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WO2014172871A1 - Dihydrobenzofuran derivatives as insecticidal compounds - Google Patents

Dihydrobenzofuran derivatives as insecticidal compounds Download PDF

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Publication number
WO2014172871A1
WO2014172871A1 PCT/CN2013/074708 CN2013074708W WO2014172871A1 WO 2014172871 A1 WO2014172871 A1 WO 2014172871A1 CN 2013074708 W CN2013074708 W CN 2013074708W WO 2014172871 A1 WO2014172871 A1 WO 2014172871A1
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substituted
formula
compounds
alkyl
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PCT/CN2013/074708
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French (fr)
Inventor
Long Lu
Jérome Yves CASSAYRE
Torsten LUKSCH
Myriem El Qacemi
Yaming Wu
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Syngenta Participations Ag
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Priority to PCT/CN2013/074708 priority Critical patent/WO2014172871A1/en
Publication of WO2014172871A1 publication Critical patent/WO2014172871A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Definitions

  • the present invention relates to certain dihydrobenzofuran derivatives, to processes and intermediates for preparing these derivatives, to insecticidal, acaricidal, nematicidal and molluscicidal compositions comprising these derivatives and to methods of using these derivatives to control insect, acarine, nematode and mollusc pests.
  • isoxazoline derivatives with insecticidal properties are disclosed, for example, in EP 1,731,512.
  • new biologically active compounds as well as new biologically active compounds displaying superior properties for use as agrochemical active ingredients, for example greater biological activity, different spectrum of activity, increased safety profile, or increased biodegradability.
  • the present invention provides compounds of formula (I)
  • Q is Ql or Q2
  • G 1 is oxygen or sulfur
  • Y 1 is oxygen, sulfur or CH 2 ;
  • Y 3 J and Y 4 are each independently C-H, C-R 5 or nitrogen, wherein no more than one Y 3 J and Y 4 is C-R 5 ;
  • Y 5 is hydrogen, halogen, CpCgalkyl, Ci-Cghaloalkyl or Ca-Cgcycloalkyl;
  • Y 6 is hydrogen, halogen, cyano, Ci-Cgalkyl, Ci-Cghaloalkyl or CrCgcycloalkyl;
  • R la is hydrogen, C r C 8 alkyl, Q-Cgalkoxy, CpCgalkylcarbonyl or CpCgalkoxycarbonyl;
  • R lb is hydrogen, Ci-Qalkyl, CpCgalkylcarbonyl or CpCgalkoxycarbonyl;
  • R 2a is CpCgalkyl or CpCgalkyl substituted by one to five R 7 , C 2 -Cgalkenyl or C 2 -Cgalkenyl substituted by one to five R 7 , C 2 -C 8 alkynyl or C 2 -Cgalkynyl substituted by one to five R 7 , Cr
  • Ciocycloalkyl or CrCiocycloalkyl substituted by one to five R 8 C 3 -Ciocycloalkyl-Ci-C 4 alkylene or C 3 - Ciocycloalkyl-Ci-C 4 alkylene substituted by one to five R 8 , aryl-Ci-C 4 alkylene- or aryl-Ci-C 4 alkylene- substituted by one to five R 9 , heterocyclyl-Ci-C 4 alkylene- or heterocyclyl-Ci-C 4 alkylene- substituted by one to five R 9 , aryl or aryl substituted by one to five R 9 , heterocyclyl or heterocyclyl substituted by one to five R 9 , Ci-C 8 alkylaminocarbonyl-Ci-C 4 alkylene, Ci-C 8 haloalkylaminocarbonyl-Ci-C alkylene, C 3 -
  • R 2b is C r C 8 alkyl or CpQalkyl substituted by one to five R 7 , C 2 -C 8 alkenyl or C 2 -C 8 alkenyl substituted by one to five R 7 , C 2 -C 8 alkynyl or C 2 -C 8 alkynyl substituted by one to five R 7 , Ci-C 8 alkoxy- Ci-C 8 alkyl or Ci-C 8 alkoxy-Ci-C 8 alkyl substituted by one to five R 7 , C3-Ciocycloalkyl or C3-Ciocycloalkyl substituted by one to five R 8 , C3-Ciocycloalkyl-Ci-C 4 alkylene or C3-Ciocycloalkyl-Ci-C 4 alkylene substituted by one to five R 8 , aryl-Ci-C 4 alkylene- or aryl-Ci-C 4 alkylene- substituted by one to five R 9
  • R 3 is Ci-Cghaloalkyl
  • R 4 is aryl or aryl substituted by one to five R 10 , or heteroaryl or heteroaryl substituted by one to five R 10 ;
  • each R 5 is independently halogen, cyano, CrQalkyl, Ci-C haloalkyl, CpQalkoxy or C r
  • R a is hydrogen, cyano, Ci-C 8 alkyl, Ci-C 8 haloalkyl or C3-C 8 cycloalkyl;
  • R b is hydrogen, cyano, CpC 8 alkyl, Ci-C 8 haloalkyl or C3-C 8 cycloalkyl;
  • R a and R b together with the carbon atom to which they are attached may form a 3 to 6- membered carbocyclic ring;
  • each R 7 is independently halogen, cyano, nitro, hydroxy, amino, C r C 8 alkyl, C 2 -C 8 alkenyl, C 2 - C 8 alkynyl, Ci-C 8 alkylamino, (Ci-C 8 alkyl) 2 amino, Ci-C 8 alkylcarbonylamino, Cp
  • R 8 is independently halogen, cyano, Ci-C 8 alkyl, Ci-C 8 haloalkyl, C 2 -C 8 alkenyl, C 2 - C 8 haloalkenyl, C 2 -C 8 alkynyl, C 2 -C 8 haloalkynyl, Ci-C 8 alkoxy, Ci-C 8 haloalkoxy, C3-C 6 cycloalkyl or Cp C 8 akoxycarbonyl;
  • each R 9 is independently halogen, cyano, nitro, Ci-C 8 alkyl, Ci-C 8 haloalkyl, Ci-C 8 cyanoalkyl, C 2 - C 8 alkenyl, C 2 -C 8 haloalkenyl, C 2 -C 8 alkynyl, C 2 -C 8 haloalkynyl, C3-Ciocycloalkyl, C3-Ciocycloalkyl-Cr C 4 alkylene, hydroxy, CpCgalkoxy, CpCghaloalkoxy, mercapto, C r C 8 alkylthio, CpCghaloalkylthio, C r
  • each R 10 is independently halogen, cyano, nitro, Ci-C 8 alkyl, Ci-C 8 haloalkyl, C 2 -C 8 alkenyl, C 2 - Cghaloalkenyl, C 2 -C 8 alkynyl, C 2 -C 8 haloalkynyl, hydroxy, Ci-C 8 alkoxy, CpCghaloalkoxy, mercapto, Cp Cgalkylthio, Ci-C 8 haloalkylthio, Ci-C 8 alkylsulfmyl, Ci-C 8 haloalkylsulfinyl, Ci-C 8 alkylsulfonyl, Cp Cghaloalkylsulfonyl, d-C 8 alkylcarbonyl or CpC 8 alkoxycarbonyl;
  • each R 11 is independently halogen, cyano, nitro, Ci-C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 alkoxy or Cp Qhaloalkoxy;
  • the compounds of formula (I) may exist in different geometric or optical isomers or tautomeric forms.
  • the compounds of the invention may contain one or more asymmetric carbon atoms and may exist as enantiomers (or as pairs of diastereoisomers) or as mixtures of such. This invention covers all such isomers and tautomers and mixtures thereof in all proportions as well as isotopic forms such as deuterated compounds.
  • the compounds of the invention include N-oxides and salts.
  • Alkyl groups can be in the form of a straight or branched chain and are, for example, methyl, ethyl, propyl, prop-2-yl, butyl, but-2-yl, 2-methyl-prop-l -yl or 2-methyl-prop-2- yl.
  • the alkyl groups are preferably C r C 6 , more preferably Ci-C , most preferably C 1 -C3 alkyl groups. Where an alkyl moiety is said to be substituted, the alkyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.
  • Alkylene groups can be in the form of a straight or branched chain and are, for example, -CH 2 - , -CH 2 -CH 2 -, -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 -, or -CH(CH 2 CH 3 )-.
  • the alkylene groups are preferably C 1 -C3, more preferably C 1 -C 2 , most preferably C ⁇ alkylene groups. Where an alkylene moiety is said to be substituted, the alkyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.
  • Alkenyl groups can be in the form of straight or branched chains, and can be, where appropriate, of either the (E)- or (Z)-configuration. Examples are vinyl and allyl.
  • the alkenyl groups are preferably C 2 -C ⁇ 5, more preferably C 2 -C , most preferably C 2 -C 3 alkenyl groups. Where an alkenyl moiety is said to be substituted, the alkyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.
  • Alkynyl groups can be in the form of straight or branched chains. Examples are ethynyl and propargyl.
  • the alkynyl groups are preferably C 2 -C6, more preferably C 2 -C4, most preferably C 2 -C3 alkynyl groups. Where an alkynyl moiety is said to be substituted, the alkyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.
  • Halogen is fluorine, chlorine, bromine or iodine.
  • Haloalkyl groups are alkyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, difluoromethyl, trifluoromethyl,
  • Haloalkenyl groups are alkenyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, 2,2-difluoro-vinyl or 1 ,2-dichloro-2-fluoro-vinyl.
  • Haloalkynyl groups are alkynyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, l-chloro-prop-2-ynyl.
  • Cycloalkyl groups or carbocyclic rings can be in mono- or bi-cyclic form and are, for example, cyclopropyl, cyclobutyl, cyclohexyl and bicyclo[2.2.1]heptan-2-yl.
  • the cycloalkyl groups are preferably C3-C8, more preferably C3-C6 cycloalkyl groups.
  • the cycloalkyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.
  • Aryl groups are aromatic ring systems which can be in mono-, bi- or tricyclic form. Examples of such rings include phenyl, naphthyl, anthracenyl, indenyl or phenanthrenyl. Preferred aryl groups are phenyl and naphthyl, phenyl being most preferred. Where an aryl moiety is said to be substituted, the aryl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.
  • Heteroaryl groups are aromatic ring systems containing at least one heteroatom and consisting either of a single ring or of two or more fused rings.
  • single rings will contain up to three heteroatoms and bicyclic systems up to four heteroatoms which will preferably be chosen from nitrogen, oxygen and sulfur.
  • monocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl (e.g.
  • bicyclic groups include purinyl, quinolinyl, cinnolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzothiophenyl and benzothiazolyl.
  • Monocyclic heteroaryl groups are preferred, pyridyl being most preferred. Where a heteroaryl moiety is said to be substituted, the heteroaryl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.
  • Heterocyclyl groups or heterocyclic rings are defined to include heteroaryl groups and in addition their unsaturated or partially unsaturated analogues.
  • Preferred heterocyclyl groups are a 4 to 7-membered heterocyclic rings containing one to three heteroatoms independently selected from O, S, SO, S0 2 , N, and N(R 14 ) as ring atoms, wherein R 14 is hydrogen, oxygen or R 9 .
  • monocyclic groups include isoxazolyl, thietanyl, pyrrolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, dihydrothiophenyl, [l,3]dioxolanyl, piperidinyl, piperazinyl, [l,4]dioxanyl, morpholinyl, thiophenyl, [l,3]dioxolanyl, piperidinyl,
  • bicyclic groups examples include 2,3-dihydro-benzofuranyl, benzo[l,4]dioxolanyl,
  • heterocyclyl moiety is said to be substituted, the heterocyclyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.
  • Prefered heterocyclyl groups are thiophene, thiophene 1 -oxide, thiophene 1 , 1 -dioxide, dihydrothiophene, dihydrothiophene 1 -oxide, dihydrothiophene 1 , 1 -dioxide, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and tetrazoyl.
  • Somespecific examples of heterocycles are groups A1-A12 wherein q is 0,1 or 2, and Bl to B6 wherein R 14 is hydrogen or R 9 .
  • Heterocyclyl groups (and heteroaryl groups) according to the present invention do not contain adjacent oxygen atoms, adjacent sulphur atoms, or adjacent sulphur and oxygen atoms.
  • Preferred values of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , G 1 , R la , R lb , R 2a , R 2b , R 3 , R 4 , R 5 , R a , R b , R 7 , R 8 , R 9 ' R 10 , R 11 are, in any combination (including combinations of preferred values with the original values) as set out below.
  • G 1 is oxygen
  • Y 1 is oxygen
  • Y 2 , Y 3 and Y 4 are nitrogen.
  • Y 2 is C-H or N, more preferably C-H.
  • Y 3 isC-H or C-R 5 , more preferably C-H.
  • Y 4 is C-H or C-R 5 , more preferably C-H.
  • Y 5 is hydrogen, halogen, C r C 8 alkyl or CpQhaloalkyl, more preferably hydrogen, halogen, Ci-C 4 alkyl or Ci-C 4 haloalkyl, even more preferably hydrogen, halogen, Ci-C 2 alkyl or C r C 2 haloalkyl, most preferably hydrogen, methyl, chloro, bromo or trifluoromethyl.
  • Y is hydrogen, halogen, cyano, CpC 8 alkyl or Ci-C 8 haloalkyl, more preferably hydrogen, halogen, cyano, Ci-C 4 alkyl or Ci-Czihaloalkyl, even more preferably hydrogen, halogen, cyano, Ci-C 2 alkyl or Ci-C 2 haloalkyl, most preferably hydrogen or methyl.
  • At least one of Y 5 and Y 6 is hydrogen.
  • R la is hydrogen, methyl, halomethyl, ethyl, haloethyl, methylcarbonyl or
  • methoxycarbonyl more preferably hydrogen, methyl, halomethyl, ethyl or haloethyl most preferably hydrogen.
  • R la is hydrogen, methyl, halomethyl, ethyl, haloethyl, methylcarbonyl or
  • methoxycarbonyl more preferably hydrogen, methyl, halomethyl, ethyl or haloethyl most preferably hydrogen.
  • R 2a is Ci-C 8 alkyl or C r C 8 alkyl substituted by one to five R 7 , C 2 -C 8 alkenyl or C 2 - Qalkenyl substituted by one to five R 7 , C 2 -C 8 alkynyl or C 2 -C 8 alkynyl substituted by one to five R 7 , C 3 - Ciocycloalkyl or CrCiocycloalkyl substituted by one to five R 8 , C3-Ciocycloalkyl-C(R 12 )(R 13 )- or Cr C 10 cycloalkyl-C(R 12 )(R 13 )- wherein the cycloalkyl is substituted by one to five R 8 , aryl-C(R 12 )(R 13 )- or aryl-C(R 12 )(R 13 )- wherein the aryl is substituted by one to five R 9 , heterocyclyl-C(R 12 )
  • heterocyclyl is a 4 to 7-membered heterocyclic ring containing one to three heteroatoms independently selected from O, S, SO, S0 2 , N and N(R 14 ) as ring atoms;
  • aryl is phenyl
  • R 12 and R 13 are independently hydrogen, cyano, halogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, Cp C 4 alkoxy, Ci-C 4 haloalkoxy or C 3 -C 6 cycloalkyl;
  • R 12 and R 13 together form a three to six membered carbocycle
  • R 14 is hydrogen, oxygen or R 9 ;
  • R la and R 2a together form a 4- or 5-membered ring fragment containing carbon atoms as ring members, optionally substituted by one to five R 9 .
  • R 2a is Ci-Cealkyl or Ci-Cealkyl substituted by one to five R 7 , C 2 -Cealkenyl or C 2 - Cealkenyl substituted by one to five R 7 , C 2 -Cealkynyl or C 2 -Cealkynyl substituted by one to five R 7 , C 3 - C 8 cycloalkyl or C 3 -C 8 cycloalkyl substituted by one to five R 8 , CrC 8 cycloalkyl-C(R 12 )(R 13 )- or Cr C 8 cycloalkyl-C(R 12 )(R 13 )- wherein the cycloalkyl is substituted by one to five R 8 , aryl-C(R 12 )(R 13 )- or aryl-C(R 12 )(R 13 )- wherein the aryl is substituted by one to five R 9 , heterocyclyl-C(R 12 )
  • heterocyclyl is a 4- to 6-membered saturated or partially saturated heterocyclic ring containing one or two heteroatoms independently selected from O, S, SO, SO 2 , N and N(R 14 ) as ring atoms;
  • heterocyclyl is a 5- or 6-membered heteroaryl ring containing one to three heteroatoms independently selected from O, N and S as ring atoms;
  • aryl is phenyl
  • R 12 is hydrogen or CrQalkyl
  • R 13 is hydrogen or Ci-C 4 alkyl
  • R 14 is hydrogen, oxygen or R 9 ;
  • R la and R 2a together form a 4- or 5-membered ring fragment containing carbon atoms as ring members, optionally substituted by one to five R 9 .
  • R 2a is Ci-C 6 alkyl or Ci-C 6 alkyl substituted by one to three R 7 , C 2 -C 6 alkenyl or C 2 -C 6 alkenyl substituted by one to three R 7 , C 2 -C 6 alkynyl or C 2 -C 6 alkynyl substituted by one to three R 7 , C 3 -C 8 cycloalkyl or C 3 -C 8 cycloalkyl substituted by one to three R 8 , C 3 -C 8 cycloalkyl-C(R 12 )(R 13 )- or C 3 -C 8 cycloalkyl-C(R 12 )(R 13 )- wherein the cycloalkyl is substituted by one to three R 8 , aryl-C(R 12 )(R 13 )- or aryl-C(R 12 )(R 13 )- wherein the aryl is substituted by one to threeR 9 , heterocycl
  • heterocyclyl is a 4- to 6-membered saturated or partially saturated heterocyclic ring containing one or two heteroatoms independently selected from O, S, SO, S0 2 , N and N(R 14 ) as ring atoms;
  • heterocyclyl is a 5- or 6-membered heteroaryl ring containing one to three heteroatoms independently selected from O, N and S as ring atoms;
  • aryl is phenyl
  • each R 7 is independently halogen, cyano,hydroxy, Ci-C alkyl, C 2 -C alkenyl, C 2 - Qalkynyl, Q-Qalkoxy, C -C cycloalkyl, mercapto, Ci-C 8 alkylthio, Ci-C 8 haloalkylthio, C r
  • each R 8 is independently halogen, cyano, CrQalkyl or C 3 -C 4 cycloalkyl;
  • each R 9 is independently halogen, cyano, nitro, CrQalkyl, Ci-C 4 haloalkyl, d-Qalkoxy or Ci-C 4 haloalkoxy;
  • R 12 is hydrogen or CrQalkyl
  • R 13 is hydrogen or Ci-C 4 alkyl; and wherein R 14 is hydrogen, oxygen or R 9 ;
  • R la and R 2a together form a 4- or 5-membered ring fragment containing carbon atoms as ring members, optionally substituted by one to three R 9 .
  • R 2a is Ci-C 6 alkyl or Ci-C 6 alkyl substituted by one to three R 7 , C 2 -C 6 alkenyl or C 2 -C 6 alkenyl substituted by one to three R 7 , C 2 -Cealkynyl or C 2 -Cealkynyl substituted by one to three R 7 , C 3 -C 8 cycloalkyl or C 3 -C 8 cycloalkyl substituted by one to three R 8 , C 3 -C 8 cycloalkyl-C(R 12 )(R 13 )- or C 3 -C 8 cycloalkyl-C(R 12 )(R 13 )- wherein the cycloalkyl is substituted by one to three R 8 , aryl-C(R 12 )(R 13 )- or aryl-C(R 12 )(R 13 )- wherein the aryl is substituted by one to threeR 9 , heterocycly
  • heterocyclyl is pyridyl, pyridyl-N-oxide, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl or group Al to A12 (preferably pyridyl or A2);
  • aryl is phenyl
  • each R 7 is independently halogen, cyano, hydroxy, Ci-C 4 alkyl, C 2 -C 4 alkenyl, C 2 - C 4 alkynyl, Ci-C 4 alkoxy, C 3 -C 4 cycloalkyl,mercapto, Ci-C 4 alkylthio, Ci-C 4 haloalkylthio, Cp
  • each R 8 is independently halogen, cyano, Ci-C 4 alkyl or C -C 4 cycloalkyl;
  • each R 9 is independently halogen, cyano, nitro, Ci-C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 alkoxy or Ci-C 4 haloalkoxy;
  • R 12 is hydrogen or methyl
  • R 13 is hydrogen or methyl
  • R 14 is hydrogen, oxygen or R 9 ;
  • R la and R 2a together form a 4- or 5-membered ring fragment containing carbon atoms as ring members, optionally substituted by one to three R 9 .
  • R 2a is CpCealkyl or CpCealkyl substituted by one to three R 7 or C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkyl substituted by one to five R 8 , wherein each R 7 is independently halogen, cyano, Ci-C 4 alkoxy, C -C 4 cycloalkyl, Ci-C 4 alkylthio, Ci-C 4 haloalkylthio, C r C 4 alkylsulfinyl, Ci-C 4 haloalkylsulfinyl, Ci-C 4 alkylsulfonyl or Ci-C 4 haloalkylsulfonyl and each R 8 is independently halogen, Ci-C 4 alkyl or Ci-C 4 haloalkyl.
  • R 2b is C r C 8 alkyl or C r C 8 alkyl substituted by one to five R 7 , C 2 -C 8 alkenyl or C 2 - C 8 alkenyl substituted by one to five R 7 , C 2 -C 8 alkynyl or C 2 -C 8 alkynyl substituted by one to five R 7 , Cp C 6 alkoxy-Ci-C 6 alkyl or Ci-Cealkoxy-Ci-Cealkyl substituted by one to five R 7 , C 3 -Ciocycloalkyl or C 3 - Ciocycloalkyl substituted by one to five R 8 , C 3 -Ciocycloalkyl-C(R 12 )(R 13 )-or C 3 -Ciocycloalkyl- C(R 12 )(R 13 )-substituted by one to five R 8 , aryl-C(R 12 )(R 13 )-substi
  • aryl is phenyl
  • heterocyclyl is a 4- to 7-membered heterocyclic ring containing one to four heteroatoms independently selected from O, S, SO, SO 2 , N and N(R 14 ) as ring atoms;
  • R 12 and R 13 are independently hydrogen, cyano, halogen, Ci-C 4 alkyl, Ci-Czihaloalkyl, Cp C 4 alkoxy, Ci-Czihaloalkoxy or C3-C 6 cycloalkyl, preferably hydrogen or Ci-C 4 alkyl;
  • R 14 is hydrogen, oxygen or R 9 .
  • R 2b is C r C 6 alkyl or Ci-C 6 alkyl substituted by one to five R 7 , C 2 -C 6 alkenyl or C 2 - Cealkenyl substituted by one to five R 7 , C 2 -Cealkynyl or C 2 -Cealkynyl substituted by one to five R 7 , Cp C 6 alkoxy-Ci-C 6 alkyl or Ci-Cealkoxy-Ci-Cealkyl substituted by one to five R 7 , C3-Ciocycloalkyl or C3- Ciocycloalkyl substituted by one to five R 8 , C3-Ciocycloalkyl-C(R 12 )(R 13 )-or C3-Ciocycloalkyl- C(R 12 )(R 13 )-substituted by one to five R 8 , aryl-C(R 12 )(R 13 )- or aryl-Cl substitute
  • aryl is phenyl
  • heterocyclyl is a 4- to 7-membered heterocyclic ring containing one to four heteroatoms independently selected from O, S, SO, SO 2 , N and N(R 14 ) as ring atoms;
  • each R 7 is independently halogen, cyano, hydroxy, Ci-C 4 alkyl, C 2 -C 4 alkenyl, C 2 - C 4 alkynyl, Ci-C 4 alkoxy, C 3 -C cycloalkyl, mercapto, Ci-C alkylthio, Ci-C haloalkylthio, Cp
  • each R 8 is independently halogen, cyano, CrQalkyl or C3-C 4 cycloalkyl;
  • each R 9 is independently halogen, cyano, nitro, CrQalkyl, Ci-C 4 haloalkyl, d-Qalkoxy or Ci-C 4 haloalkoxy;
  • R 12 is hydrogen or d-Qalkyl
  • R 13 is hydrogen or Ci-C alkyl
  • R 14 is hydrogen, oxygen or R 9 .
  • R 2b is CpCealkyl or CpCealkyl substituted by one to five R 7 , C 2 -Cealkenyl or C 2 - Cealkenyl substituted by one to five R 7 , C 2 -Cealkynyl or C 2 -Cealkynyl substituted by one to five R 7 , Cp C 6 alkoxy-Ci-C 6 alkyl or Ci-C 6 alkoxy-Ci-C 6 alkyl substituted by one to five R 7 , C 3 -Ciocycloalkyl or C 3 - Ciocycloalkyl substituted by one to five R 8 , C 3 -Ciocycloalkyl-C(R 12 )(R 13 )-or C 3 -Ci 0 cycloalkyl- C(R 12 )(R 13 )-substituted by one to five R 8 , aryl-C(R 12 )(R 13 )- or
  • heterocyclyl is pyridyl, pyridyl-N-oxide, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl or group Al to A12 (preferably pyridyl or A2);
  • aryl is phenyl; wherein each R 7 is independently halogen, cyano, hydroxy, Ci-C 4 alkyl, C 2 -C 4 alkenyl, C 2 - C 4 alkynyl, Ci-C 4 alkoxy, C 3 -C cycloalkyl, mercapto, Ci-C alkylthio, Ci-C haloalkylthio, Cp
  • each R 8 is independently halogen, cyano, CrQalkyl or C 3 -C cycloalkyl;
  • each R 9 is independently halogen, cyano, nitro, CrQalkyl, Ci-C 4 haloalkyl, d-Qalkoxy or Ci-C 4 haloalkoxy;
  • R 12 is hydrogen or methyl
  • R 13 is hydrogen or methyl
  • R 14 is hydrogen, oxygen or R 9 ;
  • R 2b is CpCealkyl or CpCealkyl substituted by one to three R 7 or C3-C 6 cycloalkyl or C3-C 6 cycloalkyl substituted by one to five R 8 , wherein each R 7 is independently halogen, cyano, Cp Qalkoxy, C3-C 4 cycloalkyl, Ci-C 4 alkylthio, Ci-C 4 haloalkylthio, Ci-C 4 alkylsulfinyl, Ci-C 4 haloalkyl- sulfinyl, Ci-C 4 alkylsulfonyl or Ci-C 4 haloalkylsulfonyl and each R 8 is independently halogen, Ci-C 4 alkyl or Ci-C haloalkyl.
