomethyl ether, p-xylene, toluene, triethyl phosphate, triethylene glycol, xylene sulfonic acid, paraffin, mineral oil, trichloroethylene, perchloroethylene, ethyl acetate, amyl acetate, butyl acetate, methanol, ethanol, isopropanol, and higher molecular weight alcohols such as amyl alcohol, tetrahydrofurfuryl alcohol, hexanol, octanol, etc., ethylene glycol, propylene glycol, glycerine, and N- methyl-2-pyrrolidinone. Water is generally the carrier of choice for the dilution of concentrates. Suitable solid carriers include, for example, talc, titanium dioxide, pyrophyllite clay, silica, attapulgite clay, kieselguhr, chalk, diatomaxeous earth, lime, calcium carbonate, bentonite clay, fuller’s earth, cotton seed hulls, wheat flour, soybean flour, pumice, wood flour, walnut shell flour and lignin.
A broad range of surface-active agents are advantageously employed in both said liquid and solid compositions, especially those designed to be diluted with carrier before application. These agents, when used, normally comprise from 0.1 % to 15% by weight of the formulation. They can be anionic, cationic, non-ionic or polymeric in character and can be employed as emulsifying agents, wetting agents, suspending agents or for other purposes. Typical surface-active agents include salts of alkyl sulfates, such as diethanolammonium lauryl sulphate; alkylarylsulfonate salts, such as calcium dodecylbenzenesulfonate; alkylphenol-alkylene oxide addition products, such as nonylphenol-C.sub. 18 ethoxylate; alcohol-alkylene oxide addition products, such as tridecyl alcohol-C.sub. 16 ethoxylate; soaps, such as sodium stearate; alkylnaphthalenesulfonate salts, such as sodium dibutylnaphthalenesulfonate; dialkyl esters of sulfosuccinate salts, such as sodium di(2 ethylhexyl) sulfosuccinate; sorbitol esters, such as sorbitol oleate; quaternary amines, such as lauryl trimethylammonium chloride; polyethylene glycol esters of fatty acids, such as polyethylene glycol stearate; block copolymers of ethylene oxide and propylene oxide; and salts of mono and dialkyl phosphate esters.
Other adjuvants commonly utilized in agricultural compositions include crystallisation inhibitors, viscosity modifiers, suspending agents, spray droplet modifiers, pigments, antioxidants, foaming agents, anti-foaming agents, light-blocking agents, compatibilizing agents, antifoam agents, sequestering agents, neutralising agents and buffers, corrosion inhibitors, dyes, odorants, spreading agents, penetration aids, micronutrients, emollients, lubricants and sticking agents.
In addition, further, other biocidal active ingredients or compositions may be combined with the compositions of the invention and used in the methods of the invention and applied simultaneously or sequentially with the compositions of the invention. When applied simultaneously, these further active ingredients may be formulated together with the compositions of the invention or mixed in, for example, the spray tank. These further biocidal active ingredients may be fungicides, herbicides, insecticides, bactericides, acaricides, nematicides and/or plant growth regulators.
Pesticidal agents are referred to herein using their common name are known, for example, from "The Pesticide Manual", 15th Ed., British Crop Protection Council 2009.
In addition, the compositions of the invention may also be applied with one or more systemically acquired resistance inducers (“SAR” inducer). SAR inducers are known and described in, for example, United States Patent No. US 6,919,298 and include, for example, salicylates and the commercial SAR inducer acibenzolar- S-methyl.
The compounds of formula (I) according to the invention are normally used in the form of agrochemical compositions and can be applied to the crop area or plant to be treated, simultaneously or in succession with further compounds. These further compounds can be e.g., fertilizers or micronutrient donors or other preparations, which influence the growth of plants. They can also be selective herbicides or non-selective herbicides as well as insecticides, fungicides, bactericides, nematicides, molluscicides or mixtures of several of these preparations, if desired together with further carriers, surfactants or application promoting adjuvants customarily employed in the art of formulation.
The compounds of formula (I) according to the invention may be used in the form of (fungicidal) compositions for controlling or protecting against phytopathogenic microorganisms, comprising as active ingredient at least one compound of formula (I) or of at least one preferred individual compound as defined herein, in free form or in agrochemical usable salt form, and at least one of the above-mentioned adjuvants.
The invention therefore provides a composition, preferably a fungicidal composition, comprising at least one compound of formula (I) according to the invention, an agriculturally acceptable carrier and optionally an adjuvant. An agricultural acceptable carrier is for example a carrier that is suitable for agricultural use. Agricultural carriers are well known in the art. Preferably, said composition may comprise at least one or more pesticidal-active compounds, for example an additional fungicidal active ingredient in addition to the compound of formula (I).
The compound of formula (I) according to the invention may be the sole active ingredient of a composition or it may be admixed with one or more additional active ingredients such as a pesticide, fungicide, synergist, herbicide or plant growth regulator where appropriate. An additional active ingredient may, in some cases, result in unexpected synergistic activities.
Examples of suitable additional active ingredients include the following: acycloamino acid fungicides, aliphatic nitrogen fungicides, amide fungicides, anilide fungicides, antibiotic fungicides, aromatic fungicides, arsenical fungicides, aryl phenyl ketone fungicides, benzamide fungicides, benzanilide fungicides, benzimidazole fungicides, benzothiazole fungicides, botanical fungicides, bridged diphenyl fungicides, carbamate fungicides, carbanilate fungicides, conazole fungicides, copper fungicides, dicarboximide fungicides, dinitrophenol fungicides, dithiocarbamate fungicides, dithiolane fungicides, furamide fungicides, furanilide fungicides, hydrazide fungicides, imidazole fungicides, mercury fungicides, morpholine fungicides, organophosphorous fungicides, organotin fungicides, oxathiin fungicides, oxazole fungicides, phenylsulfamide fungicides, polysulfide fungicides, pyrazole fungicides, pyridine fungicides, pyrimidine fungicides, pyrrole fungicides, quaternary ammonium fungicides, quinoline fungicides, quinone fungicides, quinoxaline fungicides, strobilurin fungicides, sulfonanilide fungicides, thiadiazole fungicides, thiazole fungicides, thiazolidine fungicides, thiocarbamate fungicides, thiophene fungicides, triazine fungicides, triazole fungicides, triazolopyrimidine fungicides, urea fungicides, valinamide fungicides, and zinc fungicides.
Examples of suitable additional active ingredients include the following: petroleum oils, 1 ,1 -bis(4-chlorophenyl)- 2-ethoxyethanol, 2,4-dichlorophenyl benzenesulfonate, 2-fluoro-N-methyl-N-1 -naphthylacetamide, 4- chlorophenyl phenyl sulfone, acetoprole, aldoxycarb, amidithion, amidothioate, amiton, amiton hydrogen oxalate, amitraz, aramite, arsenous oxide, azobenzene, azothoate, benomyl, benoxa-fos, benzyl benzoate, bixafen, brofenvalerate, bromocyclen, bromophos, bromopropylate, buprofezin, butocarboxim, butoxycarboxim, butylpyridaben, calcium polysulfide, camphechlor, carbanolate, carbophenothion, cymiazole, chinomethionat, chlorbenside, chlordimeform, chlordimeform hydrochloride, chlorfenethol, chlorfenson, chlorfensulfide, chlorobenzilate, chloromebuform, chloromethiuron, chloropropylate, chlorthiophos, cinerin I, cinerin II, cinerins, closantel, coumaphos, crotamiton, crotoxyphos, cufraneb, cyanthoate, DCPM, DDT, demephion, demephion-O, demephion-S, demeton-methyl, demeton-O, demeton-O-methyl, demeton-S, demeton-S-methyl, demeton-S-methylsulfon, dichlofluanid, dichlorvos, dicliphos, dienochlor, dimefox, dinex, dinex-diclexine, dinocap-4, dinocap-6, dinocton, dinopenton, dinosulfon, dinoterbon, dioxathion, diphenyl sulfone, disulfiram, DNOC, dofenapyn, doramectin, endothion, eprinomectin, ethoate-methyl, etrimfos, fenazaflor, fenbutatin oxide, fenothiocarb, fenpyrad, fenpyroximate, fenpyrazamine, fenson, fentrifanil, flubenzimine, flucycloxuron, fluenetil, fluorbenside, FMC 1137, formetanate, formetanate hydrochloride, formparanate, gamma-HCH, glyodin, halfenprox, hexadecyl cyclopropanecarboxylate, isocarbophos, jasmolin I, jasmolin II, jodfenphos, lindane, malonoben, mecarbam, mephosfolan, mesulfen, methacrifos, methyl bromide, metolcarb, mexacarbate, milbemycin oxime, mipafox, monocrotophos, morphothion, moxidectin, naled, 4-chloro-2-(2-chloro-2-methyl-propyl)-5-[(6-iodo-3-pyridyl)methoxy]pyridazin-3-one, nifluridide, nikkomycins, nitrilacarb, nitrilacarb 1 :1 zinc chloride complex, omethoate, oxydeprofos, oxydisulfoton, pp'-DDT, parathion, permethrin, phenkapton, phosalone, phosfolan, phosphamidon, polychloroterpenes, polynactins, proclonol, promacyl, propoxur, prothidathion, prothoate, pyrethrin I, pyrethrin II, pyrethrins, pyridaphenthion, pyrimitate, quinalphos, quintiofos, R-1492, phosglycin, rotenone, schradan, sebufos, selamectin, sophamide, SSI-121 , sulfiram, sulfluramid, sulfotep, sulfur, diflovidazin, tau-fluvalinate, TEPP, terbam, tetradifon, tetrasul, thiafenox, thiocarboxime, thiofanox, thiometon, thioquinox, thuringiensin, triamiphos, triarathene, triazophos, triazuron, trifenofos, trinactin, vamidothion, vaniliprole, bethoxazin, copper dioctanoate, copper sulfate, cybutryne, dichlone, dichlorophen, endothal, fentin, hydrated lime, nabam, quinoclamine, quinonamid, simazine, triphenyltin acetate, triphenyltin hydroxide, crufomate, piperazine, thiophanate, chloralose, fenthion, pyridin-4-amine, strychnine, 1 -hydroxy-1 H-pyridine-2-thione, 4-(quinoxalin-2-ylamino)benzenesulfonamide, 8- hydroxyquinoline sulfate, bronopol, copper hydroxide, cresol, dipyrithione, dodicin, fenaminosulf, formaldehyde, hydrargaphen, kasugamycin, kasugamycin hydrochloride hydrate, nickel bis(dimethyldithiocarbamate), nitrapyrin, octhilinone, oxolinic acid, oxytetracycline, potassium hydroxyquinoline sulfate, probenazole, streptomycin, streptomycin sesquisulfate, tecloftalam, thiomersal,
Adoxophyes orana GV, Agrobacterium radiobacter, Amblyseius spp., Anagrapha falcifera NPV, Anagrus atomus, Aphelinus abdominalis, Aphidius colemani, Aphidoletes aphidimyza, Autographa californica NPV, Bacillus sphaericus Neide, Beauveria brongniartii, Chrysoperla carnea, Cryptolaemus montrouzieri, Cydia pomonella GV, Dacnusa sibirica, Diglyphus isaea, Encarsia formosa, Eretmocerus eremicus, Heterorhabditis bacteriophora and H. megidis, Hippodamia convergens, Leptomastix dactylopii, Macrolophus caliginosus, Mamestra brassicae NPV, Metaphycus helvolus, Metarhizium anisopliae var. acridum, Metarhizium anisopliae var. anisopliae, Neodiprion sertifer NPV and N. lecontei NPV, Orius spp., Paecilomyces fumosoroseus, Phytoseiulus persimilis, Steinernema bibionis, Steinernema carpocapsae, Steinernema feltiae, Steinernema glaseri, Steinernema riobrave, Steinernema riobravis, Steinernema scapterisci, Steinernema spp., Trichogramma spp., Typhlodromus occidentalis, Verticillium lecanii, apholate, bisazir, busulfan, dimatif, hemel, hempa, metepa, methiotepa, methyl apholate, morzid, penfluron, tepa, thiohempa, thiotepa, tretamine, uredepa, (E)-dec-5-en-1-yl acetate with (E)-dec-5-en-1 -ol, (E)-tridec-4-en-1-yl acetate, (E)-6-methylhept-2-en- 4-ol, (E,Z)-tetradeca-4,10-dien-1-yl acetate, (Z)-dodec-7-en-1-yl acetate, (Z)-hexadec-l 1-enal, (Z)-hexadec- 11-en-1-yl acetate, (Z)-hexadec-13-en-11-yn-1-yl acetate, (Z)-icos-13-en-10-one, (Z)-tetradec-7-en-1-al, (Z)- tetradec-9-en-1-ol, (Z)-tetradec-9-en-1-yl acetate, (7E,9Z)-dodeca-7,9-dien-1-yl acetate, (9Z,11 E)-tetradeca- 9,11-dien-1-yl acetate, (9Z,12E)-tetradeca-9,12-dien-1-yl acetate, 14-methyloctadec-1-ene, 4-methylnonan-5- ol with 4-methylnonan-5-one, alpha-multistriatin, brevicomin, codlelure, codlemone, cuelure, disparlure, dodec- 8-en-1-yl acetate, dodec-9-en-1-yl acetate, dodeca-8,10-dien-1-yl acetate, dominicalure, ethyl 4- methyloctanoate, eugenol, frontalin, grandlure, grandlure I, grandlure II, grandlure III, grandlure IV, hexalure, ipsdienol, ipsenol, japonilure, lineatin, litlure, looplure, medlure, megatomoic acid, methyl eugenol, muscalure, octadeca-2,13-dien-1-yl acetate, octadeca-3,13-dien-1-yl acetate, orfralure, oryctalure, ostramone, siglure, sordidin, sulcatol, tetradec-11 -en-1 -yl acetate, trimedlure, trimedlure A, trimedlure B1 , trimedlure B2, trimedlure C, trunc-call, 2-(octylthio)ethanol, butopyronoxyl, butoxy(polypropylene glycol), dibutyl adipate, dibutyl phthalate, dibutyl succinate, diethyltoluamide, dimethyl carbate, dimethyl phthalate, ethyl hexanediol, hexamide, methoquin-butyl, methylneodecanamide, oxamate, picaridin, 1 -dichloro-1 -nitroethane, 1 ,1 -dichloro- 2,2-bis(4-ethylphenyl)ethane, 1 ,2-dichloropropane with 1 ,3-dichloropropene, 1 -bromo-2-chloroethane, 2,2,2- trichloro-1-(3,4-dichlorophenyl)ethyl acetate, 2,2-dichlorovinyl 2-ethylsulfinylethyl methyl phosphate, 2-(1 ,3- dithiolan-2-yl)phenyl dimethylcarbamate, 2-(2-butoxyethoxy)ethyl thiocyanate, 2-(4,5-dimethyl-1 ,3-dioxolan-2- yl)phenyl methylcarbamate, 2-(4-chloro-3,5-xylyloxy)ethanol, 2-chlorovinyl diethyl phosphate, 2-imidazolidone,
2-isovalerylindan-1 ,3-dione, 2-methyl(prop-2-ynyl)aminophenyl methylcarbamate, 2-thiocyanatoethyl laurate,
3-bromo-1 -chloroprop-1 -ene, 3-methyl-1 -phenylpyrazol-5-yl dimethylcarbamate, 4-methyl(prop-2-ynyl)amino- 3,5-xylyl methylcarbamate, 5,5-dimethyl-3-oxocyclohex-1-enyl dimethylcarbamate, acethion, acrylonitrile, aldrin, allosamidin, allyxycarb, alpha-ecdysone, aluminium phosphide, aminocarb, anabasine, athidathion, azamethiphos, Bacillus thuringiensis delta endotoxins, barium hexafluorosilicate, barium polysulfide, barthrin, Bayer 22/190, Bayer 22408, beta-cyfluthrin, beta-cypermethrin, bioethanomethrin, biopermethrin, bis(2- chloroethyl) ether, borax, bromfenvinfos, bromo-DDT, bufencarb, butacarb, butathiofos, butonate, calcium arsenate, calcium cyanide, carbon disulfide, carbon tetrachloride, cartap hydrochloride, cevadine, chlorbicyclen, chlordane, chlordecone, chloroform, chloropicrin, chlorphoxim, chlorprazophos, cis-resmethrin, cismethrin, clocythrin, copper acetoarsenite, copper arsenate, copper oleate, coumithoate, cryolite, CS 708, cyanofenphos, cyanophos, cyclethrin, cythioate, d-tetramethrin, DAEP, dazomet, decarbofuran, diamidafos, dicapthon, dichlofenthion, dicresyl, dicyclanil, dieldrin, diethyl 5-methylpyrazol-3-yl phosphate, dilor, dimefluthrin, dimetan, dimethrin, dimethylvinphos, dimetilan, dinoprop, dinosam, dinoseb, diofenolan, dioxabenzofos, dithicrofos, DSP, ecdysterone, El 1642, EMPC, EPBP, etaphos, ethiofencarb, ethyl formate, ethylene dibromide, ethylene dichloride, ethylene oxide, EXD, fenchlorphos, fenethacarb, fenitrothion, fenoxacrim, fenpirithrin, fensulfothion, fenthion-ethyl, flucofuron, fosmethilan, fospirate, fosthietan, furathiocarb, furethrin, guazatine, guazatine acetates, sodium tetrathiocarbonate, halfenprox, HCH, HEOD, heptachlor, heterophos, HHDN, hydrogen cyanide, hyquincarb, IPSP, isazofos, isobenzan, isodrin, isofenphos, isolane, isoprothiolane, isoxathion, juvenile hormone I, juvenile hormone II, juvenile hormone III, kelevan, kinoprene, lead arsenate, leptophos, lirimfos, lythidathion, m-cumenyl methylcarbamate, magnesium phosphide, mazidox, mecarphon, menazon, mercurous chloride, mesulfenfos, metam, metam-potassium, metam-sodium, methanesulfonyl fluoride, methocrotophos, methoprene, methothrin, methoxychlor, methyl isothiocyanate, methylchloroform, methylene chloride, metoxadiazone, mirex, naftalofos, naphthalene, NC- 170, nicotine, nicotine sulfate, nithiazine, nornicotine, 0-5-dichloro-4-iodophenyl O-ethyl ethylphosphonothioate, O,O-diethyl 0-4-methyl-2-oxo-2H-chromen-7-yl phosphorothioate, O,O-diethyl 0-6- methyl-2-propylpyrimidin-4-yl phosphorothioate, 0,0,0',0'-tetrapropyl dithiopyrophosphate, oleic acid, paradichlorobenzene, parathion-methyl, pentachlorophenol, pentachlorophenyl laurate, PH 60-38, phenkapton, phosnichlor, phosphine, phoxim-methyl, pirimetaphos, polychlorodicyclopentadiene isomers, potassium arsenite, potassium thiocyanate, precocene I, precocene II, precocene III, primidophos, profluthrin, promecarb, prothiofos, pyrazophos, pyresmethrin, quassia, quinalphos-methyl, quinothion, rafoxanide, resmethrin, rotenone, kadethrin, ryania, ryanodine, sabadilla, schradan, sebufos, SI-0009, thiapronil, sodium arsenite, sodium cyanide, sodium fluoride, sodium hexafluorosilicate, sodium pentachlorophenoxide, sodium selenate, sodium thiocyanate, sulcofuron, sulcofuron-sodium, sulfuryl fluoride, sulprofos, tar oils, tazimcarb, TDE, tebupirimfos, temephos, terallethrin, tetrachloroethane, thicrofos, thiocyclam, thiocyclam hydrogen oxalate, thionazin, thiosultap, thiosultap-sodium, tralomethrin, transpermethrin, triazamate, trichlormetaphos-3, trichloronat, trimethacarb, tolprocarb, triclopyricarb, triprene, veratridine, veratrine, XMC, zetamethrin, zinc phosphide, zolaprofos, meperfluthrin, tetramethylfluthrin, bis(tributyltin) oxide, bromoacetamide, ferric