  • R 3 is trifluoromethyl, difluoromethyl or chlorodifluoromethyl, most preferably trifluoromethyl.
  • R 4 is aryl or aryl substituted by one to five R 10 , more preferably aryl substituted by one to three R 10 , more preferably phenyl substituted by one to three R 10 .
  • R 4 is group (A)
  • X 2 is C-X 4 or nitrogen (preferably C-X 4 );
  • X 1 , X 3 and X 4 are independently hydrogen, halogen or trihalomethyl, e.g. wherein at least two of X 1 , X 3 and X 4 are not hydrogen.
  • R 4 is 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 3-fluoro-4-chlorophenyl, 3,4- dichlorophenyl, 3-chloro-4-bromophenyl, 3,5-dichloro-4-fluorophenyl, 3,4,5-trichlorophenyl, 3,5- dichloro-4-iodophenyl, 3,4,5-trifluorophenyl, 3-chloro-5-bromophenyl, 3 -chloro-5 -fluorophenyl, 3- chloro-5-(trifluoromethyl)phenyl, 3,4-dichloro-5-(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, 4-chloro-3,5-bis(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 2,6-dichloro-4-pyridyl, 2,6- bis(trifluoromethyl)-4
  • R 4 is 3,5-dichloro-4-fluorophenyl-. In one group of compounds R 4 is 3,4,5-trichlorophenyl-. In one group of compounds R 4 is 3,5-bis(trifluoromethyl)phenyl.
  • each R 5 is independently halogen, cyano, methyl, halomethyl, methoxy or
  • halomethoxy more preferably chloro, fluoro, cyano or methyl.
  • R a is hydrogen, cyano, Ci-C 4 alkyl more preferably hydrogen, cyano, Ci-C 2 alkyl orCi-C 2 haloalkyl,even more preferably hydrogen or methyl.
  • R b is hydrogen, cyano, Ci-C 4 alkyl or Ci-C 4 haloalkyl, more preferably hydrogen, cyano, Ci-C 2 alkyl or Ci-C 2 haloalkyl, even more preferably hydrogen or methyl, most preferably hydrogen.
  • Ci-C 4 haloalkylthio Ci-C 4 haloalkylthio,Ci-C 4 alkylsulfinyl or Ci-C 4 alkylsulfonyl, even more preferably halogen, cyano, Ci-C 4 alkoxy, Ci-C 4 haloalkylthio, Ci-C 4 alkylsulfinyl, Ci-C 4 haloalkylsulfinyl, Ci-C 4 alkylsulfonyl or most preferably halogen, cyano, methoxy, methylthio, methylsulfinyl or methysulfonyl.
  • each R 8 is independently halogen, cyano, Ci-C 4 alkyl Ci-C 4 alkoxy or C 3 -C 6 cycloalkyl, more preferably halogen, cyano, methyl, propyl or butyl, more preferably chloro, fluoro, cyano, methyl or propyl, most preferably fluoro, cyano, methyl or propyl.
  • each R 9 is independently halogen, cyano, nitro, CpCgalkyl, Ci-Cghaloalkyl, hydroxy, CpCgalkoxy, CpCghaloalkoxy, mercapto, CpCgalkylthio, CpCghaloalkylthio, Ci-Cgalkylsulfinyl, Cp Cghaloalkylsulfinyl, Ci-Cgalkylsulfonyl or Ci-Cghaloalkylsulfonyl, more preferably halogen, cyano, nitro, Ci-C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 alkoxy or Ci-C 4 haloalkoxy, most preferably halogen, cyano, methyl, halomethyl, methoxy or halomethoxy.
  • each R 10 is independently halogen, CpCgalkyl, Ci-Cghaloalkyl, CpCgalkoxy, Cp Cghaloalkoxy, CpCgalkylthio or Ci-Cghaloalkylthio, more preferably bromo, chloro, fluoro,
  • trifluoromethyl methoxy or methylthio, most preferably trifluoromethyl, fluoro or chloro.
  • each R 11 is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy, more preferably bromo, chloro, fluoro, nitro, or methyl, most preferably chloro, fluoro or methyl.
  • the compound of formula I is in the trans configuration.
  • E1Q is Ql.
  • E2 Q is Q2.
  • Embodiment E5 is embodiment El wherein the compound of formula I is in the trans configuration.
  • Embodiment E6 is embodiment E2 wherein the compound of formula I is in the trans configuration.
  • Embodiment E7 is embodiment E2 wherein Y 5 and Y 6 are hydrogen.
  • Embodiment E8 is embodiment El wherein G 1 is oxygen.
  • Embodiment E9 is embodiment E2 wherein G 1 is oxygen.
  • E10Y 2 is C-H and Y 3 and Y 4 are C-H or C-R 5 wherein no more than one of Y 3 and Y 4 is C-R 5 .
  • Embodiment El 1 is embodiment E10 wherein Y 1 is oxygen.
  • Embodiment El 2 is embodiment E10 wherein R 3 is trifluoromethyl, difluoromethyl or chlorodifluoromethyl.
  • Embodiment El 3 is embodiment E10 wherein R 4 is group A.
  • Embodiment El 4 is embodiment El l wherein R 3 is trifluoromethyl, difluoromethyl or chlorodifluoromethyl.
  • Embodiment El 5 is embodiment El l wherein R 4 is group A.
  • Embodiment El 6 is embodiment E14 wherein R 4 is group A.
  • Embodiment El 7 is embodiment E10 wherein G 1 is oxy ⁇ *en.
  • Embodiment El 8 is embodiment El l wherein G 1 is oxy ⁇ *en.
  • Embodiment El 9 is embodiment E12 wherein G 1 is oxy ⁇ *en.
  • Embodiment E20 is embodiment E13 wherein G 1 is oxy ⁇ *en.
  • Embodiment E21 is embodiment E14 wherein G 1 is oxy ⁇ *en.
  • Embodiment E22 is embodiment E15 wherein G 1 is oxy ⁇ *en.
  • Embodiment E22 is embodiment E16 wherein G 1 is oxy ⁇ *en.
  • G 1 is oxygen; Y 1 is oxygen;
  • Y 2 is C-H
  • Y 3 and Y 4 are C-H or C-R 5 ,wherein no more than one of Y 3 and Y 4 is C-R 5 ;
  • Y 5 is hydrogen, halogen, Ci-C 4 alkyl or Ci-C 4 haloalkyl
  • Y 6 is hydrogen, halogen, cyano, Ci-C 4 alkyl or Ci-C 4 haloalkyl;
  • R la is hydrogen, methyl, halomethyl, ethyl or haloethyl
  • R lb is hydrogen, methyl, halomethyl, ethyl or haloethyl
  • R 2a is CpCgalkyl or CpCgalkyl substituted by one to five R 7 , C 2 -Cgalkenyl or C 2 -Cgalkenyl substituted by one to five R 7 , C 2 -C 8 alkynyl or C 2 -Cgalkynyl substituted by one to five R 7 , C3- Ciocycloalkyl or C 3 -Ci 0 cycloalkyl substituted by one to five R 8 , C 3 -Ci 0 cycloalkyl-C(R 12 )(R 13 )- or C 3 - Ciocycloalkyl-C(R 12 )(R 13 )- wherein the cycloalkyl is substituted by one to five R 8 , aryl-C(R 12 )(R 13 )- or aryl-C(R 12 )(R 13 )- wherein the aryl is substituted by one to five R 9 , heterocyclyl-C(R 12
  • heterocyclyl is a 4 to 7-membered heterocyclic ring containing one to three heteroatoms independently selected from O, S, SO, S0 2 , N, and N(R 14 ) as ring atoms;
  • aryl is phenyl
  • R la and R 2a together form a 4- or 5-membered ring fragment containing carbon atoms as ring members, optionally substituted by one to five R 9 ;
  • R 2b is C r C 8 alkyl or Ci-C 8 alkyl substituted by one to five R 7 , C 2 -C 8 alkenyl or C 2 -C 8 alkenyl substituted by one to five R 7 , C 2 -C 8 alkynyl or C 2 -Cgalkynyl substituted by one to five R 7 , CpCealkoxy- CpCealkyl or Ci-Cealkoxy-Ci-Cealkyl substituted by one to five R 7 , C3-Ciocycloalkyl or C3-Ciocycloalkyl substituted by one to five R 8 , C 3 -Ci 0 cycloalkyl-C(R 12 )(R 13 )-or C 3 -Ci 0 cycloalkyl-C(R 12 )(R 13 )-substituted by one to five R 8 , aryl-C(R 12 )(R 13 )- or
  • aryl is phenyl
  • heterocyclyl is a 4- to 7-membered heterocyclic ring containing one to four heteroatoms independently selected from O, S, SO, S0 2 , N and N(R 14 ) as ring atoms;
  • R 3 is trifluoromethyl, difluoromethyl or chlorodifluoromethyl
  • R 4 is group A, wherein X 2 is C-X 4 or nitrogen and X 1 , X 3 and X 4 are independently hydrogen, halogen or trihalomethyl, providing that at least one of X 1 , X 3 and X 4 is not hydrogen;
  • R 5 is halogen, cyano, Ci-C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 alkoxy or Ci-C 4 haloalkoxy;
  • R a is hydrogen, cyano, Ci-C 4 alkyl or Ci-C 4 haloalkyl
  • R b is hydrogen, cyano, d-Qalkyl or Ci-C 4 haloalkyl.
  • R 12 and R 13 are independently hydrogen, cyano, halogen, CpQalkyl, Ci-C haloalkyl, Q- Qalkoxy, Ci-C 4 haloalkoxy or C3-C 6 cycloalkyl; or R 12 and R 13 together form a three to six membered carbocycle; and
  • R 14 is hydrogen, oxygen or R 9 .
  • G 1 is oxygen
  • Y 1 is oxygen
  • Y 2 is C-H
  • Y 3 and Y 4 are C-H or C-R 5 , wherein no more than one of Y 3 and Y 4 is C-R 5 ;
  • Y 5 is hydrogen, halogen, Ci-C 2 alkyl or Ci-C 2 haloalkyl
  • Y 6 is hydrogen, halogen, cyano, Ci-C 2 alkyl or Ci-C 2 haloalkyl;
  • R la is hydrogen, methyl, halomethyl, ethyl or haloethyl
  • R lb is hydrogen, methyl, halomethyl, ethyl or haloethyl
  • R 2a is CpCealkyl or CpCealkyl substituted by one to five R 7 , C 2 -Cealkenyl or C 2 -Cealkenyl substituted by one to five R 7 , C 2 -Cealkynyl or C 2 -Cealkynyl substituted by one to five R 7 , Ca-Cgcycloalkyl or C3-C 8 cycloalkyl substituted by one to five R 8 , C3-C 8 cycloalkyl-C(R 12 )(R 13 )- or Ca-Cgcycloalkyl- C(R 12 )(R 13 )- wherein the cycloalkyl is substituted by one to five R 8 , aryl-C(R 12 )(R 13 )- or aryl-C(R 12 )(R 13 )- wherein the aryl is substituted by one to five R 9 , heterocyclyl-C(R 12 )(R
  • heterocyclyl is a 4- to 6-membered saturated or partially saturated heterocyclic ring containing one or two heteroatoms independently selected from O, S, SO, S0 2 , N and N(R 14 ) as ring atoms;
  • heterocyclyl is a 5- or 6-membered heteroaryl ring containing one to three heteroatoms independently selected from O, N and S as ring atoms;
  • aryl is phenyl
  • R la and R 2a together form a 4- or 5 -membered ring fragment containing carbon atoms as ring members, optionally substituted by one to five R 9 ;
  • R 2b is C r C 6 alkyl or Ci-C 6 alkyl substituted by one to five R 7 , C 2 -C 6 alkenyl or C 2 -C 6 alkenyl substituted by one to five R 7 , C 2 -Cealkynyl or C 2 -Cealkynyl substituted by one to five R 7 , CpCealkoxy- CpCealkyl or Ci-Cealkoxy-Ci-Cealkyl substituted by one to five R 7 , C3-Ciocycloalkyl or C3-Ciocycloalkyl substituted by one to five R 8 , C 3 -C 10 cycloalkyl-C(R 12 )(R 13 )-or C 3 -C 10 cycloalkyl-C(R 12 )(R 13 )-substituted by one to five R 8 , aryl-C(R 12 )(R 13 )- or aryl-
  • aryl is phenyl
  • heterocyclyl is a 4- to 7-membered heterocyclic ring containing one to four heteroatoms independently selected from O, S, SO, SO 2 , N and N(R 14 ) as ring atoms;
  • R 3 is trifluoromethyl, difluoromethyl or chlorodifluoromethyl
  • R 4 is group A, wherein X 2 is C-X 4 or nitrogen and X 1 , X 3 and X 4 are independently hydrogen, halogen or trihalomethyl, proving that at least one of X 1 , X 3 and X 4 is not hydrogen;
  • R 5 is halogen, cyano, methyl, halomethyl, methoxy or halomethoxy
  • R a is hydrogen, cyano, Ci-C 2 alkyl or Ci-C 2 haloalkyl
  • R b is hydrogen, cyano, Ci-C 2 alkyl or Ci-C 2 haloalkyl
  • each R 7 is independently halogen, cyano, hydroxy, Ci-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, Cp Cgalkoxy, C3-C 4 cycloalkyl, mercapto, Ci-Cgalkylthio, Ci-Cghaloalkylthio, Ci-Cgalkylsulfmyl, Cp Cghaloalkylsulfinyl, Ci-Cgalkylsulfonyl or Ci-Cghaloalkylsulfonyl;
  • each R 8 is independently halogen, cyano, C r C 4 alkyl or C 3 -C 4 cycloalkyl;
  • each R 9 is independently halogen, cyano, nitro, Ci-C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 alkoxy or Q- C 4 haloalkoxy;
  • R 12 is hydrogen or Ci-C 4 alkyl
  • R 13 is hydrogen, cyano, halogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkoxy or C 3 -C 6 cycloalkyl;
  • R 12 and R 13 together form a 3 - to 6-membered carbocycle
  • R 14 is hydrogen, oxygen or R 9 .
  • G 1 is oxygen
  • Y 1 is oxygen
  • Y 2 , Y 3 and Y 4 are C-H;
  • Y 5 is hydrogen, methyl, chloro, bromo or trifluoromethyl
  • Y 6 is hydrogen or methyl
  • R la is hydrogen, methyl, halomethyl, ethyl or haloethyl
  • R lb is hydrogen, methyl, halomethyl, ethyl or haloethyl
  • R 2a is Ci-C 6 alkyl or Ci-C 6 alkyl substituted by one to three R 7 , C 2 -C 6 alkenyl or C 2 -C 6 alkenyl substituted by one to three R 7 , C 2 -C 6 alkynyl or C 2 -C 6 alkynyl substituted by one to three R 7 , C 3 - Cgcycloalkyl or Ca-Cgcycloalkyl substituted by one to three R 8 , C3-C 8 cycloalkyl-C(R 12 )(R 13 )- or C3- C 8 cycloalkyl-C(R 12 )(R 13 )- wherein the cycloalkyl is substituted by one to three R 8 , aryl-C(R 12 )(R 13 )- or aryl-C(R )(R )- wherein the aryl is substituted by one to three R , heterocyclyl-C(R )(R )
  • heterocyclyl is pyridyl, pyridyl-N-oxide, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl or group Al to A12 (preferably pyridyl or A2);
  • aryl is phenyl; or R la and R 2a together form a 4- or 5-membered ring fragment containing carbon atoms as ring members, optionally substituted by one to three R 9 .
  • R 2b is Ci-C 6 alkyl or Ci-C 6 alkyl substituted by one to three R 7 , C 2 -C 6 alkenyl or C 2 -C 6 alkenyl substituted by one to three R 7 , C 2 -C 6 alkynyl or C 2 -C 6 alkynyl substituted by one to three R 7 ,
  • heterocyclyl is pyridyl, pyridyl-N-oxide, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl or group Al to A12 (preferably pyridyl or A2);
  • aryl is phenyl
  • R 3 is trifluoromethyl
  • R 4 is group A, wherein X 2 is C-X 4 and X 1 , X 3 and X 4 are independently hydrogen, halogen or trihalomethyl, proving that at least one of X 1 , X 3 and X 4 is not hydrogen;
  • R a is hydrogen or methyl
  • R b is hydrogen or methyl
  • each R 7 is independently halogen, cyano, hydroxy, Ci-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C r C 4 alkoxy, C 3 -C 4 cycloalkyl, mercapto, Ci-C 4 alkylthio, Ci-C 4 haloalkylthio, Ci-C 4 alkylsulfinyl, Cp C 4 haloalkylsulfinyl, Ci-C 4 alkylsulfonyl or Ci-C 4 haloalkylsulfonyl;
  • each R 8 is independently halogen, cyano, C r C 4 alkyl or C -C 4 cycloalkyl;
  • each R 9 is independently halogen, cyano, nitro, Ci-C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 alkoxy or Cp C 4 haloalkoxy;
  • R 12 is hydrogen or methyl
  • R 13 is hydrogen or methyl.
  • G 1 is oxygen
  • Y 1 is oxygen
  • Y 2 , Y 3 and Y 4 are C-H;
  • Y 5 is hydrogen, methyl, chloro, bromo or trifluoromethyl
  • Y 6 is hydrogen or methyl
  • R la is hydrogen, methyl, halomethyl, ethyl or haloethyl
  • R 2a is CpCealkyl or CpCealkyl substituted by one to three R 7 , C 2 -Cealkenyl or C 2 -Cealkenyl substituted by one to three R 7 , C 2 -Cealkynyl or C 2 -Cealkynyl substituted by one to three R 7 , C 3 - Cgcycloalkyl or CrCgcycloalkyl substituted by one to three R 8 , C 3 -C 8 cycloalkyl-C(R 12 )(R 13 )- or C 3 - C 8 cycloalkyl-C(R 12 )(R 13 )- wherein the cycloalkyl is substituted by one to three R 8 , aryl-C(R 12 )(R 13 )- or
  • aryl-C(R )(R )- wherein the aryl is substituted by one to three R , heterocyclyl-C(R )(R )-, aryl or aryl substituted by one to three R 9 , heterocyclyl or heterocyclyl substituted by one to three R 9 , C r C 4 alkyl-0-
  • heterocyclyl is pyridyl, pyridyl-N-oxide, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, tnazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl or group Al to A12 (preferably pyridyl or A2);
  • aryl is phenyl
  • R la and R 2a together form a 4- or 5-membered ring fragment containing carbon atoms as ring members, optionally substituted by one to three R 9 .
  • R 3 is trifluoromethyl
  • R 4 is group A, wherein X 2 is C-X 4 and X 1 , X 3 and X 4 are independently hydrogen, halogen or trihalomethyl, proving that at least one of X 1 , X 3 and X 4 is not hydrogen;
  • each R 7 is independently halogen, cyano, hydroxy, Ci-C 4 alkyl, C2-C 4 alkenyl, C2-C 4 alkynyl, Cp Qalkoxy, C 3 -C cycloalkyl, mercapto, Ci-C alkylthio, Ci-C haloalkylthio, Ci-C alkylsulfinyl, C r Qhaloalkylsulfinyl, Ci-C alkylsulfonyl or Ci-C haloalkylsulfonyl;
  • each R 8 is independently halogen, cyano, C r C alkyl, or C 3 -C cycloalkyl;
  • each R 9 is independently halogen, cyano, nitro, CrQalkyl, Ci-C haloalkyl, CpQalkoxy or Q- Qhaloalkoxy;
  • R 12 is hydrogen or methyl
  • R 13 is hydrogen or methyl.
  • G 1 is oxygen
  • Y 1 is oxygen
  • Y 2 , Y 3 and Y 4 are C-H;
  • Y 5 is hydrogen or methyl
  • Y 6 is hydrogen or methyl
  • R lb is hydrogen, methyl, halomethyl, ethyl or haloethyl
  • R 2b is Ci-C 6 alkyl or Ci-C 6 alkyl substituted by one to three R 7 , C 2 -C 6 alkenyl or C 2 -C 6 alkenyl substituted by one to three R 7 , C 2 -C 6 alkynyl or C 2 -C 6 alkynyl substituted by one to three R 7 ,
  • heterocyclyl is pyridyl, pyridyl-N-oxide, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl or group Al to A12 (preferably pyridyl or A2);
  • aryl is phenyl;
  • R 3 is trifluoromethyl;
  • R 4 is group A, wherein X 2 is C-X 4 and X 1 , X 3 and X 4 are independently hydrogen, halogen or trihalomethyl, proving that at least one of X 1 , X 3 and X 4 is not hydrogen;
  • R a is hydrogen or methyl
  • R b is hydrogen or methyl
  • each R 7 is independently halogen, cyano, hydroxy, Ci-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, Cp C 4 alkoxy, C3-C 4 cycloalkyl, mercapto, Ci-C 4 alkylthio, Ci-C 4 haloalkylthio, Ci-C 4 alkylsulfinyl, Cp C 4 haloalkylsulfinyl, Ci-C 4 alkylsulfonyl or Ci-C 4 haloalkylsulfonyl;
  • each R 8 is independently halogen, cyano, C r C 4 alkyl, or C 3 -C 4 cycloalkyl;
  • each R 9 is independently halogen, cyano, nitro, Ci-C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 alkoxy or Q- C 4 haloalkoxy;
  • R 12 is hydrogen or methyl
  • R 13 is hydrogen or methyl.
  • Y 1 is oxygen
  • Y 1 is sulfur
  • Y 1 is CH 2 .
  • Q is Ql and R 2a is CpCgalkyl or CpCgalkyl substituted by one to five R 7 , C 2 -C 8 alkenyl or C 2 -C 8 alkenyl substituted by one to five R 7 , C 2 -C 8 alkynyl or C 2 -C 8 alkynyl substituted by one to five R 7 .
  • Q is Ql and R 2a is C 3 -Ci 0 cycloalkyl or C 3 -Ciocycloalkyl substituted by one to five R 8 , C 3 -Ciocycloalkyl-Ci-C 4 alkylene or C -Ci 0 cycloalkyl-Ci-C 4 alkylene substituted by one to five R 8 .
  • Q is Ql and R 2a is aryl-Ci-C 4 alkylene- or aryl-Ci-C 4 alkylene- substituted by one to five R 9 , aryl or aryl substituted by one to five R 9 .
  • Q is Ql and R 2a is heterocyclyl-Ci-C 4 alkylene- or heterocyclyl-Cr C 4 alkylene- substituted by one to five R 9 , heterocyclyl or heterocyclyl substituted by one to five R 9 .
  • Q is Q2 and R 2b is CpCgalkyl or CpCgalkyl substituted by one to five R 7 , C 2 -C 8 alkenyl or C 2 -C 8 alkenyl substituted by one to five R 7 , C 2 -C 8 alkynyl or C 2 -C 8 alkynyl substituted by one to five R 7 , Ci-Cgalkoxy-CpCgalkyl or CpCgalkoxy-Ci-Cgalkyl substituted by one to five R 7 .
  • Q is Q2 and R 2b is C 3 -Ci 0 cycloalkyl or C 3 -Ci 0 cycloalkyl substituted by one to five R 8 , C -Ci 0 cycloalkyl-Ci-C 4 alkylene or C -Ci 0 cycloalkyl-Ci-C 4 alkylene substituted by one to five R 8 .
  • Q is Q2 and R 2b is aryl-Ci-C 4 alkylene- or aryl-Ci-C 4 alkylene- substituted by one to five R 9 , aryl or aryl substituted by one to five R 9 .
  • Q is Q2 and R 2b is heterocyclyl-Ci-C 4 alkylene- or heterocyclyl-Cr C 4 alkylene- substituted by one to five R 9 , heterocyclyl or heterocyclyl substituted by one to five R 9 .
  • the present invention also provides intermediates useful for the preparation of compounds of formula I.
  • Y , Y , Y% Y , Y Y , R , R j , R , R 6a and R 6b are as defined for compounds of formula I, or a salt or N-oxide thereof
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , R 1 , R 3 , R 4 , R a and R b are as defined for compounds of formula I.
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , R 3 , R 4 , R a and R b are as defined for compounds of formula I and or a salt or N-oxide thereof
  • the preferred definitions of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , R 1 , R 4 , R a and R b are as defined for compounds of formula I.
  • R is a leaving group (preferably hydroxy, C r C 15 alkoxy, CI, F or Br),and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , G 1 , R 3 and R 4 are as defined for compounds of formula I and or a salt or N-oxide thereof.
  • a leaving group is for example 1 -pyrrolyl, 1 -benzotriazolyl, 1 -pyrazolyl, 1 -tetrazolyl, N-succinimidyloxy, N- phthalimidyloxy, 1 -benzotriazolyloxy, N-piperidyloxy, N-l,2,3-benzotriazin-4-onyloxy, SCl -ClOalkyl, SAryl, pentafluorophenoxy, 4-nitrophenoxy, 3-pyridyloxy, 2,4,5 -trichlorophenoxy, or
  • R a is hydroxy, PPh 3 , Br or CI
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , R 3 and R 4 are as defined for compounds of formula I or a salt or N-oxide thereof.
  • the preferred definitions of Y , Y , Y , Y , Y , R and R are as defined for compounds of formula I.
  • R a is OH.
  • In another group of compounds of formula Int-IV R a is PPh 3 .
  • Int-IV is Br or CI.
  • Y 1 is hydroxy
  • R b is nitro or halogen
  • R 31 is nitro, cyano, fluoro, chloro, bromo, iodo or C(0)R' wherein R' is hydroxy, Ci-Ci 5 alkoxyor Ci 2 3 4 3 4
  • Y 6 is hydrogen, hydroxy, halogen, CpCgalkyl, CpCghaloalkyl or C 3 -C 8 cycloalkyl and Y 1 , Y 2 , Y 3 , Y 4 , R 3 and R 4 are as defined for compounds of formula I, or a salt or N-oxide thereof.
  • R c is NH 2 or R , wherein R is nitro, cyano, halogen (e.g. fluoro, chloro, bromo,
  • each R JJ is independently C r C 6 alkyland Y , Y ⁇ Y ⁇ Y Y°, R J and R" are as defined for compounds of formula I, or a salt or N-oxide thereof.
  • the preferred definitions of and Y 1 , Y 2 , Y 3 , Y 4 , Y 6 , R 3 and R 4 are as defined for compounds of formula I.
  • compounds of formula I** are more biologically active than compounds of formula I*.
  • the invention includes mixtures of compounds I* and I** in any ratio e.g. in a molar ratio of 1 :99 to 99: 1, e.g. 10:1 to 1 : 10, e.g. a substantially 50:50 molar ratio.
  • the molar proportion of compound I** compared to the total amount of both enantiomers (or epimers) is for example greater than 50%, e.g. at least 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or at least 99%.
  • the molar proportion of the compound of formula I* compared to the total amount of both enantiomers (or epimers) is for example greater than 50%, e.g. at least 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or at least 99%.
  • Enantiomerically (or epimerically) enriched mixtures of formula I** are preferred.Each compound disclosed in Tables 1 to 179represents a disclosure of a compound according to the compound of formula I*, and a disclosure according to the compound of formula I**.
  • Table 1 provides 192 compounds of formula IA wherein R2a is l-oxo-tetrahydrofuran-3-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 2 provides 192 compounds of formula LA wherein R2a is l -oxo-thietan-3-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 3 provides 192 compounds of formula LA wherein R2a is l,l-dioxo-tetrahydrofuran-3-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 4 provides 192 compounds of formula LA wherein R2a is l,l -dioxo-thietan-3-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 5 provides 192 compounds of formula IA wherein R2a is (l,l -dioxo-thietan-2-yl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 6 provides 192 compounds of formula IA wherein R2a is 4-oxo-2-(trifluoromethyl)-l,3- oxazinan-5-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 7 provides 192 compounds of formula LA wherein R2a is 3-oxo-2-(cyclopropylmethyl)- isoxazolidin-4-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 8 provides 192 compounds of formula IA wherein R2a is 2,5 -dioxo-1 -(2,2,2- trifluoroethyl)pyrrolidin-3-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 9 provides 192 compounds of formula LA wherein R2a is N-(3,3,3-trifluoropropyl)acetamid-2- yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 10 provides 192 compounds of formula LA wherein R2a is N-(2,2,2-trifluoroethyl)acetamid-2- yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 11 provides 192 compounds of formula IA wherein R2a is 2-methoxy-ethyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 12 provides 192 compounds of formula IA wherein R2a is 3-chloroprop-l -yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 13 provides 192 compounds of formula LA wherein R2a is 3,3,3-trifluoro-propyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 14 provides 192 compounds of formula LA wherein R2a is (thietan-2-yl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 15 provides 192 compounds of formula IA wherein R2a is l-oxo-thietan-3-yl-methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 16 provides 192 compounds of formula IA wherein R2a is (oxetan-2-yl)-methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 17 provides 192 compounds of formula LA wherein R2a is (thiazol-4-yl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 18 provides 192 compounds of formula IA wherein R2a is (2-pyrimid-2-yl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 19 provides 192 compounds of formula LA wherein R2a is (thietan-3-yl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 20 provides 192 compounds of formula LA wherein R2a is (l,l-dioxo-thietan-3-yl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 21 provides 192 compounds of formula LA wherein R2a is (N-methoxypiperid-4-yl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 22 provides 192 compounds of formula LA wherein R2a is (tetrahydrofuran-2-yl)-methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 23 provides 192 compounds of formula IA wherein R2a is (2-pyridyl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 24 provides 192 compounds of formula LA wherein R2a is phenylmethyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 25 provides 192 compounds of formula IA wherein R2a is (cyclobutyl)methyl, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 26 provides 192 compounds of formula IA wherein R2a is (2-fluorophenyl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 27 provides 192 compounds of formula LA wherein R2a is N-ethylacetamid-2-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 28 provides 192 compounds of formula IA wherein R2a is N-(but-2-yl)acetamid-2-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 29 provides 192 compounds of formula IA wherein R2a is 2,2,2-trifluoro-ethyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 30 provides 192 compounds of formula IA wherein R2a is tetrahydrofuran-2-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 31 provides 192 compounds of formula LA wherein R2a is thietan-3-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 32 provides 192 compounds of formula LA wherein R2a is 3-oxo-2-(3,3,3-trifluoro-propyl)- isoxazolidin-4-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 33 provides 192 compounds of formula IA wherein R2a is 3-oxetanyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 34 provides 192 compounds of formula LA wherein R2a is tetrahydrofuran-2-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 35 provides 192 compounds of formula LA wherein R2a is 2-oxo-l -(2,2,2- trifluoroethyl)pyrrolidin-3-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 36 provides 192 compounds of formula IA wherein R2a is cyclobutyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 37 provides 192 compounds of formula LA wherein R2a is 2-norbornyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 38 provides 192 compounds of formula LA wherein R2a is cyclopropyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 39 provides 192 compounds of formula LA wherein R2a is 3-(hydroxyimino)-cyclobutyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 40 provides 192 compounds of formula LA wherein R2a is 3-(ethoxyimino)-cyclobutyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 41 provides 192 compounds of formula LA wherein R2a is 2-oxopyrrolidin-3-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 42 provides 192 compounds of formula LA wherein R2a is 3-oxo-2-(2,2,2-trifluoro-ethyl)- isoxazolidin-4-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 43 provides 192 compounds of formula LA wherein R2a is 3-oxo-2-(2,2-difluoro-ethyl)- isoxazolidin-4-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 44 provides 192 compounds of formula LA wherein R2a is 3-methyloxetan-3-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 45 provides 192 compounds of formula LA wherein R2a is l -phenyleth-l-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 46 provides 192 compounds of formula IA wherein R2a is 1 -cyanocyclopropyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 47 provides 192 compounds of formula IA wherein R2a is 2-fluoro-cycloprop-l -yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 48 provides 192 compounds of formula IA wherein R2a is l,l,l-trifluoroprop-2-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 49 provides 192 compounds of formula LA wherein R2a is 2-methylsulfanyl-ethyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 50 provides 192 compounds of formula IA wherein R2a is N-methoxyethaniminyl, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 51 provides 192 compounds of formula LA wherein R2a is 3-(methoxyimino)-cyclobutyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 52 provides 192 compounds of formula LA wherein R2a is N-ethoxyethaniminyl, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 53 provides 192 compounds of formula LA wherein R2a is 3-oxo-2-ethylisoxazolidin-4-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 54 provides 192 compounds of formula LA wherein R2a is 2-oxo-l-(ethyl)pyrrolidin-3-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 55 provides 192 compounds of formula LA wherein R2a is but-l-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 56 provides 192 compounds of formula LA wherein R2a is but-2-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 57 provides 192 compounds of formula IA wherein R2a is 1 -methoxy-prop-2-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 58 provides 192 compounds of formula LA wherein R2a is 2-oxo-l-methylpyrrolidin-3-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 59 provides 192 compounds of formula LA wherein R2a is 3-oxo-2-methylisoxazolidin-4-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 60 provides 192 compounds of formula LA wherein R2a is prop-2-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 61 provides 192 compounds of formula LA wherein R2a is methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 62 provides 192 compounds of formula IA wherein R2a is ethyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 63 provides 192 compounds of formula LA wherein R2a is prop-l -yl, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 64 provides 192 compounds of formula IA wherein R2a is 2,2-difluoro-ethyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 65 provides 192 compounds of formula IA wherein R2a is l -oxo-thietan-3-yl-ethyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 66 provides 192 compounds of formula IA wherein R2a is tetrahydropyran-4-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 67 provides 192 compounds of formula LA wherein R2a is 2-fluoro-ethyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 68 provides 192 compounds of formula LA wherein R2a is thietan-3-yl-ethyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 69 provides 192 compounds of formula LA wherein R2a is cyclopentyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 70 provides 192 compounds of formula LA wherein R2a is (2-cyclopropyl-l-oxa-3,4-diazol-5- yl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 71 provides 192 compounds of formula LA wherein R2a is 2-thiazolinyl, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 72 provides 192 compounds of formula LA wherein R2a is 4-cyanopyrimid-2-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 73 provides 192 compounds of formula IA wherein R2a is (pyrimidin-5-yl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 74 provides 192 compounds of formula LA wherein R2a is 2-chloropyrid-5-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 75 provides 192 compounds of formula LA wherein R2a is (pyrazin-2-yl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 76 provides 192 compounds of formula LA wherein R2a is (2-chlorothiazol-5-yl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 77 provides 192 compounds of formula IA wherein R2a is 2-methylsulfmyl-ethyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 78 provides 192 compounds of formula LA wherein R2a is 2-(methylsulfonyl)-ethyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 79 provides 192 compounds of formula LA wherein R2a is N-methylpiperidin-4-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 80 provides 192 compounds of formula IA wherein R2a is N-(3,3,3- trifluoropropanoyl)piperidin-4-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 81 provides 192 compounds of formula LA wherein R2a is l-(2-chloro-pyrid-5-yl)eth-l-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 82 provides 192 compounds of formula LA wherein R2a is N-cyclopropylacetamid-2-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 83 provides 192 compounds of formula IA wherein R2a is (2-chloro-pyrid-3-yl)-methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 84 provides 192 compounds of formula IA wherein R2a is 3-oxo-2-propargylisoxazolidin-4- yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 85 provides 192 compounds of formula IA wherein R2a is (3-fluorophenyl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 86 provides 192 compounds of formula IA wherein R2a is (2-fluorophenyl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 87 provides 192 compounds of formula IA wherein R2a is (l -oxo-thietan-3-yl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 88 provides 192 compounds of formula IA wherein R2a is N-(cyclopropyl)acetamid-2-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 89 provides 192 compounds of formula IA wherein R2a is (4-chlorophenyl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 90 provides 192 compounds of formula IA wherein R2a is l-methyl-l -(pyrid-2-yl)eth-l -yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 91 provides 192 compounds of formula IA wherein R2a is 1 -(2-pyridyl)cyclopropyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 92 provides 192 compounds of formula IA wherein R2a is (2-chloro-pyrid-5-yl)-methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 93 provides 192 compounds of formula IA wherein R2a is (2-chloro-pyrid-4-yl)-methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 94 provides 192 compounds of formula IA wherein R2a is N-(benzyl)acetamid-2-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 95 provides 192 compounds of formula IA wherein R2a is N-(2-fluorobenzyl)acetamid-2-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
  • Table 96 provides 144 compounds of formula IB wherein R2b is ethyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 97 provides 144 compounds of formula IB wherein R2b is 2,2,2-trifluoro-ethyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 98 provides 144 compounds of formula IB wherein R2b is prop-2-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 99 provides 144 compounds of formula IB wherein R2b is methyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 100 provides 144 compounds of formula IB wherein R2b is 2-fluoro-cycloprop-l-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 101 provides 144 compounds of formula IB wherein R2b is prop-l -yl, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 102 provides 144 compounds of formula IB wherein R2b is 2-fluoro-ethyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 103 provides 144 compounds of formula IB wherein R2b is 2-cyano-ethyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 104 provides 144 compounds of formula IB wherein R2b is 1 -fluoroethyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 105 provides 144 compounds of formula IB wherein R2b is 2-methylprop-l-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 106 provides 144 compounds of formula IB wherein R2b is propen-2-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 107 provides 144 compounds of formula IB wherein R2b is cyclopropylmethyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 108 provides 144 compounds of formula IB wherein R2b is 2-methoxy-ethyl-, R3 is
  • R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 109 provides 144 compounds of formula IB wherein R2b is 3-methyloxetan-3-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 110 provides 144 compounds of formula IB wherein R2b is 1 -methylcyclopropyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 111 provides 144 compounds of formula IB wherein R2b is dihydrofuran-4-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 112 provides 144 compounds of formula IB wherein R2b is cyclopropyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 113 provides 144 compounds of formula IB wherein R2b is cyclobutyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 114
  • Table 114 provides 144 compounds of formula IB wherein R2b is methylsulfonylmethyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 115 provides 144 compounds of formula IB wherein R2b is propen-l -yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 116 provides 144 compounds of formula IB wherein R2b is methylsulfanylmethyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 117 provides 144 compounds of formula IB wherein R2b is 1 -methoxyeth-l-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 118 provides 144 compounds of formula IB wherein R2b is 5-pyrimidyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 119 provides 144 compounds of formula IB wherein R2b is but-2-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 120 provides 144 compounds of formula IB wherein R2b is l -fluoroprop-2-yl-, R3 is
  • R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 121 provides 144 compounds of formula IB wherein R2b is 2-methylpropen-l-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 122 provides 144 compounds of formula IB wherein R2b is 1 -cyanocyclopropyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 123 provides 144 compounds of formula IB wherein R2b is N-formylaminomethyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 124 provides 144 compounds of formula IB wherein R2b is 2-methylsulfinyl-ethyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 125 provides 144 compounds of formula IB wherein R2b is 2-(methylsulfonyl)-ethyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 126 provides 144 compounds of formula IB wherein R2b is l -oxo-tetrahydrofuran-3-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 127 provides 144 compounds of formula IB wherein R2b is l-oxo-thietan-3-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 128 provides 144 compounds of formula IB wherein R2b is l,l-dioxo-tetrahydrofuran-3-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 129 provides 144 compounds of formula IB wherein R2b is l,l -dioxo-thietan-3-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 130 provides 144 compounds of formula IB wherein R2b is 3-chloroprop-l-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 131 provides 144 compounds of formula IB wherein R2b is 3,3,3-trifluoro-propyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 132 provides 144 compounds of formula IB wherein R2b is 3,3,3-trifluoro-propyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 132 provides 144 compounds of formula IB wherein R2b is 3,3,3-trifluoro-propyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 132 provides 144 compounds of formula IB wherein R2b is 3,3,3-trifluoro-propyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and
  • Table 132 provides 144 compounds of formula IB wherein R2b is thietan-3-yl-, R3 is tnfluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 133 provides 144 compounds of formula IB wherein R2b is 3-oxetanyl-, R3 is tnfluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 134 provides 144 compounds of formula IB wherein R2b is tetrahydrofuran-2-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 135 provides 144 compounds of formula IB wherein R2b is l,l,l-trifluoroprop-2-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 136 provides 144 compounds of formula IB wherein R2b is but-l-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 137 provides 144 compounds of formula IB wherein R2b is 2,2-difluoro-ethyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 138 provides 144 compounds of formula IB wherein R2b is ethyl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 139 provides 144 compounds of formula IB wherein R2b is 2,2,2-trifluoro-ethyl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 140 provides 144 compounds of formula IB wherein R2b is prop-2-yl-, R3 is
  • Table 141 provides 144 compounds of formula IB wherein R2b is methyl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 142 provides 144 compounds of formula IB wherein R2b is 2-fluoro-cycloprop-l-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 143 provides 144 compounds of formula IB wherein R2b is prop-l-yl, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 144 provides 144 compounds of formula IB wherein R2b is 2-fluoro-ethyl-, R3 is
  • Table 145 provides 144 compounds of formula IB wherein R2b is 2-cyano-ethyl-, R3 is
  • Table 146 provides 144 compounds of formula IB wherein R2b is 1 -fluoroethyl-, R3 is
  • Table 147 provides 144 compounds of formula IB wherein R2b is 2-methylprop-l-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 148 provides 144 compounds of formula IB wherein R2b is propen-2-yl-, R3 is
  • Table 149 provides 144 compounds of formula IB wherein R2b is cyclopropylmethyl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 150
  • Table 150 provides 144 compounds of formula IB wherein R2b is 2-methoxy-ethyl-, R3 is
  • Table 151 provides 144 compounds of formula IB wherein R2b is 3-methyloxetan-3-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 152 provides 144 compounds of formula IB wherein R2b is 1 -methylcyclopropyl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 153 provides 144 compounds of formula IB wherein R2b is dihydrofuran-4-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 154 provides 144 compounds of formula IB wherein R2b is cyclopropyl-, R3 is
  • Table 155 provides 144 compounds of formula IB wherein R2b is cyclobutyl-, R3 is
  • Table 156 provides 144 compounds of formula IB wherein R2b is methylsulfonylmethyl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 157 provides 144 compounds of formula IB wherein R2b is propen-l -yl-, R3 is
  • Table 158 provides 144 compounds of formula IB wherein R2b is methylsulfanylmethyl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 159 provides 144 compounds of formula IB wherein R2b is 1 -methoxyeth-l-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 160 provides 144 compounds of formula IB wherein R2b is 5-pyrimidyl-, R3 is
  • Table 161 provides 144 compounds of formula IB wherein R2b is but-2-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 162 provides 144 compounds of formula IB wherein R2b is l -fluoroprop-2-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 163 provides 144 compounds of formula IB wherein R2b is 2-methylpropen-l-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 164 provides 144 compounds of formula IB wherein R2b is 1 -cyanocyclopropyl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 165 provides 144 compounds of formula IB wherein R2b is N-formylaminomethyl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 166 provides 144 compounds of formula IB wherein R2b is 2-methylsulfinyl-ethyl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 167 provides 144 compounds of formula IB wherein R2b is 2-(methylsulfonyl)-ethyl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 168
  • Table 168 provides 144 compounds of formula IB wherein R2b is l -oxo-tetrahydrofuran-3-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 169 provides 144 compounds of formula IB wherein R2b is l -oxo-thietan-3-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 170 provides 144 compounds of formula IB wherein R2b is l,l -dioxo-tetrahydrofuran-3-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 171 provides 144 compounds of formula IB wherein R2b is l,l -dioxo-thietan-3-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 172 provides 144 compounds of formula IB wherein R2b is 3-chloroprop-l-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 173 provides 144 compounds of formula IB wherein R2b is 3,3,3-trifluoro-propyl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 174 provides 144 compounds of formula IB wherein R2b is thietan-3-yl-, R3 is
  • Table 175 provides 144 compounds of formula IB wherein R2b is 3-oxetanyl-, R3 is
  • Table 176 provides 144 compounds of formula IB wherein R2b is tetrahydrofuran-2-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 177 provides 144 compounds of formula IB wherein R2b is l,l,l-trifluoroprop-2-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 178 provides 144 compounds of formula IB wherein R2b is but-l -yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • Table 179 provides 144 compounds of formula IB wherein R2b is 2,2-difluoro-ethyl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
  • the compounds of the invention may be made by a variety of methods as shown in the following Schemes.
  • Compounds of formula (la) wherein G 1 is oxygen can be prepared by reacting an amine of formula (II) with a compound of formula (III) wherein G 1 is oxygen and X A is OH, Ci-C 6 alkoxy or CI, F or Br.
  • X A is OH
  • a coupling reagent such as ⁇ , ⁇ '-dicyclohexyl-carbo-diimide (“DCC”), l-ethyl-3-(3-dimethyl-amino-propyl)-carbodiimide hydrochloride (“EDC”) or bis(2-oxo-3-oxazolidinyl)phosphonic chloride (“BOP-C1”)
  • DCC ⁇ , ⁇ '-dicyclohexyl-carbo-diimide
  • EDC l-ethyl-3-(3-dimethyl-amino-propyl)-carbodiimide hydrochloride
  • BOP-C1 bis(2-oxo-3-oxazolidinyl)phosphonic chloride
  • HOBT hydroxybenzo-triazole
  • X A is CI
  • such reactions are usually carried out in the presence of a base, and optionally in the presence of a nucleophilic catalyst for example dimethylaminopyridine.
  • a nucleophilic catalyst for example dimethylaminopyridine.
  • X A is CpCealkoxy it is sometimes possible to convert the ester directly to the amide by heating the ester and amine together in a thermal process.
  • Suitable bases include pyridine, triethylamine, 4-(dimethylamino)-pyridine (“DMAP”) or diisopropylethylamine (Hunig's base).
  • Preferred solvents are NN-dimethylacetamide, tetrahydrofuran, dioxane, 1 ,2-dimethoxyethane, ethyl acetate and toluene.
  • the reaction is carried out at a temperature of from 0°C to 100°C, preferably from 15°C to 30°C, in particular at ambient temperature.
  • Compounds of formula (III) are either known in the literature or can be prepared using methods known to a person skilled in the art. Some of these methods are described in the preparation Examples.
  • Compounds of formula (la), wherein G 1 is sulfur may be made by treatment of a compound of formula (III), wherein G 1 is oxygen and X A is OH, Ci-C 6 alkoxy or CI, F or Br, with a thio-transfer reagent such as Lawesson's reagent or phosphorus pentasulfide prior to progressing to compounds of formula (la), as described under 1).
  • a thio-transfer reagent such as Lawesson's reagent or phosphorus pentasulfide prior to progressing to compounds of formula (la), as described under 1).
  • R When R is OH such reactions are usually carried out in the presence of a coupling reagent, such as ⁇ , ⁇ '-dicyclohexylcarbodiimide (“DCC”), l-ethyl-3-(3- dimethylamino-propyl)carbodiimide hydrochloride (“EDC”) or bis(2-oxo-3-oxazolidinyl)phosphonic chloride (“BOP-Cl”), in the presence of a base, and optionally in the presence of a nucleophilic catalyst, such as hydroxybenzotriazole (“HOBT").
  • DCC ⁇ , ⁇ '-dicyclohexylcarbodiimide
  • EDC l-ethyl-3-(3- dimethylamino-propyl)carbodiimide hydrochloride
  • BOP-Cl bis(2-oxo-3-oxazolidinyl)phosphonic chloride
  • R When R is CI, such reactions are usually carried out in the presence of
  • a biphasic system comprising an organic solvent, preferably ethyl acetate, and an aqueous solvent, preferably a solution of sodium hydrogen carbonate.
  • R is Ci-C 6 alkoxy it is sometimes possible to convert the ester directly to the amide by heating the ester and amine together in a thermal process.
  • Suitable bases include pyridine, triethylamine, 4-(dimethylamino)-pyridine (“DMAP”) or diisopropylethylamme (Hunig's base).
  • Preferred solvents are NN-dimethylacetamide, tetrahydrofuran, dioxane, 1 ,2-dimethoxyethane, ethyl acetate and toluene.
  • the reaction is carried out at a temperature of from 0°C to 100°C, preferably from 15°C to 30°C, in particular at ambient temperature.
  • Amines of formula (XI) are either known in the literature or can be prepared using methods known to a person skilled in the art. Some of these methods are described in the preparation Examples.
  • Acid halides of formula (IX), wherein G 1 is oxygen and R is CI, F or Br, may be made from carboxylic acids of formula (IX), wherein G 1 is oxygen and R is OH, under standard conditions, as described for example in WO 2009/080250.
  • Carboxylic acids of formula (IX), wherein G 1 is oxygen and R is OH may be formed from esters of formula (IX), wherein G 1 is oxygen and R is Q-Cealkoxy as described for example in WO 2009/080250.
  • Phosphonium (XIV) is deprotonated with a strong base for example K 2 C0 3 , BuLi, tBuOK, LiHMDS or LDA in an aprotic solvent for example toluene or THF and then adding a carbonyl or formula (XIII).
  • a strong base for example K 2 C0 3 , BuLi, tBuOK, LiHMDS or LDA
  • an aprotic solvent for example toluene or THF
  • R is aryl and X is CI or Br can be prepared by treating compounds of formula (XIX) wherein X is CI or Br with a phosphine of formula (XVI) wherein R is aryl using conditions described in 17).
  • Alcohols of formula of formula (XX) wherein Y 5 is hydrogen, CpCgalkyl, CpCghaloalkyl or C 3 -C 8 cycloalkyl can be prepared by reduction of carbonyls of formula (XXI) using a hydride source for example NaBH 4 , LiAlH 4 , diisobutylaluminum hydride, H 2 in presence of a transition catalyst such as Ni and Pd using well-established methods known to a person skilled in the art specific examples are described in the experimental section.
  • a hydride source for example NaBH 4 , LiAlH 4 , diisobutylaluminum hydride, H 2
  • a transition catalyst such as Ni and Pd
  • Alcohols of formula of formula (XX) wherein Y 5 is hydrogen, CpCgalkyl, Cp Cghaloalkyl or C 3 -Cgcycloalkyl can be prepared by reduction of compounds of formula (XXII) wherein R 31 is C0 2 R using a hydride source for example LiAlH 4 or diisobutylaluminum hydride when R is Cp C 6 alkyl and BH 3 when R is hydrogen using well-established methods known to a person skilled in the art and specific examples are described in the experimental section.