phosphate, niclosamide-olamine, tributyltin oxide, pyrimorph, trifenmorph, 1 ,2-dibromo-3-chloropropane, 1 ,3- dichloropropene, 3,4-dichlorotetrahydrothiophene 1 ,1-dioxide, 3-(4-chlorophenyl)-5-methylrhodanine, 5- methyl-6-thioxo-1 ,3,5-thiadiazinan-3-ylacetic acid, 6-isopentenylaminopurine, anisiflupurin, benclothiaz, cytokinins, DCIP, furfural, isamidofos, kinetin, Myrothecium verrucaria composition, tetrachlorothiophene, xylenols, zeatin, potassium ethylxanthate, acibenzolar, acibenzolar-S-methyl, Reynoutria sachalinensis extract, alpha-chlorohydrin, antu, barium carbonate, bisthiosemi, brodifacoum, bromadiolone, bromethalin, chlorophacinone, cholecalciferol, coumachlor, coumafuryl, coumatetralyl, crimidine, difenacoum, difethialone, diphacinone, ergocalciferol, flocoumafen, fluoroacetamide, flupropadine, flupropadine hydrochloride, norbormide, phosacetim, phosphorus, pindone, pyrinuron, scilliroside, sodium fluoroacetate, thallium sulfate, warfarin, 2-(2-butoxyethoxy)ethyl piperonylate, 5-(1 ,3-benzodioxol-5-yl)-3-hexylcyclohex-2-enone, farnesol with nerolidol, verbutin, MGK 264, piperonyl butoxide, piprotal, propyl isomer, S421 , sesamex, sesasmolin, sulfoxide, anthraquinone, copper naphthenate, copper oxychloride, dicyclopentadiene, thiram, zinc naphthenate, ziram, imanin, ribavirin, chloroinconazide, mercuric oxide, thiophanate-methyl, azaconazole, bitertanol, bromuconazole, cyproconazole, difenoconazole, diniconazole, epoxiconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, furametpyr, hexaconazole, imazalil, imibenconazole, ipconazole, metconazole, myclobutanil, paclobutrazole, pefurazoate, penconazole, prothioconazole, pyrifenox, prochloraz, propiconazole, pyrisoxazole, simeconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triflumizole, triticonazole, ancymidol, fenarimol, nuarimol, bupirimate, dimethirimol, ethirimol, dodemorph, fenpropidin, fenpropimorph, spiroxamine, tridemorph, cyprodinil, mepanipyrim, pyrimethanil, fenpiclonil, fludioxonil, benalaxyl, furalaxyl, metalaxyl, R-metalaxyl, ofurace, oxadixyl, carbendazim, debacarb, fuberidazole, thiabendazole, chlozolinate, dichlozoline, myclozoline, procymidone, vinclozoline, boscalid, carboxin, fenfuram, flutolanil, mepronil, oxycarboxin, penthiopyrad, thifluzamide, dodine, iminoctadine, azoxystrobin, dimoxystrobin, enestroburin, fenaminstrobin, flufenoxystrobin, fluoxastrobin, kresoxim-methyl, metominostrobin, trifloxystrobin, orysastrobin, picoxystrobin, pyraclostrobin, pyrametostrobin, pyraoxystrobin, ferbam, mancozeb, maneb, metiram, propineb, zineb, captafol, captan, fluoroimide, folpet, tolylfluanid, bordeaux mixture, copper oxide, mancopper, oxine-copper, nitrothal-isopropyl, edifenphos, iprobenphos, phosdiphen, tolclofos-methyl, anilazine, benthiavalicarb, blasticidin-S, chloroneb, chlorothalonil, cyflufenamid, cymoxanil, cyclobutrifluram, diclocymet, diclomezine, dicloran, diethofencarb, dimethomorph, flumorph, dithianon, ethaboxam, etridiazole, famoxadone, fenamidone, fenoxanil, ferimzone, fluazinam, flumetylsulforim.fluopicolide, fluoxytioconazole, flusulfamide, fluxapyroxad, fenhexamid, fosetylaluminium, hymexazol, iprovalicarb, cyazofamid, methasulfocarb, metrafenone, pencycuron, phthalide, polyoxins, propamocarb, pyribencarb, proquinazid, pyroquilon, pyriofenone, quinoxyfen, quintozene, tiadinil, triazoxide, tricyclazole, triforine, validamycin, valifenalate, zoxamide, mandipropamid, flubeneteram, isopyrazam, sedaxane, benzovindiflupyr, pydiflumetofen, 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid (3',4',5'- trifluoro-biphenyl-2-yl)-amide, isoflucypram, isotianil, dipymetitrone, 6-ethyl-5,7-dioxo- pyrrolo[4,5][1 ,4]dithiino[1 ,2-c]isothiazole-3-carbonitrile, 2-(difluoromethyl)-N-[3-ethyl-1 ,1-dimethyl-indan-4- yl]pyridine-3-carboxamide, 4-(2,6-difluorophenyl)-6-methyl-5-phenyl-pyridazine-3-carbonitrile, (R)-3- (difluoromethyl)-1-methyl-N-[1 ,1 ,3-trimethylindan-4-yl]pyrazole-4-carboxamide, 4-(2-bromo-4-fluoro-phenyl)- N-(2-chloro-6-fluoro-phenyl)-2,5-dimethyl-pyrazol-3-amine, 4- (2- bromo- 4- fluorophenyl) - N- (2- chloro- 6- fluorophenyl) - 1 , 3- dimethyl- 1 H- pyrazol- 5- amine, fluindapyr, coumethoxystrobin (jiaxiangjunzhi), Ivbenmixianan, dichlobentiazox, mandestrobin, 3-(4,4-difluoro-3,4-dihydro-3,3-dimethylisoquinolin-1- yl)quinolone, 2-[2-fluoro-6-[(8-fluoro-2-methyl-3-quinolyl)oxy]phenyl]propan-2-ol, oxathiapiprolin, tert-butyl N- [6-[[[(1-methyltetrazol-5-yl)-phenyl-methylene]amino]oxymethyl]-2-pyridyl]carbamate, pyraziflumid, inpyrfluxam, trolprocarb, mefentrifluconazole, ipfentrifluconazole, 2-(difluoromethyl)-N-[(3R)-3-ethyl-1 ,1- dimethyl-indan-4-yl]pyridine-3-carboxamide, N'-(2,5-dimethyl-4-phenoxy-phenyl)-N-ethyl-N-methyl- formamidine, N'-[4-(4,5-dichlorothiazol-2-yl)oxy-2,5-dimethyl-phenyl]-N-ethyl-N-methyl-formamidine, [2-[3-[2- [1-[2-[3,5-bis(difluoromethyl)pyrazol-1-yl]acetyl]-4-piperidyl]thiazol-4-yl]-4,5-dihydroisoxazol-5-yl]-3-chloro- phenyl] methanesulfonate, but-3-ynyl N-[6-[[(Z)-[(1 -methyltetrazol-5-yl)-phenyl-methylene]amino]oxymethyl]- 2-pyridyl]carbamate, methyl N-[[5-[4-(2,4-dimethylphenyl)triazol-2-yl]-2-methyl-phenyl]methyl]carbamate, 3- chloro-6-methyl-5-phenyl-4-(2,4,6-trifluorophenyl)pyridazine, pyridachlometyl, 3-(difluoromethyl)-1-methyl-N- [1 ,1 ,3-trimethylindan-4-yl]pyrazole-4-carboxamide, 1-[2-[[1-(4-chlorophenyl)pyrazol-3-yl]oxymethyl]-3-methyl- phenyl]-4-methyl-tetrazol-5-one, 1-methyl-4-[3-methyl-2-[[2-methyl-4-(3,4,5-trimethylpyrazol-1- yl)phenoxy]methyl]phenyl]tetrazol-5-one, aminopyrifen, ametoctradin, amisulbrom, penflufen, (Z,2E)-5-[1-(4- chlorophenyl)pyrazol-3-yl]oxy-2-methoxyimino-N,3-dimethyl-pent-3-enamide, florylpicoxamid, fenpicoxamid, metarylpicoxamid, tebufloquin, ipflufenoquin, quinofumelin, isofetamid, ethyl 1-[[4-[[2-(trifluoromethyl)-1 ,3- dioxolan-2-yl]methoxy]phenyl]methyl]pyrazole-3-carboxylate (may be prepared from the methods described in W02020/056090), ethyl 1-[[4-[(Z)-2-ethoxy-3,3,3-trifluoro-prop-1-enoxy]phenyl]methyl]pyrazole-3-carboxylate (may be prepared from the methods described in W02020/056090), methyl N-[[4-[1-(4-cyclopropyl-2,6- difluoro-phenyl)pyrazol-4-yl]-2-methyl-phenyl]methyl]carbamate (may be prepared from the methods described in W02020/097012), methyl N-[[4-[1-(2,6-difluoro-4-isopropyl-phenyl)pyrazol-4-yl]-2-methyl- phenyl]methyl]carbamate (may be prepared from the methods described in W02020/097012), 6-chloro-3-(3- cyclopropyl-2-fluoro-phenoxy)-N-[2-(2,4-dimethylphenyl)-2,2-difluoro-ethyl]-5-methyl-pyridazine-4- carboxamide (may be prepared from the methods described in W02020/109391), 6-chloro-N-[2-(2-chloro-4- methyl-phenyl)-2,2-difluoro-ethyl]-3-(3-cyclopropyl-2-fluoro-phenoxy)-5-methyl-pyridazine-4-carboxamide (may be prepared from the methods described in W02020/109391), 6-chloro-3-(3-cyclopropyl-2-fluoro- phenoxy)-N-[2-(3,4-dimethylphenyl)-2,2-difluoro-ethyl]-5-methyl-pyridazine-4-carboxamide (may be prepared from the methods described in W02020/109391),N-[2-[2,4-dichloro-phenoxy]phenyl]-3-(difluoromethyl)-1- methyl-pyrazole-4-carboxamide, N-[2-[2-chloro-4-(trifluoromethyl)phenoxy]phenyl]-3-(difluoromethyl)-1- methyl-pyrazole-4-carboxamide, benzothiostrobin, phenamacril, 5-amino-1 ,3,4-thiadiazole-2-thiol zinc salt (2:1), fluopyram, flufenoxadiazam, flutianil, fluopimomide, pyrapropoyne, picarbutrazox, 2-(difluoromethyl)-N- (3-ethyl-1 ,1-dimethyl-indan-4-yl)pyridine-3-carboxamide, 2-(difluoromethyl)-N-((3R)-1 ,1 ,3-trimethylindan-4-yl) pyridine-3-carboxamide, 4-[[6-[2-(2,4-difluorophenyl)-1 ,1-difluoro-2-hydroxy-3-(1 ,2,4-triazol-1-yl)propyl]-3- pyridyl]oxy]benzonitrile, metyltetraprole, a- (1 ,1- dimethylethyl)-a-[4'-(trifluoromethoxy) [1 ,1'-biphenyl]-4-yl] -5- pyrimidinemethanol, fluoxapiprolin, enoxastrobin, methyl (Z)-3-methoxy-2-[2-methyl-5-[4- (trifluoromethyl)triazol-2-yl]phenoxy]prop-2-enoate, methyl (Z)-3-methoxy-2-[2-methyl-5-(4-propyltriazol-2- yl)phenoxy]prop-2-enoate, methyl (Z)-2-[5-(3-isopropylpyrazol-1-yl)-2-methyl-phenoxy]-3-methoxy-prop-2- enoate, methyl (Z)-3-methoxy-2-[2-methyl-5-(3-propylpyrazol-1-yl)phenoxy]prop-2-enoate, methyl (Z)-3- methoxy-2-[2-methyl-5-[3-(trifluoromethyl)pyrazol-1-yl]phenoxy]prop-2-enoate (these compounds may be prepared from the methods described in W02020/079111), methyl (Z)-2-(5-cyclohexyl-2-methyl-phenoxy)-3- methoxy-prop-2-enoate, methyl (Z)-2-(5-cyclopentyl-2-methyl-phenoxy)-3-methoxy-prop-2-enoate (these compounds may be prepared from the methods described in W02020/193387), 4-[[6-[2-(2,4-difluorophenyl)- 1 ,1-difluoro-2-hydroxy-3-(1 ,2,4-triazol-1-yl)propyl]-3-pyridyl]oxy] benzonitrile, 4-[[6-[2-(2,4-difluorophenyl)-1 ,1- difluoro-2-hydroxy-3-(5-sulfanyl-1 ,2,4-triazol-1-yl)propyl]-3-pyridyl]oxy] benzonitrile, 4-[[6-[2-(2,4- difluorophenyl)-1 ,1-difluoro-2-hydroxy-3-(5-thioxo-4H-1 ,2,4-triazol-1-yl)propyl]-3-pyridyl]oxy]benzonitrile, trinexapac, coumoxystrobin, zhongshengmycin, thiodiazole copper, zinc thiazole, amectotractin, iprodione, seboctylamine, N'-[5-bromo-2-methyl-6-[(1S)-1-methyl-2-propoxy-ethoxy]-3-pyridyl]-N-ethyl-N-methyl- formamidine, N'-[5-bromo-2-methyl-6-[(1 R)-1-methyl-2-propoxy-ethoxy]-3-pyridyl]-N-ethyl-N-methyl- formamidine, N'-[5-bromo-2-methyl-6-(1-methyl-2-propoxy-ethoxy)-3-pyridyl]-N-ethyl-N-methyl-formamidine, N'-[5-chloro-2-methyl-6-(1-methyl-2-propoxy-ethoxy)-3-pyridyl]-N-ethyl-N-methyl-formamidine, N'-[5-bromo-2- methyl-6-(1-methyl-2-propoxy-ethoxy)-3-pyridyl]-N-isopropyl-N-methyl-formamidine (these compounds may be prepared from the methods described in WO2015/155075); N'-[5-bromo-2-methyl-6-(2-propoxypropoxy)-3- pyridyl]-N-ethyl-N-methyl-formamidine (this compound may be prepared from the methods described in IPCOM000249876D); N-isopropyl-N’-[5-methoxy-2-methyl-4-(2, 2, 2-trifluoro-1 -hydroxy-1 -phenyl- ethyl)phenyl]-N-methyl-formamidine, N’-[4-(1-cyclopropyl-2,2,2-trifluoro-1-hydroxy-ethyl)-5-methoxy-2-methyl- phenyl]-N-isopropyl-N-methyl-formamidine (these compounds may be prepared from the methods described in WO2018/228896); N-ethyl-N’-[5-methoxy-2-methyl-4-[(2-trifluoromethyl)oxetan-2-yl]phenyl]-N-methyl- formamidine, N-ethyl-N’-[5-methoxy-2-methyl-4-[(2-trifuoromethyl)tetrahydrofuran-2-yl]phenyl]-N-methyl- formamidine (these compounds may be prepared from the methods described in WO2019/110427); N-[(1 R)- 1-benzyl-3-chloro-1-methyl-but-3-enyl]-8-fluoro-quinoline-3-carboxamide, N-[(1 S)-1-benzyl-3-chloro-1-methyl- but-3-enyl]-8-fluoro-quinoline-3-carboxamide, N-[(1 R)-1-benzyl-3,3,3-trifluoro-1-methyl-propyl]-8-fluoro- quinoline-3-carboxamide, N-[(1 S)-1-benzyl-3,3,3-trifluoro-1-methyl-propyl]-8-fluoro-quinoline-3-carboxamide, N-[(1 R)-1-benzyl-1 ,3-dimethyl-butyl]-7,8-difluoro-quinoline-3-carboxamide, N-[(1 S)-1-benzyl-1 ,3-dimethyl- butyl]-7,8-difluoro-quinoline-3-carboxamide, 8-fluoro-N-[(1 R)-1-[(3-fluorophenyl)methyl]-1 ,3-dimethyl- butyl]quinoline-3-carboxamide, 8-fluoro-N-[(1 S)-1-[(3-fluorophenyl)methyl]-1 ,3-dimethyl-butyl]quinoline-3- carboxamide, N-[(1 R)-1-benzyl-1 ,3-dimethyl-butyl]-8-fluoro-quinoline-3-carboxamide, N-[(1 S)-1-benzyl-1 ,3- dimethyl-butyl]-8-fluoro-quinoline-3-carboxamide, N-((1 R)-1 -benzyl-3-chloro-1 -methyl-but-3-enyl)-8-fluoro- quinoline-3-carboxamide, N-((1 S)-1-benzyl-3-chloro-1-methyl-but-3-enyl)-8-fluoro-quinoline-3-carboxamide (these compounds may be prepared from the methods described in WO2017/153380); 1 -(6,7- dimethylpyrazolo[1 ,5-a]pyridin-3-yl)-4,4,5-trifluoro-3,3-dimethyl-isoquinoline, 1 -(6,7-dimethylpyrazolo[1 ,5- a]pyridin-3-yl)-4,4,6-trifluoro-3,3-dimethyl-isoquinoline, 4,4-difluoro-3,3-dimethyl-1-(6-methylpyrazolo[1 ,5- a] py rid i n-3-y I) isoq u i n ol ine , 4,4-difluoro-3,3-dimethyl-1 -(7-methylpyrazolo[1 ,5-a]pyridin-3-yl)isoquinoline, 1 -(6- chloro-7-methyl-pyrazolo[1 ,5-a]pyridin-3-yl)-4,4-difluoro-3,3-dimethyl-isoquinoline (these compounds may be prepared from the methods described in WO2017/025510); 1-(4,5-dimethylbenzimidazol-1-yl)-4,4,5-trifluoro-
3.3-dimethyl-isoquinoline, 1 -(4,5-dimethylbenzimidazol-1 -yl)-4,4-difluoro-3,3-dimethyl-isoquinoline, 6-chloro-
4.4-difluoro-3,3-dimethyl-1-(4-methylbenzimidazol-1 -yl)isoquinoline, 4,4-difluoro-1-(5-fluoro-4-methyl- benzimidazol-1-yl)-3,3-dimethyl-isoquinoline, 3-(4,4-difluoro-3,3-dimethyl-1-isoquinolyl)-7,8-dihydro-6H- cyclopenta[e]benzimidazole (these compounds may be prepared from the methods described in WO2016/156085); N-methoxy-N-[[4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]phenyl]methyl] cyclopropane carboxamide, N,2-dimethoxy-N-[[4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]phenyl]methyl]propanamide, N- ethyl-2-methyl-N-[[4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]phenyl]methyl]propanamide, 1-methoxy-3- methyl-1 -[[4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]phenyl]methyl]urea, 1 ,3-dimethoxy-1 -[[4-[5-
(trifluoromethyl)-l ,2,4-oxadiazol-3-yl]phenyl]methyl]urea, 3-ethyl-1-methoxy-1-[[4-[5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl]phenyl]methyl]urea, N-[[4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]phenyl]methyl]propanamide,
4.4-dimethyl-2-[[4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]phenyl]methyl]isoxazolidin-3-one, 5,5-dimethyl-2- [[4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]phenyl]methyl]isoxazolidin-3-one, ethyl 1 -[[4-[5-(trifluoromethyl)-
1 .2.4-oxadiazol-3-yl]phenyl]methyl]pyrazole-4-carboxylate, N,N-dimethyl-1-[[4-[5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl]phenyl]methyl]-1 ,2,4-triazol-3-amine (these compounds may be prepared from the methods described in WO2017/055473, WO2017/055469, WO2017/093348 and WO2017/1 18689); 2-[6-(4- chlorophenoxy)-2-(trifluoromethyl)-3-pyridyl]-1-(1 ,2,4-triazol-1-yl)propan-2-ol (this compound may be prepared from the methods described in WO2017/029179); 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)-3-pyridyl]-1- (1 ,2,4-triazol-1-yl)propan-2-ol (this compound may be prepared from the methods described in WO2017/029179); 3-[2-(1 -chlorocyclopropyl)-3-(2-fluorophenyl)-2-hydroxy-propyl]imidazole-4-carbonitrile
(this compound may be prepared from the methods described in WO2016/156290); 3-[2-(1-chlorocyclopropyl)- 3-(3-chloro-2-fluoro-phenyl)-2-hydroxy-propyl]imidazole-4-carbonitrile (this compound may be prepared from the methods described in WO2016/156290); (4-phenoxyphenyl)methyl 2-amino-6-methyl-pyridine-3- carboxylate (this compound may be prepared from the methods described in WO2014/006945); 2,6-Dimethyl- 1 H,5H-[1 ,4]dithiino[2,3-c:5,6-c']dipyrrole-1 ,3,5,7(2H,6H)-tetrone (this compound may be prepared from the methods described in WO2011/138281) N-methyl-4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl]benzenecarbothioamide; N-methyl-4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]benzamide; (Z,2E)-5-[1 -(2,4- dichlorophenyl)pyrazol-3-yl]oxy-2-methoxyimino-N,3-dimethyl-pent-3-enamide (this compound may be prepared from the methods described in WO2018/153707); N'-(2-chloro-5-methyl-4-phenoxy-phenyl)-N-ethyl- N-methyl-formamidine; N'-[2-chloro-4-(2-fluorophenoxy)-5-methyl-phenyl]-N-ethyl-N-methyl-formamidine (this compound may be prepared from the methods described in WO2016/202742); 2-(difluoromethyl)-N-[(3S)-3- ethyl-1 ,1-dimethyl-indan-4-yl]pyridine-3-carboxamide (this compound may be prepared from the methods described in WO2014/095675); (5-methyl-2-pyridyl)-[4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl]phenyl]methanone, (3-methylisoxazol-5-yl)-[4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]phenyl]methanone (these compounds may be prepared from the methods described in WO2017/220485); 2-oxo-N-propyl-2-[4- [5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]phenyl]acetamide (this compound may be prepared from the methods described in WO2018/065414); ethyl 1-[[5-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]-2-thienyl]methyl]pyrazole- 4-carboxylate (this compound may be prepared from the methods described in WO2018/158365); 2,2-difluoro- N-methyl-2-[4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]phenyl]acetamide, N-[(E)-methoxyiminomethyl]-4-[5- (trifluoromethyl)-l ,2,4-oxadiazol-3-yl]benzamide, N-[(Z)-methoxyiminomethyl]-4-[5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl]benzamide, N-[N-methoxy-methyl-carbonimidoyl]-4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl]benzamide (these compounds may be prepared from the methods described in WO2018/202428).
The compounds of the invention may also be used in combination with anthelmintic agents. Such anthelmintic agents include, compounds selected from the macrocyclic lactone class of compounds such as ivermectin, avermectin, abamectin, emamectin, eprinomectin, doramectin, selamectin, moxidectin, nemadectin and milbemycin derivatives as described in EP0357460, EP0444964 and EP0594291 . Additional anthelmintic agents include semisynthetic and biosynthetic avermectin/milbemycin derivatives such as those described in US5, 015,630, WO9415944 and WO9522552. Additional anthelmintic agents include the benzimidazoles such as albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, and other members of the class. Additional anthelmintic agents include imidazothiazoles and tetrahydropyrimidines such as tetramisole, levamisole, pyrantel pamoate, oxantel or morantel. Additional anthelmintic agents include flukicides, such as triclabendazole and clorsulon and the cestocides, such as praziquantel and epsiprantel.