  • a hydride source for example LiAlH 4 or diisobutylaluminum hydride when R is Cp C 6 alkyl
  • BH 3 when R is hydrogen
  • Ketone of formula of formula (XXI) wherein Y 5 CpCgalkyl or C 3 -Cgcycloalkyl can be prepared by treating compounds of formula (XXII) wherein R 31 is cyano or C(0)NMeOMe with an organomagnesium reagent of formula Y 5 MgX wherein X is CI, Br or I or with an organolithium reagent of formula Y 5 Li in an aprotic solvent for example tetrahydrofiiran using well-established methods known to a person skilled in the art and described in the experimental section.
  • ketones of formula of formula (XXI) wherein Y 5 CpCgalkyl, CpCghaloalkyl or C 3 -C 8 cycloalkyl can be prepared by treating compounds of formula (XXII) wherein R 31 is bromo or iodo with an organolithium, for example butyllithium, or an organomagnesium, for example
  • Alcohols of formula of formula (XX) wherein Y 5 CpCghaloalkyl can be prepared by reaction aldehydes of formula (XXI) wherein Y 5 is hydrogen with nucleophilic haloalkyl source for example trimethylsilyltrifluoromethane in presence of a nucleophilic activator for example CsF.
  • nucleophilic haloalkyl source for example trimethylsilyltrifluoromethane
  • CsF nucleophilic activator for example CsF
  • Ketone of formula (XXI) wherein Y 5 is hydrogen, CpCgalkyl or CpCghaloalkyl can be prepared by oxidation of alcohols of formula of formula (XX) wherein Y 5 is hydrogen, CpCgalkyl or Cp Cghaloalkyl with oxidants for example pyridinium chlorochromate, Dess-Martin periodinane or Swern- type oxidations using well-established methods known to a person skilled in the art and specific examples are described in the experimental section.
  • Cgcycloalkyl and Y 6 is hydrogen, a halogen, Ci-Qalkyl, Ci-C 8 haloalkyl, C -C 8 cycloalkyl or cyano can be prepared through a Horner-Wadsworth-Emmons reaction between carbonyl (XXI) wherein Y 5 is hydrogen, CpCgalkyl, CpCghaloalkyl, or C -C 8 cycloalkyland phosphonate (XXIII) wherein A 1 is C r C 4 alkyl or or aryl, Y 6 is hydrogen, a halogen, CpCgalkyl, Ci-Cghaloalkyl, or C 3 - Cgcycloalkyl, G 1 is oxygen or sulfur and R is Ci-C 4 alkoxy or NR la R 2a wherein R la and R 2a are as defined in claim 1.
  • Phosphonates (XXIII) are treated with a strong base for example NaH, KHMDS, tBuOK, or a weaker base DBU with an additional activator such as LiCl or MgC ⁇ in an aprotic solvent for example tetrahydrofuran or dimethoxyethane and then carbonyl (XXI) is added.
  • a strong base for example NaH, KHMDS, tBuOK, or a weaker base DBU
  • an additional activator such as LiCl or MgC ⁇
  • an aprotic solvent for example tetrahydrofuran or dimethoxyethane
  • Y 5 is hydrogen, CpCgalkyl, CpCghaloalkyl, or C 3 - Cgcycloalkyl
  • Y 6 is hydrogen, CpCgalkyl, CpCghaloalkyl, Q-Cgcycloalkyl or cyano
  • Y 5 is hydrogen, CpCgalkyl, CpCghaloalkyl, Q-Cgcycloalkyl or cyano
  • Y 5 is hydrogen, CpCgalkyl, CpCghaloalkyl, Q-Cgcycloalkyl or cyano
  • Y 6 is hydrogen, CpCgalkyl, CpCghaloalkyl, Q-Cgcycloalkyl or cyano
  • a palladium catalyst for example Pd(OAc) 2 (DTPF) (DTPF: l,l '-bis(ditertbutylphosphino)ferrocene), and a base for example dicyclohexylmethylamine, an
  • Aledhydes of formula (XXV) wherein X is bromo or chloro and Y 6 is hydrogen, CpCgalkyl, CpCghaloalkyl, C 3 -C 8 cycloalkyl or cyano can be obtained by reacting ketones of formula (XXVI)with Vilsmeyer reagent, obtained from reaction of POX 3 or COX 2 wherein X is chloro or bromo with dimethylformamide using well-established methods known to a person skilled in the art and specific examples are described in the experimental section.
  • Ketones of formula (XXVI) wherein Y 6 is hydrogen, CpCgalkyl, CpCghaloalkyl, C3- Cgcycloalkyl or cyano can be obtained by treating ketones of formula (XXI) wherein Y 6 is Ci-C 9 alkyl, Ci- 7 haloalkylmethyl, Ca-Cgcycloalkylmethyl or cyanomethyl with ⁇ , ⁇ -dimethylformamide dimethyl acetal in a polar solvent for example dimethylformamide using well-established methods known to a person skilled in the art and specific examples are described in the experimental section.
  • Anilines of formula (XXVIII) can be obtained by reduction of compounds of formula (XXXVII) by using a suitable reducing agent as described extensively in Kabalka, G. W.; Varma, R. S., Reduction of Nitro and Nitroso Compounds. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, L, Eds. Pergamon Press: Oxford, 1991 ; Vol. 8, p 363.
  • Suitable reducing agent can be for example iron, magnesium, zinc, tin(II) chloride in protic solvent for example water, ethanol, methanol, acetic acid, aqueous HC1.

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Abstract

The present invention relates to compounds of formula (I) wherein Q is (Q1) or (Q2) G1 is oxygen or sulfur; Y1 is oxygen, sulfur or CH2; Y2, Y3 and Y4 are each independently C-H, C-R5 or nitrogen, wherein no more than one of Y2, Y3 and Y4 is C-R5; Y5 is hydrogen, halogen, C1-C8alkyl, C1-C8haloalkyl or C3-C8cycloalkyl; Y6 is hydrogen, halogen, cyano, C1-C8alkyl, C1-C8haloalkyl or C3-C8cycloalkyl; R1a is hydrogen, C1-C8alkyl, C1-C8alkoxy, C1-C8alkylcarbonyl or C1-C8alkoxycarbonyl; R1b is hydrogen, C1-C8alkyl, C1-C8alkylcarbonyl or C1-C8alkoxycarbonyl; R3 is C1-C8haloalkyl; R4 is aryl or aryl substituted by one to five R10, or heteroaryl or heteroaryl substituted by one to five R10; R6a is hydrogen, cyano, C1-C8alkyl, C1-C8haloalkyl or C3-C8cycloalkyl; R6b is hydrogen, cyano, C1-C8alkyl, C1-C8haloalkyl or C3-C8cycloalkyl; or R6a and R6b together with the carbon atom to which they are attached may form a 3 to 6-membered carbocyclic ring; and R2a, R2b, R and R are as defined in the claims. The invention also relates to methods of controlling insects, acarines, nematodes or molluscs which comprises applying to a pest, to a locus of a pest, or to a plant susceptible to attack by a pest an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula I.

Description

DIHYDROBENZOFURAN DERIVATIVES AS INSECTICIDAL COMPOUNDS
The present invention relates to certain dihydrobenzofuran derivatives, to processes and intermediates for preparing these derivatives, to insecticidal, acaricidal, nematicidal and molluscicidal compositions comprising these derivatives and to methods of using these derivatives to control insect, acarine, nematode and mollusc pests.
Certain isoxazoline derivatives with insecticidal properties are disclosed, for example, in EP 1,731,512. However there is a continuing need to find new biologically active compounds as well as new biologically active compounds displaying superior properties for use as agrochemical active ingredients, for example greater biological activity, different spectrum of activity, increased safety profile, or increased biodegradability.
It has now surprisingly been found that certain dihydrobenzofuranderivatives have highly potent insecticidal properties.
The present invention provides compounds of formula (I)
Figure imgf000002_0001
Q is Ql or Q2
Figure imgf000002_0002
G1 is oxygen or sulfur;
Y1 is oxygen, sulfur or CH2;
Figure imgf000002_0003
Y 3J and Y 4 are each independently C-H, C-R 5 or nitrogen, wherein no more than one Y 3J and Y4 is C-R5;
Y5 is hydrogen, halogen, CpCgalkyl, Ci-Cghaloalkyl or Ca-Cgcycloalkyl;
Y6 is hydrogen, halogen, cyano, Ci-Cgalkyl, Ci-Cghaloalkyl or CrCgcycloalkyl;
Rla is hydrogen, CrC8alkyl, Q-Cgalkoxy, CpCgalkylcarbonyl or CpCgalkoxycarbonyl;
Rlb is hydrogen, Ci-Qalkyl, CpCgalkylcarbonyl or CpCgalkoxycarbonyl;
R2a is CpCgalkyl or CpCgalkyl substituted by one to five R7, C2-Cgalkenyl or C2-Cgalkenyl substituted by one to five R7, C2-C8alkynyl or C2-Cgalkynyl substituted by one to five R7, Cr
Ciocycloalkyl or CrCiocycloalkyl substituted by one to five R8, C3-Ciocycloalkyl-Ci-C4alkylene or C3- Ciocycloalkyl-Ci-C4alkylene substituted by one to five R8, aryl-Ci-C4alkylene- or aryl-Ci-C4alkylene- substituted by one to five R9, heterocyclyl-Ci-C4alkylene- or heterocyclyl-Ci-C4alkylene- substituted by one to five R9, aryl or aryl substituted by one to five R9, heterocyclyl or heterocyclyl substituted by one to five R9, Ci-C8alkylaminocarbonyl-Ci-C4alkylene, Ci-C8haloalkylaminocarbonyl-Ci-C alkylene, C3-
C8cycloalkyl-aminocarbonyl-Ci-C4 alkylene, aryl-CH2-aminocarbonyl-Ci-C4alkylene or aryl-CH2- aminocarbonyl-Ci-C alkylene wherein the aryl is substituted by one to five R9, Ci-C8alkylaminocarbonyl, Ci-C8haloalkylaminocarbonyl, C3-C6cycloalkylaminocarbonyl,
Figure imgf000003_0001
Ci-C6haloalkyl-0- N=CH-, Ci-C6alkyl-0-N=CH-Ci-C4alkylene- or
Figure imgf000003_0002
substituted by one to five R7, and wherein alkylene groups may be substituted by a fused 3- to 6-membered carbocyclic ring; or Rla and R2a together form a 4- or 5-membered ring fragment containing carbon atoms as ring members, optionally substituted by one to five R9;
R2b is CrC8alkyl or CpQalkyl substituted by one to five R7, C2-C8alkenyl or C2-C8alkenyl substituted by one to five R7, C2-C8alkynyl or C2-C8alkynyl substituted by one to five R7, Ci-C8alkoxy- Ci-C8alkyl or Ci-C8alkoxy-Ci-C8alkyl substituted by one to five R7, C3-Ciocycloalkyl or C3-Ciocycloalkyl substituted by one to five R8, C3-Ciocycloalkyl-Ci-C4alkylene or C3-Ciocycloalkyl-Ci-C4alkylene substituted by one to five R8, aryl-Ci-C4alkylene- or aryl-Ci-C4alkylene- substituted by one to five R9, heterocyclyl-Ci-C alkylene- or heterocyclyl-Ci-C alkylene- substituted by one to five R9, aryl or aryl substituted by one to five R9, heterocyclyl or heterocyclyl substituted by one to five R9, and wherein alkylene groups may be substituted by a fused 3- to 6-membered carbocyclic ring;
R3 is Ci-Cghaloalkyl;
R4 is aryl or aryl substituted by one to five R10, or heteroaryl or heteroaryl substituted by one to five R10;
each R5 is independently halogen, cyano, CrQalkyl, Ci-C haloalkyl, CpQalkoxy or Cr
Qhaloalkoxy;
R a is hydrogen, cyano, Ci-C8alkyl, Ci-C8haloalkyl or C3-C8cycloalkyl;
R b is hydrogen, cyano, CpC8alkyl, Ci-C8haloalkyl or C3-C8cycloalkyl;
or R a and R b together with the carbon atom to which they are attached may form a 3 to 6- membered carbocyclic ring;
each R7 is independently halogen, cyano, nitro, hydroxy, amino, CrC8alkyl, C2-C8alkenyl, C2- C8alkynyl, Ci-C8alkylamino, (Ci-C8alkyl)2amino, Ci-C8alkylcarbonylamino, Cp
C8haloalkylcarbonylamino, carbonylamino, (carbonyl)(Ci-C8alkyl)amino, (Ci-C8alkylcarbonyl)(Cr C8alkyl)amino, (Ci-C8haloalkylcarbonyl)(Ci-C8alkyl)amino, Ci-C8alkoxy, Ci-C8haloalkoxy, C3- C6cycloalkyl, CrC8alkylcarbonyl, CrC8alkoxycarbonyl, mercapto, Ci-C8alkylthio, Ci-C8haloalkylthio, Ci-C8alkylsulfinyl, CrC8haloalkylsulfinyl, CpQalkylsulfonyl, CrC8haloalkylsulfonyl, aryl-Cr
Qalkylthio or aryl-Ci-C alkylthio wherein the aryl moiety is substituted by one to five R11, or two R7 are together OH-N= or CrC6alkoxy-N- each R8 is independently halogen, cyano, Ci-C8alkyl, Ci-C8haloalkyl, C2-C8alkenyl, C2- C8haloalkenyl, C2-C8alkynyl, C2-C8haloalkynyl, Ci-C8alkoxy, Ci-C8haloalkoxy, C3-C6cycloalkyl or Cp C8akoxycarbonyl;
each R9 is independently halogen, cyano, nitro, Ci-C8alkyl, Ci-C8haloalkyl, Ci-C8cyanoalkyl, C2- C8alkenyl, C2-C8haloalkenyl, C2-C8alkynyl, C2-C8haloalkynyl, C3-Ciocycloalkyl, C3-Ciocycloalkyl-Cr C4alkylene, hydroxy, CpCgalkoxy, CpCghaloalkoxy, mercapto, CrC8alkylthio, CpCghaloalkylthio, Cr
Cgalkylsulfinyl, Ci-C8haloalkylsulfinyl, CrC8alkylsulfonyl, Ci-C8haloalkylsulfonyl, Cr
C8alkylaminosulfonyl, (Ci-C8alkyl)2aminosulfonyl, Ci-C8alkylcarbonyl, CpCghaloalkylcarbonyl, Q- C8alkoxycarbonyl orCpCghaloalkoxycarbonyl;
each R10 is independently halogen, cyano, nitro, Ci-C8alkyl, Ci-C8haloalkyl, C2-C8alkenyl, C2- Cghaloalkenyl, C2-C8alkynyl, C2-C8haloalkynyl, hydroxy, Ci-C8alkoxy, CpCghaloalkoxy, mercapto, Cp Cgalkylthio, Ci-C8haloalkylthio, Ci-C8alkylsulfmyl, Ci-C8haloalkylsulfinyl, Ci-C8alkylsulfonyl, Cp Cghaloalkylsulfonyl, d-C8alkylcarbonyl or CpC8alkoxycarbonyl;
each R11 is independently halogen, cyano, nitro, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy or Cp Qhaloalkoxy;
or a salt or N-oxide thereof.
The compounds of formula (I) may exist in different geometric or optical isomers or tautomeric forms. In particular, the compounds of the invention may contain one or more asymmetric carbon atoms and may exist as enantiomers (or as pairs of diastereoisomers) or as mixtures of such.This invention covers all such isomers and tautomers and mixtures thereof in all proportions as well as isotopic forms such as deuterated compounds. The compounds of the invention include N-oxides and salts.
Alkyl groups (either alone or as part of a larger group, such as alkoxy-, alkylthio-, alkylsulfinyl-, alkylsulfonyl-, alkylcarbonyl- or alkoxycarbonyl-) can be in the form of a straight or branched chain and are, for example, methyl, ethyl, propyl, prop-2-yl, butyl, but-2-yl, 2-methyl-prop-l -yl or 2-methyl-prop-2- yl. The alkyl groups are preferably CrC6, more preferably Ci-C , most preferably C1-C3 alkyl groups. Where an alkyl moiety is said to be substituted, the alkyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.
Alkylene groups can be in the form of a straight or branched chain and are, for example, -CH2- , -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(CH3)-CH2-, or -CH(CH2CH3)-. The alkylene groups are preferably C1-C3, more preferably C1-C2, most preferably C\ alkylene groups. Where an alkylene moiety is said to be substituted, the alkyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.
Alkenyl groups can be in the form of straight or branched chains, and can be, where appropriate, of either the (E)- or (Z)-configuration. Examples are vinyl and allyl. The alkenyl groups are preferably C2-C<5, more preferably C2-C , most preferably C2-C3 alkenyl groups. Where an alkenyl moiety is said to be substituted, the alkyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.
Alkynyl groups can be in the form of straight or branched chains. Examples are ethynyl and propargyl. The alkynyl groups are preferably C2-C6, more preferably C2-C4, most preferably C2-C3 alkynyl groups. Where an alkynyl moiety is said to be substituted, the alkyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.
Halogen is fluorine, chlorine, bromine or iodine. Haloalkyl groups (either alone or as part of a larger group, such as haloalkoxy-, haloalkylthio-, haloalkylsulfinyl- or haloalkylsulfonyl-) are alkyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, difluoromethyl, trifluoromethyl,
chlorodifluoromethyl or 2,2,2-trifluoro-ethyl.
Haloalkenyl groups are alkenyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, 2,2-difluoro-vinyl or 1 ,2-dichloro-2-fluoro-vinyl.
Haloalkynyl groups are alkynyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, l-chloro-prop-2-ynyl.
Cycloalkyl groups or carbocyclic rings can be in mono- or bi-cyclic form and are, for example, cyclopropyl, cyclobutyl, cyclohexyl and bicyclo[2.2.1]heptan-2-yl. The cycloalkyl groups are preferably C3-C8, more preferably C3-C6 cycloalkyl groups. Where a cycloalkyl moiety is said to be substituted, the cycloalkyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.
Aryl groups (either alone or as part of a larger group, such as aryl-alkylene-) are aromatic ring systems which can be in mono-, bi- or tricyclic form. Examples of such rings include phenyl, naphthyl, anthracenyl, indenyl or phenanthrenyl. Preferred aryl groups are phenyl and naphthyl, phenyl being most preferred. Where an aryl moiety is said to be substituted, the aryl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.
Heteroaryl groups (either alone or as part of a larger group, such as heteroaryl-alkylene-) are aromatic ring systems containing at least one heteroatom and consisting either of a single ring or of two or more fused rings. Preferably, single rings will contain up to three heteroatoms and bicyclic systems up to four heteroatoms which will preferably be chosen from nitrogen, oxygen and sulfur. Examples of monocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl (e.g. 1.2.4 triazoyl), furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, tetrazolyl and thiadiazolyl. Examples of bicyclic groups include purinyl, quinolinyl, cinnolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzothiophenyl and benzothiazolyl. Monocyclic heteroaryl groups are preferred, pyridyl being most preferred. Where a heteroaryl moiety is said to be substituted, the heteroaryl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.
Heterocyclyl groups or heterocyclic rings (either alone or as part of a larger group, such as heterocyclyl-alkylene-) are defined to include heteroaryl groups and in addition their unsaturated or partially unsaturated analogues. Preferred heterocyclyl groups are a 4 to 7-membered heterocyclic rings containing one to three heteroatoms independently selected from O, S, SO, S02, N, and N(R14) as ring atoms, wherein R14 is hydrogen, oxygen or R9.Examples of monocyclic groups include isoxazolyl, thietanyl, pyrrolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, dihydrothiophenyl, [l,3]dioxolanyl, piperidinyl, piperazinyl, [l,4]dioxanyl, morpholinyl, thiophenyl, oxetanyl, tetrahydropyranyl, 3-oxo-isoxazolidinyl-, 2,5-dioxo-l-pyrrolidinyl-, 2-oxo-l -pyrrolidinyl-, 4- oxo-l,3-oxazinanyl, l-oxa-3,4-diazolyl, 1-oxo-thietanyl, 1 , 1 -dioxo-thietanyl, thiophene 1 -oxide, thiophene 1 , 1 -dioxide, dihydrothiophenyl, dihydrothiophen 1 -oxide, and dihydrothiophene 1 , 1 -dioxide.
Examples of bicyclic groups include 2,3-dihydro-benzofuranyl, benzo[l,4]dioxolanyl,
benzo[l,3]dioxolanyl, chromenyl, and 2,3-dihydro-benzo[l,4]dioxinyl. Where a heterocyclyl moiety is said to be substituted, the heterocyclyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents. Prefered heterocyclyl groups are thiophene, thiophene 1 -oxide, thiophene 1 , 1 -dioxide, dihydrothiophene, dihydrothiophene 1 -oxide, dihydrothiophene 1 , 1 -dioxide, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and tetrazoyl. Somespecific examples of heterocycles are groups A1-A12 wherein q is 0,1 or 2, and Bl to B6 wherein R14 is hydrogen or R9.
Figure imgf000006_0001
Heterocyclyl groups (and heteroaryl groups) according to the present invention do not contain adjacent oxygen atoms, adjacent sulphur atoms, or adjacent sulphur and oxygen atoms.
Preferred values of Y1, Y2, Y3, Y4, Y5, Y6, G1, Rla, Rlb, R2a, R2b, R3, R4, R5, R a, R b, R7, R8, R9' R10, R11 are, in any combination (including combinations of preferred values with the original values) as set out below.
Preferably G1 is oxygen.
Preferably Y1 is oxygen.
Preferably no more than two of Y2, Y3 and Y4 are nitrogen.
Preferably Y2 is C-H or N, more preferably C-H. Preferably Y3 isC-H or C-R5, more preferably C-H.
Preferably Y4 is C-H or C-R5, more preferably C-H.
Preferably Y5is hydrogen, halogen, CrC8alkyl or CpQhaloalkyl, more preferably hydrogen, halogen, Ci-C4alkyl or Ci-C4haloalkyl, even more preferably hydrogen, halogen, Ci-C2alkyl or Cr C2haloalkyl, most preferably hydrogen, methyl, chloro, bromo or trifluoromethyl.
Preferably Y is hydrogen, halogen, cyano, CpC8alkyl or Ci-C8haloalkyl, more preferably hydrogen, halogen, cyano, Ci-C4alkyl or Ci-Czihaloalkyl, even more preferably hydrogen, halogen, cyano, Ci-C2alkyl or Ci-C2haloalkyl, most preferably hydrogen or methyl.
Preferably at least one of Y5 and Y6 is hydrogen.
Preferably Rla is hydrogen, methyl, halomethyl, ethyl, haloethyl, methylcarbonyl or
methoxycarbonyl, more preferably hydrogen, methyl, halomethyl, ethyl or haloethyl most preferably hydrogen.
Preferably Rla is hydrogen, methyl, halomethyl, ethyl, haloethyl, methylcarbonyl or
methoxycarbonyl, more preferably hydrogen, methyl, halomethyl, ethyl or haloethyl most preferably hydrogen.
Preferably R2a is Ci-C8alkyl or CrC8alkyl substituted by one to five R7, C2-C8alkenyl or C2- Qalkenyl substituted by one to five R7, C2-C8alkynyl or C2-C8alkynyl substituted by one to five R7, C3- Ciocycloalkyl or CrCiocycloalkyl substituted by one to five R8, C3-Ciocycloalkyl-C(R12)(R13)- or Cr C10cycloalkyl-C(R12)(R13)- wherein the cycloalkyl is substituted by one to five R8, aryl-C(R12)(R13)- or aryl-C(R12)(R13)- wherein the aryl is substituted by one to five R9, heterocyclyl-C(R12)(R13)- or heterocyclyl-C(R12)(R13)- wherein the heterocyclyl is substituted by one to five R9, aryl or aryl substituted by one to five R9, heterocyclyl or heterocyclyl substituted by one to five R9, Ci-C6alkyl-0-N=CH-, Cp C6haloalkyl-0-N=CH-, C1-C4alkyl-0-N=CH-C(R12)(R13)-,C1-C4haloalkyl-0-N=CH-C(R12)(R13)-, d- C4alkylaminocarbonyl-CH2- or Ci-C4haloalkylaminocarbonyl-CH2-;
wherein heterocyclyl is a 4 to 7-membered heterocyclic ring containing one to three heteroatoms independently selected from O, S, SO, S02, N and N(R14) as ring atoms;
wherein aryl is phenyl;
wherein R12 and R13 are independently hydrogen, cyano, halogen, Ci-C4alkyl, Ci-C4haloalkyl, Cp C4alkoxy, Ci-C4haloalkoxy or C3-C6cycloalkyl;
or R12 and R13 together form a three to six membered carbocycle;
and wherein R14 is hydrogen, oxygen or R9;
or Rla and R2a together form a 4- or 5-membered ring fragment containing carbon atoms as ring members, optionally substituted by one to five R9.
More preferably R2a is Ci-Cealkyl or Ci-Cealkyl substituted by one to five R7, C2-Cealkenyl or C2- Cealkenyl substituted by one to five R7, C2-Cealkynyl or C2-Cealkynyl substituted by one to five R7, C3- C8cycloalkyl or C3-C8cycloalkyl substituted by one to five R8, CrC8cycloalkyl-C(R12)(R13)- or Cr C8cycloalkyl-C(R12)(R13)- wherein the cycloalkyl is substituted by one to five R8, aryl-C(R12)(R13)- or aryl-C(R12)(R13)- wherein the aryl is substituted by one to five R9, heterocyclyl-C(R12)(R13)- or heterocyclyl-C(R12)(R13)- wherein the heterocycle is substituted by one to five R9, aryl or aryl substituted by one to five R9, heterocyclyl or heterocyclyl substituted by one to five R9, CrC alkyl-0-N=CH-, Cr C4haloalkyl-0-N=CH-, CrC4alkyl-0-N=CH-C(R12)(R13)-, CrC4haloalkyl-0-N=CH-C(R12)(R13)-, Cr C alkylaminocarbonyl-CH2- or Ci-C haloalkylaminocarbonyl-CH2-;
wherein heterocyclyl is a 4- to 6-membered saturated or partially saturated heterocyclic ring containing one or two heteroatoms independently selected from O, S, SO, SO2, N and N(R14) as ring atoms;
or heterocyclyl is a 5- or 6-membered heteroaryl ring containing one to three heteroatoms independently selected from O, N and S as ring atoms;
wherein aryl is phenyl;
wherein R12 is hydrogen or CrQalkyl;
wherein R13is hydrogen or Ci-C4alkyl;
and wherein R14 is hydrogen, oxygen or R9;
or Rla and R2a together form a 4- or 5-membered ring fragment containing carbon atoms as ring members, optionally substituted by one to five R9.
Even more preferably R2a is Ci-C6alkyl or Ci-C6alkyl substituted by one to three R7, C2-C6alkenyl or C2-C6alkenyl substituted by one to three R7, C2-C6alkynyl or C2-C6alkynyl substituted by one to three R7, C3-C8cycloalkyl or C3-C8cycloalkyl substituted by one to three R8, C3-C8cycloalkyl-C(R12)(R13)- or C3-C8cycloalkyl-C(R12)(R13)- wherein the cycloalkyl is substituted by one to three R8, aryl-C(R12)(R13)- or aryl-C(R12)(R13)- wherein the aryl is substituted by one to threeR9, heterocyclyl-C(R12)(R13)- or heterocyclyl-C(R12)(R13)- wherein the heterocycle is substituted by one to five R9, aryl or aryl substituted by one to threeR9, heterocyclyl or heterocyclyl substituted by one to threeR9, Ci-C4alkyl-0-N=CH, Q- C4haloalkyl-0-N=CH-, CrC4alkyl-0-N=CH-C(R12)(R13)-, CrC4haloalkyl-0-N=CH-C(R12)(R13)-, Cr C4alkylaminocarbonyl-CH2- or Ci-C4haloalkylaminocarbonyl-CH2-;
wherein heterocyclyl is a 4- to 6-membered saturated or partially saturated heterocyclic ring containing one or two heteroatoms independently selected from O, S, SO, S02, N and N(R14) as ring atoms;
or heterocyclyl is a 5- or 6-membered heteroaryl ring containing one to three heteroatoms independently selected from O, N and S as ring atoms;
wherein aryl is phenyl;
wherein each R7 is independently halogen, cyano,hydroxy, Ci-C alkyl, C2-C alkenyl, C2- Qalkynyl, Q-Qalkoxy, C -C cycloalkyl, mercapto, Ci-C8alkylthio, Ci-C8haloalkylthio, Cr
C8alkylsulfinyl, Ci-C8haloalkylsulfinyl, CrC8alkylsulfonyl or Ci-C8haloalkylsulfonyl;
wherein each R8 is independently halogen, cyano, CrQalkyl or C3-C4cycloalkyl;
wherein each R9 is independently halogen, cyano, nitro, CrQalkyl, Ci-C4haloalkyl, d-Qalkoxy or Ci-C4haloalkoxy;
wherein R12 is hydrogen or CrQalkyl;
wherein R13is hydrogen or Ci-C4alkyl; and wherein R14 is hydrogen, oxygen or R9;
or Rla and R2a together form a 4- or 5-membered ring fragment containing carbon atoms as ring members, optionally substituted by one to three R9.
Even morepreferably R2a is Ci-C6alkyl or Ci-C6alkyl substituted by one to three R7, C2-C6alkenyl or C2-C6alkenyl substituted by one to three R7, C2-Cealkynyl or C2-Cealkynyl substituted by one to three R7, C3-C8cycloalkyl or C3-C8cycloalkyl substituted by one to three R8, C3-C8cycloalkyl-C(R12)(R13)- or C3-C8cycloalkyl-C(R12)(R13)- wherein the cycloalkyl is substituted by one to three R8, aryl-C(R12)(R13)- or aryl-C(R12)(R13)- wherein the aryl is substituted by one to threeR9, heterocyclyl-C(R12)(R13)- or heterocyclyl-C(R12)(R13)- wherein the heterocycle is substituted by one to five R9, aryl or aryl substituted by one to threeR9, heterocyclyl or heterocyclyl substituted by one to three R9, Ci-C4alkyl-0-N=CH- or CrC4haloalkyl-0-N=CH-, CrC4alkyl-0-N=CH-C(R12)(R13)-, CrC4haloalkyl-0-N=CH-C(R12)(R13)-, Cr C4alkylaminocarbonyl-CH2- or Ci-C4haloalkylaminocarbonyl-CH2-;
wherein heterocyclyl is pyridyl, pyridyl-N-oxide, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl or group Al to A12 (preferably pyridyl or A2);
wherein aryl is phenyl;
wherein each R7 is independently halogen, cyano, hydroxy, Ci-C4alkyl, C2-C4alkenyl, C2- C4alkynyl, Ci-C4alkoxy, C3-C4cycloalkyl,mercapto, Ci-C4alkylthio, Ci-C4haloalkylthio, Cp
C4alkylsulfinyl, Ci-C4haloalkylsulfinyl, Ci-C4alkylsulfonyl or Ci-C4haloalkylsulfonyl;
wherein each R8 is independently halogen, cyano, Ci-C4alkyl or C -C4cycloalkyl;
wherein each R9 is independently halogen, cyano, nitro, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy or Ci-C4haloalkoxy;
wherein R12 is hydrogen or methyl;
wherein R13is hydrogen or methyl;
and wherein R14 is hydrogen, oxygen or R9;
or Rla and R2a together form a 4- or 5-membered ring fragment containing carbon atoms as ring members, optionally substituted by one to three R9.
In one very preferred group of compounds R2a is CpCealkyl or CpCealkyl substituted by one to three R7 or C3-C6cycloalkyl or C3-C6cycloalkyl substituted by one to five R8, wherein each R7 is independently halogen, cyano, Ci-C4alkoxy, C -C4cycloalkyl, Ci-C4alkylthio, Ci-C4haloalkylthio, Cr C4alkylsulfinyl, Ci-C4haloalkylsulfinyl, Ci-C4alkylsulfonyl or Ci-C4haloalkylsulfonyl and each R8 is independently halogen, Ci-C4alkyl or Ci-C4haloalkyl.
Preferably R2b is CrC8alkyl or CrC8alkyl substituted by one to five R7, C2-C8alkenyl or C2- C8alkenyl substituted by one to five R7, C2-C8alkynyl or C2-C8alkynyl substituted by one to five R7, Cp C6alkoxy-Ci-C6alkyl or Ci-Cealkoxy-Ci-Cealkyl substituted by one to five R7, C3-Ciocycloalkyl or C3- Ciocycloalkyl substituted by one to five R8, C3-Ciocycloalkyl-C(R12)(R13)-or C3-Ciocycloalkyl- C(R12)(R13)-substituted by one to five R8, aryl-C(R12)(R13)- or aryl-C(R12)(R13)- substituted by one to five R9, heterocyclyl-C(R12)(R13)- or heterocyclyl-C(R12)(R13)- substituted by one to five R9, aryl or aryl substituted by one to five R9, heterocyclyl or heterocyclyl substituted by one to five R9;
wherein aryl is phenyl;
wherein heterocyclyl is a 4- to 7-membered heterocyclic ring containing one to four heteroatoms independently selected from O, S, SO, SO2, N and N(R14) as ring atoms;
wherein R12 and R13 are independently hydrogen, cyano, halogen, Ci-C4alkyl, Ci-Czihaloalkyl, Cp C4alkoxy, Ci-Czihaloalkoxy or C3-C6cycloalkyl, preferably hydrogen or Ci-C4alkyl; and
wherein R14 is hydrogen, oxygen or R9.
More preferably R2b is CrC6alkyl or Ci-C6alkyl substituted by one to five R7, C2-C6alkenyl or C2- Cealkenyl substituted by one to five R7, C2-Cealkynyl or C2-Cealkynyl substituted by one to five R7, Cp C6alkoxy-Ci-C6alkyl or Ci-Cealkoxy-Ci-Cealkyl substituted by one to five R7, C3-Ciocycloalkyl or C3- Ciocycloalkyl substituted by one to five R8, C3-Ciocycloalkyl-C(R12)(R13)-or C3-Ciocycloalkyl- C(R12)(R13)-substituted by one to five R8, aryl-C(R12)(R13)- or aryl-C(R12)(R13)- substituted by one to five R9, heterocyclyl-C(R12)(R13)- or heterocyclyl-C(R12)(R13)- substituted by one to five R9, aryl or aryl substituted by one to five R9, heterocyclyl or heterocyclyl substituted by one to five R9;
wherein aryl is phenyl;
wherein heterocyclyl is a 4- to 7-membered heterocyclic ring containing one to four heteroatoms independently selected from O, S, SO, SO2, N and N(R14) as ring atoms;
wherein each R7 is independently halogen, cyano, hydroxy, Ci-C4alkyl, C2-C4alkenyl, C2- C4alkynyl, Ci-C4alkoxy, C3-C cycloalkyl, mercapto, Ci-C alkylthio, Ci-C haloalkylthio, Cp
Qalkylsulfinyl, Ci-C haloalkylsulfinyl, Ci-C alkylsulfonyl or Ci-C haloalkylsulfonyl;
wherein each R8 is independently halogen, cyano, CrQalkyl or C3-C4cycloalkyl;
wherein each R9 is independently halogen, cyano, nitro, CrQalkyl, Ci-C4haloalkyl, d-Qalkoxy or Ci-C4haloalkoxy;
wherein R12 is hydrogen or d-Qalkyl;
wherein R13is hydrogen or Ci-C alkyl;
wherein R14 is hydrogen, oxygen or R9.
More preferably R2b is CpCealkyl or CpCealkyl substituted by one to five R7, C2-Cealkenyl or C2- Cealkenyl substituted by one to five R7, C2-Cealkynyl or C2-Cealkynyl substituted by one to five R7, Cp C6alkoxy-Ci-C6alkyl or Ci-C6alkoxy-Ci-C6alkyl substituted by one to five R7, C3-Ciocycloalkyl or C3- Ciocycloalkyl substituted by one to five R8, C3-Ciocycloalkyl-C(R12)(R13)-or C3-Ci0cycloalkyl- C(R12)(R13)-substituted by one to five R8, aryl-C(R12)(R13)- or aryl-C(R12)(R13)- substituted by one to five R9, heterocyclyl-C(R12)(R13)- or heterocyclyl-C(R12)(R13)- substituted by one to five R9, aryl or aryl substituted by one to five R9, heterocyclyl or heterocyclyl substituted by one to five R9;
wherein heterocyclyl is pyridyl, pyridyl-N-oxide, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl or group Al to A12 (preferably pyridyl or A2);
wherein aryl is phenyl; wherein each R7 is independently halogen, cyano, hydroxy, Ci-C4alkyl, C2-C4alkenyl, C2- C4alkynyl, Ci-C4alkoxy, C3-C cycloalkyl, mercapto, Ci-C alkylthio, Ci-C haloalkylthio, Cp
C alkylsulfinyl, Ci-C haloalkylsulfinyl, Ci-C alkylsulfonyl or Ci-C haloalkylsulfonyl;
wherein each R8 is independently halogen, cyano, CrQalkyl or C3-C cycloalkyl;
wherein each R9 is independently halogen, cyano, nitro, CrQalkyl, Ci-C4haloalkyl, d-Qalkoxy or Ci-C4haloalkoxy;
wherein R12 is hydrogen or methyl;
wherein R13is hydrogen or methyl;
and wherein R14 is hydrogen, oxygen or R9;
Most preferably R2b is CpCealkyl or CpCealkyl substituted by one to three R7 or C3-C6cycloalkyl or C3-C6cycloalkyl substituted by one to five R8, wherein each R7 is independently halogen, cyano, Cp Qalkoxy, C3-C4cycloalkyl, Ci-C4alkylthio, Ci-C4haloalkylthio, Ci-C4alkylsulfinyl, Ci-C4haloalkyl- sulfinyl, Ci-C4alkylsulfonyl or Ci-C4haloalkylsulfonyl and each R8 is independently halogen, Ci-C4alkyl or Ci-C haloalkyl.
Preferably R3 is trifluoromethyl, difluoromethyl or chlorodifluoromethyl, most preferably trifluoromethyl.
Preferably R4 is aryl or aryl substituted by one to five R10, more preferably aryl substituted by one to three R10, more preferably phenyl substituted by one to three R10.
In one preferred group of compounds R4is group (A)
Figure imgf000011_0001
wherein X2 is C-X4 or nitrogen (preferably C-X4); X1, X3 and X4 are independently hydrogen, halogen or trihalomethyl, e.g. wherein at least two of X1, X3 and X4 are not hydrogen.
Preferably R4 is 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 3-fluoro-4-chlorophenyl, 3,4- dichlorophenyl, 3-chloro-4-bromophenyl, 3,5-dichloro-4-fluorophenyl, 3,4,5-trichlorophenyl, 3,5- dichloro-4-iodophenyl, 3,4,5-trifluorophenyl, 3-chloro-5-bromophenyl, 3 -chloro-5 -fluorophenyl, 3- chloro-5-(trifluoromethyl)phenyl, 3,4-dichloro-5-(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, 4-chloro-3,5-bis(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 2,6-dichloro-4-pyridyl, 2,6- bis(trifluoromethyl)-4-pyridyl,2-chloro-4-pyridyl-, 2-trifluoromethyl-4-pyridyl, more preferably 3,5- dichloro-phenyl, 3-chloro-5-bromophenyl,3-chloro-5-(trifluoromethyl)phenyl,3,5-dichloro-4- fluorophenyl,3 ,4,5 -trichlorophenyl,3 ,5 -bis(trifluoromethyl)phenyl,3 -(trifluoromethyl)phenyl,2,6-dichloro- 4-pyridyl,2,6-bis(trifluoromethyl)-4-pyridyl,3,5-dichloro-4-bromophenyl,3-bromo-5- (trifluoromethyl)phenyl,3,5-dibromophenyl, or 3,4-dichlorophenyl,2-chloro-4-pyridyl-, 2-trifluoromethyl- 4-pyridyl, even more preferably 3,5-dichloro-phenyl, 3,5-dichloro-4-fluorophenyl,3,4,5- trichlorophenyl,3-(trifluoromethyl)phenyl,3,5-bis(trifluoromethyl)phenyl,most preferably 3,5-dichloro- phenyl, 3,5-dichloro-4-fluorophenyl, or3,4,5-trichlorophenyl-.In one group of compounds R4 is 3,5- dichloro-phenyl. In one group of compounds R4 is 3,5-dichloro-4-fluorophenyl-. In one group of compounds R4 is 3,4,5-trichlorophenyl-. In one group of compounds R4 is 3,5-bis(trifluoromethyl)phenyl.
Preferably each R5 is independently halogen, cyano, methyl, halomethyl, methoxy or
halomethoxy, more preferably chloro, fluoro, cyano or methyl.
Preferably R a is hydrogen, cyano, Ci-C4alkyl
Figure imgf000012_0001
more preferably hydrogen, cyano, Ci-C2alkyl orCi-C2haloalkyl,even more preferably hydrogen or methyl.
Preferably R b is hydrogen, cyano, Ci-C4alkyl or Ci-C4haloalkyl, more preferably hydrogen, cyano, Ci-C2alkyl or Ci-C2haloalkyl, even more preferably hydrogen or methyl, most preferably hydrogen.
Preferably each R7 is independently halogen, cyano, nitro, hydroxy, CpCgalkyl, C2-Cgalkenyl, C2- Cgalkynyl, CpCgalkoxy, CpCghaloalkoxy, CpCgalkylcarbonyl, CpCgalkoxycarbonyl, mercapto, Cp Cgalkylthio, Ci-Cghaloalkylthio, Ci-Cgalkylsulfinyl, CpCghaloalkylsulfinyl, CpCgalkylsulfonyl, or Cp Cghaloalkylsulfonyl, or two R7 are together OH-N= or more preferably halogen, cyano, hydroxy, Ci-C4alkyl, C2-C4alkenyl, C2-C4alkynyl,Ci-C4alkoxy, Ci-C4haloalkoxy, mercapto, Cr
C4alkylthio, Ci-C4haloalkylthio,Ci-C4alkylsulfinyl or Ci-C4alkylsulfonyl, even more preferably halogen, cyano, Ci-C4alkoxy, Ci-C4haloalkylthio, Ci-C4alkylsulfinyl, Ci-C4haloalkylsulfinyl, Ci-C4alkylsulfonyl or
Figure imgf000012_0003
most preferably halogen, cyano, methoxy, methylthio, methylsulfinyl or methysulfonyl.
Preferably each R8 is independently halogen, cyano, Ci-C4alkyl Ci-C4alkoxy or C3-C6cycloalkyl, more preferably halogen, cyano, methyl, propyl or butyl, more preferably chloro, fluoro, cyano, methyl or propyl, most preferably fluoro, cyano, methyl or propyl.
Preferably each R9 is independently halogen, cyano, nitro, CpCgalkyl, Ci-Cghaloalkyl, hydroxy, CpCgalkoxy, CpCghaloalkoxy, mercapto, CpCgalkylthio, CpCghaloalkylthio, Ci-Cgalkylsulfinyl, Cp Cghaloalkylsulfinyl, Ci-Cgalkylsulfonyl or Ci-Cghaloalkylsulfonyl, more preferably halogen, cyano, nitro, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy or Ci-C4haloalkoxy, most preferably halogen, cyano, methyl, halomethyl, methoxy or halomethoxy.
Preferably each R10 is independently halogen, CpCgalkyl, Ci-Cghaloalkyl, CpCgalkoxy, Cp Cghaloalkoxy, CpCgalkylthio or Ci-Cghaloalkylthio, more preferably bromo, chloro, fluoro,
trifluoromethyl, methoxy or methylthio, most preferably trifluoromethyl, fluoro or chloro.
Preferably each R11 is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy, more preferably bromo, chloro, fluoro, nitro, or methyl, most preferably chloro, fluoro or methyl.
Compounds of formula I may exist in the cis or trans configuration:
Figure imgf000013_0001
Preferably the compound of formula I is in the trans configuration.
The following represent preferred embodiments of the invention, which may be combined with each other and with the preferred substituent definitions where possible.
In embodiment E1Q is Ql.
In embodiment E2 Q is Q2.
In embodiment E3 the compound of formula I is in the transconfiguration.
In embodiment E4 the compound of formula I is in the cis configuration.
Embodiment E5 is embodiment El wherein the compound of formula I is in the trans configuration.
Embodiment E6 is embodiment E2 wherein the compound of formula I is in the trans configuration.
Embodiment E7 is embodiment E2 wherein Y5 and Y6 are hydrogen.
Embodiment E8 is embodiment El wherein G1 is oxygen.
Embodiment E9 is embodiment E2 wherein G1 is oxygen.
In embodiment E10Y2is C-H and Y3and Y4 are C-H or C-R5 wherein no more than one of Y3 and Y4 is C-R5.
Embodiment El 1 is embodiment E10 wherein Y1 is oxygen.
Embodiment El 2 is embodiment E10 wherein R3 is trifluoromethyl, difluoromethyl or chlorodifluoromethyl.
Embodiment El 3 is embodiment E10 wherein R4 is group A.
Embodiment El 4 is embodiment El l wherein R3 is trifluoromethyl, difluoromethyl or chlorodifluoromethyl.
Embodiment El 5 is embodiment El l wherein R4 is group A.
Embodiment El 6 is embodiment E14 wherein R4 is group A.
Embodiment El 7 is embodiment E10 wherein G1 is oxy^ *en.
Embodiment El 8 is embodiment El l wherein G1 is oxy^ *en.
Embodiment El 9 is embodiment E12 wherein G1 is oxy^ *en.
Embodiment E20 is embodiment E13 wherein G1 is oxy^ *en.
Embodiment E21 is embodiment E14 wherein G1 is oxy^ *en.
Embodiment E22 is embodiment E15 wherein G1 is oxy^ *en.
Embodiment E22 is embodiment E16 wherein G1 is oxy^ *en.
In another embodiment (E23):
G1 is oxygen; Y1 is oxygen;
Y2is C-H, Y3and Y4 are C-H or C-R5,wherein no more than one of Y3 and Y4 is C-R5;
Y5 is hydrogen, halogen, Ci-C4alkyl or Ci-C4haloalkyl;
Y6 is hydrogen, halogen, cyano, Ci-C4alkyl or Ci-C4haloalkyl;
Rla is hydrogen, methyl, halomethyl, ethyl or haloethyl;
Rlb is hydrogen, methyl, halomethyl, ethyl or haloethyl;
R2a is CpCgalkyl or CpCgalkyl substituted by one to five R7, C2-Cgalkenyl or C2-Cgalkenyl substituted by one to five R7, C2-C8alkynyl or C2-Cgalkynyl substituted by one to five R7, C3- Ciocycloalkyl or C3-Ci0cycloalkyl substituted by one to five R8, C3-Ci0cycloalkyl-C(R12)(R13)- or C3- Ciocycloalkyl-C(R12)(R13)- wherein the cycloalkyl is substituted by one to five R8, aryl-C(R12)(R13)- or aryl-C(R12)(R13)- wherein the aryl is substituted by one to five R9, heterocyclyl-C(R12)(R13)- or heterocyclyl-C(R12)(R13)- wherein the heterocyclyl is substituted by one to five R9, aryl or aryl substituted by one to five R9, heterocyclyl or heterocyclyl substituted by one to five R9, Ci-C6alkyl-0-N=CH-, Q- C6haloalkyl-0-N=CH-, CrC4alkyl-0-N=CH-C(R12)(R13)-, CrC4haloalkyl-0-N=CH-C(R12)(R13)-, Cr C alkylaminocarbonyl-CH2- or Ci-C haloalkylaminocarbonyl-CH2-;
wherein heterocyclyl is a 4 to 7-membered heterocyclic ring containing one to three heteroatoms independently selected from O, S, SO, S02, N, and N(R14) as ring atoms;
wherein aryl is phenyl;
or Rla and R2a together form a 4- or 5-membered ring fragment containing carbon atoms as ring members, optionally substituted by one to five R9;
R2b is CrC8alkyl or Ci-C8alkyl substituted by one to five R7, C2-C8alkenyl or C2-C8alkenyl substituted by one to five R7, C2-C8alkynyl or C2-Cgalkynyl substituted by one to five R7, CpCealkoxy- CpCealkyl or Ci-Cealkoxy-Ci-Cealkyl substituted by one to five R7, C3-Ciocycloalkyl or C3-Ciocycloalkyl substituted by one to five R8, C3-Ci0cycloalkyl-C(R12)(R13)-or C3-Ci0cycloalkyl-C(R12)(R13)-substituted by one to five R8, aryl-C(R12)(R13)- or aryl-C(R12)(R13)- substituted by one to five R9, heterocyclyl- (R 12 )(R13 12 13 9
C )- or heterocyclyl-C(R )(R )- substituted by one to five R , aryl or aryl substituted by one to five R9, heterocyclyl or heterocyclyl substituted by one to five R9;
wherein aryl is phenyl;
wherein heterocyclyl is a 4- to 7-membered heterocyclic ring containing one to four heteroatoms independently selected from O, S, SO, S02, N and N(R14) as ring atoms;
R3 is trifluoromethyl, difluoromethyl or chlorodifluoromethyl;
R4 is group A, wherein X2 is C-X4 or nitrogen and X1, X3 and X4 are independently hydrogen, halogen or trihalomethyl, providing that at least one of X1, X3 and X4 is not hydrogen;
R5 is halogen, cyano, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy or Ci-C4haloalkoxy;
R a is hydrogen, cyano, Ci-C4alkyl or Ci-C4haloalkyl;
R b is hydrogen, cyano, d-Qalkyl or Ci-C4haloalkyl.
R12 and R13 are independently hydrogen, cyano, halogen, CpQalkyl, Ci-C haloalkyl, Q- Qalkoxy, Ci-C4haloalkoxy or C3-C6cycloalkyl; or R12 and R13 together form a three to six membered carbocycle; and
R14 is hydrogen, oxygen or R9.