The compounds of the invention may be used in combination with derivatives and analogues of the paraherquamide/marcfortine class of anthelmintic agents, as well as the antiparasitic oxazolines such as those disclosed in US5478855, US4639771 and DE-19520936.
The compounds of the invention may be used in combination with derivatives and analogues of the general class of dioxomorpholine antiparasitic agents as described in WO9615121 and also with anthelmintic active cyclic depsipeptides such as those described in WO961 1945, WO9319053, WO9325543, EP0626375, EP0382173, WO9419334, EP0382173, and EP0503538. The compounds of the invention may be used in combination with other ectoparasiticides; for example, fipronil; pyrethroids; organophosphates; insect growth regulators such as lufenuron; ecdysone agonists such as tebufenozide and the like; neonicotinoids such as imidacloprid and the like.
The compounds of the invention may be used in combination with terpene alkaloids, for example those described in WO95/19363 or W004/72086, particularly the compounds disclosed therein.
Other examples of such biologically active compounds that the compounds of the invention may be used in combination with include but are not restricted to the following:
Organophosphates: acephate, azamethiphos, azinphos-ethyl, azinphos- methyl, bromophos, bromophos- ethyl, cadusafos, chlorethoxyphos, chlorpyrifos, chlorfenvinphos, chlormephos, demeton, demeton-S-methyl, demeton-S-methyl sulphone, dialifos, diazinon, dichlorvos, dicrotophos, dimethoate, disulfoton, ethion, ethoprophos, etrimfos, famphur, fenamiphos, fenitrothion, fensulfothion, fenthion, flupyrazofos, fonofos, formothion, fosthiazate, heptenophos, isazophos, isothioate, isoxathion, malathion, methacriphos, methamidophos, methidathion, methyl- parathion, mevinphos, monocrotophos, naled, omethoate, oxydemeton-methyl, paraoxon, parathion, parathion-methyl, phenthoate, phosalone, phosfolan, phosphocarb, phosmet, phosphamidon, phorate, phoxim, pirimiphos, pirimiphos- methyl, profenofos, propaphos, proetamphos, prothiofos, pyraclofos, pyridapenthion, quinalphos, sulprophos, temephos, terbufos, tebupirimfos, tetrachlorvinphos, thimeton, triazophos, trichlorfon, vamidothion.
Carbamates: alanycarb, aldicarb, 2-sec-butylphenyl methylcarbamate, benfuracarb, carbaryl, carbofuran, carbosulfan, cloethocarb, ethiofencarb, fenoxycarb, fenthiocarb, furathiocarb, HCN-801 , isoprocarb, indoxacarb, methiocarb, methomyl, 5-methyl-m-cumenylbutyryl(methyl)carbamate, oxamyl, pirimicarb, propoxur, thiodicarb, thiofanox, triazamate, UC-51717.
Pyrethroids: acrinathin, allethrin, alphametrin, 5-benzyl-3-furylmethyl (E)-(1 R)-cis-2,2-dimethyl-3-(2- oxothiolan-3-ylidenemethyl)cyclopropanecarboxylate, bifenthrin, beta-cyfluthrin, cyfluthrin, a-cypermethrin, beta-cypermethrin, bioallethrin, bioallethrin((S)-cyclopentylisomer), bioresmethrin, bifenthrin, NCI-85193, cycloprothrin, cyhalothrin, cythithrin, cyphenothrin, deltamethrin, empenthrin, esfenvalerate, ethofenprox, fenfluthrin, fenpropathrin, fenvalerate, flucythrinate, flumethrin, fluvalinate (D isomer), imiprothrin, cyhalothrin, lambda-cyhalothrin, permethrin, phenothrin, prallethrin, pyrethrins (natural products), resmethrin, tetramethrin, transfluthrin, theta-cypermethrin, silafluofen, t-fluvalinate, tefluthrin, tralomethrin, Zeta-cypermethrin.
Arthropod growth regulators: a) chitin synthesis inhibitors: benzoylureas: chlorfluazuron, diflubenzuron, fluazuron, flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, novaluron, teflubenzuron, triflumuron, buprofezin, diofenolan, hexythiazox, etoxazole, chlorfentazine; b) ecdysone antagonists: halofenozide, methoxyfenozide, tebufenozide; c) juvenoids: pyriproxyfen, methoprene (including S-methoprene), fenoxycarb; d) lipid biosynthesis inhibitors: spirodiclofen.
Other antiparasitics: acequinocyl, amitraz, AKD-1022, ANS-118, azadirachtin, Bacillus thuringiensis, bensultap, bifenazate, binapacryl, bromopropylate, BTG-504, BTG-505, camphechlor, cartap, chlorobenzilate, chlordimeform, chlorfenapyr, chromafenozide, clothianidine, cyromazine, diacloden, diafenthiuron, DBI-3204, dinactin, dihydroxymethyldihydroxypyrrolidine, dinobuton, dinocap, endosulfan, ethiprole, ethofenprox, fenazaquin, flumite, MTI-800, fenpyroximate, fluacrypyrim, flubenzimine, flubrocythrinate, flufenzine, flufenprox, fluproxyfen, halofenprox, hydramethylnon, IKI-220, kanemite, NC-196, neem guard, nidinorterfuran, nitenpyram, SD-35651 , WL-108477, pirydaryl, propargite, protrifenbute, pymethrozine, pyridaben, pyrimidifen, NC-1111 , R-195, RH-0345, RH-2485, RYI-210, S-1283, S-1833, SI-8601 , silafluofen, silomadine, spinosad, tebufenpyrad, tetradifon, tetranactin, thiacloprid, thiocyclam, thiamethoxam, tolfenpyrad, triazamate, triethoxyspinosyn, trinactin, verbutin, vertalec, YI-5301.
Biological agents: Bacillus thuringiensis ssp. aizawai, kurstaki, Bacillus thuringiensis delta endotoxin, baculovirus, entomopathogenic bacteria, virus, and fungi.
Bactericides: chlortetracycline, oxytetracycline, streptomycin.
Other biological agents: enrofloxacin, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, omeprazole, tiamulin, benazepril, pyriprole, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, carprofen, metaflumizone, praziquarantel, triclabendazole.
The following mixtures of the compounds of Formula (I) with active ingredients are preferred. The abbreviation “TX” means one compound selected from compounds of formula (I), (l-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (l-B), (l-C), or (l-D), or compounds selected from compounds listed in Tables A-1 to A-26, or compounds listed in Table P (below), and a compound selected from the group of substances consisting of petroleum oils + TX, 1 ,1-bis(4-chlorophenyl)-2-ethoxyethanol + TX, 2,4-dichlorophenyl benzenesulfonate + TX, 2-fluoro-N-methyl- N-1 -naphthylacetamide + TX, 4-chlorophenyl phenyl sulfone + TX, acetoprole + TX, aldoxycarb + TX, amidithion + TX, amidothioate + TX, amiton + TX, amiton hydrogen oxalate + TX, amitraz + TX, aramite + TX, arsenous oxide + TX, azobenzene + TX, azothoate + TX, benomyl + TX, benoxafos + TX, benzyl benzoate + TX, bixafen + TX, brofenvalerate + TX, bromocyclen + TX, bromophos + TX, bromopropylate + TX, buprofezin + TX, butocarboxim + TX, butoxycarboxim + TX, butylpyridaben + TX, calcium polysulfide + TX, camphechlor + TX, carbanolate + TX, carbophenothion + TX, cymiazole + TX, chinomethionat + TX, chlorbenside + TX, chlordimeform + TX, chlordimeform hydrochloride + TX, chlorfenethol + TX, chlorfenson + TX, chlorfensulfide + TX, chlorobenzilate + TX, chloromebuform + TX, chloromethiuron + TX, chloropropylate + TX, chlorthiophos + TX, cinerin I + TX, cinerin II + TX, cinerins + TX, closantel + TX, coumaphos + TX, crotamiton + TX, crotoxyphos + TX, cufraneb + TX, cyanthoate + TX, DCPM + TX, DDT + TX, demephion + TX, demephion-O + TX, demephion-S + TX, demeton-methyl + TX, demeton-O + TX, demeton-O-methyl + TX, demeton-S + TX, demeton-S-methyl + TX, demeton-S-methylsulfon + TX, dichlofluanid + TX, dichlorvos + TX, dicliphos + TX, dienochlor + TX, dimefox + TX, dinex + TX, dinex-diclexine + TX, dinocap-4 + TX, dinocap-6 + TX, dinocton + TX, dinopenton + TX, dinosulfon + TX, dinoterbon + TX, dioxathion + TX, diphenyl sulfone + TX, disulfiram + TX, DNOC + TX, dofenapyn + TX, doramectin + TX, endothion + TX, eprinomectin + TX, ethoate-methyl + TX, etrimfos + TX, fenazaflor + TX, fenbutatin oxide + TX, fenothiocarb + TX, fenpyrad + TX, fenpyroximate + TX, fenpyrazamine + TX, fenson + TX, fentrifanil + TX, flubenzimine + TX, flucycloxuron + TX, fluenetil + TX, fluorbenside + TX, FMC 1137 + TX, formetanate + TX, formetanate hydrochloride + TX, formparanate + TX, gamma-HCH + TX, glyodin + TX, halfenprox + TX, hexadecyl cyclopropanecarboxylate + TX, isocarbophos + TX, jasmolin I + TX, jasmolin II + TX, jodfenphos + TX, lindane + TX, malonoben + TX, mecarbam + TX, mephosfolan + TX, mesulfen + TX, methacrifos + TX, methyl bromide + TX, metolcarb + TX, mexacarbate + TX, milbemycin oxime + TX, mipafox + TX, monocrotophos + TX, morphothion + TX, moxidectin + TX, naled + TX, 4-chloro-2-(2-chloro-2-methyl-propyl)-5-[(6-iodo-3-pyridyl)methoxy]pyridazin-3-one + TX, nifluridide + TX, nikkomycins + TX, nitrilacarb + TX, nitrilacarb 1 :1 zinc chloride complex + TX, omethoate + TX, oxydeprofos + TX, oxydisulfoton + TX, pp'-DDT + TX, parathion + TX, permethrin + TX, phenkapton + TX, phosalone + TX, phosfolan + TX, phosphamidon + TX, polychloroterpenes + TX, polynactins + TX, proclonol + TX, promacyl + TX, propoxur + TX, prothidathion + TX, prothoate + TX, pyrethrin I + TX, pyrethrin II + TX, pyrethrins + TX, pyridaphenthion + TX, pyrimitate + TX, quinalphos + TX, quintiofos + TX, R-1492 + TX, phosglycin + TX, rotenone + TX, schradan + TX, sebufos + TX, selamectin + TX, sophamide + TX, SSI-121 + TX, sulfiram + TX, sulfluramid + TX, sulfotep + TX, sulfur + TX, diflovidazin + TX, tau-fluvalinate + TX, TEPP + TX, terbam + TX, tetradifon + TX, tetrasul + TX, thiafenox + TX, thiocarboxime + TX, thiofanox + TX, thiometon + TX, thioquinox + TX, thuringiensin + TX, triamiphos + TX, triarathene + TX, triazophos + TX, triazuron + TX, trifenofos + TX, trinactin + TX, vamidothion + TX, vaniliprole + TX, bethoxazin + TX, copper dioctanoate + TX, copper sulfate + TX, cybutryne + TX, dichlone + TX, dichlorophen + TX, endothal + TX, fentin + TX, hydrated lime + TX, nabam + TX, quinoclamine + TX, quinonamid + TX, simazine + TX, triphenyltin acetate + TX, triphenyltin hydroxide + TX, crufomate + TX, piperazine + TX, thiophanate + TX, chloralose + TX, fenthion + TX, pyridin-4-amine + TX, strychnine + TX, 1 -hydroxy-1 H-pyridine-2-thione + TX, 4-(quinoxalin- 2-ylamino)benzenesulfonamide + TX, 8-hydroxyquinoline sulfate + TX, bronopol + TX, copper hydroxide + TX, cresol + TX, dipyrithione + TX, dodicin + TX, fenaminosulf + TX, formaldehyde + TX, hydrargaphen + TX, kasugamycin + TX, kasugamycin hydrochloride hydrate + TX, nickel bis(dimethyldithiocarbamate) + TX, nitrapyrin + TX, octhilinone + TX, oxolinic acid + TX, oxytetracycline + TX, potassium hydroxyquinoline sulfate + TX, probenazole + TX, streptomycin + TX, streptomycin sesquisulfate + TX, tecloftalam + TX, thiomersal + TX, Adoxophyes orana GV + TX, Agrobacterium radiobacter + TX, Amblyseius spp. + TX, Anagrapha falcifera NPV + TX, Anagrus atomus + TX, Aphelinus abdominalis + TX, Aphidius colemani + TX, Aphidoletes aphidimyza + TX, Autographa californica NPV + TX, Bacillus sphaericus Neide + TX, Beauveria brongniartii + TX, Chrysoperla carnea + TX, Cryptolaemus montrouzieri + TX, Cydia pomonella GV + TX, Dacnusa sibirica + TX, Diglyphus isaea + TX, Encarsia formosa + TX, Eretmocerus eremicus + TX, Heterorhabditis bacteriophora and H. megidis + TX, Hippodamia convergens + TX, Leptomastix dactylopii + TX, Macrolophus caliginosus + TX, Mamestra brassicae NPV + TX, Metaphycus helvolus + TX, Metarhizium anisopliae var. acridum + TX, Metarhizium anisopliae var. anisopliae + TX, Neodiprion sertifer NPV and N. lecontei NPV + TX, Orius spp. + TX, Paecilomyces fumosoroseus + TX, Phytoseiulus persimilis + TX, Steinernema bibionis + TX, Steinernema carpocapsae + TX, Steinernema feltiae + TX, Steinernema glaseri + TX, Steinernema riobrave + TX, Steinernema riobravis + TX, Steinernema scapterisci + TX, Steinernema spp. + TX, Trichogramma spp. + TX, Typhlodromus occidentalis + TX, Verticillium lecanii + TX, apholate + TX, bisazir + TX, busulfan + TX, dimatif + TX, hemel + TX, hempa + TX, metepa + TX, methiotepa + TX, methyl apholate + TX, morzid + TX, penfluron + TX, tepa + TX, thiohempa + TX, thiotepa + TX, tretamine + TX, uredepa + TX, (E)-dec-5-en-1-yl acetate with (E)-dec-5-en-1-ol + TX, (E)-tridec-4-en-1-yl acetate + TX, (E)-6-methylhept-2- en-4-ol + TX, (E,Z)-tetradeca-4,10-dien-1-yl acetate + TX, (Z)-dodec-7-en-1-yl acetate + TX, (Z)-hexadec-l 1- enal + TX, (Z)-hexadec-11-en-1-yl acetate + TX, (Z)-hexadec-13-en-11-yn-1-yl acetate + TX, (Z)-icos-13-en- 10-one + TX, (Z)-tetradec-7-en-1-al + TX, (Z)-tetradec-9-en-1-ol + TX, (Z)-tetradec-9-en-1-yl acetate + TX, (7E,9Z)-dodeca-7,9-dien-1-yl acetate + TX, (9Z,11 E)-tetradeca-9,11-dien-1-yl acetate + TX, (9Z,12E)- tetradeca-9,12-dien-1-yl acetate + TX, 14-methyloctadec-1-ene + TX, 4-methylnonan-5-ol with 4-methylnonan- 5-one + TX, alpha-multistriatin + TX, brevicomin + TX, codlelure + TX, codlemone + TX, cuelure + TX, disparlure + TX, dodec-8-en-1-yl acetate + TX, dodec-9-en-1-yl acetate + TX, dodeca-8,10-dien-1-yl acetate + TX, dominicalure + TX, ethyl 4-methyloctanoate + TX, eugenol + TX, frontalin + TX, grandlure + TX, grandlure I + TX, grandlure II + TX, grandlure III + TX, grandlure IV + TX, hexalure + TX, ipsdienol + TX, ipsenol + TX, japonilure + TX, lineatin + TX, litlure + TX, looplure + TX, medlure + TX, megatomoic acid + TX, methyl eugenol + TX, muscalure + TX, octadeca-2,13-dien-1-yl acetate + TX, octadeca-3,13-dien-1-yl acetate + TX, orfralure + TX, oryctalure + TX, ostramone + TX, siglure + TX, sordidin + TX, sulcatol + TX, tetradec-11 -en-1 -yl acetate + TX, trimedlure + TX, trimedlure A + TX, trimedlure Bi + TX, trimedlure B2 + TX, trimedlure C + TX, trunc-call + TX, 2-(octylthio)ethanol + TX, butopyronoxyl + TX, butoxy(polypropylene glycol) + TX, dibutyl adipate + TX, dibutyl phthalate + TX, dibutyl succinate + TX, diethyltoluamide + TX, dimethyl carbate + TX, dimethyl phthalate + TX, ethyl hexanediol + TX, hexamide + TX, methoquin-butyl + TX, methylneodecanamide + TX, oxamate + TX, picaridin + TX, 1-dichloro-1 -nitroethane + TX, 1 ,1-dichloro-2,2-bis(4-ethylphenyl)ethane + TX, 1 ,2- dichloropropane with 1 ,3-dichloropropene + TX, 1-bromo-2-chloroethane + TX, 2,2,2-trichloro-1-(3,4-dichloro- phenyl)ethyl acetate + TX, 2,2-dichlorovinyl 2-ethylsulfinylethyl methyl phosphate + TX, 2-(1 ,3-dithiolan-2- yl)phenyl dimethylcarbamate + TX, 2-(2-butoxyethoxy)ethyl thiocyanate + TX, 2-(4,5-dimethyl-1 ,3-dioxolan-2- yl)phenyl methylcarbamate + TX, 2-(4-chloro-3,5-xylyloxy)ethanol + TX, 2-chlorovinyl diethyl phosphate + TX, 2-imidazolidone + TX, 2-isovalerylindan-1 ,3-dione + TX, 2-methyl(prop-2-ynyl)aminophenyl methylcarbamate + TX, 2-thiocyanatoethyl laurate + TX, 3-bromo-1-chloroprop-1-ene + TX, 3-methyl-1-phenylpyrazol-5-yl dimethylcarbamate + TX, 4-methyl(prop-2-ynyl)amino-3,5-xylyl methylcarbamate + TX, 5,5-dimethyl-3- oxocyclohex-1-enyl dimethylcarbamate + TX, acethion + TX, acrylonitrile + TX, aldrin + TX, allosamidin + TX, allyxycarb + TX, alpha-ecdysone + TX, aluminium phosphide + TX, aminocarb + TX, anabasine + TX, athidathion + TX, azamethiphos + TX, Bacillus thuringiensis delta endotoxins + TX, barium hexafluorosilicate + TX, barium polysulfide + TX, barthrin + TX, Bayer 22/190 + TX, Bayer 22408 + TX, beta-cyfluthrin + TX, beta-cypermethrin + TX, bioethanomethrin + TX, biopermethrin + TX, bis(2-chloroethyl) ether + TX, borax + TX, bromfenvinfos + TX, bromo-DDT + TX, bufencarb + TX, butacarb + TX, butathiofos + TX, butonate + TX, calcium arsenate + TX, calcium cyanide + TX, carbon disulfide + TX, carbon tetrachloride + TX, cartap hydrochloride + TX, cevadine + TX, chlorbicyclen + TX, chlordane + TX, chlordecone + TX, chloroform + TX, chloropicrin + TX, chlorphoxim + TX, chlorprazophos + TX, cis-resmethrin + TX, cismethrin + TX, clocythrin + TX, copper acetoarsenite + TX, copper arsenate + TX, copper oleate + TX, coumithoate + TX, cryolite + TX, CS 708 + TX, cyanofenphos + TX, cyanophos + TX, cyclethrin + TX, cythioate + TX, d-tetramethrin + TX, DAEP + TX, dazomet + TX, decarbofuran + TX, diamidafos + TX, dicapthon + TX, dichlofenthion + TX, dicresyl + TX, dicyclanil + TX, dieldrin + TX, diethyl 5-methylpyrazol-3-yl phosphate + TX, dilor + TX, dimefluthrin + TX, dimetan + TX, dimethrin + TX, dimethylvinphos + TX, dimetilan + TX, dinoprop + TX, dinosam + TX, dinoseb + TX, diofenolan + TX, dioxabenzofos + TX, dithicrofos + TX, DSP + TX, ecdysterone + TX, El 1642 + TX, EMPC + TX, EPBP + TX, etaphos + TX, ethiofencarb + TX, ethyl formate + TX, ethylene dibromide + TX, ethylene dichloride + TX, ethylene oxide + TX, EXD + TX, fenchlorphos + TX, fenethacarb + TX, fenitrothion + TX, fenoxacrim + TX, fenpirithrin + TX, fensulfothion + TX, fenthion-ethyl + TX, flucofuron + TX, fosmethilan + TX, fospirate + TX, fosthietan + TX, furathiocarb + TX, furethrin + TX, guazatine + TX, guazatine acetates + TX, sodium tetrathiocarbonate + TX, halfenprox + TX, HCH + TX, HEOD + TX, heptachlor + TX, heterophos + TX, HHDN + TX, hydrogen cyanide + TX, hyquincarb + TX, IPSP + TX, isazofos + TX, isobenzan + TX, isodrin + TX, isofenphos + TX, isolane + TX, isoprothiolane + TX, isoxathion + TX, juvenile hormone I + TX, juvenile hormone II + TX, juvenile hormone III + TX, kelevan + TX, kinoprene + TX, lead arsenate + TX, leptophos + TX, lirimfos + TX, lythidathion + TX, m-cumenyl methylcarbamate + TX, magnesium phosphide + TX, mazidox + TX, mecarphon + TX, menazon + TX, mercurous chloride + TX, mesulfenfos + TX, metam + TX, metam- potassium + TX, metam-sodium + TX, methanesulfonyl fluoride + TX, methocrotophos + TX, methoprene + TX, methothrin + TX, methoxychlor + TX, methyl isothiocyanate + TX, methylchloroform + TX, methylene chloride + TX, metoxadiazone + TX, mirex + TX, naftalofos + TX, naphthalene + TX, NC-170 + TX, nicotine + TX, nicotine sulfate + TX, nithiazine + TX, nornicotine + TX, 0-5-dichloro-4-iodophenyl O-ethyl ethylphosphonothioate + TX, O,O-diethyl 0-4-methyl-2-oxo-2H-chromen-7-yl phosphorothioate + TX, 0,0- diethyl 0-6-methyl-2-propylpyrimidin-4-yl phosphorothioate + TX, 0,0,0',0'-tetrapropyl dithiopyrophosphate + TX, oleic acid + TX, para-dichlorobenzene + TX, parathion-methyl + TX, pentachlorophenol + TX, pentachlorophenyl laurate + TX, PH 60-38 + TX, phenkapton + TX, phosnichlor + TX, phosphine + TX, phoximmethyl + TX, pirimetaphos + TX, polychlorodicyclopentadiene isomers + TX, potassium arsenite + TX, potassium thiocyanate + TX, precocene I + TX, precocene II + TX, precocene III + TX, primidophos + TX, profluthrin + TX, promecarb + TX, prothiofos + TX, pyrazophos + TX, pyresmethrin + TX, quassia + TX, quinalphos-methyl + TX, quinothion + TX, rafoxanide + TX, resmethrin + TX, rotenone + TX, kadethrin + TX, ryania + TX, ryanodine + TX, sabadilla) + TX, schradan + TX, sebufos + TX, SI-0009 + TX, thiapronil + TX, sodium arsenite + TX, sodium cyanide + TX, sodium fluoride + TX, sodium hexafluorosilicate + TX, sodium pentachlorophenoxide + TX, sodium selenate + TX, sodium thiocyanate + TX, sulcofuron + TX, sulcofuron- sodium + TX, sulfuryl fluoride + TX, sulprofos + TX, tar oils + TX, tazimcarb + TX, TDE + TX, tebupirimfos + TX, temephos + TX, terallethrin + TX, tetrachloroethane + TX, thicrofos + TX, thiocyclam + TX, thiocyclam hydrogen oxalate + TX, thionazin + TX, thiosultap + TX, thiosultap-sodium + TX, tralomethrin + TX, transpermethrin + TX, triazamate + TX, trichlormetaphos-3 + TX, trichloronat + TX, trimethacarb + TX, tolprocarb + TX, triclopyricarb + TX, triprene + TX, veratridine + TX, veratrine + TX, XMC + TX, zetamethrin + TX, zinc phosphide + TX, zolaprofos + TX, and meperfluthrin + TX, tetramethylfluthrin + TX, bis(tributyltin) oxide + TX, bromoacetamide + TX, ferric phosphate + TX, niclosamide-olamine + TX, tributyltin oxide + TX, pyrimorph + TX, trifenmorph + TX, 1 ,2-dibromo-3-chloropropane + TX, 1 ,3-dichloropropene + TX, 3,4- dichlorotetrahydrothiophene 1 ,1-dioxide + TX, 3-(4-chlorophenyl)-5-methylrhodanine + TX, 5-methyl-6-thioxo- 1 ,3,5-thiadiazinan-3-ylacetic acid + TX, 6-isopentenylaminopurine + TX, 2-fluoro-N-(3-methoxyphenyl)-9H- purin-6-amine + TX, benclothiaz + TX, cytokinins + TX, DCIP + TX, furfural + TX, isamidofos + TX, kinetin + TX, Myrothecium verrucaria composition + TX, tetrachlorothiophene + TX, xylenols + TX, zeatin + TX, potassium ethylxanthate + TX, acibenzolar + TX, acibenzolar-S-methyl + TX, Reynoutria sachalinensis extract + TX, alpha-chlorohydrin + TX, antu + TX, barium carbonate + TX, bisthiosemi + TX, brodifacoum + TX, bromadiolone + TX, bromethalin + TX, chlorophacinone + TX, cholecalciferol + TX, coumachlor + TX, coumafuryl + TX, coumatetralyl + TX, crimidine + TX, difenacoum + TX, difethialone + TX, diphacinone + TX, ergocalciferol + TX, flocoumafen + TX, fluoroacetamide + TX, flupropadine + TX, flupropadine hydrochloride + TX, norbormide + TX, phosacetim + TX, phosphorus + TX, pindone + TX, pyrinuron + TX, scilliroside + TX, sodium fluoroacetate + TX, thallium sulfate + TX, warfarin + TX, 2-(2-butoxyethoxy)ethyl piperonylate + TX, 5- (1 ,3-benzodioxol-5-yl)-3-hexylcyclohex-2-enone + TX, farnesol with nerolidol + TX, verbutin + TX, MGK 264 + TX, piperonyl butoxide + TX, piprotal + TX, propyl isomer + TX, S421 + TX, sesamex + TX, sesasmolin + TX, sulfoxide + TX, anthraquinone + TX, copper naphthenate + TX, copper oxychloride + TX, dicyclopentadiene + TX, thiram + TX, zinc naphthenate + TX, ziram + TX, imanin + TX, ribavirin + TX, mercuric oxide + TX, thiophanate-methyl + TX, azaconazole + TX, bitertanol + TX, bromuconazole + TX, cyproconazole + TX, difenoconazole + TX, diniconazole + TX, epoxiconazole + TX, fenbuconazole + TX, fluquinconazole + TX, flusilazole + TX, flutriafol + TX, furametpyr + TX, hexaconazole + TX, imazalil + TX, imibenconazole + TX, ipconazole + TX, metconazole + TX, myclobutanil + TX, paclobutrazole + TX, pefurazoate + TX, penconazole + TX, proth ioconazole + TX, pyrifenox + TX, prochloraz + TX, propiconazole + TX, pyrisoxazole + TX, - simeconazole + TX, tebuconazole + TX, tetraconazole + TX, triadimefon + TX, triadimenol + TX, triflumizole + TX, triticonazole + TX, ancymidol + TX, fenarimol + TX, nuarimol + TX, bupirimate + TX, dimethirimol + TX, ethirimol + TX, dodemorph + TX, fenpropidin + TX, fenpropimorph + TX, spiroxamine + TX, tridemorph + TX, cyprodinil + TX, mepanipyrim + TX, pyrimethanil + TX, fenpiclonil + TX, fludioxonil + TX, benalaxyl + TX, furalaxyl + TX, metalaxyl + TX, R-metalaxyl + TX, ofurace + TX, oxadixyl + TX, carbendazim + TX, debacarb + TX, fuberidazole + TX, thiabendazole + TX, chlozolinate + TX, dichlozoline + TX, myclozoline + TX, procymidone + TX, vinclozoline + TX, boscalid + TX, carboxin + TX, fenfuram + TX, flutolanil + TX, mepronil + TX, oxycarboxin + TX, penthiopyrad + TX, thifluzamide + TX, dodine + TX, iminoctadine + TX, azoxystrobin + TX, dimoxystrobin + TX, enestroburin + TX, fenaminstrobin + TX, flufenoxystrobin + TX, fluoxastrobin + TX, kresoxim-methyl + TX, metominostrobin + TX, trifloxystrobin + TX, orysastrobin + TX, picoxystrobin + TX, pyraclostrobin + TX, pyrametostrobin + TX, pyraoxystrobin + TX, ferbam + TX, mancozeb + TX, maneb + TX, metiram + TX, propineb + TX, zineb + TX, captafol + TX, captan + TX, fluoroimide + TX, folpet + TX, tolylfluanid + TX, bordeaux mixture + TX, copper oxide + TX, mancopper + TX, oxine-copper + TX, nitrothal-isopropyl + TX, edifenphos + TX, iprobenphos + TX, phosdiphen + TX, tolclofos-methyl + TX, anilazine + TX, benthiavalicarb + TX, blasticidin-S + TX, chloroneb + TX, chlorothalonil + TX, cyflufenamid + TX, cymoxanil + TX, cyclobutrifluram + TX, diclocymet + TX, diclomezine + TX, dicloran + TX, diethofencarb + TX, dimethomorph + TX, flumorph + TX, dithianon + TX, ethaboxam + TX, etridiazole + TX, famoxadone + TX, fenamidone + TX, fenoxanil + TX, ferimzone + TX, fluazinam + TX, fluopicolide + TX, flusulfamide + TX, fluxapyroxad + TX, fenhexamid + TX, fosetyl-aluminium + TX, hymexazol + TX, iprovalicarb + TX, cyazofamid + TX, methasulfocarb + TX, metrafenone + TX, pencycuron + TX, phthalide + TX, polyoxins + TX, propamocarb + TX, pyribencarb + TX, proquinazid + TX, pyroquilon + TX, pyriofenone + TX, quinoxyfen + TX, quintozene + TX, tiadinil + TX, triazoxide + TX, tricyclazole + TX, triforine + TX, validamycin + TX, valifenalate + TX, zoxamide + TX, mandipropamid + TX, flubeneteram + TX, isopyrazam + TX, sedaxane + TX, benzovindiflupyr + TX, pydiflumetofen + TX, 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid (3',4',5'-trifluoro-biphenyl- 2-yl)-amide + TX, isoflucypram + TX, isotianil + TX, dipymetitrone + TX, 6-ethyl-5,7-dioxo- pyrrolo[4,5][1 ,4]dithiino[1 ,2-c]isothiazole-3-carbonitrile + TX, 2-(difluoromethyl)-N-[3-ethyl-1 ,1-dimethyl-indan- 4-yl]pyridine-3-carboxamide + TX, 4-(2,6-difluorophenyl)-6-methyl-5-phenyl-pyridazine-3-carbonitrile + TX, (R)-3-(difluoromethyl)-1-methyl-N-[1 ,1 ,3-trimethylindan-4-yl]pyrazole-4-carboxamide + TX, 4-(2-bromo-4- fluoro-phenyl)-N-(2-chloro-6-fluoro-phenyl)-2,5-dimethyl-pyrazol-3-amine + TX, 4- (2- bromo- 4- fluorophenyl) - N- (2- chloro- 6- fluorophenyl) - 1 , 3- dimethyl- 1 H- pyrazol- 5- amine + TX, fluindapyr + TX, coumethoxystrobin (jiaxiangjunzhi) + TX, Ivbenmixianan + TX, dichlobentiazox + TX, mandestrobin + TX, 3-(4,4-difluoro-3,4- dihydro-3,3-dimethylisoquinolin-1-yl)quinolone + TX, 2-[2-fluoro-6-[(8-fluoro-2-methyl-3- quinolyl)oxy]phenyl]propan-2-ol + TX, oxathiapiprolin + TX, tert-butyl N-[6-[[[(1-methyltetrazol-5-yl)-phenyl- methylene]amino]oxymethyl]-2-pyridyl]carbamate + TX, pyraziflumid + TX, inpyrfluxam + TX, trolprocarb + TX, mefentrifluconazole + TX, ipfentrifluconazole+ TX, 2-(difluoromethyl)-N-[(3R)-3-ethyl-1 ,1-dimethyl-indan-4- yl]pyridine-3-carboxamide + TX, N'-(2,5-dimethyl-4-phenoxy-phenyl)-N-ethyl-N-methyl-formamidine + TX, N'- [4-(4,5-dichlorothiazol-2-yl)oxy-2,5-dimethyl-phenyl]-N-ethyl-N-methyl-formamidine + TX, [2-[3-[2-[1-[2-[3,5- bis(difluoromethyl)pyrazol-1-yl]acetyl]-4-piperidyl]thiazol-4-yl]-4,5-dihydroisoxazol-5-yl]-3-chloro-phenyl] methanesulfonate + TX, but-3-ynyl N-[6-[[(Z)-[(1-methyltetrazol-5-yl)-phenyl-methylene]amino]oxymethyl]-2- pyridyl]carbamate + TX, methyl N-[[5-[4-(2,4-dimethylphenyl)triazol-2-yl]-2-methyl-phenyl]methyl]carbamate + TX, 3-chloro-6-methyl-5-phenyl-4-(2,4,6-trifluorophenyl)pyridazine + TX, pyridachlometyl + TX, 3- (difluoromethyl)-1-methyl-N-[1 ,1 ,3-trimethylindan-4-yl]pyrazole-4-carboxamide + TX, 1 -[2-[[1-(4- chlorophenyl)pyrazol-3-yl]oxymethyl]-3-methyl-phenyl]-4-methyl-tetrazol-5-one + TX, 1 -methyl-4-[3-methyl-2- [[2-methyl-4-(3,4,5-trimethylpyrazol-1-yl)phenoxy]methyl]phenyl]tetrazol-5-one + TX, aminopyrifen + TX, ametoctradin + TX, amisulbrom + TX, penflufen + TX, (Z,2E)-5-[1-(4-chlorophenyl)pyrazol-3-yl]oxy-2- methoxyimino-N,3-dimethyl-pent-3-enamide + TX, florylpicoxamid + TX, fenpicoxamid + TX, tebufloquin + TX, ipflufenoquin + TX, quinofumelin + TX, isofetamid + TX, N-[2-[2,4-dichloro-phenoxy]phenyl]-3-(difluoromethyl)- 1 -methyl-pyrazole-4-carboxamide + TX, N-[2-[2-chloro-4-(trifluoromethyl)phenoxy]phenyl]-3-(difluoromethyl)-
1-methyl-pyrazole-4-carboxamide + TX, benzothiostrobin + TX, phenamacril + TX, 5-amino-1 ,3,4-thiadiazole-
2-thiol zinc salt (2:1) + TX, fluopyram + TX, flutianil + TX, fluopimomide + TX, pyrapropoyne + TX, picarbutrazox + TX, 2-(difluoromethyl)-N-(3-ethyl-1 ,1-dimethyl-indan-4-yl)pyridine-3-carboxamide + TX, 2-(difluoromethyl)-N- ((3R)-1 ,1 ,3- trimethylindan-4-yl)pyridine-3-carboxamide + TX, 4-[[6-[2-(2,4-difluorophenyl)-1 , 1 -difluoro-2- hydroxy-3-(1 ,2,4-triazol-1-yl)propyl]-3-pyridyl]oxy]benzonitrile + TX, metyltetraprole + TX, a- (1 ,1- dimethylethyl)- a- [4'- (trifluoromethoxy) [1 , 1 '-biphenyl]-4-yl] -5- pyrimidinemethanol + TX, fluoxapiprolin + TX, enoxastrobin + TX, 4-[[6-[2-(2,4-difluorophenyl)-1 ,1 -difluoro-2-hydroxy-3-(1 ,2,4-triazol-1-yl)propyl]-3- pyridyl]oxy] benzonitrile + TX, 4-[[6-[2-(2,4-difluorophenyl)-1 ,1-difluoro-2-hydroxy-3-(5-sulfanyl-1 ,2,4-triazol-1 - yl)propyl]-3-pyridyl]oxy] benzonitrile + TX, 4-[[6-[2-(2,4-difluorophenyl)-1 ,1-difluoro-2-hydroxy-3-(5-thioxo-4H- 1 ,2,4-triazol-1-yl)propyl]-3-pyridyl]oxy]benzonitrile + TX, trinexapac + TX, coumoxystrobin + TX, zhongshengmycin + TX, thiodiazole copper + TX, zinc thiazole + TX, amectotractin + TX, iprodione + TX, N-octyl-N'-[2-(octylamino)ethyl]ethane-1 ,2-diamine + TX; N'-[5-bromo-2-methyl-6-[(1 S)-1-methyl-2- propoxy-ethoxy]-3-pyridyl]-N-ethyl-N-methyl-formamidine + TX, N'-[5-bromo-2-methyl-6-[(1 R)-1-methyl-2- propoxy-ethoxy]-3-pyridyl]-N-ethyl-N-methyl-formamidine + TX, N'-[5-bromo-2-methyl-6-(1 -methyl-2-propoxy- ethoxy)-3-pyridyl]-N-ethyl-N-methyl-formamidine + TX, N'-[5-chloro-2-methyl-6-(1-methyl-2-propoxy-ethoxy)- 3-pyridyl]-N-ethyl-N-methyl-formamidine + TX, N'-[5-bromo-2-methyl-6-(1 -methyl-2-propoxy-ethoxy)-3- pyridyl]-N-isopropyl-N-methyl-formamidine + TX (these compounds may be prepared from the methods described in WO2015/155075); N'-[5-bromo-2-methyl-6-(2-propoxypropoxy)-3-pyridyl]-N-ethyl-N-methyl- formamidine + TX (this compound may be prepared from the methods described in IPCOM000249876D); N- isopropyl-N’-[5-methoxy-2-methyl-4-(2,2,2-trifluoro-1-hydroxy-1-phenyl-ethyl)phenyl]-N-methyl-formamidine+ TX, N’-[4-(1-cyclopropyl-2,2,2-trifluoro-1-hydroxy-ethyl)-5-methoxy-2-methyl-phenyl]-N-isopropyl-N-methyl- formamidine + TX (these compounds may be prepared from the methods described in WO2018/228896); N- ethyl-N’-[5-methoxy-2-methyl-4-[2-trifluoromethyl)oxetan-2-yl]phenyl]-N-methyl-formamidine + TX, N-ethyl-N’- [5-methoxy-2-methyl-4-[2-trifuoromethyl)tetrahydrofuran-2-yl]phenyl]-N-methyl-formamidine + TX (these compounds may be prepared from the methods described in WO2019/110427); N-[(1 R)-1-benzyl-3-chloro-1- methyl-but-3-enyl]-8-fluoro-quinoline-3-carboxamide + TX, N-[(1 S)-1 -benzyl-3-chloro-1 -methyl-but-3-enyl]-8- fluoro-quinoline-3-carboxamide + TX, N-[(1 R)-1-benzyl-3,3,3-trifluoro-1-methyl-propyl]-8-fluoro-quinoline-3- carboxamide + TX, N-[(1 S)-1-benzyl-3,3,3-trifluoro-1 -methyl-propyl]-8-fluoro-quinoline-3-carboxamide + TX, N-[(1 R)-1-benzyl-1 ,3-dimethyl-butyl]-7,8-difluoro-quinoline-3-carboxamide + TX, N-[(1 S)-1-benzyl-1 ,3- dimethyl-butyl]-7,8-difluoro-quinoline-3-carboxamide + TX, 8-fluoro-N-[(1 R)-1-[(3-fluorophenyl)methyl]-1 ,3- dimethyl-butyl]quinoline-3-carboxamide + TX, 8-fluoro-N-[(1 S)-1 -[(3-fluorophenyl)methyl]-1 ,3-dimethyl- butyl]quinoline-3-carboxamide + TX, N-[(1 R)-1-benzyl-1 ,3-dimethyl-butyl]-8-fluoro-quinoline-3-carboxamide + TX, N-[(1 S)-1-benzyl-1 ,3-dimethyl-butyl]-8-fluoro-quinoline-3-carboxamide + TX, N-((1 R)-1-benzyl-3-chloro-1- methyl-but-3-enyl)-8-fluoro-quinoline-3-carboxamide + TX, N-((1 S)-1 -benzyl-3-chloro-1 -methyl-but-3-enyl)-8- fluoro-quinoline-3-carboxamide + TX (these compounds may be prepared from the methods described in WO2017/153380); 1-(6,7-dimethylpyrazolo[1 ,5-a]pyridin-3-yl)-4,4,5-trifluoro-3,3-dimethyl-isoquinoline + TX, 1-(6,7-dimethylpyrazolo[1 ,5-a]pyridin-3-yl)-4,4,6-trifluoro-3,3-dimethyl-isoquinoline + TX, 4,4-difluoro-3,3- dimethyl-1-(6-methylpyrazolo[1 ,5-a]pyridin-3-yl)isoquinoline + TX, 4,4-difluoro-3,3-dimethyl-1-(7- methylpyrazolo[1 ,5-a]pyridin-3-yl)isoquinoline + TX, 1-(6-chloro-7-methyl-pyrazolo[1 ,5-a]pyridin-3-yl)-4,4- difluoro-3,3-dimethyl-isoquinoline + TX (these compounds may be prepared from the methods described in WO2017/025510); 1-(4,5-dimethylbenzimidazol-1-yl)-4,4,5-trifluoro-3,3-dimethyl-isoquinoline + TX, 1-(4,5- dimethylbenzimidazol-1-yl)-4,4-difluoro-3,3-dimethyl-isoquinoline + TX, 6-chloro-4,4-difluoro-3,3-dimethyl-1- (4-methylbenzimidazol-1 -y I) isoq u i n o I ine + TX, 4,4-difluoro-1 -(5-fluoro-4-methyl-benzimidazol-1 -y l)-3 , 3- dimethyl-isoquinoline + TX, 3-(4,4-difluoro-3,3-dimethyl-1-isoquinolyl)-7,8-dihydro-6H- cyclopenta[e]benzimidazole + TX (these compounds may be prepared from the methods described in WO2016/156085); N-methoxy-N-[[4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl]phenyl]methyl]cyclopropanecarboxamide + TX, N,2-dimethoxy-N-[[4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl]phenyl]methyl]propanamide + TX, N-ethyl-2-methyl-N-[[4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl]phenyl]methyl]propanamide + TX, 1-methoxy-3-methyl-1-[[4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl]phenyl]methyl]urea + TX, 1 ,3-dimethoxy-1-[[4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]phenyl]methyl]urea + TX, 3-ethyl-1-methoxy-1-[[4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]phenyl]methyl]urea + TX, N-[[4-[5- (trifluoromethyl)-l ,2,4-oxadiazol-3-yl]phenyl]methyl]propanamide + TX, 4,4-dimethyl-2-[[4-[5-(trifluoromethyl)-
1 .2.4-oxadiazol-3-yl]phenyl]methyl]isoxazolidin-3-one + TX, 5,5-dimethyl-2-[[4-[5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl]phenyl]methyl]isoxazolidin-3-one + TX, ethyl 1 -[[4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl]phenyl]methyl]pyrazole-4-carboxylate + TX, N,N-dimethyl-1-[[4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl]phenyl]methyl]-1 ,2,4-triazol-3-amine + TX. The compounds in this paragraph may be prepared from the methods described in WO2017/055473, WO2017/055469, WO2017/093348 and WO2017/118689; 2-[6-(4- chlorophenoxy)-2-(trifluoromethyl)-3-pyridyl]-1-(1 ,2,4-triazol-1-yl)propan-2-ol + TX (this compound may be prepared from the methods described in WO2017/029179); 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)-3- pyridyl]-1-(1 ,2,4-triazol-1-yl)propan-2-ol + TX (this compound may be prepared from the methods described in WO2017/029179); 3-[2-(1-chlorocyclopropyl)-3-(2-fluorophenyl)-2-hydroxy-propyl]imidazole-4-carbonitrile + TX (this compound may be prepared from the methods described in WO2016/156290); 3-[2-(1- chlorocyclopropyl)-3-(3-chloro-2-fluoro-phenyl)-2-hydroxy-propyl]imidazole-4-carbonitrile + TX (this compound may be prepared from the methods described in WO2016/156290); (4- phenoxyphenyl)methyl 2-amino-6-methyl-pyridine-3-carboxylate + TX (this compound may be prepared from the methods described in WO2014/006945); 2,6-Dimethyl-1 H,5H-[1 ,4]dithiino[2,3-c:5,6-c']dipyrrole- 1 ,3,5,7(2H,6H)-tetrone + TX (this compound may be prepared from the methods described in WO2011/138281); N-methyl-4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]benzenecarbothioamide + TX; N- methyl-4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]benzamide + TX; (Z,2E)-5-[1-(2,4-dichlorophenyl)pyrazol-3- yl]oxy-2-methoxyimino-N,3-dimethyl-pent-3-enamide + TX (this compound may be prepared from the methods described in WO2018/153707); N'-(2-chloro-5-methyl-4-phenoxy-phenyl)-N-ethyl-N-methyl-formamidine + TX; N'-[2-chloro-4-(2-fluorophenoxy)-5-methyl-phenyl]-N-ethyl-N-methyl-formamidine + TX (this compound may be prepared from the methods described in WO2016/202742); 2-(difluoromethyl)-N-[(3S)-3-ethyl-1 ,1-dimethyl- indan-4-yl]pyridine-3-carboxamide + TX (this compound may be prepared from the methods described in WO2014/095675); (5-methyl-2-pyridyl)-[4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]phenyl]methanone + TX, (3- methylisoxazol-5-yl)-[4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]phenyl]methanone + TX (these compounds may be prepared from the methods described in WO2017/220485); 2-oxo-N-propyl-2-[4-[5-(trifluoromethyl)-
1 .2.4-oxadiazol-3-yl]phenyl]acetamide + TX (this compound may be prepared from the methods described in WO2018/065414); ethyl 1-[[5-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]-2-thienyl]methyl]pyrazole-4- carboxylate + TX (this compound may be prepared from the methods described in WO2018/158365) ; 2,2- difluoro-N-methyl-2-[4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]phenyl]acetamide + TX, N-[(E)- methoxyiminomethyl]-4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]benzamide + TX, N-[(Z)- methoxyiminomethyl]-4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]benzamide + TX, N-[N-methoxy-C-methyl- carbonimidoyl]-4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]benzamide + TX (these compounds may be prepared from the methods described in WO2018/202428), chloroinconazide + TX, flumetylsulforim + TX, fluoxytioconazole + TX, flufenoxadiazam +TX, metarylpicoxamid +TX.