In another embodiment (E24):
G1 is oxygen;
Y1 is oxygen;
Y2is C-H, Y3and Y4 are C-H or C-R5, wherein no more than one of Y3 and Y4 is C-R5;
Y5 is hydrogen, halogen, Ci-C2alkyl or Ci-C2haloalkyl;
Y6 is hydrogen, halogen, cyano, Ci-C2alkyl or Ci-C2haloalkyl;
Rla is hydrogen, methyl, halomethyl, ethyl or haloethyl;
Rlb is hydrogen, methyl, halomethyl, ethyl or haloethyl;
R2a is CpCealkyl or CpCealkyl substituted by one to five R7, C2-Cealkenyl or C2-Cealkenyl substituted by one to five R7, C2-Cealkynyl or C2-Cealkynyl substituted by one to five R7, Ca-Cgcycloalkyl or C3-C8cycloalkyl substituted by one to five R8, C3-C8cycloalkyl-C(R12)(R13)- or Ca-Cgcycloalkyl- C(R12)(R13)- wherein the cycloalkyl is substituted by one to five R8, aryl-C(R12)(R13)- or aryl-C(R12)(R13)- wherein the aryl is substituted by one to five R9, heterocyclyl-C(R12)(R13)-, aryl or aryl substituted by one to five R9, heterocyclyl or heterocyclyl substituted by one to five R9,
Figure imgf000015_0001
Cr
C4haloalkyl-0-N=CH-, CrC4alkyl-0-N=CH-C(R12)(R13)-, CrC4haloalkyl-0-N=CH-C(R12)(R13)-, Cr C4alkylaminocarbonyl-CH2- or Ci-C4haloalkylaminocarbonyl-CH2-;
wherein heterocyclyl is a 4- to 6-membered saturated or partially saturated heterocyclic ring containing one or two heteroatoms independently selected from O, S, SO, S02, N and N(R14) as ring atoms;
or heterocyclyl is a 5- or 6-membered heteroaryl ring containing one to three heteroatoms independently selected from O, N and S as ring atoms;
wherein aryl is phenyl;
or Rla and R2a together form a 4- or 5 -membered ring fragment containing carbon atoms as ring members, optionally substituted by one to five R9;
R2b is CrC6alkyl or Ci-C6alkyl substituted by one to five R7, C2-C6alkenyl or C2-C6alkenyl substituted by one to five R7, C2-Cealkynyl or C2-Cealkynyl substituted by one to five R7, CpCealkoxy- CpCealkyl or Ci-Cealkoxy-Ci-Cealkyl substituted by one to five R7, C3-Ciocycloalkyl or C3-Ciocycloalkyl substituted by one to five R8, C3-C10cycloalkyl-C(R12)(R13)-or C3-C10cycloalkyl-C(R12)(R13)-substituted by one to five R8, aryl-C(R12)(R13)- or aryl-C(R12)(R13)- substituted by one to five R9, heterocyclyl-
12 13 12 13 9
C(R )(R )- or heterocyclyl-C(R )(R )- substituted by one to five R , aryl or aryl substituted by one to five R9, heterocyclyl or heterocyclyl substituted by one to five R9;
wherein aryl is phenyl;
wherein heterocyclyl is a 4- to 7-membered heterocyclic ring containing one to four heteroatoms independently selected from O, S, SO, SO2, N and N(R14) as ring atoms;
R3 is trifluoromethyl, difluoromethyl or chlorodifluoromethyl; R4 is group A, wherein X2 is C-X4 or nitrogen and X1, X3 and X4 are independently hydrogen, halogen or trihalomethyl, proving that at least one of X1, X3 and X4 is not hydrogen;
R5 is halogen, cyano, methyl, halomethyl, methoxy or halomethoxy;
R a is hydrogen, cyano, Ci-C2alkyl or Ci-C2haloalkyl;
R b is hydrogen, cyano, Ci-C2alkyl or Ci-C2haloalkyl;
each R7 is independently halogen, cyano, hydroxy, Ci-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, Cp Cgalkoxy, C3-C4cycloalkyl, mercapto, Ci-Cgalkylthio, Ci-Cghaloalkylthio, Ci-Cgalkylsulfmyl, Cp Cghaloalkylsulfinyl, Ci-Cgalkylsulfonyl or Ci-Cghaloalkylsulfonyl;
each R8 is independently halogen, cyano, CrC4alkyl or C3-C4cycloalkyl;
each R9 is independently halogen, cyano, nitro, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy or Q- C4haloalkoxy;
R12 is hydrogen or Ci-C4alkyl;
R13is hydrogen, cyano, halogen, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy, Ci-C4haloalkoxy or C3-C6cycloalkyl;
or R12 and R13 together form a 3 - to 6-membered carbocycle; and
R14 is hydrogen, oxygen or R9.
In another embodiment (E25):
G1 is oxygen;
Y1 is oxygen;
Y2, Y3 and Y4 are C-H;
Y5 is hydrogen, methyl, chloro, bromo or trifluoromethyl;
Y6 is hydrogen or methyl;
wherein at least one of Y5 and Y6 is hydrogen;
Rla is hydrogen, methyl, halomethyl, ethyl or haloethyl;
Rlb is hydrogen, methyl, halomethyl, ethyl or haloethyl;
R2a is Ci-C6alkyl or Ci-C6alkyl substituted by one to three R7, C2-C6alkenyl or C2-C6alkenyl substituted by one to three R7, C2-C6alkynyl or C2-C6alkynyl substituted by one to three R7, C3- Cgcycloalkyl or Ca-Cgcycloalkyl substituted by one to three R8, C3-C8cycloalkyl-C(R12)(R13)- or C3- C8cycloalkyl-C(R12)(R13)- wherein the cycloalkyl is substituted by one to three R8, aryl-C(R12)(R13)- or aryl-C(R )(R )- wherein the aryl is substituted by one to three R , heterocyclyl-C(R )(R )-, aryl or aryl substituted by one to three R9, heterocyclyl or heterocyclyl substituted by one to three R9, CrC4alkyl-0- N=CH- or CrC4haloalkyl-0-N=CH-, C1-C4alkyl-0-N=CH-C(R12)(R13)-,C1-C4haloalkyl-0-N=CH- C(R12)(R13)-, Ci-C4alkylaminocarbonyl-CH2- or Ci-C4haloalkylaminocarbonyl-CH2-;
wherein heterocyclyl is pyridyl, pyridyl-N-oxide, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl or group Al to A12 (preferably pyridyl or A2);
wherein aryl is phenyl; or Rla and R2a together form a 4- or 5-membered ring fragment containing carbon atoms as ring members, optionally substituted by one to three R9.
R2b is Ci-C6alkyl or Ci-C6alkyl substituted by one to three R7, C2-C6alkenyl or C2-C6alkenyl substituted by one to three R7, C2-C6alkynyl or C2-C6alkynyl substituted by one to three R7,
C3-C6cycloalkyl or C3-C6cycloalkyl substituted by one to five R8, C3-C6cycloalkyl-C(R12)(R13)- or C3- C6cycloalkyl-C(R12)(R13)- substituted by one to five R8, aryl-C(R12)(R13)- or aryl-C(R12)(R13)- substituted
9 12 13 9 by one to three R , heterocyclyl-C(R )(R )-, or aryl or aryl substituted by one to three R ;
wherein heterocyclyl is pyridyl, pyridyl-N-oxide, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl or group Al to A12 (preferably pyridyl or A2);
wherein aryl is phenyl;
R3 is trifluoromethyl;
R4 is group A, wherein X2 is C-X4 and X1, X3 and X4 are independently hydrogen, halogen or trihalomethyl, proving that at least one of X1, X3 and X4 is not hydrogen;
R a is hydrogen or methyl;
R b is hydrogen or methyl;
each R7 is independently halogen, cyano, hydroxy, Ci-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, Cr C4alkoxy, C3-C4cycloalkyl, mercapto, Ci-C4alkylthio, Ci-C4haloalkylthio, Ci-C4alkylsulfinyl, Cp C4haloalkylsulfinyl, Ci-C4alkylsulfonyl or Ci-C4haloalkylsulfonyl;
each R8 is independently halogen, cyano, CrC4alkyl or C -C4cycloalkyl;
each R9 is independently halogen, cyano, nitro, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy or Cp C4haloalkoxy;
R12 is hydrogen or methyl; and
R13is hydrogen or methyl.
In another embodiment (E26):
Q is Ql;
G1 is oxygen;
Y1 is oxygen;
Y2, Y3 and Y4 are C-H;
Y5 is hydrogen, methyl, chloro, bromo or trifluoromethyl;
Y6 is hydrogen or methyl;
wherein at least one of Y5 and Y6 is hydrogen;
Rla is hydrogen, methyl, halomethyl, ethyl or haloethyl;
R2a is CpCealkyl or CpCealkyl substituted by one to three R7, C2-Cealkenyl or C2-Cealkenyl substituted by one to three R7, C2-Cealkynyl or C2-Cealkynyl substituted by one to three R7, C3- Cgcycloalkyl or CrCgcycloalkyl substituted by one to three R8, C3-C8cycloalkyl-C(R12)(R13)- or C3- C8cycloalkyl-C(R12)(R13)- wherein the cycloalkyl is substituted by one to three R8, aryl-C(R12)(R13)- or
12 13 9 12 13
aryl-C(R )(R )- wherein the aryl is substituted by one to three R , heterocyclyl-C(R )(R )-, aryl or aryl substituted by one to three R9, heterocyclyl or heterocyclyl substituted by one to three R9, CrC4alkyl-0-
N=CH- or CrC4haloalkyl-0-N=CH-, CrC4alkyl-0-N=CH-C(R12)(R13)- or CrC4haloalkyl-0-N=CH- C(R12)(R13)-, Ci-C alkylaminocarbonyl-CH2-, Ci-C haloalkylaminocarbonyl-CH2-;
wherein heterocyclyl is pyridyl, pyridyl-N-oxide, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, tnazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl or group Al to A12 (preferably pyridyl or A2);
wherein aryl is phenyl;
or Rla and R2a together form a 4- or 5-membered ring fragment containing carbon atoms as ring members, optionally substituted by one to three R9.
R3 is trifluoromethyl;
R4 is group A, wherein X2 is C-X4 and X1, X3 and X4 are independently hydrogen, halogen or trihalomethyl, proving that at least one of X1, X3 and X4 is not hydrogen;
each R7 is independently halogen, cyano, hydroxy, Ci-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, Cp Qalkoxy, C3-C cycloalkyl, mercapto, Ci-C alkylthio, Ci-C haloalkylthio, Ci-C alkylsulfinyl, Cr Qhaloalkylsulfinyl, Ci-C alkylsulfonyl or Ci-C haloalkylsulfonyl;
each R8 is independently halogen, cyano, CrC alkyl, or C3-C cycloalkyl;
each R9 is independently halogen, cyano, nitro, CrQalkyl, Ci-C haloalkyl, CpQalkoxy or Q- Qhaloalkoxy;
R12 is hydrogen or methyl; and
R13is hydrogen or methyl.
In another embodiment (27):
Q s Q2;
G1 is oxygen;
Y1 is oxygen;
Y2, Y3 and Y4 are C-H;
Y5 is hydrogen or methyl;
Y6 is hydrogen or methyl;
wherein at least one of Y5 and Y6 is hydrogen;
Rlb is hydrogen, methyl, halomethyl, ethyl or haloethyl;
R2b is Ci-C6alkyl or Ci-C6alkyl substituted by one to three R7, C2-C6alkenyl or C2-C6alkenyl substituted by one to three R7, C2-C6alkynyl or C2-C6alkynyl substituted by one to three R7,
C3-C6cycloalkyl or C3-C6cycloalkyl substituted by one to five R8, C3-C6cycloalkyl-C(R12)(R13)- or C3- C6cycloalkyl-C(R12)(R13)- substituted by one to five R8, aryl-C(R12)(R13)- or aryl-C(R12)(R13)- substituted
9 12 13 9 by one to three R , heterocyclyl-C(R )(R )-, or aryl or aryl substituted by one to three R ;
wherein heterocyclyl is pyridyl, pyridyl-N-oxide, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl or group Al to A12 (preferably pyridyl or A2);
wherein aryl is phenyl; R3 is trifluoromethyl;
R4 is group A, wherein X2 is C-X4 and X1, X3 and X4 are independently hydrogen, halogen or trihalomethyl, proving that at least one of X1, X3 and X4 is not hydrogen;
R a is hydrogen or methyl;
R b is hydrogen or methyl;
each R7 is independently halogen, cyano, hydroxy, Ci-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, Cp C4alkoxy, C3-C4cycloalkyl, mercapto, Ci-C4alkylthio, Ci-C4haloalkylthio, Ci-C4alkylsulfinyl, Cp C4haloalkylsulfinyl, Ci-C4alkylsulfonyl or Ci-C4haloalkylsulfonyl;
each R8 is independently halogen, cyano, CrC4alkyl, or C3-C4cycloalkyl;
each R9 is independently halogen, cyano, nitro, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy or Q- C4haloalkoxy;
R12 is hydrogen or methyl; and
R13is hydrogen or methyl.
In another embodiment (E28) Y1 is oxygen.
In another embodiment (E29) Y1 is sulfur.
In another embodiment (E30) Y1 is CH2.
In another embodiment (E31) Q is Ql and R2a is CpCgalkyl or CpCgalkyl substituted by one to five R7, C2-C8alkenyl or C2-C8alkenyl substituted by one to five R7, C2-C8alkynyl or C2-C8alkynyl substituted by one to five R7.
In another embodiment (E32) Q is Ql and R2a is C3-Ci0cycloalkyl or C3-Ciocycloalkyl substituted by one to five R8, C3-Ciocycloalkyl-Ci-C4alkylene or C -Ci0cycloalkyl-Ci-C4alkylene substituted by one to five R8.
In another embodiment (E33) Q is Ql and R2a is aryl-Ci-C4alkylene- or aryl-Ci-C4alkylene- substituted by one to five R9, aryl or aryl substituted by one to five R9.
In another embodiment (E33) Q is Ql and R2a is heterocyclyl-Ci-C4alkylene- or heterocyclyl-Cr C4alkylene- substituted by one to five R9, heterocyclyl or heterocyclyl substituted by one to five R9.
In another embodiment (E34) Q is Q2 and R2b is CpCgalkyl or CpCgalkyl substituted by one to five R7, C2-C8alkenyl or C2-C8alkenyl substituted by one to five R7, C2-C8alkynyl or C2-C8alkynyl substituted by one to five R7, Ci-Cgalkoxy-CpCgalkyl or CpCgalkoxy-Ci-Cgalkyl substituted by one to five R7.
In another embodiment (E35) Q is Q2 and R2b is C3-Ci0cycloalkyl or C3-Ci0cycloalkyl substituted by one to five R8, C -Ci0cycloalkyl-Ci-C4alkylene or C -Ci0cycloalkyl-Ci-C4alkylene substituted by one to five R8.
In another embodiment (E36) Q is Q2 and R2b is aryl-Ci-C4alkylene- or aryl-Ci-C4alkylene- substituted by one to five R9, aryl or aryl substituted by one to five R9.
In another embodiment (E37) Q is Q2 and R2b is heterocyclyl-Ci-C4alkylene- or heterocyclyl-Cr C4alkylene- substituted by one to five R9, heterocyclyl or heterocyclyl substituted by one to five R9. The present invention also provides intermediates useful for the preparation of compounds of formula I.
One group of novel intermediates are compounds of formula Int-I
Figure imgf000020_0001
wherein Y , Y , Y% Y , Y Y , R , Rj, R , R6a and R6b are as defined for compounds of formula I, or a salt or N-oxide thereof The preferred definitions of Y1, Y2, Y3, Y4, Y5, Y6, R1, R3, R4, R a and R bare as defined for compounds of formula I.
Another group of novel intermediates are compounds of formula Int-II
Figure imgf000020_0002
wherein R 21 and R 22 are independently CpCgalkylcarbonyl, CpCgalkoxy ^ccaarrbboonn}yl, or R 21 and R 22 together are -C(=0)-(CH2)r-C(=0)- wherein r is 1 to 4, -C(Ci-C3alkyl)=C-C=(Ci-C3alkyl)C-, or group B
Figure imgf000020_0003
and Y1, Y2, Y3, Y4, Y5, Y6, R3, R4, R a and R b are as defined for compounds of formula I and or a salt or N-oxide thereof The preferred definitions of Y1, Y2, Y3, Y4, Y5, Y6, R1, R4, R a and R bare as defined for compounds of formula I.
Another group of novel intermediates are compounds of formula Int-III
Figure imgf000020_0004
wherein R is a leaving group (preferably hydroxy, CrC15alkoxy, CI, F or Br),and Y1, Y2, Y3, Y4, Y5, Y6, G1, R3 and R4 are as defined for compounds of formula I and or a salt or N-oxide thereof The preferred
1 2 3 4 5 6 1 3 4
definitions of Y , Y , YJ, Y Y , Y°, G , RJ and R" are as defined for compounds of formula I. A leaving group is for example 1 -pyrrolyl, 1 -benzotriazolyl, 1 -pyrazolyl, 1 -tetrazolyl, N-succinimidyloxy, N- phthalimidyloxy, 1 -benzotriazolyloxy, N-piperidyloxy, N-l,2,3-benzotriazin-4-onyloxy, SCl -ClOalkyl, SAryl, pentafluorophenoxy, 4-nitrophenoxy, 3-pyridyloxy, 2,4,5 -trichlorophenoxy, or
pentachlorophenoxy.
Another group of novel intermediates are compounds of formula Int-IV
Figure imgf000021_0001
wherein Ra is hydroxy, PPh3, Br or CI, and Y1, Y2, Y3, Y4, Y5, R3 and R4 are as defined for compounds of formula I or a salt or N-oxide thereof. The preferred definitions of Y , Y , Y , Y , Y , R and R are as defined for compounds of formula I. In one group of compounds of formula Int-IV Ra is OH. In another group of compounds of formula Int-IV Ra is PPh3. In another group of compounds Int-IV is Br or CI.
Another group of novel intermediates are compounds of formula Int-V
Figure imgf000021_0002
wherein Y1 is hydroxy, Rb is nitro or halogen, R31is nitro, cyano, fluoro, chloro, bromo, iodo or C(0)R' wherein R' is hydroxy, Ci-Ci5alkoxyor Ci 2 3 4 3 4
-C4alkyl, and Y , Y , Y , R and R are as defined for
2 3 4 3 4 compounds of formula I, or a salt or N-oxide thereof. The preferred definitions of Y , Y , Y , R and R are as defined for compounds of formula I. In one group of compounds of formula V Rb is nitro. In one group of compounds of formula V Rb is halogen Preferably when Rb is bromo R31 is not bromo or iodo, and when Rb is iodo, R31 is not halogen.
Another group of novel intermediates are compounds of formula Int-VI
Figure imgf000021_0003
wherein Y6 is hydrogen, hydroxy, halogen, CpCgalkyl, CpCghaloalkyl or C3-C8cycloalkyl and Y1, Y2, Y3, Y4, R3 and R4 are as defined for compounds of formula I, or a salt or N-oxide thereof.The preferred
1 2 3 4 3 4
definitions of Y , Y Y\ Y RJ and R" are as defined for compounds of formula I.
Another group of novel intermediates are compounds of formula Int-VII
Figure imgf000021_0004
wherein Rc is NH2 or R , wherein R is nitro, cyano, halogen (e.g. fluoro, chloro, bromo,
iodo),-C(0)N(R")OR",-C(0)R' or C(0)OR", wherein R' is CrC15alkoxy or CrC4alkyl,and each R" is
1 2 3 4 3 4
indepedently CrC6alkyl, and Y , Y Y Y RJ and R" are as defined for compounds of formula I, or a 1 2 3 4 3 4
salt or N-oxide thereof. The preferred definitions of Y , Y , Y , Y , R and R are as defined for compounds of formula I.
Another group of novel intermediates are compounds of formula Int-VIII
Figure imgf000022_0001
1 2 3 4 6 3 4
wherein X is chloro or bromo and Y , Y , Y , Y , Y , R and R are as defined for compounds of formula
1 2 3 4 6 3 4
I, or a salt or N-oxide thereof. The preferred definitions of and Y , Y , Y , Y , Y , R and R are as defined for compounds of formula I.
Another group of novel intermediates are compounds of formula Int-IX
Figure imgf000022_0002
33 1 2 3 4 6 3 4
wherein each RJJ is independently CrC6alkyland Y , Y\ Y\ Y Y°, RJ and R" are as defined for compounds of formula I, or a salt or N-oxide thereof. The preferred definitions of and Y1, Y2, Y3, Y4, Y6, R3 and R4 are as defined for compounds of formula I.
Compounds of formula I include at least one chiral centre and may exist as compounds of formula I* or compounds of formula I**:
Figure imgf000022_0003
Generally compounds of formula I** are more biologically active than compounds of formula I*. The invention includes mixtures of compounds I* and I** in any ratio e.g. in a molar ratio of 1 :99 to 99: 1, e.g. 10:1 to 1 : 10, e.g. a substantially 50:50 molar ratio. In an enantiomerically (or epimerically) enriched mixture of formula I**, the molar proportion of compound I** compared to the total amount of both enantiomers (or epimers) is for example greater than 50%, e.g. at least 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or at least 99%. Likewise, in enantiomerically (or epimerically) enriched mixture of formula I*, the molar proportion of the compound of formula I* compared to the total amount of both enantiomers (or epimers) is for example greater than 50%, e.g. at least 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or at least 99%. Enantiomerically (or epimerically) enriched mixtures of formula I** are preferred.Each compound disclosed in Tables 1 to 179represents a disclosure of a compound according to the compound of formula I*, and a disclosure according to the compound of formula I**.
The tables below illustrate compounds of the invention.
Table P
Figure imgf000023_0001
chlorodifluoromethyl 3 , 5 -dichlorophenyl- CF3 H cis trifluoromethyl 3,4,5-trichlorophenyl- CF3 H cis chlorodifluoromethyl 3,4,5-trichlorophenyl- CF3 H cis trifluoromethyl 3,5-dichloro-4-fluorophenyl- CF3 H cis chlorodifluoromethyl 3,5-dichloro-4-fluorophenyl- CF3 H cis trifluoromethyl 3 -trifluoromethylphenyl- CF3 H cis chlorodifluoromethyl 3 -trifluoromethylphenyl- CF3 H cis trifluoromethyl 3 ,5 -bis(trifluoromethyl)phenyl- CF3 H cis chlorodifluoromethyl 3 ,5 -bis(trifluoromethyl)phenyl- CF3 H cis trifluoromethyl 3 -chloro-5 -trifluoromethylphenyl- CF3 H cis chlorodifluoromethyl 3 -chloro-5 -trifluoromethylphenyl- CF3 H cis trifluoromethyl 3 , 5 -dichlorophenyl- Me Me cis chlorodifluoromethyl 3 , 5 -dichlorophenyl- Me Me cis trifluoromethyl 3,4,5-trichlorophenyl- Me Me cis chlorodifluoromethyl 3,4,5-trichlorophenyl- Me Me cis trifluoromethyl 3,5-dichloro-4-fluorophenyl- Me Me cis chlorodifluoromethyl 3,5-dichloro-4-fluorophenyl- Me Me cis trifluoromethyl 3 -trifluoromethylphenyl- Me Me cis chlorodifluoromethyl 3 -trifluoromethylphenyl- Me Me cis trifluoromethyl 3 ,5 -bis(trifluoromethyl)phenyl- Me Me cis chlorodifluoromethyl 3 ,5 -bis(trifluoromethyl)phenyl- Me Me cis trifluoromethyl 3 -chloro-5 -trifluoromethylphenyl- Me Me cis chlorodifluoromethyl 3 -chloro-5 -trifluoromethylphenyl- Me Me cis trifluoromethyl 3 , 5 -dichlorophenyl- CI Me cis chlorodifluoromethyl 3 , 5 -dichlorophenyl- CI Me cis trifluoromethyl 3,4,5-trichlorophenyl- CI Me cis chlorodifluoromethyl 3,4,5-trichlorophenyl- CI Me cis trifluoromethyl 3,5-dichloro-4-fluorophenyl- CI Me cis chlorodifluoromethyl 3,5-dichloro-4-fluorophenyl- CI Me cis trifluoromethyl 3 -trifluoromethylphenyl- CI Me cis chlorodifluoromethyl 3 -trifluoromethylphenyl- CI Me cis trifluoromethyl 3 ,5 -bis(trifluoromethyl)phenyl- CI Me cis chlorodifluoromethyl 3 ,5 -bis(trifluoromethyl)phenyl- CI Me cis trifluoromethyl 3 -chloro-5 -trifluoromethylphenyl- CI Me cis chlorodifluoromethyl 3 -chloro-5 -trifluoromethylphenyl- CI Me cis trifluoromethyl 3 , 5 -dichlorophenyl- Br Me cis chlorodifluoromethyl 3 , 5 -dichlorophenyl- Br Me cis trifluoromethyl 3,4,5-trichlorophenyl- Br Me cis chlorodifluoromethyl 3,4,5-trichlorophenyl- Br Me cis trifluoromethyl 3,5-dichloro-4-fluorophenyl- Br Me cis chlorodifluoromethyl 3,5-dichloro-4-fluorophenyl- Br Me cis trifluoromethyl 3 -trifluoromethylphenyl- Br Me cis chlorodifluoromethyl 3 -trifluoromethylphenyl- Br Me cis trifluoromethyl 3 ,5 -bis(trifluoromethyl)phenyl- Br Me cis chlorodifluoromethyl 3 ,5 -bis(trifluoromethyl)phenyl- Br Me cis trifluoromethyl 3 -chloro-5 -trifluoromethylphenyl- Br Me cis chlorodifluoromethyl 3 -chloro-5 -trifluoromethylphenyl- Br Me cis 85 trifluoromethyl 3 , 5 -dichlorophenyl- CF3 Me cis
86 chlorodifluoromethyl 3 , 5 -dichlorophenyl- CF3 Me cis
87 trifluoromethyl 3,4,5-trichlorophenyl- CF3 Me cis
88 chlorodifluoromethyl 3,4,5-trichlorophenyl- CF3 Me cis
89 trifluoromethyl 3,5-dichloro-4-fluorophenyl- CF3 Me cis
90 chlorodifluoromethyl 3,5-dichloro-4-fluorophenyl- CF3 Me cis
91 trifluoromethyl 3 -trifluoromethylphenyl- CF3 Me cis
92 chlorodifluoromethyl 3 -trifluoromethylphenyl- CF3 Me cis
93 trifluoromethyl 3 ,5 -bis(trifluoromethyl)phenyl- CF3 Me cis
94 chlorodifluoromethyl 3 ,5 -bis(trifluoromethyl)phenyl- CF3 Me cis
95 trifluoromethyl 3 -chloro-5 -trifluoromethylphenyl- CF3 Me cis
96 chlorodifluoromethyl 3 -chloro-5 -trifluoromethylphenyl- CF3 Me cis
97 trifluoromethyl 3 , 5 -dichlorophenyl- Me H trans
98 chlorodifluoromethyl 3 , 5 -dichlorophenyl- Me H trans
99 trifluoromethyl 3,4,5-trichlorophenyl- Me H trans
100 chlorodifluoromethyl 3,4,5-trichlorophenyl- Me H trans
101 trifluoromethyl 3,5-dichloro-4-fluorophenyl- Me H trans
102 chlorodifluoromethyl 3,5-dichloro-4-fluorophenyl- Me H trans
103 trifluoromethyl 3 -trifluoromethylphenyl- Me H trans
104 chlorodifluoromethyl 3 -trifluoromethylphenyl- Me H trans
105 trifluoromethyl 3 ,5 -bis(trifΓuoromethyl)phenyl- Me H trans
106 chlorodifluoromethyl 3 ,5 -bis(trifluoromethyl)phenyl- Me H trans
107 trifluoromethyl 3 -chloro-5 -trifluoromethylphenyl- Me H trans
108 chlorodifluoromethyl 3 -chloro-5 -trifluoromethylphenyl- Me H trans
109 trifluoromethyl 3 , 5 -dichlorophenyl- CI H trans
110 chlorodifluoromethyl 3 , 5 -dichlorophenyl- CI H trans
111 trifluoromethyl 3,4,5-trichlorophenyl- CI H trans
112 chlorodifluoromethyl 3,4,5-trichlorophenyl- CI H trans
113 trifluoromethyl 3,5-dichloro-4-fluorophenyl- CI H trans
114 chlorodifluoromethyl 3,5-dichloro-4-fluorophenyl- CI H trans
115 trifluoromethyl 3 -trifluoromethylphenyl- CI H trans
116 chlorodifluoromethyl 3 -trifluoromethylphenyl- CI H trans
117 trifluoromethyl 3 ,5 -bis(trifΓuoromethyl)phenyl- CI H trans
118 chlorodifluoromethyl 3 ,5 -bis(trifluoromethyl)phenyl- CI H trans
119 trifluoromethyl 3 -chloro-5 -trifluoromethylphenyl- CI H trans
120 chlorodifluoromethyl 3 -chloro-5 -trifluoromethylphenyl- CI H trans
121 trifluoromethyl 3 , 5 -dichlorophenyl- Br H trans
122 chlorodifluoromethyl 3 , 5 -dichlorophenyl- Br H trans
123 trifluoromethyl 3,4,5-trichlorophenyl- Br H trans
124 chlorodifluoromethyl 3,4,5-trichlorophenyl- Br H trans
125 trifluoromethyl 3,5-dichloro-4-fluorophenyl- Br H trans
126 chlorodifluoromethyl 3,5-dichloro-4-fluorophenyl- Br H trans
127 trifluoromethyl 3 -trifluoromethylphenyl- Br H trans
128 chlorodifluoromethyl 3 -trifluoromethylphenyl- Br H trans
129 trifluoromethyl 3 ,5 -bis(trifluoromethyl)phenyl- Br H trans
130 chlorodifluoromethyl 3 ,5 -bis(trifluoromethyl)phenyl- Br H trans
131 trifluoromethyl 3 -chloro-5 -trifluoromethylphenyl- Br H trans 132 chlorodifluoromethyl 3 -chloro-5 -trifluoromethylphenyl- Br H trans
133 trifluoromethyl 3 , 5 -dichlorophenyl- CF3 H trans
134 chlorodifluoromethyl 3 , 5 -dichlorophenyl- CF3 H trans
135 trifluoromethyl 3,4,5-trichlorophenyl- CF3 H trans
136 chlorodifluoromethyl 3,4,5-trichlorophenyl- CF3 H trans
137 trifluoromethyl 3,5-dichloro-4-fluorophenyl- CF3 H trans
138 chlorodifluoromethyl 3,5-dichloro-4-fluorophenyl- CF3 H trans
139 trifluoromethyl 3 -trifluoromethylphenyl- CF3 H trans
140 chlorodifluoromethyl 3 -trifluoromethylphenyl- CF3 H trans
141 trifluoromethyl 3 ,5 -bis(trifΓuoromethyl)phenyl- CF3 H trans
142 chlorodifluoromethyl 3 ,5 -bis(trifluoromethyl)phenyl- CF3 H trans
143 trifluoromethyl 3 -chloro-5 -trifluoromethylphenyl- CF3 H trans
144 chlorodifluoromethyl 3 -chloro-5 -trifluoromethylphenyl- CF3 H trans
145 trifluoromethyl 3 , 5 -dichlorophenyl- Me Me trans
146 chlorodifluoromethyl 3 , 5 -dichlorophenyl- Me Me trans
147 trifluoromethyl 3,4,5-trichlorophenyl- Me Me trans
148 chlorodifluoromethyl 3,4,5-trichlorophenyl- Me Me trans
149 trifluoromethyl 3,5-dichloro-4-fluorophenyl- Me Me trans
150 chlorodifluoromethyl 3,5-dichloro-4-fluorophenyl- Me Me trans
151 trifluoromethyl 3 -trifluoromethylphenyl- Me Me trans
152 chlorodifluoromethyl 3 -trifluoromethylphenyl- Me Me trans
153 trifluoromethyl 3 ,5 -bis(trifΓuoromethyl)phenyl- Me Me trans
154 chlorodifluoromethyl 3 ,5 -bis(trifluoromethyl)phenyl- Me Me trans
155 trifluoromethyl 3 -chloro-5 -trifluoromethylphenyl- Me Me trans
156 chlorodifluoromethyl 3 -chloro-5 -trifluoromethylphenyl- Me Me trans
157 trifluoromethyl 3 , 5 -dichlorophenyl- CI Me trans
158 chlorodifluoromethyl 3 , 5 -dichlorophenyl- CI Me trans
159 trifluoromethyl 3,4,5-trichlorophenyl- CI Me trans
160 chlorodifluoromethyl 3,4,5-trichlorophenyl- CI Me trans
161 trifluoromethyl 3,5-dichloro-4-fluorophenyl- CI Me trans
162 chlorodifluoromethyl 3,5-dichloro-4-fluorophenyl- CI Me trans
163 trifluoromethyl 3 -trifluoromethylphenyl- CI Me trans
164 chlorodifluoromethyl 3 -trifluoromethylphenyl- CI Me trans
165 trifluoromethyl 3 ,5 -bis(trifΓuoromethyl)phenyl- CI Me trans
166 chlorodifluoromethyl 3 ,5 -bis(trifluoromethyl)phenyl- CI Me trans
167 trifluoromethyl 3 -chloro-5 -trifluoromethylphenyl- CI Me trans
168 chlorodifluoromethyl 3 -chloro-5 -trifluoromethylphenyl- CI Me trans
169 trifluoromethyl 3 , 5 -dichlorophenyl- Br Me trans
170 chlorodifluoromethyl 3 , 5 -dichlorophenyl- Br Me trans
171 trifluoromethyl 3,4,5-trichlorophenyl- Br Me trans
172 chlorodifluoromethyl 3,4,5-trichlorophenyl- Br Me trans
173 trifluoromethyl 3,5-dichloro-4-fluorophenyl- Br Me trans
174 chlorodifluoromethyl 3,5-dichloro-4-fluorophenyl- Br Me trans
175 trifluoromethyl 3 -trifluoromethylphenyl- Br Me trans
176 chlorodifluoromethyl 3 -trifluoromethylphenyl- Br Me trans
177 trifluoromethyl 3 ,5 -bis(trifluoromethyl)phenyl- Br Me trans
178 chlorodifluoromethyl 3 ,5 -bis(trifluoromethyl)phenyl- Br Me trans 179 trifluoromethyl 3 -chloro-5 -trifluoromethylphenyl- Br Me trans
180 chlorodifluoromethyl 3 -chloro-5 -trifluoromethylphenyl- Br Me trans
181 trifluoromethyl 3 , 5 -dichlorophenyl- CF3 Me trans
182 chlorodifluoromethyl 3 , 5 -dichlorophenyl- CF3 Me trans
183 trifluoromethyl 3,4,5-trichlorophenyl- CF3 Me trans
184 chlorodifluoromethyl 3,4,5-trichlorophenyl- CF3 Me trans
185 trifluoromethyl 3,5-dichloro-4-fluorophenyl- CF3 Me trans
186 chlorodifluoromethyl 3,5-dichloro-4-fluorophenyl- CF3 Me trans
187 trifluoromethyl 3 -trifluoromethylphenyl- CF3 Me trans
188 chlorodifluoromethyl 3 -trifluoromethylphenyl- CF3 Me trans
189 trifluoromethyl 3 ,5 -bis(trifluoromethyl)phenyl- CF3 Me trans
190 chlorodifluoromethyl 3 ,5 -bis(trifluoromethyl)phenyl- CF3 Me trans
191 trifluoromethyl 3 -chloro-5 -trifluoromethylphenyl- CF3 Me trans
192 chlorodifluorome -chloro-5 -trifluoromethylphenyl- CF3 Me trans
Figure imgf000027_0001
Table 1
Table 1 provides 192 compounds of formula IA wherein R2a is l-oxo-tetrahydrofuran-3-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 2
Table 2 provides 192 compounds of formula LA wherein R2a is l -oxo-thietan-3-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 3
Table 3 provides 192 compounds of formula LA wherein R2a is l,l-dioxo-tetrahydrofuran-3-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 4
Table 4 provides 192 compounds of formula LA wherein R2a is l,l -dioxo-thietan-3-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 5
Table 5 provides 192 compounds of formula IA wherein R2a is (l,l -dioxo-thietan-2-yl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 6
Table 6 provides 192 compounds of formula IA wherein R2a is 4-oxo-2-(trifluoromethyl)-l,3- oxazinan-5-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 7
Table 7 provides 192 compounds of formula LA wherein R2a is 3-oxo-2-(cyclopropylmethyl)- isoxazolidin-4-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 8
Table 8 provides 192 compounds of formula IA wherein R2a is 2,5 -dioxo-1 -(2,2,2- trifluoroethyl)pyrrolidin-3-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 9
Table 9 provides 192 compounds of formula LA wherein R2a is N-(3,3,3-trifluoropropyl)acetamid-2- yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 10
Table 10 provides 192 compounds of formula LA wherein R2a is N-(2,2,2-trifluoroethyl)acetamid-2- yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 11 Table 11 provides 192 compounds of formula IA wherein R2a is 2-methoxy-ethyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 12
Table 12 provides 192 compounds of formula IA wherein R2a is 3-chloroprop-l -yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 13
Table 13 provides 192 compounds of formula LA wherein R2a is 3,3,3-trifluoro-propyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 14
Table 14 provides 192 compounds of formula LA wherein R2a is (thietan-2-yl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 15
Table 15 provides 192 compounds of formula IA wherein R2a is l-oxo-thietan-3-yl-methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 16
Table 16 provides 192 compounds of formula IA wherein R2a is (oxetan-2-yl)-methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 17
Table 17 provides 192 compounds of formula LA wherein R2a is (thiazol-4-yl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 18
Table 18 provides 192 compounds of formula IA wherein R2a is (2-pyrimid-2-yl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 19
Table 19 provides 192 compounds of formula LA wherein R2a is (thietan-3-yl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 20
Table 20 provides 192 compounds of formula LA wherein R2a is (l,l-dioxo-thietan-3-yl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 21
Table 21 provides 192 compounds of formula LA wherein R2a is (N-methoxypiperid-4-yl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 22
Table 22 provides 192 compounds of formula LA wherein R2a is (tetrahydrofuran-2-yl)-methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 23
Table 23 provides 192 compounds of formula IA wherein R2a is (2-pyridyl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 24
Table 24 provides 192 compounds of formula LA wherein R2a is phenylmethyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 25
Table 25 provides 192 compounds of formula IA wherein R2a is (cyclobutyl)methyl, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 26
Table 26 provides 192 compounds of formula IA wherein R2a is (2-fluorophenyl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 27
Table 27 provides 192 compounds of formula LA wherein R2a is N-ethylacetamid-2-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 28
Table 28 provides 192 compounds of formula IA wherein R2a is N-(but-2-yl)acetamid-2-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 29 Table 29 provides 192 compounds of formula IA wherein R2a is 2,2,2-trifluoro-ethyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 30
Table 30 provides 192 compounds of formula IA wherein R2a is tetrahydrofuran-2-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 31
Table 31 provides 192 compounds of formula LA wherein R2a is thietan-3-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 32
Table 32 provides 192 compounds of formula LA wherein R2a is 3-oxo-2-(3,3,3-trifluoro-propyl)- isoxazolidin-4-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 33
Table 33 provides 192 compounds of formula IA wherein R2a is 3-oxetanyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 34
Table 34 provides 192 compounds of formula LA wherein R2a is tetrahydrofuran-2-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 35
Table 35 provides 192 compounds of formula LA wherein R2a is 2-oxo-l -(2,2,2- trifluoroethyl)pyrrolidin-3-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 36
Table 36 provides 192 compounds of formula IA wherein R2a is cyclobutyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 37
Table 37 provides 192 compounds of formula LA wherein R2a is 2-norbornyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 38
Table 38 provides 192 compounds of formula LA wherein R2a is cyclopropyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 39
Table 39 provides 192 compounds of formula LA wherein R2a is 3-(hydroxyimino)-cyclobutyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 40
Table 40 provides 192 compounds of formula LA wherein R2a is 3-(ethoxyimino)-cyclobutyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 41
Table 41 provides 192 compounds of formula LA wherein R2a is 2-oxopyrrolidin-3-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 42
Table 42 provides 192 compounds of formula LA wherein R2a is 3-oxo-2-(2,2,2-trifluoro-ethyl)- isoxazolidin-4-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 43
Table 43 provides 192 compounds of formula LA wherein R2a is 3-oxo-2-(2,2-difluoro-ethyl)- isoxazolidin-4-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 44
Table 44 provides 192 compounds of formula LA wherein R2a is 3-methyloxetan-3-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 45
Table 45 provides 192 compounds of formula LA wherein R2a is l -phenyleth-l-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 46
Table 46 provides 192 compounds of formula IA wherein R2a is 1 -cyanocyclopropyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 47 Table 47 provides 192 compounds of formula IA wherein R2a is 2-fluoro-cycloprop-l -yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 48
Table 48 provides 192 compounds of formula IA wherein R2a is l,l,l-trifluoroprop-2-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 49
Table 49 provides 192 compounds of formula LA wherein R2a is 2-methylsulfanyl-ethyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 50
Table 50 provides 192 compounds of formula IA wherein R2a is N-methoxyethaniminyl, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 51
Table 51 provides 192 compounds of formula LA wherein R2a is 3-(methoxyimino)-cyclobutyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 52
Table 52 provides 192 compounds of formula LA wherein R2a is N-ethoxyethaniminyl, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 53
Table 53 provides 192 compounds of formula LA wherein R2a is 3-oxo-2-ethylisoxazolidin-4-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 54
Table 54 provides 192 compounds of formula LA wherein R2a is 2-oxo-l-(ethyl)pyrrolidin-3-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 55
Table 55 provides 192 compounds of formula LA wherein R2a is but-l-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 56
Table 56 provides 192 compounds of formula LA wherein R2a is but-2-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 57
Table 57 provides 192 compounds of formula IA wherein R2a is 1 -methoxy-prop-2-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 58
Table 58 provides 192 compounds of formula LA wherein R2a is 2-oxo-l-methylpyrrolidin-3-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 59
Table 59 provides 192 compounds of formula LA wherein R2a is 3-oxo-2-methylisoxazolidin-4-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 60
Table 60 provides 192 compounds of formula LA wherein R2a is prop-2-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 61
Table 61 provides 192 compounds of formula LA wherein R2a is methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 62
Table 62 provides 192 compounds of formula IA wherein R2a is ethyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 63
Table 63 provides 192 compounds of formula LA wherein R2a is prop-l -yl, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 64
Table 64 provides 192 compounds of formula IA wherein R2a is 2,2-difluoro-ethyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 65 Table 65 provides 192 compounds of formula IA wherein R2a is l -oxo-thietan-3-yl-ethyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 66
Table 66 provides 192 compounds of formula IA wherein R2a is tetrahydropyran-4-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 67
Table 67 provides 192 compounds of formula LA wherein R2a is 2-fluoro-ethyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 68
Table 68 provides 192 compounds of formula LA wherein R2a is thietan-3-yl-ethyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 69
Table 69 provides 192 compounds of formula LA wherein R2a is cyclopentyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 70
Table 70 provides 192 compounds of formula LA wherein R2a is (2-cyclopropyl-l-oxa-3,4-diazol-5- yl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 71
Table 71 provides 192 compounds of formula LA wherein R2a is 2-thiazolinyl, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 72
Table 72 provides 192 compounds of formula LA wherein R2a is 4-cyanopyrimid-2-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 73
Table 73 provides 192 compounds of formula IA wherein R2a is (pyrimidin-5-yl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 74
Table 74 provides 192 compounds of formula LA wherein R2a is 2-chloropyrid-5-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 75
Table 75 provides 192 compounds of formula LA wherein R2a is (pyrazin-2-yl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 76
Table 76 provides 192 compounds of formula LA wherein R2a is (2-chlorothiazol-5-yl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 77
Table 77 provides 192 compounds of formula IA wherein R2a is 2-methylsulfmyl-ethyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 78
Table 78 provides 192 compounds of formula LA wherein R2a is 2-(methylsulfonyl)-ethyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 79
Table 79 provides 192 compounds of formula LA wherein R2a is N-methylpiperidin-4-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 80
Table 80 provides 192 compounds of formula IA wherein R2a is N-(3,3,3- trifluoropropanoyl)piperidin-4-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 81
Table 81 provides 192 compounds of formula LA wherein R2a is l-(2-chloro-pyrid-5-yl)eth-l-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 82
Table 82 provides 192 compounds of formula LA wherein R2a is N-cyclopropylacetamid-2-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 83 Table 83 provides 192 compounds of formula IA wherein R2a is (2-chloro-pyrid-3-yl)-methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 84
Table 84 provides 192 compounds of formula IA wherein R2a is 3-oxo-2-propargylisoxazolidin-4- yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 85
Table 85 provides 192 compounds of formula IA wherein R2a is (3-fluorophenyl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 86
Table 86 provides 192 compounds of formula IA wherein R2a is (2-fluorophenyl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 87
Table 87 provides 192 compounds of formula IA wherein R2a is (l -oxo-thietan-3-yl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 88
Table 88 provides 192 compounds of formula IA wherein R2a is N-(cyclopropyl)acetamid-2-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 89
Table 89 provides 192 compounds of formula IA wherein R2a is (4-chlorophenyl)methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 90
Table 90 provides 192 compounds of formula IA wherein R2a is l-methyl-l -(pyrid-2-yl)eth-l -yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 91
Table 91 provides 192 compounds of formula IA wherein R2a is 1 -(2-pyridyl)cyclopropyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 92
Table 92 provides 192 compounds of formula IA wherein R2a is (2-chloro-pyrid-5-yl)-methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 93
Table 93 provides 192 compounds of formula IA wherein R2a is (2-chloro-pyrid-4-yl)-methyl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 94
Table 94 provides 192 compounds of formula IA wherein R2a is N-(benzyl)acetamid-2-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table 95
Table 95 provides 192 compounds of formula IA wherein R2a is N-(2-fluorobenzyl)acetamid-2-yl-, and R3, R4, Y5, Y6 and cis/trans are as defined in Table P.