The references in brackets behind the active ingredients, e.g. [3878-19-1] refer to the Chemical Abstracts Registry number. The above described mixing partners are known. Where the active ingredients are included in "The Pesticide Manual" [The Pesticide Manual - A World Compendium; Thirteenth Edition; Editor: C. D. S. TomLin; The British Crop Protection Council], they are described therein underthe entry number given in round brackets hereinabove for the particular compound; for example, the compound "abamectin" is described under entry number (1). Where "[CCN]" is added hereinabove to the particular compound, the compound in question is included in the "Compendium of Pesticide Common Names", which is accessible on the internet [A. Wood; Compendium of Pesticide Common Names, Copyright © 1995-2004]; for example, the compound "acetoprole" is described under the internet address http://www.alanwood.net/pesticides/acetoprole.html.
Most of the active ingredients described above are referred to hereinabove by a so-called "common name", the relevant "ISO common name" or another "common name" being used in individual cases. If the designation is not a "common name", the nature of the designation used instead is given in round brackets for the particular compound; in that case, the IUPAC name, the lUPAC/Chemical Abstracts name, a "chemical name", a "traditional name", a "compound name" or a "development code" is used or, if neither one of those designations nor a "common name" is used, an "alternative name" is employed. “CAS Reg. No” means the Chemical Abstracts Registry Number.
The active ingredient mixture of the compound selected from compounds of (I), (l-A), (I-A1), (I-A2), (I-A3), (I- A4), (I-A5), (l-B), (l-C), or (l-D), or compounds selected from compounds listed in Tables A-1 to A-26, or compounds listed in Table P (below), is preferably in a mixing ratio of from 100:1 to 1 :100, 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, and still more especially from 5:1 to 1 :5 Those mixing ratios are by weight.
The mixtures as described above can be used in a method for controlling pests, which comprises applying a composition comprising a mixture 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 practised on the human or animal body.
The mixtures comprising a compound selected from compounds of formula (I), (l-A), (I-A1), (I-A2), (I-A3), (I- A4), (I-A5), (l-B), (l-C), or (l-D), or compounds selected from compounds listed in Tables A-1 to A-26, or compounds listed in Table P (below), 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 composed 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 sequential manner, i.e. one after the other with a reasonably short period, such as a few hours or days. The order of applying a compound selected from compounds of (I), (l-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (l-B), (l-C), or (l-D), or compounds selected from compounds listed in Tables A-1 to A-26, or compounds listed in Table P (below), and the active ingredients) as described above, is not essential for working the present invention.
The 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.
The 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). These processes for the preparation of the compositions and the use of the compounds (I) for the preparation of these compositions are also a subject of the invention.
Another aspect of the invention is related to the use of a compound of formula (I) according to the invention or of a preferred individual compound as defined herein, of a composition comprising at least one compound of formula (I) or at least one preferred individual compound as defined herein, or of a fungicidal or insecticidal mixture comprising at least one compound of formula (I) or at least one preferred individual compound as defined herein, in admixture with other fungicides or insecticides as described above, for controlling or preventing infestation of plants, e.g. useful plants such as crop plants, propagation material thereof, e.g. seeds, harvested crops, e.g. harvested food crops, or non-living materials by insects or by phytopathogenic microorganisms, preferably fungal organisms.
A further aspect of invention is related to a method of controlling or preventing an infestation of plants, e.g. useful plants such as crop plants, propagation material thereof, e.g. seeds, harvested crops, e.g. harvested food crops, or of non-living materials by phytopathogenic or spoilage microorganisms or organisms potentially harmful to man, especially fungal organisms, which comprises the application of a compound of formula (I) according to the invention or of a preferred individual compound as defined herein as active ingredient to the plants, to parts of the plants or to the locus thereof, to the propagation material thereof, or to any part of the non-living materials.
Controlling or preventing means reducing infestation by insects or by phytopathogenic or spoilage microorganisms or organisms potentially harmful to man, especially fungal organisms, to such a level that an improvement is demonstrated.
A preferred method of controlling or preventing an infestation of crop plants by phytopathogenic microorganisms, especially fungal organisms, or insects which comprises the application of a compound of formula (I) according to the invention, or an agrochemical composition which contains at least one compound of formula (I), is foliar application. The frequency of application and the rate of application will depend on the risk of infestation by the corresponding pathogen or insect. However, the compounds of formula (I) according to the invention can also penetrate the plant through the roots via the soil (systemic action) by drenching the locus of the plant with a liquid formulation, or by applying the compounds in solid form to the soil, e.g. in granular form (soil application). In crops of water rice such granulates can be applied to the flooded rice field. The compounds of formula (I) may also be applied to seeds (coating) by impregnating the seeds or tubers either with a liquid formulation of the fungicide or coating them with a solid formulation. A formulation, e.g. a composition containing the compound of formula (I) according to the invention and, if desired, a solid or liquid adjuvant or monomers for encapsulating the compound of formula (I), may be prepared in a known manner, typically by intimately mixing and/or grinding the compound with extenders, for example solvents, solid carriers and, optionally, surface active compounds (surfactants).
Advantageous rates of application are normally from 5g to 2kg of active ingredient (a.i.) per hectare (ha), preferably from 10g to I kg a.i./ha, most preferably from 20g to 600g a.i./ha. When used as seed drenching agent, convenient dosages are from 10mg to 1 g of active substance per kg of seeds.
The term “g a.i./ha” as used herein refer to the application rate given in gram [g] of active ingredient [a.i.] per unit of surface [ha]. The unit hectare (symbol ha) is the metric unit of area that equals a square with 100 m side (1 hm2) or 10,000 square meters. Hectare is a commonly used unit of area in the metric system.
When the combinations of the present invention are used for treating seed, rates of 0.001 to 50 g of a compound of formula (I) per kg of seed, preferably from 0.01 to 10g per kg of seed are generally sufficient.
Suitably, a composition comprising a compound of formula (I) according to the present invention is applied either preventative, meaning prior to disease development or curative, meaning after disease development.
The compositions of the invention may be employed in any conventional form, for example in the form of a twin pack, a powder for dry seed treatment (DS), an emulsion for seed treatment (ES), a flowable concentrate for seed treatment (FS), a solution for seed treatment (LS), a water dispersible powder for seed treatment (WS), a capsule suspension for seed treatment (CF), a gel for seed treatment (GF), an emulsion concentrate (EC), a suspension concentrate (SC), a suspo-emulsion (SE), a capsule suspension (CS), a water dispersible granule (WG), an emulsifiable granule (EG), an emulsion, water in oil (EG), an emulsion, oil in water (EW), a micro-emulsion (ME), an oil dispersion (OD), an oil miscible flowable (OF), an oil miscible liquid (OL), a soluble concentrate (SL), an ultra-low volume suspension (SU), an ultra-low volume liquid (UL), a technical concentrate (TK), a dispersible concentrate (DC), a wettable powder (WP) or any technically feasible formulation in combination with agriculturally acceptable adjuvants.
Such compositions may be produced in conventional manner, e.g. by mixing the active ingredients with appropriate formulation inerts (diluents, solvents, fillers and optionally other formulating ingredients such as surfactants, biocides, anti-freeze, stickers, thickeners and compounds that provide adjuvancy effects). Also conventional slow release formulations may be employed where long lasting efficacy is intended. Particularly formulations to be applied in spraying forms, such as water dispersible concentrates (e.g. EC, SC, DC, OD, SE, EW, EO and the like), wettable powders and granules, may contain surfactants such as wetting and dispersing agents and other compounds that provide adjuvancy effects, e.g. the condensation product of formaldehyde with naphthalene sulphonate, an alkylarylsulphonate, a lignin sulphonate, a fatty alkyl sulphate, and ethoxylated alkylphenol and an ethoxylated fatty alcohol.
A seed dressing formulation is applied in a manner known per se to the seeds employing the combination of the invention and a diluent in suitable seed dressing formulation form, e.g. as an aqueous suspension or in a dry powder form having good adherence to the seeds. Such seed dressing formulations are known in the art. Seed dressing formulations may contain the single active ingredients or the combination of active ingredients in encapsulated form, e.g., as slow release capsules or microcapsules.
In general, the formulations include from 0.01 to 90% by weight of active agent, from 0 to 20% agriculturally acceptable surfactant and 10 to 99.99% solid or liquid formulation inerts and adjuvant(s), the active agent consisting of at least the compound of formula (I) according to the invention optionally together with other active agents, particularly microbiocides or conservatives or the like. Concentrated forms of compositions generally contain in between about 2 and 80%, preferably between about 5 and 70% by weight of active agent. Application forms of formulation may for example contain from 0.01 to 20% by weight, preferably from 0.01 to 5% by weight of active agent. Whereas commercial products will preferably be formulated as concentrates, the end user will normally employ diluted formulations.
Whereas it is preferred to formulate commercial products as concentrates, the end user will normally use 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 %, preferably 15 to 90 %
Granules: active ingredient: 0.1 to 30 %, preferably 0.1 to 15 % solid carrier: 99.5 to 70 %, preferably 97 to 85 % The disclosure in the present application makes available each and every combination of embodiments disclosed herein.
The compounds according to the following Tables A-1 to A-26 may 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 any of Tables A-1 to A-26 below, the presence of one or more possible asymmetric carbon atoms in a compound of formula (I) according to the invention means that the compounds may occur in chiral isomeric forms, i.e., enantiomeric or diastereomeric forms.
Table A: This table discloses 75 compounds of formula (la) according to the invention wherein: w
Figure imgf000077_0001
as defined below:
Figure imgf000077_0002
Figure imgf000078_0001
Figure imgf000079_0001
The following compounds represent specific compounds of formula (la) as described in Tables A-1 to A-26 wherein G is as defined in Table A. For instance, the compound A-1.G1 represents a compound of formula (la) wherein R2, R4, R5, R6, R7, R8, R9, R10 and B2 are as defined in Table A-1 and G is G1 as defined in Table A.
Table A-1 : This table provides 75 compounds A-1.G1 to A-1.G75 of formula (la) wherein R2, R4, R5, R6, R7, R8, R9, R10 are H, B2 is CH, and G is as defined in Table A. For example, compound A-1 ,G3 has the following structure:
Figure imgf000080_0001
Compound A-1 ,G3
Table A-2: This table provides 75 compounds A-2.G1 to A-2.G75 of formula (la) wherein R2 is CH3, R4, R5, R6, R7, R8, R9, R10 are H, B2 is CH, and G is as defined in Table A. For example, compound A-2.G2 has the following structure:
Figure imgf000080_0002
Compound A-2.G2
Table A-3: This table provides 75 compounds A-3.G1 to A-3.G75 of formula (la) wherein R2 is F, R4, R5, R6, R7, R8, R9, R10 are H, B2 is CH, and G is as defined in Table A.
Table A-4: This table provides 75 compounds A-4.G1 to A-4.G75 of formula (la) wherein R2 is Cl, R4, R5, R6, R7, R8, R9, R10 are H, B2 is CH, and G is as defined in Table A. Table A-5: This table provides 75 compounds A-5.G1 to A-5.G75 of formula (la) wherein R2 is cyclopropyl, R4, R5, R6, R7, R8, R9, R10 are H, B2 is CH, and G is as defined in Table A.
Table A-6: This table provides 75 compounds A-6.G1 to A-6.G75 of formula (la) wherein R2 is COCH3, R4, R5, R6, R7, R8, R9, R10 are H, B2 is CH, and G is as defined in Table A.
Table A-7: This table provides 75 compounds A-7.G1 to A-7.G75 of formula (la) wherein R2 is C=N(OCH3)CH3, R4, R5, R6, R7, R8, R9, R10 are H, B2 is CH, and G is as defined in Table A.
Table A-8: This table provides 75 compounds A-8.G1 to A-8.G75 of formula (la) wherein R2, R5, R6, R7, R8, R9, R10 are H, R4 is CH3, B2 is CH, and G is as defined in Table A. For example, compound A-8.G32 has the following structure:
Figure imgf000080_0003
Compound A-8.G32 Table A-9: This table provides 75 compounds A-9.G1 to A-9.G75 of formula (la) wherein R5, R6, R7, R8, R9, R10 are H, R2 and R4 are CH3, B2 is CH, and G is as defined in Table A.
Table A-10: This table provides 75 compounds A-10.G1 to A-10.G75 of formula (la) wherein R5, R6, R7, R8, R9, R10 are H, R2 and R4 are CH3, B2 is N, and G is as defined in Table A.
Table A-11 : This table provides 75 racem/c-compounds A-11 ,G1 to A-11 .G75 of formula (la) wherein R5, R6, R8, R9, R10 are H, R2 and R7 are CH3, B2 is CH, and G is as defined in Table A. In this table, the pyrazole substituent and the R7 CH3 substituent have a syn-relationship to each other. For example, compound rac-A- 11 ,G2 has the following structure
Figure imgf000081_0001
Compound rac-A-11 ,G2
Table A-12: This table provides 75 racem/c-compounds A-12.G1 to A-12.G75 of formula (la) wherein R5, R6, R8, R9, R10 are H, R2 is Cl, R7 is CH3, B2 is CH and G is as defined in Table A. In this table, the pyrazole substituent and the R7 CH3 substituent have a syn-relationship to each other. For example, compound rac-A- 12.G67 has the following structure;
Figure imgf000081_0002
Compound rac-A-12.67
Table A-13: This table provides 75 compounds A-13.G1 to A-13.G75 of formula (la) wherein R5, R6, R8, R9, R10 are H, R2, R7, and R4 are CH3, B2 is CH, and G is as defined in Table A.
Table A-14: This table provides 75 racem/c-compounds A-14.G1 to A-14.G75 of formula (la) wherein R5, R6, R8, R9, R10 are H, R2 and R7 are CH3, B2 is C-Br, and G is as defined in Table A. In this table, the pyrazole substituent and the R7 CH3 substituent have a syn-relationship to each other.
Table A-15: This table provides 75 racem/c-compounds A-15.G1 to A-15.G75 of formula (la) wherein R5, R6, R8, R9, R10 are H, R2 and R7 are CH3, B2 is C-CN, and G is as defined in Table A. In this table, the pyrazole substituent and the R7 CH3 substituent have a syn-relationship to each other. Table A-16: This table provides 75 /'acem/c-compounds A-16.G1 to A-16.G75 of formula (la) wherein R5, R6, R8, R9, R10 are H, R2 is Cl, R7 is CH3, B2 is C-CI, and G is as defined in Table A. In this table, the pyrazole substituent and the R7 CH3 substituent have a syn-relationship to each other.
Table A-17: This table provides 75 /'acem/c-compounds A-17.G1 to A-17.G75 of formula (la) wherein R5, R6, R8, R9, R10 are H, R2 is Cl, R7 is CH3, B2 is C-CN, and G is as defined in Table A. In this table, the pyrazole substituent and the R7 CH3 substituent have a syn-relationship to each other. For example, compound rac-A- 17.G53 has the following structure;
Figure imgf000082_0001
Compound rac-k-Vl .G53
Table A-18: This table provides 15 compounds A-18.G1 to A-18.G15 of formula (la) wherein R4, R5, R6, R8, R9, and R10 are H, R2 and R7 are CH3, B2 is N and G is as defined in Table A.
Table A-19: This table provides 15 racem/c-compounds A-19.G1 to A-19.G15 of formula (la) wherein R4, R5, R6, R8, and R10 are H, R9 is OCH3, R2 and R7 are CH3, B2 is C-CI, and G is as defined in Table A. In this table, the pyrazole substituent and the R7 CH3 substituent have a syn-relationship to each other. For example, compound rac-A-19.G15 has the following structure
Figure imgf000082_0002
compound rac-A-19.G15
Table A-20: This table provides 15 /'acem/c-compounds A-20.G1 to A-20.G15 of formula (la) wherein R4, R5, R6, R8, and R10 are H, R9 is OCH3, R2 and R7 are CH3, B2 is C-H, and G is as defined in Table A. In this table, the pyrazole substituent and the R7 CH3 substituent have a syn-relationship to each other.
Table A-21 : This table provides 15 /'acem/c-compounds A-21 ,G1 to A-21 ,G15 of formula (la) wherein R4, R5, R6, R8, and R10 are H, R9 is Br, R2 and R7 are CH3, B2 is C-H, and G is as defined in Table A. In this table, the pyrazole substituent and the R7 CH3 substituent have a syn-relationship to each other.
Table A-22: This table provides 15 /'acem/c-compounds A-22.G1 to A-22.G15 of formula (la) wherein R4, R5, R6, R8, and R10 are H, R9 is Cl, R2 and R7 are CH3, B2 is C-H, and G is as defined in Table A. In this table, the pyrazole substituent and the R7 CH3 substituent have a syn-relationship to each other. Table A-23: This table provides 15 racem/c-compounds A-23.G1 to A-23.G15 of formula (la) wherein R4, R5, R6, R8, and R10 are H, R9 is CN, R2 and R7 are CH3, B2 is C-H, and G is as defined in Table A. In this table, the pyrazole substituent and the R7 CH3 substituent have a syn-relationship to each other.
Table A-24: This table provides 15 /'acem/c-compounds A-24.G1 to A-24.G15 of formula (la) wherein R4, R5, R6, R8, and R9 are H, R10 is Br, R2 and R7 are CH3, B2 is C-H, and G is as defined in Table A. In this table, the pyrazole substituent and the R7 CH3 substituent have a syn-relationship to each other.
Table A-25: This table provides 15 /'acem/c-compounds A-25.G1 to A-25.G15 of formula (la) wherein R4, R5, R6, R8, and R9 are H, R10 is Cl, R2 and R7 are CH3, B2 is C-H, and G is as defined in Table A. In this table, the pyrazole substituent and the R7 CH3 substituent have a syn-relationship to each other.
Table A-26: This table provides 15 /'acem/c-compounds A-26.G1 to A-26.G15 of formula (la) wherein R4, R5, R6, R8, and R9 are H, R10 is CN, R2 and R7 are CH3, B2 is C-H, and G is as defined in Table A. In this table, the pyrazole substituent and the R7 CH3 substituent have a syn-relationship to each other. For example, compound A-26.G6 has the following structure:
Figure imgf000083_0001
compound rac-/\-2Q.GQ
EXAMPLES
The Examples which follow serve to illustrate the invention and are not meant in any way to limit the invention.
The compounds of the invention can be distinguished from known compounds by virtue of greater efficacy at low application rates, which can be verified by a person skilled in the art using the experimental procedures outlined in the Examples, using lower application rates if necessary, for example 60 ppm, 20 ppm or 2 ppm.
Compounds of formula (I) may possess any number of benefits including, inter alia, advantageous levels of biological activity for protecting plants against diseases that are caused by fungi or superior properties for use as agrochemical active ingredients (for example, greater biological activity, an advantageous spectrum of activity, an increased safety profile (including improved crop tolerance), improved physico-chemical properties, or increased biodegradability). Throughout this description, temperatures are given in degrees Celsius and “m.p.” means melting point. LC/MS means Liquid Chromatography Mass Spectroscopy and the description of the apparatus, and the methods is as follows.
1H NMR and 19F NMR measurements were recorded on a Bruker 400MHz spectrometer, chemical shifts are given in ppm relevant to a TMS (1H) and CFCI3 (19F) standard. Spectra measured in deuterated solvents as indicated. Either one of the LCMS methods below was used to characterize the compounds. 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)-.
LC-MS Method A: Spectra were recorded on a mass spectrometer from Waters (SQD, SQDII Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive and negative ions, Capillary: 3.00 kV, Cone range: 30 V, Extractor: 2.00 V, Source Temperature: 150°C, Desolvation Temperature: 350°C, Cone Gas Flow: 50 l/h, Desolvation Gas Flow: 650 l/h, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: binary pump, heated column compartment, diode-array detector and ELSD detector. Column: Waters UPLC HSS T3, 1.8 pm, 30 x 2.1 mm, Temperature: 60°C, DAD Wavelength range (nm): 210 to 500, Solvent Gradient: A = water + 5% MeOH + 0.05% HCOOH, B = Acetonitrile + 0.05% HCOOH, gradient: 10-100% B in 1.2 min; Flow (ml/min): 0.85.
LC-MS Method B: Spectra were recorded on a ACQUITY Mass Spectrometer from Waters Corporations (SQD or SQDII Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive or negative ions, Capillary: 3.0 kV, Cone: 30V, Extractor: 3.00 V, Source Temperature: 150°C, Desolvation Temperature: 400°C, Cone Gas Flow: 60 L/hr, Desolvation Gas Flow: 700 L/hr, Mass range: 140 to 800 Da) and an ACQUITY UPLC from Waters Corporations with solvent degasser, binary pump, heated column compartment and diode-array detector. Column: Waters UPLC HSS T3, 1.8 pm, 30 x 2.1 mm, Temp: 60°C, DAD Wavelength range (nm): 210 to 400, Solvent Gradient: A = Water/Methanol 9:1 + 0.1 % formic acid, B= Acetonitrile + 0.1 % formic acid, gradient: 0-100% B in 2.5 min; Flow (ml/min) 0.75.
LC-MS Method C: Spectra were recorded on a Mass Spectrometer from Waters (Acquity QDa Mass Spectrometer) equipped with an electrospray source (Polarity: Positive and Negative Polarity Switch), Capillary: 0.8 kV, Cone range: 25 V, Extractor: V (No extractor voltage for Qda detector) Source Temperature: 120°C, Desolvation Temperature: 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. Column: Acquity UPLC HSS T3 C18, 1 .8 pm, 30 x 2.1 mm, Temp: 40°C, DAD Wavelength range (nm): 200 to 400, Solvent Gradient: A = water + 5% Acetonitrile + 0.1 % HCOOH, B= Acetonitrile + 0.05 % HCOOH: gradient: 0 min 10% B; 0.-0.2 min 10-50% B; 0.2-0.6 min 50-100% B; 0.6-1 .3 min 100% B; 1 .3-1 .4 min 100-10% B; 1 .4-1 .6 min 10% B; Flow (mL/min) 0.6.
LC-MS Method D: 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. Column: Acquity UPLC HSS T3 C18, 1 .8 pm, 30 x 2.1 mm, Temp: 40°C, DAD Wavelength range (nm): 200 to 400, Solvent Gradient: A = water + 5% Acetonitrile + 0.1 % HCOOH, B= Acetonitrile + 0.05 % HCOOH: gradient: 0 min 10% B; 0.-0.2 min 10-50% B; 0.2-0.6 min 50-100% B; 0.6-1 .3 min 100% B; 1.3-1 .4 min 100- 10% B; 1.4-1 .6 min 10% B; Flow (mL/min) 0.6.
LC-MS Method E: Spectra were recorded on a Mass Spectrometer from Agilent Technologies (6410 Triple Quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive or negative ions, MS2 Scan, Capillary: 4.00 kV, Fragmentor: 100 V, Desolvation Temperature: 350°C, Gas Flow: 11 L/min, Nebulizer Gas: 45 psi, Mass range: 110 to 1000 Da) and a 1200 Series HPLC from Agilent: quaternary pump, heated column compartment and VWD detector. Column: KINETEX EVO C18, 2.6 pm, 50 x 4.6 mm, Temp: 40 °C, Detector VWD Wavelength: 254 nm, Solvent Gradient: A = water + 5% Acetonitrile + 0.1 % HCOOH, B= Acetonitrile + 0.1 % HCOOH: gradient: 0 min 10% B, 90%A; 0.9-1 .8 min 100% B; 1.8-2.2 min 100-10% B; 2.2- 2.5 min 10%B; Flow (mL/min) 1.8.
Formulation Examples
Wettable powders a) b) c) active ingredients 25 % 50 % 75 % sodium lignosulfonate 5 % 5 % - sodium lauryl sulfate 3 % - 5 % sodium diisobutylnaphthalenesulfonate 6 % 10 % phenol polyethylene glycol ether (7-8 mol ethylene oxide) - 2 % - highly dispersed silicic acid 5 % 10 % 10 % Kaolin 62 % 27 % -
The combination is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording wettable powders that can be diluted with water to give suspensions of the desired concentration.
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 %
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 dodecylbenzene sulfonate 3 % castor oil polyglycol ether (35 mol of ethylene oxide) 4 %
Cyclohexanone 30 % xylene mixture 50 %
Emulsions of any required dilution, which can be used in plant protection, can be obtained from this concentrate by dilution with water.
Dusts a) b) c)
Active ingredients 5 % 6 % 4 %
Talcum 95 % -
Kaolin 94 % - mineral filler 96 %
Ready-for-use dusts are obtained by mixing the combination with the carrier and grinding the mixture in a suitable mill. Such dusts can also be used for dry dressings for seed.
Extruder granules Active ingredients 15 % sodium lignosulfonate 2 % carboxymethylcellulose 1 %
Kaolin 82 %
The combination is mixed and ground with the adjuvants, and the mixture is moistened with water. The mixture is extruded and then dried in a stream of air.
Coated granules
Active ingredients 8% polyethylene glycol (mol. wt. 200) 3 %
Kaolin 89 %
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.
Suspension concentrate active ingredients 40 % propylene glycol 10 % nonylphenol polyethylene glycol ether (15 mol of ethylene oxide) 6 %
Sodium lignosulfonate 10 % carboxymethylcellulose 1 % silicone oil (in the form of a 75 % emulsion in water) 1 %
Water 32 %
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. Using such dilutions, living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or immersion.
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 %
The finely ground combination is intimately mixed with the adjuvants, giving a flowable concentrate from which solutions of any desired dilution can be obtained by dilution with water, that can be used directly for seed treatment. Using such dilutions, living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or immersion.
Slow Release Capsule Suspension
28 parts of the combination are mixed with 2 parts of an aromatic solvent and 7 parts of toluene diisocyanate/polymethylene-polyphenylisocyanate-mixture (8:1). This mixture is emulsified in a mixture of 1.2 parts of polyvinylalcohol, 0.05 parts of a defoamer and 51 .6 parts of water until the desired particle size is achieved. To this emulsion a mixture of 2.8 parts 1 ,6-diaminohexane in 5.3 parts of water is added. The mixture is agitated until the polymerization reaction is completed. The obtained capsule suspension is stabilized by adding 0.25 parts of a thickener and 3 parts of a dispersing agent. The capsule suspension formulation contains 28% of the active ingredients. The medium capsule diameter is 8-15 microns. The resulting formulation is applied to seeds as an aqueous suspension in an apparatus suitable for that purpose.
Formulation types include an emulsion concentrate (EC), a suspension concentrate (SC), a suspo-emulsion (SE), a capsule suspension (CS), a water dispersible granule (WG), an emulsifiable granule (EG), an emulsion, water in oil (EO), an emulsion, oil in water (EW), a micro-emulsion (ME), an oil dispersion (OD), an oil miscible flowable (OF), an oil miscible liquid (OL), a soluble concentrate (SL), an ultra-low volume suspension (SU), an ultra-low volume liquid (UL), a technical concentrate (TK), a dispersible concentrate (DC), a wettable powder (WP), a soluble granule (SG) or any technically feasible formulation in combination with agriculturally acceptable adjuvants.
ABBREVIATIONS
CDCh deuterated chloroform
DABCO 1 ,4-diazabicyclo[2.2.2]octane, also known as triethylenediamine or TEDA
DCC dicyclohexyl carbodiimide
DMF dimethylformamide
DMSO dimethyl sulfoxide DMSO-d6 deuterated Dimethyl sulfoxide
EDC 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide
EtsN triethylamine
EtOAc ethylacetate
HATU 1-[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium-3-oxide-hexafluoro phosphate
HCI hydrochloric acid h/hrs hour/hours
LC-MS Liquid Chromatography Mass Spectrometry (LC-MS or LCMS) rh relative humidity rt room temperature
Rt retention time ssp. subspecies
T3P propanephosphonic acid anhydride, also called 2,4,6-tripropyl-1 , 3, 5, 2,4,6- trioxatriphosphorinane-2,4,6-trioxide
THF tetrahydrofuran
PREPARATORY EXAMPLES
The compounds of formula (I) according to the invention may be prepared using the synthetic techniques described both above and below.
“Mp” means melting point in °C. Free radicals represent methyl groups. 1H NMR and 19F NMR measurements were recorded on a Bruker 400MHz spectrometer (or 600MHz as indicated), chemical shifts are given in ppm relevant to a TMS (1H) and CFCI3 (19F) standard. Spectra measured in deuterated solvents as indicated. Either one of the LC-MS methods below was used to characterize the compounds. 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)’.
Example P1 : Synthesis of [5-(3,5-difluoro-2-pyridyl)isoxazol-3-yl1-[rac-(1 S,4S)-4-(1 ,5-dimethylpyrazol-4-yl)-1- methyl-3,4-dihydro-1 H-isoquinolin-2-yl1methanone (Compound P-6, Table P)
Figure imgf000088_0001
(Compound P-6, Table P)
Step 1 : Preparation of 3,5-difluoro-N-methoxy-N-methyl-pyridine-2-carboxamide
Figure imgf000089_0001
A suspension of 3,5-difluoropyridine-2-carboxylic acid (CAS: [745784-04-7], 2.0 g, 11.94 mmol) and N,O- dimethylhydroxylamine hydrochloride (1.248 g, 12.54 mmol) in EtOAc (47 mL) was treated 1 - propanephosphonic anhydride 50 % mass in EtOAc (14.22 mL, 23.89 mmol) followed by the N,N- diisopropyethylamine (6.26 mL, 35.83 mmol), under an argon atmosphere. The resulting reaction mixture was stirred for 18 hr at rt under argon and then diluted with aqueous Na2COs, water and EtOAc. The aqueous phase was extracted with EtOAc, and the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo afford the title compound, which was used without further purification.
LC-MS (Method A): 203 [M+H], Rt: 0.56 min
1H NMR (400 MHz, CDCI3) 6 ppm: 3.41 (br s, 3 H) 3.62 (br s, 3 H) 7.30 - 7.33 (dd, 1 H) 8.39 (d, J=2.18 Hz, 1 H)
Step 2: Preparation of 1-(3,5-difluoro-2-pyridyl)ethenone
Figure imgf000089_0002
Methyl magnesium bromide solution (7.9 mL, 23.59 mmol) was added dropwise to a cooled pale brown solution (0-5°C) of 3,5-difluoro-N-methoxy-N-methyl-pyridine-2-carboxamide (2.38 g, 11 .79 mmol) in THF (35 mL) under argon. The resulting suspension was allowed to reach rt and stirred for 30 minutes under an argon atmosphere. The reaction mixture was slowly quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the title compound.
LC-MS (Method A): 158 [M+H], Rt: 0.62 min
1H NMR (400 MHz, CDCb) 6 ppm: 2.71 (d, J=1 .09 Hz, 3 H) 7.29 - 7.36 (m, 1 H) 8.40 - 8.44 (d, 1 H)
Step 3: Preparation of ethyl 4-(3,5-difluoro-2-pyridyl)-2,4-dioxo-butanoate
Figure imgf000089_0003
A solution of 1-(3,5-difluoro-2-pyridyl)ethanone (1.79 g, 11.4 mmol) in toluene (11.4 mL) was treated with diethyl oxalate (1 .72 mL, 12.5 mmol) followed by potassium tert-butoxide (1 .58 g, 13.7 mmol) at rt. The resulting suspension was stirred for 17 hours at rt. The reaction mixture was then slowly quenched with aqueous HCI 2N and extracted twice EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product which was purified by flash chromatography eluting with EtOAc/cyclohexane to afford the title compound.
LC-MS (Method A): 258 [M+H], Rt: 0.88 min
1H NMR (400 MHz, CDCb) 6 ppm: 1 .38 - 1 .48 (t, 3 H) 4.43 (q, 3=7.27 Hz, 2 H) 7.38 (ddd, J=10.35, 7.99, 2.36 Hz, 1 H) 7.51 (s, 1 H) 8.49 (d, J=2.18 Hz, 1 H) 14.23 - 14.68 (br s, 1 H)
Step 4: Preparation of ethyl 5-(3,5-difluoro-2-pyridyl)isoxazole-3-carboxylate
Figure imgf000090_0001
A sample of hydroxylamine hydrochloride (0.153 g, 2.18 mmol) was added to a stirred pale brown suspension of ethyl 4-(3,5-difluoro-2-pyridyl)-2,4-dioxo-butanoate (0.374 g, 1.45 mmol) in ethanol (5 mL), and the resulting suspension stirred for 22 hours at 50°C. The reaction mixture was concentrated in vacuo and the residue partitioned between aqueous saturated Na2COs and EtOAc. The aqueous phase was extracted with EtOAc, and the combined organic phases were dried over anhydrous Na2SC>4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography over silica gel eluting with EtOAc/cyclohexane to yield the title compound.
LC-MS (Method A): 255 [M+H], Rt: 0.89 min
1H NMR (400 MHz, CDCb) 6 ppm: 1.45 - 1.51 (t, 3 H) 4.48 - 4.55 (q, 2 H) 7.27 - 7.29 (d, 1 H) 7.43 (ddd, J=10.08, 7.72, 2.18 Hz, 1 H) 8.55 (d, J=2.54 Hz, 1 H)
Step 5: Preparation of 5-(3,5-difluoro-2-pyridyl)isoxazole-3-carboxylic acid
Figure imgf000090_0002
A solution of ethyl 5-(3,5-difluoro-2-pyridyl)isoxazole-3-carboxylate (0.1 11 g, 0.437 mmol) in THF (2 mL) and H2O (0.5 mL) was treated with lithium hydroxide mono hydrate (0.027 g, 0.65 mmol) was then added and the reaction mixture was stirred for 19 hours at rt. After this time, the mixture was acidified with aqueous HCI 1 N and extracted with EtOAc (X3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield the title compound as a white solid.
LC-MS (Method A): 227 [M+H], Rt: 0.52 min
Step 6: Preparation of (1 ,5-dimethylpyrazol-4-yD-phenyl-methanol
Figure imgf000091_0001
A sample of 1 -methyl- 1 H-pyrazole-4-carbaldehyde (25 g, 201 .39 mmol) dissolved in THF (400 mL) was treated with phenyl magnesium bromide 1 molar in THF (228 mL, 227.57 mmol) was added dropwise at 0-5°C under argon atmosphere for 15 minutes. After the addition, the ice-bath was removed, and the white suspension was stirred at room temperature for 3hr. The reaction mixture was poured into saturated ammonium chloride solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SC>4, and concentrated in vacuo to afford the crude product as a colorless oil. The crude material was purified over SiC>2, eluting with EtOAc:EtOH 3:1/Cyclohexane gradient to afford the desired product (1 -methylpyrazol-4-yl)- phenyl-methanol as a colorless oil.
LCMS (Method A): m/z (M+H) 203, retention time 0.68 min
1H NMR (400 MHz, CDCb) 6 ppm: 2.23 (s, 3 H) 2.28 (d, J=4.00 Hz, 1 H) 3.76 (s, 3 H) 5.80 (d, J=3.63 Hz, 1 H) 7.22 (s, 1 H) 7.27 - 7.32 (m, 1 H) 7.33 - 7.44 (m, 4 H)
Step 7: Preparation of 2-(1 ,5-dimethylpyrazol-4-yl)-2-phenyl-acetonitrile
Figure imgf000091_0002
A round-bottom flask, equipped with a magnetic stirrer bar and condenser, was charged with (1 -methylpyrazol- 4-yl)-phenyl-methanol (4.5 g, 22 mmol) and DCM (45 mL). Then, lithium carbonate (0.33 g, 4.4 mmol), trimethylsilyl cyanide (10 g, 13 mL, 100 mmol) and Iodine (10 g, 40 mmol) were added successively at rt. The reaction mixture was stirred at 35°C for 1 hr. The reaction mixture was then cooled to rt and poured into saturated sodium thiosulphate (250 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were washed with brine, dried over Na2SC>4, and concentrated in vacuo to afford the crude product which was purified by combi flash (silica gel, gradient: EtOAC in cyclohexane) to afford desired title compound as a yellow oil.
LCMS (Method A): m/z (M+H) 212, retention time 0.82 min
1H NMR (400 MHz, CDCb-d) 6 ppm: 7.46 - 7.28 (m, 6H), 5.05 (s, 1 H), 3.78 (s, 3H), 2.18 (s, 3H)
Step 8: Preparation of 2-(1 ,5-dimethylpyrazol-4-yl)-2-phenyl-ethanamine (Option A)
Figure imgf000092_0001
A 750 mL-3-necked flask, equipped with a magnetic stirrer bar, was charged with 2-(1-methylpyrazol-4-yl)-2- phenyl-propanenitrile (11 g, 52.06 mmol) and THF (160 mL). To the yellow solution borane dimethyl sulfide complex (12.62 g, 15.8 mL, 156.2 mmol) was added dropwise at rt under argon atmosphere and the resulting colorless reaction mixture was stirred at 65°C for 2 hrs. The reaction mixture was cooled to 0°C before adding hydrochloric acid (23 g, 34.71 mL, 208.2 mmol) dropwise (strong gas evolution) and the reaction mixture was stirred at 65°C for 1 hour and allowed to stand overnight at rt. The mixture was diluted with water and treated with NaOH 6M (to pH 12). The mixture extracted twice with EtOAc and the combined organic layers were washed with brine, dried over Na2SC>4, and concentrated in vacuo to give the title compound as a yellow oil which was used without further purification in the next step.
LCMS (Method A): m/z (M+H) 216, retention time 0.60 min
1H NMR (400 MHz, CDCb) 6 ppm: 2.09 (s, 3 H) 3.20 (dd, J=7.45, 2.00 Hz, 2 H) 3.75 (s, 3 H) 3.79 (t, J=7.27 Hz, 1 H) 7.16 - 7.25 (m, 3 H) 7.26 - 7.33 (m, 2 H) 7.42 (s, 1 H)
Preparation of 2-(1 ,5-dimethylpyrazol-4-yl)-2-phenyl-ethanamine (Option B)
Option B-Step A: Preparation of 1 ,5-dimethyl-4-(2-nitro-1-phenyl-ethyl)pyrazole
Figure imgf000092_0002
A solution of 4-iodo-1 ,5-dimethyl-pyrazole (2.6 g, 12 mmol) in THF (40 mL) was degassed with argon and the treated with isopropylmagnesiumchlorid-lithiumchloride-complex (Turbo-Grignard, 1 .3 mol/L in THF, 12 mL, 16 mmol) at 0-5°C and under argon. The white suspension obtained was stirred for 20 min at 0-5°C and then treated with a solution of [(E)-2-nitrovinyl]benzene (1 .5 g, 9.9 mmol) in THF (5 mL) at 0-5°C. This mixture was stirred for 40 min at 0-5°C, and then 1 hr at rt, upon which LCMS analysis showed reaction completion. The reaction mixture was quenched with ice water and acidified to pH 5 by the addition of 2M HCI aqueous solution. The aqueous phase was extracted 3x with EtOAc then the combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by chromatography over silica gel, eluting with a cyclohexane + 0-40 EA/EtOH 3:1 gradient, to afford the title compound
LC-MS (Method A): 246 [M+H], Rt: 0.84 min 1H NMR (400 MHz, CDCI3) 6 ppm: 7.40 - 7.44 (m, 1 H) 7.30 - 7.36 (m, 2 H) 7.23 - 7.29 (m, 3 H) 4.88 (d, J=1 .1 Hz, 1 H) 4.86 (s, 1 H) 4.74 (d, J=7.6 Hz, 1 H) 3.77 (s, 3 H) 2.15 (s, 3 H)
The two enantiomers of the title compound were separated by chiral column using the following method: Sepiatec Prep SFC M5, Column: Daicel CHIRALPAK® IB, 5Dm, 2.0 cm x 25cm, Mobile phase: A: CO2 B: IPA isocratic: 4 % B, Backpressure: 150 bar, GLS: -, Flow rate: 90 ml/min, Detection: UV 220 nm, Sample concentration: 1.6g in 25 ml ACN/MeOH (1/1), Injection: 500pl
Option B-Step B: Preparation of 2-(1 ,5-dimethylpyrazol-4-yl)-2-phenyl-ethanamine
Figure imgf000093_0001
A solution of 1 ,5-dimethyl-4-(2-nitro-1-phenyl-ethyl)pyrazole (35 mg, 0.1427 mmol) in dry ethanol (3 mL) was treated with platinum 1 % vanadium 2 % on activated charcoal (Evonik Noblyst® P8078, 0.00014 mmol, 0.0070 g). The mixture was degassed and hydrogenated at 50°C and 10 bar H2 for 18 hours. The reaction mixture was filtered through a pad of celite and evaporated to obtain the title compound. Spectral data as for Example 1 , step 8, vide supra.
Step 9: Preparation of methyl N-[2-(1 ,5-dimethylpyrazol-4-yl)-2-phenyl-ethyl1carbamate
Figure imgf000093_0002
A three necked flask, equipped with a mechanical stirrer, was charged with 2-(1 ,5-dimethylpyrazol-4-yl)-2- phenyl-ethanamine (3.5 g, 16 mmol, sample from Option A, step 8), ethyl acetate (65 mL) and TEA (6.8 mL, 49 mmol). Then methyl chloroformate (1 .5 mL, 20 mmol) were added dropwise at 0°C under argon atmosphere during 30min and the mixture was stirred at rt for 1 h. The reaction mixture was poured into water (800mL) and extracted with EtOAc (2X150mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude material was purified by flash chromatography (80g SiO2, eluting with an EtOAc/Cyclohexane gradient) to afford methyl N-[2-(1 ,5-dimethylpyrazol-4-yl)-2-phenyl- ethyl]carbamate.
LC-MS (Method A): retention time 0.76 min, 274 (M+H)
1H NMR (400 MHz, CDCI3) 6 ppm: 2.03-2.13 (m, 3H) 3.62-3.74 (m, 5 H) 3.77 (s, 3H) 3.94-4.05 (m, 1 H) 4.72 (br s, 1 H) 7.21 -7.26 (m, 3H) 7.27-7.34 (m, 2H) 7.38 (s, 1 H) Step 10: Preparation of methyl rac-(1 S,4S)-4-(1 ,5-dimethylpyrazol-4-yl)-1-methyl-3,4-dihydro-1 H- isoquinoline-2-carboxylate
Figure imgf000094_0001
A one necked round bottom flask, equipped with a magnetic stirrer bar, was charged with methyl N-[2-(1 ,5- dimethylpyrazol-4-yl)-2-phenyl-ethyl]carbamate (2.0 g, 7.3 mmol), hydrochloric acid (cone. 37 mL, 450 mmol) and acetaldehyde (0.83 mL, 15 mmol). The reaction mixture was stirred at rt for 2h. The reaction mixture was slowly poured into water (500mL) neutralized with NaHCOs in portions slowly (strong gas evolution) to pH 8. The mixture was extracted with EtOAc (3X50mL), and the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by chromatography to afford rac-methyl (1 S,4S)-4-(1 ,5-dimethylpyrazol-4-yl)-1 -methyl-3,4-dihydro-1 H-isoquinoline-2-carboxylateas a single syn-diastereomer by 1H NMR.
LC-MS (Method A): retention time 0.87 min, 300 (M+H)
1H NMR (400 MHz, CDCI3) 6 ppm: 1.56 (d, J=6.90 Hz, 3 H); 2.18 (br s, 3 H); 3.02 - 3.27 (m, 1 H); 3.76 (br s, 3 H); 3.83 (s, 3 H); 3.97 - 4.09 (m, 1 H); 4.09 - 4.37 (m, 1 H); 5.18 - 5.45 (m, 1 H); 6.86 - 7.02 (m, 1 H); 7.04 - 7.24 (m, 4 H).
Step 11 : Preparation of rac-(1 S,4S)-4-(1 ,5-dimethylpyrazol-4-yl)-1-methyl-1 ,2,3,4-tetrahydroisoquinoline
Figure imgf000094_0002
A WOmLone necked round bottom flask, equipped with a magnetic stirrer bar, was charged with rac-methyl (1 S,4S)-4-(1 ,5-dimethylpyrazol-4-yl)-1-methyl-3,4-dihydro-1 H-isoquinoline-2-carboxylate (1.3 g, 4.1 mmol) 1 ,2-dichloroethane (21 mL) and iodotrimethylsilane (1.7 mL, 12 mmol). The reaction mixture was stirred at 60°C for 1 h under argon atmosphere. The reaction was cooled to rt then 10% aqueous HCI (22 mL) was added to the reaction under ice cooling. The organic solvent was removed in vacuo and the aqueous residue was adjusted with 10% aqueous NaOH to pH 8 and then was extracted with DCM. The combined organic layers were dried over MgSC , filtered, and concentrated in vacuo to give rac-(1S,4S)-4-(1 ,5-dimethylpyrazol-4-yl)-1- methyl-1 ,2,3,4-tetrahydroisoquinoline which was pure enough to use without further purification. LC-MS (Method A): retention time 0.35 min, 242 (M+H)
1H NMR (600 MHz, CDCb) 6 ppm: 1.86 (d, J=6.9 Hz, 3 H) 2.23 (s, 3 H) 3.27 (dd, J=12.5, 10.8 Hz, 1 H) 3.59 (dd, J=12.8, 5.6 Hz, 1 H) 3.83 (s, 3H) 4.58 (dd, J=10.6, 5.4 Hz, 1 H) 4.80 (q, J=6.8 Hz, 1 H) 7.00 (d, J=7.8 Hz, 1 H) 7.11 (s, 1 H) 7.16 (d, J=7.6 Hz, 1 H) 7.18 - 7.22 (m, 1 H) 7.25 - 7.28 (m, 1 H)
Step 12: Synthesis of [5-(3,5-difluoro-2-pyridyl)isoxazol-3-yl]-[rac-(1 S,4S)-4-(1 ,5-dimethylpyrazol-4-yl)-1- methyl-3,4-dihydro-1 H-isoquinolin-2-yl]methanone (Compound P-6, Table P)
A solution of 5-(3,5-difluoro-2-pyridyl)isoxazole-3-carboxylic acid (0.040 g, 0.18 mmol) and rac-(1 S,4S)-4-(1 ,5- dimethylpyrazol-4-yl)-1-methyl-1 ,2,3,4-tetrahydroisoquinoline (0.043 g, 0.18 mmol) in EtOAc (1 mL) were treated with 1-propanephosphonic anhydride 50 % mass in EtOAc (0.21 mL, 0.36 mmol) followed by the N,N- diisopropylethylamine (0.093 mL, 0.53 mmol), under argon. The reaction mixture was stirred for 1 hr at rt under argon diluted with EtOAc and quenched with aqueous NaHCOs. The organic phase was separated, and the aqueous phase back extracted with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography eluting with EtOAc/cyclohexane to afford the title compound.
LC-MS (Method A): 450 [M+H], Rt: 0.98 min
1H NMR (400 MHz, CDCI3) 6 ppm: 1 .65 - 1 .78 (d, 3 H) 2.20 - 2.37 (s, 3 H) 3.20 - 3.55 (m, 1 H) 3.80 - 3.89 (d, 3 H) 4.15 - 4.89 (m, 2 H) 5.62 - 5.94 (m, 1 H) 7.00 - 7.09 (m, 1 H) 7.09 - 7.30 (m, 5 H) 7.35 - 7.49 (m, 1 H) 8.55 (d, J=2.18 Hz, 1 H)
Example P2: Preparation of [5-(3,5-difluoro-2-pyridyl)-1 ,3,4-thiadiazol-2-yl]-[4-(1 ,5-dimethylpyrazol-4-yl)-3,4- dihydro-1 H-isoquinolin-2-yl1methanone (Compound P-7, Table P)
Figure imgf000095_0001
(Compound P-7, Table P)
Step 1 : Preparation of 3,5-difluoropyridine-2-carbonyl chloride
Figure imgf000095_0002
A solution of 3,5-difluoropyridine-2-carboxylic acid (CAS: [745784-04-7], 1 g, 6.28 mmol) in EtOAc (20 mL) was treated with oxalyl chloride (0.830 mL, 9.42 mmol) and then a catalytic quantity (3-4 drops) of DMF under argon atmosphere. The reaction mixture was stirred at rt for 1 hr, and then concentrated in vacuo and used immediately for the next step.
Step 2: Preparation of tert-butyl N-[(3,5-difluoropyridine-2-carbonyl)amino]carbamate
Figure imgf000096_0001
A solution of tert-butyl N-aminocarbamate (0.827 g, 6.26 mmol) and N,N-diethylethanamine (1.75 mL, 12.5 mmol) in EtOAc (12 mL) was added dropwise to a solution of 3,5-difluoropyridine-2-carbonyl chloride (1.17 g, 6.26 mmol) in EtOAc (12 mL) at rt and under an argon atmosphere. The reaction mixture was stirred at rt for 1 hr and then quenched with water, extracted with EtOAc (2x 40 ml) and the combined organic phases dried over Na2SO4 and concentrated in vacuo to give the pure title compound which was used without further purification.
LC-MS (Method C): 174 [M +H - Boc], Rt: 0.57 min
1H NMR (CDCb) 6 ppm: 1 .26 (s, 1 H) 1 .32 (s, 1 H) 1 .46 - 1 .48 (m, 1 H) 1 .51 (s, 9 H) 6.56 - 6.76 (m,1 H) 7.27 (s, 1 H) 7.36 (ddd, J=10.10, 7.97, 2.31 Hz, 1 H) 8.32 (d, J=2.25 Hz, 1 H) 9.13 (br s, 1 H)
Step 3: Preparation of 3,5-difluoropyridine-2-carbohvdrazide
Figure imgf000096_0002
A sample of tert-butyl N-[(3,5-difluoropyridine-2-carbonyl)amino]carbamate (1.7 g, 6.2 mmol) in dioxane (20 mL) was treated with hydrochloric acid 4 M (16 mL, 62 mmol) at rt. After completion of the reaction, the reaction mixture was quenched with aqueous NaHCC and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to obtain the title compound as a white solid.
LC-MS (Method C): 174 [M+H], Rt: 0.17 min
Step 4 : Preparation of methyl 2-[2-(3,5-difluoropyridine-2-carbonyl)hydrazino1-2-oxo-acetate
Figure imgf000096_0003
A solution of 3,5-difluoropyridine-2-carbohydrazide (2.0g, 12 mmol) and TEA (4 mL, 29 mmol) in acetonitrile (20 mL) was cooled to 0°C and treated dropwise with methyl oxalyl chloride (1.1 mL, 12 mmol). The reaction mixture was allowed to warm to rt and stirred for 1 hr. The reaction mixture was then diluted with water (50 ml) and extracted with EtOAc (2 X 75 ml). The combined organic layers were dried over Na2SC>4 and concentrated in vacuo to obtain the title compound as a white solid.
LC-MS (Method C): 259 [M+H], Rt: 0.15 min
Step 5 : Preparation of methyl 5-(3,5-difluoro-2-pyridyl)-1 ,3,4-thiadiazole-2-carboxylate
Figure imgf000097_0001
A solution of methyl 2-[2-(3,5-difluoropyridine-2-carbonyl)hydrazino]-2-oxo-acetate (0.5 g, 2 mmol) and phosphorus pentasulfide (0.1 mL) in toluene (5 mL) was refluxed for 3 hours. After completion of the reaction, the reaction mixture was quenched with the aq. solution of sodium acetate (1g, 10 mmol) and extracted with EtOAc (2 x 40 ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (0-25% EtOAc in Cyclohexane) to obtain the title compound.
LC-MS (Method C): 258 [M+H], Rt: 0.99
1H NMR (400 MHz, CDCI3) 6 ppm: 4.10 (s, 3 H) 7.48 (ddd, J=9.66, 7.66, 2.31 Hz, 1 H) 8.48 (d, J=2.25 Hz, 1 H)
Step 6: Preparation of 4-(1 ,5-dimethylpyrazol-4-yl)isoquinoline
Figure imgf000097_0002
In a microwave vial, a suspension of 4-bromoisoquinoline (2.0 g, 9.4204 mmol), 1 ,5-dimethyl-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (2.3484 g, 10.362 mmol.) and potassium carbonate (1.432 g, 10.36 mmol) in a toluene/methanol mixture (30mL, 5:1) was degassed with argon for several minutes, and then tetrakis(triphenylphosphaniumyl)palladium (0.545 g, 0.471 mmol) was added. The reaction mixture was heated at 100°C and stirred for 1 hour under microwave irradiation. After cooling down to rt, the reaction mixture was partitioned between water and EtOAc and the organic layer separated, dried over Na2SO4, filtered and concentrated in vacuo. Purification of the crude material by flash chromatography over silica gel (eluting with EtOAc acetate/30% methanol) afforded the title compound.
LCMS (Method A): m/z 225 [M+H], retention time 0.51 min Step 7: Preparation of 4-(1 ,5-dimethylpyrazol-4-yl)-1 ,2,3,4-tetrahydroisoquinoline
Figure imgf000098_0001
To a solution of 4-(1 ,5-dimethylpyrazol-4-yl)isoquinoline (2.00 g, 8.96 mmol) in methanol (90 mL) was added at rt sodium cyanoborohydride (3.55 g, 53.7 mmol). The reaction mixture was stirred at rt, and then hydrochloric acid (1.25 M in methanol) was added until the pH reached 2-3. After 30 minutes of stirring at rt, the reaction mixture was diluted with water and basified with 2 N sodium hydroxide, and the mixture extracted with EtOAc (X3). The combined organic layers were dried over Na2SC>4, filtered, and concentrated in vacuo. The resulting yellow oil was used without further purification.
LCMS (Method A): m/z 228 [M+H], retention time 0.29 min
The hydrochloride salt of the title product (4-(1 ,5-dimethylpyrazol-4-yl)-1 ,2,3,4-tetrahydroisoquinoline; hydrochloride) could be obtained by treating the yellow oil with 2 M HCI in diethyl ether and then concentration in vacuo.
Step 8: Preparation of [5-(3,5-difluoro-2-pyridyl)-1 ,3,4-thiadiazol-2-yl1-[4-(1 ,5-dimethylpyrazol-4-yl)-3,4- dihydro-1 H-isoquinolin-2-yl]methanone (Compound P-7, Table P)
A solution of methyl 5-(3,5-difluoro-2-pyridyl)-1 ,3,4-thiadiazole-2-carboxylate (0.05 g, 0.194 mmol, example P1 , step 4) and 4-(1 ,5-dimethylpyrazol-4-yl)-1 ,2,3,4-tetrahydroisoquinoline (0.05 g, 0.233 mmol) in toluene (1 mL) was cooled to 0°C. Then Trimethylaluminum solution (2.0 mol/L) in toluene (0.29 mL) was added carefully drop wise and the reaction mixture was kept at the same temperature for 10 min and then heated at 70°C for 2 hr. After completion of the reaction, the reaction mixture was quenched slowly with an ice cooled brine solution (Strong effervescence occurred). The resulting solution was extracted with EtOAc, and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude was purified by normal phase column chromatography (using 0-50% EtOAc in cyclohexane) to obtain the title compound we
LC-MS (Method C): 453 [M+H] Rt: 1 .13 min
1H NMR (400 MHz, CDCb) 6 ppm: 2.18 (s, 3 H) 3.69 (s, 3 H) 4.29 - 4.26 (m, 1 H) 4.40 - 4.35 (m, 1 H) 4.70- 4.66 (m, 1 H) 5.13 - 5.01 (m, 2 H) 6.93 (s, 1 H) 7.28 - 7.03 (m, 4 H) 7.46-7.28 (m, 1 H) 8.47 (m, 1 H)
Example P3: Preparation of [5-(2,6-difluoro-3-pyridyl)-1 ,3,4-thiadiazol-2-yl1-[4-(1 ,5-dimethylpyrazol-4-yl)-3,4- dihydro-1 H-isoquinolin-2-yl1methanone (Compound P-8, Table P)
Figure imgf000099_0001
(Compound P-8, Table P)
Step 1 : Preparation of 2,6-difluoropyridine-3-carbonyl chloride
Figure imgf000099_0002
The desired compound was prepared from 2,6-difluoropyridine-3-carboxylic acid and oxalyl chloride, analogously to the example described in example 2, step 1 , to afford 2,6-difluoropyridine-3-carbonyl chloride.
Step 2: Preparation of tert-butyl N-[(2,6-difluoropyridine-3-carbonyl)amino]carbamate
Figure imgf000099_0003
The desired compound was prepared as described previously for example 2, step 2 to afford tert-butyl N-[(2,6- difluoropyridine-3-carbonyl)amino]carbamate, LC-MS (Method C): 174 [M +H - Boc], Rt: 0.43 min
Step 3: Preparation of 2,6-difluoropyridine-3-carbohydrazide
Figure imgf000099_0004
A sample of tert-butyl N-[(2,6-difluoropyridine-3-carbonyl)amino]carbamate (8.9 g, 31 mmol) was dissolved in hydrochloric acid 4 M in dioxane (77 mL, 310 mmol) and the reaction mixture was stirred at rt overnight. After completion, the reaction mixture was quenched with sodium bicarbonate and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SC and concentrated in vacuo to obtain the title compound as a pale-yellow solid.
LC-MS (Method D): 174 [M+H] Rt: 0.23 min 1H NMR (400 MHz, DMSO-d6) 6 ppm: 4.63 (br s, 2 H) 7.27 (d, J=7.91 Hz, 1 H) 8.32 (dt, J=9.17, 8.07 Hz, 1 H)
9.72 (br s, 1 H)
Step 4: Preparation of methyl 2-[2-(2,6-difluoropyridine-3-carbonyl)hydrazino]-2-oxo-acetate
Figure imgf000100_0001
A solution of 2,6-difluoropyridine-3-carbohydrazide (100 mg, 0.54 mmol) in DCM (1 mL) was cooled to 0°C and added TEA (0.19 mL, 1.37 mmol) and this reaction mixture was treated dropwise with methyl oxalyl chloride (52.7 pL, 0.54 mmol). The reaction mixture was stirred for 15 min at rt, diluted with water (50 ml) and extracted with EtOAc (2 X 50 ml). The combined organic layers were dried over Na2SC>4 and concentrated in vacuo to get a pale brown residue which upon combi flash purification using 40-80% ethyl acetate in cyclohexane afforded pure methyl 2-[2-(2,6-difluoropyridine-3-carbonyl)hydrazino]-2-oxo-acetate as a pale-yellow gummy mass.
LC-MS (Method D): 260 [M +H], Rt: 0.22 min
Step 5 : Preparation of methyl 5-(2,6-difluoro-3-pyridyl)-1 ,3,4-thiadiazole-2-carboxylate
Figure imgf000100_0002
A solution of methyl 2-[2-(2,6-difluoropyridine-3-carbonyl)hydrazino]-2-oxo-acetate (2.98 g, 10.3 mmol) in dry THF (60 mL) was treated with Lawesson's reagent (4.75 g, 11 .4 mmol) and the resulting reaction mixture was refluxed for 2 hr. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude compound purified by chromatography over silica gel (using 0-50% EtOAc in cyclohexane) to obtain the title compound.
LC-MS (Method D): 258 [M +H], Rt: 1.01 min
1H NMR (400 MHz, CDCb) 6 ppm: 9.06 (td, J=8.65, 7.40 Hz, 1 H) 7.09 - 7.13 (m, 1 H) 4.11 (s, 3 H)
Step 6: Preparation of [5-(2,6-difluoro-3-pyridyl)-1 ,3,4-thiadiazol-2-yl1-[4-(1 ,5-dimethylpyrazol-4-yl)-3,4- dihydro-1 H-isoquinolin-2-yl1methanone (Compound P-8, Table P)
A suspension of methyl 5-(2,6-difluoro-3-pyridyl)-1 ,3,4-thiadiazole-2-carboxylate (0.18 g, 0.665 mmol) and 4- (1 ,5-dimethyl-1 H-pyrazol-1-ium-4-yl)-1 ,2,3,4-tetrahydroisoquinolin-2-ium;dichloride (0.21 12 g, 0.798 mmol) in toluene (4 mL) was cooled to 0°C. Then, trimethylaluminum solution (2.0 mol/L, in toluene, 1 ,0 mL, 1 .99 mmol) was added carefully drop wise and the reaction mixture was kept at the same temperature for 10 min and then was heated to 90°C for 2 hr. After completion of the reaction, the reaction mixture was quenched slowly with an ice cooled brine solution and extracted with EtOAc and the combined organic layers were dried over Na2SC>4 and concentrated in vacuo. The crude product was adsorbed over celite and purified by reverse phase column chromatography using (0-70% ACN in water) to obtain the pure compound as an off-white solid in rotameric mixture (60:40 ratio).
LC-MS (Method C): 453 [M+H] Rt: 1 .13 min
1H NMR (400 MHz, CDCb) 6 ppm: 8.91 - 9.03 (m, 2 H) 7.15 - 7.32 (m, 6 H) 7.03 - 7.13 (m, 4 H) 6.98 (s, 1 H) 5.84 (d, J=17.01 Hz, 1 H) 5.42 (d, J=16.76 Hz, 1 H) 5.01 - 5.13 (m, 2 H) 4.70 (dd, J=12.51 , 3.63 Hz, 1 H) 4.44 (dd, J=12.51 , 5.00 Hz, 1 H) 4.20 - 4.38 (m, 3 H) 3.65 - 3.76 (m, 3H) 2.16 (s, 3 H)
19F NMR (377 MHz, CDCb) 6 ppm: -61 .81 (s, 1 F) -61 .84 (s, 1 F) -64.24 (s, 1 F) -64.27 (s, 1 F)
Example P4: Preparation of [5-(2,6-difluoro-3-pyridyl)-1 ,3,4-thiadiazol-2-yl]-[rac-(1 S,4S)-4-(1 ,5- dimethylpyrazol-4-yl)-1-methyl-3,4-dihydro-1 H-isoquinolin-2-yl]methanone (Compound P-9, Table P)
Figure imgf000101_0001
(Compound P-9, Table P)
At ambient temperature under an argon atmosphere trimethylaluminum (2M solution in toluene, 0.44 mL, 0.870 mmol) was dropped via syringe over a period of a few minutes to a pale yellow suspension of (rac-1 S,4S)-4- (1 ,5-dimethylpyrazol-4-yl)-1-methyl-1 ,2,3,4-tetrahydroisoquinoline (purity 70 %, 0.150 g, 0.435mmol) and methyl 5-(2,6-difluoro-3-pyridyl)-1 ,3,4-thiadiazole-2-carboxylate (0.118 g, 0.435 mmol) in toluene (1.74 mL). After addition was completed, the reaction mixture was heated and stirred at 90°C. After ~90', the mixture was allowed to cool to rt and was then added to 10ml NaOH 2M aqueous solution. After dilution with water (30ml) the mixture was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford crude product. The crude was purified by chromatography over silica gel to afford the title compound.
LC-MS (Method C): 467 [M+H] Rt: 1.18 min
Examples of synthesized compounds of formula (I) are shown in Table P.
Table P: Synthesized compounds and Spectral and Physical Chemical Data.
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
BIOLOGICAL EXAMPLES
Example B1 : Altemaria solani / tomato / leaf disc (early blight)
Tomato leaf disks cv. Baby are placed on agar in multiwell plates (24-well format) and sprayed with the formulated test compound diluted in water. The leaf disks are inoculated with a spore suspension of the fungus 2 days after application. The inoculated leaf disks are incubated at 23°C / 21 °C (day/night) and 80% rh under a light regime of 12 h light / 12 h darkness in a climate cabinet and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears on untreated check disk leaf disks (5 to 7 days after application).
The following compounds gave at least 80% control of Altemaria solani at 200 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
P-6, P-7, P-10, P-1 1 , P-12, P-13, P-15, P-17, P-19, P-20, P-21 , P-23, P-24, P-30, P-31 , P-32, P-34, P-35, P-
38, P-39, P-40, P-41 , P-42, P-43, P-44, P-45, P-51
Example B2: Botryotinia fuckeliana (Botrytis cinerea) / liquid culture (Gray mould)
Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (Vogels broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24°C and the inhibition of growth is determined photometrically 3 to 4 days after application.
The following compounds gave at least 80% control of Botryotinia fuckeliana at 20 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
P-6, P-8, P-10, P-1 1 , P-13, P-15, P-17, P-19, P-20, P-22, P-23, P-24, P-25, P-31 , P-34, P-35, P-36, P-38, P-
39, P-40, P-41 , P-42, P-43, P-44, P-45, P-50, P-51 , P-52
Example B3: Glomerella laqenarium (Colletotrichum laqenarium) / liquid culture (Anthracnose)
Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24°C and the inhibition of growth is measured photometrically 3 to 4 days after application.
The following compounds gave at least 80% control of Glomerella lagenarium at 20 ppm when compared to untreated control under the same conditions, which showed extensive disease development: P-6, P-7, P-8, P-10, P-11 , P-12, P-13, P-15, P-17, P-19, P-20, P-22, P-23, P-24, P-25, P-31 , P-34, P-35, P-36, P-42, P-43, P-45, P-50, P-51 , P-52
Example B4: Blumeria graminis f. sp. tritici (Erysiphe graminis f. sp. tritici) / wheat / leaf disc preventative (Powdery mildew on wheat)
Wheat leaf segments cv. Kanzler are placed on agar in a multiwell plate (24-well format) and sprayed with the formulated test compound diluted in water. The leaf disks are inoculated by shaking powdery mildew infected plants above the test plates 1 day after application. The inoculated leaf disks are incubated at 20°C and 60% rh under a light regime of 24 h darkness followed by 12 h light / 12 h darkness in a climate chamber and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears on untreated check leaf segments (6 to 8 days after application).
The following compounds gave at least 80% control of Blumeria graminis f. sp. tritici at 200 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
P-6, P-10, P-15, P-17, P-19, P-20, P-24, P-31 , P-32, P-34, P-35, P-38, P-39, P-40, P-41 , P-42, P-43, P-44, P- 45
Example B5: Fusarium culmorum / liquid culture (Head blight)
Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24°C and the inhibition of growth is determined photometrically 3 to 4 days after application.
The following compounds gave at least 80% control of Fusarium culmorum at 20 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
P-6, P-10, P-11 , P-13, P-15, P-17, P-20, P-31 , P-34, P-35, P-39, P-40, P-42, P-43, P-45, P-51 , P-52
Example B6: Fusarium cu/morum / wheat / spikelet preventative (Head blight)
Wheat spikelets cv. Monsun are placed on agar in multiwell plates (24-well format) and sprayed with the formulated test compound diluted in water. The spikelets are inoculated with a spore suspension of the fungus 1 day after application. The inoculated spikelets are incubated at 20°C and 60% rh under a light regime of 72 h semi darkness followed by 12 h light / 12 h darkness in a climate chamber and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears on untreated check spikelets (6 to 8 days after application).
The following compounds gave at least 80% control of Fusarium culmorum at 200 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
P-6, P-10, P-15, P-51
Example B7: Gibberella zeae (Fusarium graminearum) / wheat / spikelet preventative (Head blight) Wheat spikelets cv. Monsun are placed on agar in multiwell plates (24-well format) and sprayed with the formulated test compound diluted in water. One day after application, the spikelets are inoculated with a spore suspension of the fungus. The inoculated test leaf disks are incubated at 20°C and 60% rh under a light regime of 72 h semi darkness followed by 12 h light / 12 h darkness in a climate chamber, the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears on untreated check spikelets (6 to 8 days after application).
The following compounds gave at least 80% control of Gibberella zeae at 200 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
P-6, P-10, P-15, P-51
Example B8: Phaeosphaeria nodorum (Septoria nodorum) / wheat / leaf disc preventative (Glume blotch)
Wheat leaf segments cv. Kanzler are placed on agar in a multiwell plate (24-well format) and sprayed with the formulated test compound diluted in water. The leaf disks are inoculated with a spore suspension of the fungus 2 days after application. The inoculated test leaf disks are incubated at 20°C and 75% rh under a light regime of 12 h light / 12 h darkness in a climate cabinet and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf disks (5 to 7 days after application).
The following compounds gave at least 80% control of Phaeosphaeria nodorum at 200 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
P-6, P-7, P-10, P-1 1 , P-13, P-15, P-17, P-19, P-20, P-22, P-23, P-30, P-31 , P-34, P-35, P-38, P-39, P-40, P- 41 , P-42, P-43, P-44, P-45
Example B9: Monoqraphella nivalis (Microdochium nivale) / liquid culture (foot rot cereals)
Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24°C and the inhibition of growth is determined photometrically 4 to 5 days after application.
The following compounds gave at least 80% control of Monographella nivalis at 20 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
P-6, P-10, P-11 , P-13, P-15, P-17, P-19, P-20, P-22, P-23, P-24, P-25, P-31 , P-34, P-35, P-36, P-38, P-39, P- 40, P-42, P-43, P-45, P-50, P-51
Example B10: Mycosphaerella arachidis (Cercospora arachidicola) / liquid culture (early leaf spot)
Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24°C and the inhibition of growth is determined photometrically 4 to 5 days after application. The following compounds gave at least 80% control of Mycosphaerella arachidis at 20 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
P-6, P-7, P-8, P-10, P-11 , P-12, P-13, P-15, P-17, P-19, P-20, P-22, P-23, P-24, P-30, P-31 , P-34, P-35, P-36, P-38, P-39, P-40, P-41 , P-42, P-43, P-44, P-45, P-50, P-51 , P-52
Example B11 : Pyrenophora teres / barley / leaf disc preventative (Net blotch)
Barley leaf segments cv. Hasso are placed on agar in a multiwell plate (24-well format) and sprayed with the formulated test compound diluted in water. The leaf segments are inoculated with a spore suspension of the fungus 2 days after application. The inoculated leaf segments are incubated at 20°C and 65% rh under a light regime of 12 h light / 12 h darkness in a climate cabinet and the activity of a compound is assessed as disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf segments (5 to 7 days after application).
The following compounds gave at least 80% control of Pyrenophora teres at 200 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
P-6, P-7, P-10, P-1 1 , P-13, P-15, P-17, P-19, P-20, P-22, P-23, P-24, P-30, P-31 , P-32, P-34, P-35, P-38, P- 39, P-40, P-41 , P-42, P-43, P-44, P-45
Example B12: Sclerotinia sclerotiorum / liquid culture (cottony rot)
Mycelia fragments of a newly grown liquid culture of the fungus are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format) the nutrient broth containing the fungal material is added. The test plates are incubated at 24°C and the inhibition of growth is determined photometrically 3 to 4 days after application.
The following compounds gave at least 80% control of Sclerotinia sclerotiorum at 20 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
P-6, P-15, P-35, P-39, P-43, P-51
Example B13: Mycosphaerella qraminicola (Septoria tritici) / liquid culture (Septoria blotch)
Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24°C and the inhibition of growth is determined photometrically 4 to 5 days after application.
The following compounds gave at least 80% control of Mycosphaerella graminicola at 20 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
P-1 , P-6, P-7, P-8, P-10, P-11 , P-12, P-13, P-15, P-17, P-19, P-20, P-22, P-23, P-24, P-25, P-30, P-31 , P-34, P-35, P-36, P-38, P-39, P-40, P-41 , P-42, P-43, P-44, P-45, P-50, P-51 , P-52, P-56
Example B14: Puccinia recondita f. sp. tritici / wheat / leaf disc curative (Brown rust) Wheat leaf segments cv. Kanzler are placed on agar in multiwell plates (24-well format). The leaf segments are inoculated with a spore suspension of the fungus. Plates are stored in darkness at 19 °C and 75% rh. The formulated test compound diluted in water is applied 1 day after inoculation. The leaf segments are incubated at 19°C and 75% rh under a light regime of 12 h light / 12 h darkness in a climate cabinet and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf segments (6 to 8 days after application).
The following compounds gave at least 80% control of Puccinia recondita f. sp. tritici at 200 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
P-29
Example B15: Puccinia recondita f. sp. tritici / wheat / leaf disc preventative (Brown rust)
Wheat leaf segments cv. Kanzler are placed on agar in multiwell plates (24-well format) and sprayed with the formulated test compound diluted in water. The leaf disks are inoculated with a spore suspension of the fungus 1 day after application. The inoculated leaf segments are incubated at 19°C and 75% rh under a light regime of 12 h light / 12 h darkness in a climate cabinet and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf segments (7 to 9 days after application).
The following compounds gave at least 80% control of Puccinia recondita f. sp. tritici at 200 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
P-11 , P-19, P-20, P-42
Example B16: Maqnaporthe qrisea (Pyricularia oryzae) / liquid culture (Rice Blast)
Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24°C and the inhibition of growth is determined photometrically 3 to 4 days after application.
The following compounds gave at least 80% control of Magnaporthe grisea at 20 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
P-6, P-10, P-31 , P-34, P-35, P-36, P-38, P-39, P-40, P-42, P-43, P-45, P-51 , P-52
Example B17: Maqnaporthe qrisea (Pyricularia oryzae) / rice / leaf disc preventative (Rice Blast)
Rice leaf segments cv. Ballila are placed on agar in a multiwell plate (24-well format) and sprayed with the formulated test compound diluted in water. The leaf segments are inoculated with a spore suspension of the fungus 2 days after application. The inoculated leaf segments are incubated at 22°C and 80% rh under a light regime of 24 h darkness followed by 12 h light / 12 h darkness in a climate cabinet and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf segments (5 to 7 days after application). The following compounds gave at least 80% control of Magnaporthe grisea at 200 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
P-38, P-39, P-40, P-41 , P-42, P-43, P-45
Example B18: Thanatephorus cucumeris (Rhizoctonia solani) / liquid culture (foot rot, damping-off) Mycelia fragments of a newly grown liquid culture of the fungus are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of the test compounds into a microtiter plate (96-well format), the nutrient broth containing the fungal material is added. The test plates are incubated at 24°C and the inhibition of growth is determined photometrically 3 to 4 days after application.
The following compounds gave at least 80% control of Thanatephorus cucumeris at 20 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
P-11 , P-15, P-20

Claims

1. A compound of formula (I)
Figure imgf000116_0001
wherein
R1 is selected from hydrogen, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, or Cs-Cecycloalkyl;
R2 is selected from hydrogen, halogen, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl, C3- Cecycloalkyl, Ci-C4-alkylcarbonyl, N-C1-C4 alkoxy-C-Ci-C4 alkyl-carbonimidoyl, N-hydroxy-C-Ci-C4 alkylcarbonimidoyl, or Ci-C4-alkoxycarbonyl;
R3 is selected from hydrogen, halogen, C1-C4 haloalkyl, or C1-C4 alkyl;
R4 is selected from hydrogen, halogen, C1-C4 haloalkyl, C3-C6 cycloalkyl, or C1-C4 alkyl;
R5 and R6 are independently selected from hydrogen, or Ci-C4-alkyl;
R7 is selected from hydrogen, Ci-C4alkyl, C1-C4 alkylcarbonyl, N-C1-C4 alkoxy-C-Ci-C4 alkylcarbonimidoyl, N-hydroxy-C-Ci-C4-alkyl-carbonimidoyl, Ci-C4alkoxycarbonyl, N-methoxy-N-methyl- carbonyl, C1-C4 alkylaminocarbonyl, di(Ci-C4alkyl)aminocarbonyl, phenyl, a 5- or 6-membered heteroaryl, or Cs-Ce-cycloalkyl; wherein any of said 5- or 6-membered heteroaryl contains 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S, with the proviso that no more than one is O or S; and wherein any of said phenyl and 5- or 6-membered heteroaryl are unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from halogen, Ci-C4haloalkyl, cyano, carboxy, Ci-C4alkyl, or Ci-C4alkoxy; and wherein said Cs-Ce-cycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from halogen, Ci-C4haloalkyl, cyano, Ci-C4alkyl, or Ci-C4alkoxy;
B1 is selected from CR10, or N;
B2 is selected from CR11, or N;
R8, R9, R10 and R11 are independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, Ci- 04 alkoxy, C1-C4 haloalkoxy, C2-C4alkenyloxy, C2-C4 alkynyloxy, C1-C4 alkylsulfanyl, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 alkoxy-Ci-C4 alkyl, N-Ci-C4alkylamino, N,N-di(Ci-C4alkyl)amino, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl, N-C1-C4 alkoxy-Ci-C4 alkyl-carbonimidoyl, N-hydroxy-Ci-C4 alkyl- carbonimidoyl, hydroxy, trifluoromethylsulfonyloxy, cyano, carboxy, amino, phenyl, 5- or 6-membered heteroaryl or C3-C6 cycloalkyl; wherein any of said 5- or 6-membered heteroaryl contains 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S, with the proviso that no more than one is O or S; and wherein any of said phenyl, 5- or 6-membered heteroaryl and Cs-Ce-cycloalkyl are unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, or Ci-C4alkoxy;
A1, A2 and A3 are independently selected from CR12, N, NR13, O or S, with the proviso that at least one of A1, A2 and A3 is selected from N, O or S, and that no more than one of A1, A2 and A3 is O or S;
R12, R13 are independently selected from hydrogen, halogen, C1-C4 alkyl, Ci-C4haloalkyl, C2-C4 alkenyl, or C2-C4 alkynyl; and
Z1 is selected from 6-membered heteroaryl containing 1 or 2 heteroatoms selected form N; wherein any of said 6-membered heteroaryl is unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from halogen, C1-C4 haloalkyl, cyano, C1-C4 alkyl, C2-C4 alkynyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylsulfanyl, C1-C4 alkylsulfinyl, or Ci-C4 alkylsulfonyl; or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof. The compound of formula (I) according to claim 1 , wherein R1 is methyl and R3 is hydrogen. The compound of formula (I) according to claim 1 or claim 2, wherein R2 is hydrogen, chlorine, or methyl. The compound of formula (I) according to any one of claims 1 to 3, wherein R4 is hydrogen or methyl and R5 and R6 are hydrogen. The compound of formula (I) according to any one of claims 1 to 4, wherein R7 is hydrogen, C1-C4 alkyl, or Cs-Ce-cycloalkyl. The compound of formula (I) according to any one of claims 1 to 5, wherein B1 is CR10 and B2 is CR11, and wherein R10 and R11 are independently selected from hydrogen, bromine, chlorine, or cyano. The compound of formula (I) according to any one of claims 1 to 6, wherein R8 is hydrogen, bromine, chlorine, or cyano and wherein R9 is hydrogen, bromine, chlorine, cyano, methyl, or methoxy. The compound of formula (I) according to any one of claims 1 to 7, wherein Z1 is selected from 2- pyridyl, 3-pyridyl, 4-pyridyl, pyrazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-yl; wherein any of said pyridyl-, pyrazin- pyridazine- or pyrimidin-moities are unsubstituted or substituted with 1 or 2 substituents selected from fluorine.
9. The compound of formula (I) according to claim 8, wherein Z1 is selected from 3-fluoro-2-pyridyl, 5- fluoro-2-pyridyl, 6-fluoro-2-pyridyl, 3,4-difluoro-2-pyridyl, 3,5-difluoro-2-pyridyl, 2-fluoro-4-pyridyl, 5- fluoropyrimidin-4-yl, 5-fluoropyrimidin-2-yl, 4-fluoropyridazin-3-yl, 5-fluoropyridazin-3-yl, 4,5- difluoropyridazin-3-yl, or 5-fluoropyridazin-4-yl. 10. A compound of formula (l-A):
Figure imgf000118_0001
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, B1, B2 and Z1 correspond to the same definitions as for the compounds of formula (I) according to any one of claims 1 to 9, and A is selected from
Figure imgf000118_0002
wherein indicates the bond to the C(=O) group and the arrow the bond to the Z1 group, and wherein R14a is selected from hydrogen or C1-C4 alkyl.
11 . The compound of formula (l-A) according to claim 10, wherein A is selected from:
Figure imgf000118_0003
wherein indicates the bond to the C(=O) group and the arrow the bond to the Z1 group, and wherein R14a is hydrogen.
12. A compound of formula (llb-1)
Figure imgf000119_0001
(llb-1) wherein
R° is Ci-C6-alkyl;
Z1 is as defined for the compounds of formula (I) according to any of the preceding claims; and
A is selected from A1 to A36
Figure imgf000119_0002
wherein
Figure imgf000119_0003
indicates the bond to the C(=O) group and the arrow the bond to the Z1 group, and wherein R12a, R13a, R14a, R12b, R13b and R14b are independently selected from hydrogen, C1-C4 alkyl, C2- C4 alkenyl or C2-C4 alkynyl 13. An agrochemical composition comprising a fungicidally effective amount of a compound of formula (I), as defined in any one of claims 1 to 9, or a compound of formula (l-A) as defined in any one of claims 10 to 11. The agrochemical composition according to claim 13, further comprising at least one additional active ingredient and/or an agrochemically-acceptable diluent or carrier A method of controlling or preventing infestation of useful plants by phytopathogenic microorganisms, wherein a fungicidally effective amount of a compound of formula (I), as defined in any one of claims 1 to 9, or a compound of formula (l-A) as defined in any one of claims 10 to 11 , or a composition comprising the compound of formula (I), or a compound of formula (l-A), is applied to the plants, to parts thereof or the locus thereof. Use of a compound according to any one of claims 1 to 11 as a fungicide.
PCT/EP2023/081908 2022-11-16 2023-11-15 Microbiocidal tetrahydroisoquinoline derivatives Ceased WO2024105104A1 (en)

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Free format text: APRESENTE NOVAS FOLHAS DAS REIVINDICACOES ADAPTADAS AO ART. 18 DA PORTARIA NO 14/2024, UMA VEZ QUE O CONTEUDO ENVIADO ENCONTRA-SE FORA DA NORMA. A EXIGENCIA DEVE SER RESPONDIDA EM ATE 60 (SESSENTA) DIAS DE SUA PUBLICACAO E DEVE SER REALIZADA POR MEIO DA PETICAO GRU CODIGO DE SERVICO 207.