Table O
Figure imgf000032_0001
3 ,5 -bis(trifluoromethyl)phenyl- Cl H H cis
3 -chloro-5 -trifluoromethylphenyl- CI H H cis
3 ,5 -dichlorophenyl- Br H H cis
3 ,4,5 -trichlorophenyl- Br H H cis
3,5-dichloro-4-fluorophenyl- Br H H cis
3 -trifluoromemylphenyl - Br H H cis
3 ,5 -bis(trifluoromethyl)phenyl- Br H H cis
3 -chloro-5 -trifluoromethylphenyl- Br H H cis
3 ,5 -dichlorophenyl- Me Me H cis
3,4,5 -trichlorophenyl- Me Me H cis
3,5-dichloro-4-fluorophenyl- Me Me H cis
3 -trifluoromethylphenyl- Me Me H cis
3 ,5 -bis(trifluoromethyl)phenyl- Me Me H cis
3 -chloro-5 -trifluoromethylphenyl- Me Me H cis
3,5-dichlorophenyl- CI Me H cis
3,4,5 -trichlorophenyl- CI Me H cis
3,5-dichloro-4-fluorophenyl- CI Me H cis
3 -trifluoromethylphenyl- CI Me H cis
3 ,5 -bis(trifluoromethyl)phenyl- CI Me H cis
3 -chloro-5 -trifluoromethylphenyl- CI Me H cis
3,5-dichlorophenyl- Br Me H cis
3,4,5 -trichlorophenyl- Br Me H cis
3,5-dichloro-4-fluorophenyl- Br Me H cis
3 -trifluoromethylphenyl- Br Me H cis
3 ,5 -bis(trifluoromethyl)phenyl- Br Me H cis
3 -chloro-5 -trifluoromethylphenyl- Br Me H cis
3 ,5 -dichlorophenyl- Me H Me cis
3 ,4,5 -trichlorophenyl- Me H Me cis
3,5-dichloro-4-fluorophenyl- Me H Me cis
3 -trifluoromemylphenyl - Me H Me cis
3 ,5 -bis(trifluoromethyl)phenyl- Me H Me cis
3 -chloro-5 -trifluoromemylphenyl - Me H Me cis
3 ,5 -dichlorophenyl- CI H Me cis
3 ,4,5 -trichlorophenyl- CI H Me cis
3,5-dichloro-4-fluorophenyl- CI H Me cis
3 -trifluoromethylphenyl- CI H Me cis
3 ,5 -bis(trifluoromethyl)phenyl- CI H Me cis
3 -chloro-5 -trifluoromethylphenyl- CI H Me cis
3 ,5 -dichlorophenyl- Br H Me cis
3 ,4,5 -trichlorophenyl- Br H Me cis
3,5-dichloro-4-fluorophenyl- Br H Me cis
3 -trifluoromethylphenyl- Br H Me cis
3 ,5 -bis(trifluoromethyl)phenyl- Br H Me cis
3 -chloro-5 -trifluoromethylphenyl- Br H Me cis
3 ,5 -dichlorophenyl- Me Me Me cis
3,4,5 -trichlorophenyl- Me Me Me cis
3,5-dichloro-4-fluorophenyl- Me Me Me cis 3 -trifluoromethylphenyl- Me Me Me cis
3 ,5 -bis(trifluoromethyl)phenyl- Me Me Me cis
3 -chloro-5 -trifluoromethylphenyl- Me Me Me cis
3,5-dichlorophenyl- CI Me Me cis
3,4,5 -trichlorophenyl- CI Me Me cis
3,5-dichloro-4-fluorophenyl- CI Me Me cis
3 -trifluoromethylphenyl- CI Me Me cis
3 ,5 -bis(trifluoromethyl)phenyl- CI Me Me cis
3 -chloro-5 -trifluoromethylphenyl- CI Me Me cis
3,5-dichlorophenyl- Br Me Me cis
3,4,5 -trichlorophenyl- Br Me Me cis
3,5-dichloro-4-fluorophenyl- Br Me Me cis
3 -trifluoromethylphenyl- Br Me Me cis
3 ,5 -bis(trifluoromethyl)phenyl- Br Me Me cis
3 -chloro-5 -trifluoromethylphenyl- Br Me Me cis
3 ,5 -dichlorophenyl- Me H H trans
3 ,4,5 -trichlorophenyl- Me H H trans
3,5-dichloro-4-fluorophenyl- Me H H trans
3 -trifluoromemylphenyl - Me H H trans
3 ,5 -bis(trifluoromethyl)phenyl- Me H H trans
3 -chloro-5 -trifluoromemylphenyl - Me H H trans
3 ,5 -dichlorophenyl- CI H H trans
3 ,4,5 -trichlorophenyl- CI H H trans
3,5-dichloro-4-fluorophenyl- CI H H trans
3 -trifluoromethylphenyl- CI H H trans
3 ,5 -bis(trifluoromethyl)phenyl- CI H H trans
3 -chloro-5 -trifluoromethylphenyl- CI H H trans
3 ,5 -dichlorophenyl- Br H H trans
3 ,4,5 -trichlorophenyl- Br H H trans
3,5-dichloro-4-fluorophenyl- Br H H trans
3 -trifluoromethylphenyl- Br H H trans
3 ,5 -bis(trifluoromethyl)phenyl- Br H H trans
3 -chloro-5 -trifluoromethylphenyl- Br H H trans
3 ,5 -dichlorophenyl- Me Me H trans
3,4,5 -trichlorophenyl- Me Me H trans
3,5-dichloro-4-fluorophenyl- Me Me H trans
3 -trifluoromethylphenyl- Me Me H trans
3 ,5 -bis(trifluoromethyl)phenyl- Me Me H trans
3 -chloro-5 -trifluoromethylphenyl- Me Me H trans
3,5-dichlorophenyl- CI Me H trans
3,4,5 -trichlorophenyl- CI Me H trans
3,5-dichloro-4-fluorophenyl- CI Me H trans
3 -trifluoromethylphenyl- CI Me H trans
3 ,5 -bis(trifluoromethyl)phenyl- CI Me H trans
3 -chloro-5 -trifluoromethylphenyl- CI Me H trans
3,5-dichlorophenyl- Br Me H trans
3,4,5 -trichlorophenyl- Br Me H trans 105 3,5-dichloro-4-fluorophenyl- Br Me H trans
106 3 -trifluoromethylphenyl- Br Me H trans
107 3 ,5 -bis(trifluoromethyl)phenyl- Br Me H trans
108 3 -chloro-5 -trifluoromethylphenyl- Br Me H trans
109 3 ,5 -dichlorophenyl- Me H Me trans
110 3 ,4,5 -trichlorophenyl- Me H Me trans
111 3 ,5 -dichloro-4-fluorophenyl- Me H Me trans
112 3 -trifluoromethylphenyl- Me H Me trans
113 3 ,5 -bis(trifluoromethyl)phenyl- Me H Me trans
114 3 -chloro-5 -trifluoromemylphenyl - Me H Me trans
115 3 ,5 -dichlorophenyl- CI H Me trans
116 3 ,4,5 -trichlorophenyl- CI H Me trans
117 3,5-dichloro-4-fluorophenyl- CI H Me trans
118 3 -trifluoromethylphenyl- CI H Me trans
119 3 ,5 -bis(trifluoromethyl)phenyl- CI H Me trans
120 3 -chloro-5 -trifluoromethylphenyl- CI H Me trans
121 3 ,5 -dichlorophenyl- Br H Me trans
122 3 ,4,5 -trichlorophenyl- Br H Me trans
123 3,5-dichloro-4-fluorophenyl- Br H Me trans
124 3 -trifluoromethylphenyl- Br H Me trans
125 3 ,5 -bis(trifluoromethyl)phenyl- Br H Me trans
126 3 -chloro-5 -trifluoromethylphenyl- Br H Me trans
127 3 ,5 -dichlorophenyl- Me Me Me trans
128 3,4,5 -trichlorophenyl- Me Me Me trans
129 3,5-dichloro-4-fluorophenyl- Me Me Me trans
130 3 -trifluoromethylphenyl- Me Me Me trans
131 3 ,5 -bis(trifluoromethyl)phenyl- Me Me Me trans
132 3 -chloro-5 -trifluoromethylphenyl- Me Me Me trans
133 3,5-dichlorophenyl- CI Me Me trans
134 3,4,5 -trichlorophenyl- CI Me Me trans
135 3,5-dichloro-4-fluorophenyl- CI Me Me trans
136 3 -trifluoromethylphenyl- CI Me Me trans
137 3 ,5 -bis(trifluoromethyl)phenyl- CI Me Me trans
138 3 -chloro-5 -trifluoromethylphenyl- CI Me Me trans
139 3,5-dichlorophenyl- Br Me Me trans
140 3,4,5 -trichlorophenyl- Br Me Me trans
141 3,5-dichloro-4-fluorophenyl- Br Me Me trans
142 3 -trifluoromethylphenyl- Br Me Me trans
143 3 ,5 -bis(trifluoromethyl)phenyl- Br Me Me trans
144 3 -chloro-5 -trifluoromethylphenyl- Br Me Me trans
Figure imgf000035_0001
Table 96
Table 96 provides 144 compounds of formula IB wherein R2b is ethyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 97
Table 97 provides 144 compounds of formula IB wherein R2b is 2,2,2-trifluoro-ethyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 98
Table 98 provides 144 compounds of formula IB wherein R2b is prop-2-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 99
Table 99 provides 144 compounds of formula IB wherein R2b is methyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 100
Table 100 provides 144 compounds of formula IB wherein R2b is 2-fluoro-cycloprop-l-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 101
Table 101 provides 144 compounds of formula IB wherein R2b is prop-l -yl, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 102
Table 102 provides 144 compounds of formula IB wherein R2b is 2-fluoro-ethyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 103
Table 103 provides 144 compounds of formula IB wherein R2b is 2-cyano-ethyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 104
Table 104 provides 144 compounds of formula IB wherein R2b is 1 -fluoroethyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 105
Table 105 provides 144 compounds of formula IB wherein R2b is 2-methylprop-l-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 106
Table 106 provides 144 compounds of formula IB wherein R2b is propen-2-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 107
Table 107 provides 144 compounds of formula IB wherein R2b is cyclopropylmethyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 108
Table 108 provides 144 compounds of formula IB wherein R2b is 2-methoxy-ethyl-, R3 is
trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 109
Table 109 provides 144 compounds of formula IB wherein R2b is 3-methyloxetan-3-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 110
Table 110 provides 144 compounds of formula IB wherein R2b is 1 -methylcyclopropyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 111
Table 111 provides 144 compounds of formula IB wherein R2b is dihydrofuran-4-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 112
Table 112 provides 144 compounds of formula IB wherein R2b is cyclopropyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 113
Table 113 provides 144 compounds of formula IB wherein R2b is cyclobutyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q. Table 114
Table 114 provides 144 compounds of formula IB wherein R2b is methylsulfonylmethyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 115
Table 115 provides 144 compounds of formula IB wherein R2b is propen-l -yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 116
Table 116 provides 144 compounds of formula IB wherein R2b is methylsulfanylmethyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 117
Table 117 provides 144 compounds of formula IB wherein R2b is 1 -methoxyeth-l-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 118
Table 118 provides 144 compounds of formula IB wherein R2b is 5-pyrimidyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 119
Table 119 provides 144 compounds of formula IB wherein R2b is but-2-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 120
Table 120 provides 144 compounds of formula IB wherein R2b is l -fluoroprop-2-yl-, R3 is
trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 121
Table 121 provides 144 compounds of formula IB wherein R2b is 2-methylpropen-l-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 122
Table 122 provides 144 compounds of formula IB wherein R2b is 1 -cyanocyclopropyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 123
Table 123 provides 144 compounds of formula IB wherein R2b is N-formylaminomethyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 124
Table 124 provides 144 compounds of formula IB wherein R2b is 2-methylsulfinyl-ethyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 125
Table 125 provides 144 compounds of formula IB wherein R2b is 2-(methylsulfonyl)-ethyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 126
Table 126 provides 144 compounds of formula IB wherein R2b is l -oxo-tetrahydrofuran-3-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 127
Table 127 provides 144 compounds of formula IB wherein R2b is l-oxo-thietan-3-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 128
Table 128 provides 144 compounds of formula IB wherein R2b is l,l-dioxo-tetrahydrofuran-3-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 129
Table 129 provides 144 compounds of formula IB wherein R2b is l,l -dioxo-thietan-3-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 130
Table 130 provides 144 compounds of formula IB wherein R2b is 3-chloroprop-l-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 131
Table 131 provides 144 compounds of formula IB wherein R2b is 3,3,3-trifluoro-propyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q. Table 132
Table 132 provides 144 compounds of formula IB wherein R2b is thietan-3-yl-, R3 is tnfluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 133
Table 133 provides 144 compounds of formula IB wherein R2b is 3-oxetanyl-, R3 is tnfluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 134
Table 134 provides 144 compounds of formula IB wherein R2b is tetrahydrofuran-2-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 135
Table 135 provides 144 compounds of formula IB wherein R2b is l,l,l-trifluoroprop-2-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 136
Table 136 provides 144 compounds of formula IB wherein R2b is but-l-yl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 137
Table 137 provides 144 compounds of formula IB wherein R2b is 2,2-difluoro-ethyl-, R3 is trifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 138
Table 138 provides 144 compounds of formula IB wherein R2b is ethyl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 139
Table 139 provides 144 compounds of formula IB wherein R2b is 2,2,2-trifluoro-ethyl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 140
Table 140 provides 144 compounds of formula IB wherein R2b is prop-2-yl-, R3 is
chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 141
Table 141 provides 144 compounds of formula IB wherein R2b is methyl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 142
Table 142 provides 144 compounds of formula IB wherein R2b is 2-fluoro-cycloprop-l-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 143
Table 143 provides 144 compounds of formula IB wherein R2b is prop-l-yl, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 144
Table 144 provides 144 compounds of formula IB wherein R2b is 2-fluoro-ethyl-, R3 is
chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 145
Table 145 provides 144 compounds of formula IB wherein R2b is 2-cyano-ethyl-, R3 is
chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 146
Table 146 provides 144 compounds of formula IB wherein R2b is 1 -fluoroethyl-, R3 is
chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 147
Table 147 provides 144 compounds of formula IB wherein R2b is 2-methylprop-l-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 148
Table 148 provides 144 compounds of formula IB wherein R2b is propen-2-yl-, R3 is
chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 149
Table 149 provides 144 compounds of formula IB wherein R2b is cyclopropylmethyl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q. Table 150
Table 150 provides 144 compounds of formula IB wherein R2b is 2-methoxy-ethyl-, R3 is
chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 151
Table 151 provides 144 compounds of formula IB wherein R2b is 3-methyloxetan-3-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 152
Table 152 provides 144 compounds of formula IB wherein R2b is 1 -methylcyclopropyl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 153
Table 153 provides 144 compounds of formula IB wherein R2b is dihydrofuran-4-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 154
Table 154 provides 144 compounds of formula IB wherein R2b is cyclopropyl-, R3 is
chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 155
Table 155 provides 144 compounds of formula IB wherein R2b is cyclobutyl-, R3 is
chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 156
Table 156 provides 144 compounds of formula IB wherein R2b is methylsulfonylmethyl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 157
Table 157 provides 144 compounds of formula IB wherein R2b is propen-l -yl-, R3 is
chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 158
Table 158 provides 144 compounds of formula IB wherein R2b is methylsulfanylmethyl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 159
Table 159 provides 144 compounds of formula IB wherein R2b is 1 -methoxyeth-l-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 160
Table 160 provides 144 compounds of formula IB wherein R2b is 5-pyrimidyl-, R3 is
chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 161
Table 161 provides 144 compounds of formula IB wherein R2b is but-2-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 162
Table 162 provides 144 compounds of formula IB wherein R2b is l -fluoroprop-2-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 163
Table 163 provides 144 compounds of formula IB wherein R2b is 2-methylpropen-l-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 164
Table 164 provides 144 compounds of formula IB wherein R2b is 1 -cyanocyclopropyl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 165
Table 165 provides 144 compounds of formula IB wherein R2b is N-formylaminomethyl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 166
Table 166 provides 144 compounds of formula IB wherein R2b is 2-methylsulfinyl-ethyl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 167
Table 167 provides 144 compounds of formula IB wherein R2b is 2-(methylsulfonyl)-ethyl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q. Table 168
Table 168 provides 144 compounds of formula IB wherein R2b is l -oxo-tetrahydrofuran-3-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 169
Table 169 provides 144 compounds of formula IB wherein R2b is l -oxo-thietan-3-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 170
Table 170 provides 144 compounds of formula IB wherein R2b is l,l -dioxo-tetrahydrofuran-3-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 171
Table 171 provides 144 compounds of formula IB wherein R2b is l,l -dioxo-thietan-3-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 172
Table 172 provides 144 compounds of formula IB wherein R2b is 3-chloroprop-l-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 173
Table 173 provides 144 compounds of formula IB wherein R2b is 3,3,3-trifluoro-propyl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 174
Table 174 provides 144 compounds of formula IB wherein R2b is thietan-3-yl-, R3 is
chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 175
Table 175 provides 144 compounds of formula IB wherein R2b is 3-oxetanyl-, R3 is
chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 176
Table 176 provides 144 compounds of formula IB wherein R2b is tetrahydrofuran-2-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 177
Table 177 provides 144 compounds of formula IB wherein R2b is l,l,l-trifluoroprop-2-yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 178
Table 178 provides 144 compounds of formula IB wherein R2b is but-l -yl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
Table 179
Table 179 provides 144 compounds of formula IB wherein R2b is 2,2-difluoro-ethyl-, R3 is chlorodifluoromethyl and R4, Y5, R6a, R6b and cis/trans are as defined in Table Q.
The compounds of the invention may be made by a variety of methods as shown in the following Schemes.
Scheme 1
Figure imgf000040_0001
1) Compounds of formula (la) wherein G1 is oxygen, can be prepared by reacting an amine of formula (II) with a compound of formula (III) wherein G1 is oxygen and XA is OH, Ci-C6alkoxy or CI, F or Br. When XA is OH such reactions are usually carried out in the presence of a coupling reagent, such as Ν,Ν'-dicyclohexyl-carbo-diimide ("DCC"), l-ethyl-3-(3-dimethyl-amino-propyl)-carbodiimide hydrochloride ("EDC") or bis(2-oxo-3-oxazolidinyl)phosphonic chloride ("BOP-C1"), in the presence of a base, and optionally in the presence of a nucleophilic catalyst, such as hydroxybenzo-triazole ("HOBT"). When XA is CI, such reactions are usually carried out in the presence of a base, and optionally in the presence of a nucleophilic catalyst for example dimethylaminopyridine. Alternatively, it is possible to conduct the reaction in a biphasic system comprising an organic solvent, preferably ethyl acetate, and an aqueous solvent, preferably a solution of sodium hydrogen carbonate. When XA is CpCealkoxy it is sometimes possible to convert the ester directly to the amide by heating the ester and amine together in a thermal process. Suitable bases include pyridine, triethylamine, 4-(dimethylamino)-pyridine ("DMAP") or diisopropylethylamine (Hunig's base). Preferred solvents are NN-dimethylacetamide, tetrahydrofuran, dioxane, 1 ,2-dimethoxyethane, ethyl acetate and toluene. The reaction is carried out at a temperature of from 0°C to 100°C, preferably from 15°C to 30°C, in particular at ambient temperature. Compounds of formula (III) are either known in the literature or can be prepared using methods known to a person skilled in the art. Some of these methods are described in the preparation Examples.
2) Compounds of formula (la), wherein G1 is sulfur, may be made by treatment of a compound of formula (III), wherein G1 is oxygen and XA is OH, Ci-C6alkoxy or CI, F or Br, with a thio-transfer reagent such as Lawesson's reagent or phosphorus pentasulfide prior to progressing to compounds of formula (la), as described under 1).
3) Alternatively compounds of formula (la), wherein G1 is sulfur, may be made by treatment of a compound of formula (la), wherein G1 is oxygen, with a thio-transfer reagent such as Lawesson's reagent or phosphorus pentasulfide.
4) Compound of formula (II) wherein Rlb is CpCgalkyl, can be prepared by alkylation of an intermediate of formula (VI) with a reagent of formula (V) wherein XB is chloro, bromo, iodo, mesylate, triflate in presence of a base such a butyl lithium, KH, NaH, K2C03, Cs2C03, NaHC03 in a solvent such as dimethylsulfoxide, acetonitrile, tetrahydrofuran, dimethylformamide or toluene. Such reactions can be carried out under well-established methods, described for example in Tetrahedron, 36(9), 1223-6; 1980 and Bioorganic & Medicinal Chemistry Letters, 21(11), 3457-3461 ;2011.
5) Compound of formula (II) wherein Rlb is CpCgalkylcarbonyl, or CpCgalkoxycarbonyl
, can be prepared by acylation of an intermediate of formula (VI) with a reagent of formula (V) , wherein XB is chloro using conditions described in 1).
6) Compounds of formula (la) wherein G1 is oxygen can be prepared by alkylation of an intermediate of formula (IV) with a reagent of formula (V) wherein XB is chloro, bromo, iodo, mesylate or triflate in presense of a strong base such as sodium hydride, lithium diisopropyl amide, or butyl lithium in a polar aprotic solvent such as dimethylsulfoxide, acetonitrile, tetrahydrofuran or dimethylformamide. Such reactions can be carried out under well established methods, described for example in Bioorganic &
Medicinal Chemistry Letters, 22(2), 1237-1241 ; 2012.
7) Compounds of formula (IV) wherein G1 is oxygen, can be prepared by reacting an amine of formula (VI) with a compound of formula (III) using conditions described in 1).
Scheme 2
Figure imgf000042_0001
8) Compounds of formula (lb) wherein G1 is oxygen, can be prepared by reacting a compound of formula (IX) wherein G1 is oxygen and R is OH, CpCealkoxy or CI, F or Br, with an amine of formula (XI) wherein Rla and R2a are as defined in claim 1. When R is OH such reactions are usually carried out in the presence of a coupling reagent, such as Ν,Ν'-dicyclohexylcarbodiimide ("DCC"), l-ethyl-3-(3- dimethylamino-propyl)carbodiimide hydrochloride ("EDC") or bis(2-oxo-3-oxazolidinyl)phosphonic chloride ("BOP-Cl"), in the presence of a base, and optionally in the presence of a nucleophilic catalyst, such as hydroxybenzotriazole ("HOBT"). When R is CI, such reactions are usually carried out in the presence of a base, and optionally in the presence of a nucleophilic catalyst. Alternatively, it is possible to conduct the reaction in a biphasic system comprising an organic solvent, preferably ethyl acetate, and an aqueous solvent, preferably a solution of sodium hydrogen carbonate. When R is Ci-C6alkoxy it is sometimes possible to convert the ester directly to the amide by heating the ester and amine together in a thermal process. Suitable bases include pyridine, triethylamine, 4-(dimethylamino)-pyridine ("DMAP") or diisopropylethylamme (Hunig's base). Preferred solvents are NN-dimethylacetamide, tetrahydrofuran, dioxane, 1 ,2-dimethoxyethane, ethyl acetate and toluene. The reaction is carried out at a temperature of from 0°C to 100°C, preferably from 15°C to 30°C, in particular at ambient temperature. Amines of formula (XI) are either known in the literature or can be prepared using methods known to a person skilled in the art. Some of these methods are described in the preparation Examples.
9) Acid halides of formula (IX), wherein G1 is oxygen and R is CI, F or Br, may be made from carboxylic acids of formula (IX), wherein G1 is oxygen and R is OH, under standard conditions, as described for example in WO 2009/080250.
10) Carboxylic acids of formula (IX), wherein G1 is oxygen and R is OH, may be formed from esters of formula (IX), wherein G1 is oxygen and R is Q-Cealkoxy as described for example in WO 2009/080250.
11) Compounds of formula (lb), wherein G1 is sulfur, may be made by treatment of a compound of formula (IX), wherein G1 is oxygen and R is OH, CpCealkoxy or CI, F or Br, with a thio-transfer reagent such as Lawesson's reagent or phosphorus pentasulfide prior to elaborating to compounds of formula (lb), as described under 8). 12) Alternatively compounds of formula (lb) wherein G1 is oxygen and Rla is Ci-C6alkyl or Cp C6haloalkyl can be prepared by alkylation of an intermediate of formula (VIII) with a reagent of formula (V) wherein XB is chloro, bromo, iodo, mesylate or triflate in presense of a strong base such as sodium hydride, lithium diisopropyl amide, or butyl lithium in a polar aprotic solvent such as dimethylsulfoxide, acetonitrile, tetrahydrofuran or dimethylformamide. Such reactions can be carried out under well- established methods, described for example in Bioorganic & Medicinal Chemistry Letters, 22(2), 1237- 1241 ; 2012.
13) Compound of formula (lb) wherein Rla is CpCgalkylcarbonyl, or CpCgalkoxycarbonyl , can be prepared by acylation of an intermediate of formula (VIII) with a reagent of formula (V) , wherein XB is chloro using conditions described in 8).
14) Compounds of formula (VIII) wherein G1 is oxygen can be prepared by reacting a compound of formula (IX) wherein G1 is oxygen and R is OH, CpCealkoxy or CI, F or Br, with an amine of formula (X) wherein R2a is as defined in claim 1 using conditions described in 8).
Scheme 3
Figure imgf000043_0001
(XV)
15) Compounds of formula (VI) wherein Y5 is hydrogen, CrC8alkyl, Ci-C8haloalkyl, or C3- Cgcycloalkyl and Y6 is hydrogen, a halogen, Ci-Qalkyl, Ci-C8haloalkyl, C3-C8cycloalkyl or cyano and R a and R b are independently hydrogen, cyano, CpCgalkyl, CpCghaloalkyl, or Ca-Cgcycloalkyl can be obtained from compounds of formula (XII) wherein R21 and R22 are independently selected from hydrogen, CpCgalkylcarbonyl, CpCgalkoxycarbonyl, or R21 and R22 together are -C(=0)-(CH2)r-C(=0)- wherein r is 1 to 4, or group B
Figure imgf000043_0002
(B)
via a deprotection reaction using conditions described in the section on protecting groups for anilines in Wuts, P. G. M.; Greene, T. W., Protective Groups in Organic Synthesis 3rd ed. John Wiley & Sons: New York, 1999.
16) Compounds of formula (XII) wherein Y5 is hydrogen, CpCgalkyl, CpCghaloalkyl, or C3- Cgcycloalkyl and Y6 is hydrogen, a halogen, CpCgalkyl, Ci-Cghaloalkyl, CrCgcycloalkyl or cyano and R a and R b are independently hydrogen, cyano, CpCgalkyl, CpCghaloalkyl, or Ca-Cgcycloalkyl and R21and R22 are as defined in 15) can be prepared through a Wittig reaction between carbonyls of formula
(XIII) and phosphoniums of formula (XIV) wherein R is aryl and X is CI or Br. Phosphonium (XIV) is deprotonated with a strong base for example K2C03, BuLi, tBuOK, LiHMDS or LDA in an aprotic solvent for example toluene or THF and then adding a carbonyl or formula (XIII). Such reactions can be carried out under well-established methods, described for example in Synthetic Communications, 16(14), 1761-70; 1986.
17) Phosphoniums of formula (XIV) wherein Y6 is hydrogen, a halogen, Ci-Cgalkyl, Q- Cghaloalkyl, Q-Cgcycloalkyl or cyano and R a and R b are independently hydrogen, cyano, CpCgalkyl, CpCghaloalkyl, or C3-C8cycloalkyl, R is aryl and X is CI or Br can be prepared by treating compounds of formula (XV) with a phosphine of formula (XVI) wherein R is aryl, in a solvent for example acetonitrile or toluene. Such reactions can be carried out under well-established methods, described for example in Bioorganic & Medicinal Chemistry Letters, 8(16), 2157-2162; 1998.
Scheme 4
Figure imgf000044_0001
18) Alternatively compounds of formula (XII) wherein Y5 is hydrogen, halogen, CpCgalkyl, Cr Cghaloalkyl or C -C8cycloalkyl and Y6 is hydrogen, CpCgalkyl, CpCghaloalkyl or C -C8cycloalkyl and R a and R b are independently hydrogen, CpCgalkyl, Ci-C8haloalkyl, or C -C8cycloalkyl and R21 and R22 are as defined in 15) can be prepare can be prepared through a Wittig reaction between carbonyls of formula (XVII) and phosphoniums of formula (XVIII) wherein R is aryl and X is CI or Br using conditions described in 14).
19) Phosphoniums of formula (XVIII) wherein Y5 is hydrogen, halogen, CpC8alkyl, Cp
Cghaloalkyl or C3-C8cycloalkyl, R is aryl and X is CI or Br can be prepared by treating compounds of formula (XIX) wherein X is CI or Br with a phosphine of formula (XVI) wherein R is aryl using conditions described in 17).
20) Compounds of formula (XIX) wherein Y5 is hydrogen, Ci-C8alkyl, Ci-C8haloalkyl or C3- Cgcycloalkyl, and X is Br or CI are prepared by treating alcohols of formula of formula (XX) with a suitable chlorinating agent when X is CI for example SOCl2, POCl3, PC13, C(0)C12 and brominating agent when X is Br for example PBr3 and SOBr3.
Scheme 5
Figure imgf000044_0002
21) Alcohols of formula of formula (XX) wherein Y5 is hydrogen, CpCgalkyl, CpCghaloalkyl or C3-C8cycloalkylcan be prepared by reduction of carbonyls of formula (XXI) using a hydride source for example NaBH4, LiAlH4, diisobutylaluminum hydride, H2 in presence of a transition catalyst such as Ni and Pd using well-established methods known to a person skilled in the art specific examples are described in the experimental section.
22) Alternatively Alcohols of formula of formula (XX) wherein Y5 is hydrogen, CpCgalkyl, Cp Cghaloalkyl or C3-Cgcycloalkylcan be prepared by reduction of compounds of formula (XXII) wherein R31 is C02R using a hydride source for example LiAlH4 or diisobutylaluminum hydride when R is Cp C6alkyl and BH3 when R is hydrogen using well-established methods known to a person skilled in the art and specific examples are described in the experimental section.
23) Ketone of formula of formula (XXI) wherein Y5 CpCgalkyl or C3-Cgcycloalkylcan be prepared by treating compounds of formula (XXII) wherein R31 is cyano or C(0)NMeOMe with an organomagnesium reagent of formula Y5MgX wherein X is CI, Br or I or with an organolithium reagent of formula Y5Li in an aprotic solvent for example tetrahydrofiiran using well-established methods known to a person skilled in the art and described in the experimental section.
24) Alternatively ketones of formula of formula (XXI) wherein Y5 CpCgalkyl, CpCghaloalkyl or C3-C8cycloalkylcan be prepared by treating compounds of formula (XXII) wherein R31 is bromo or iodo with an organolithium, for example butyllithium, or an organomagnesium, for example
isopropylmagnesium chloride, isopropylmagnesium chloride lithium chloride complex, in an aprotic solvent for example tetrahydrofiiran followed by addition of Y5C(0)R wherein R is a halogen, -NMeOMe, Ci-6alkoxy, morpholino.
25) Alcohols of formula of formula (XX) wherein Y5 CpCghaloalkyl can be prepared by reaction aldehydes of formula (XXI) wherein Y5 is hydrogen with nucleophilic haloalkyl source for example trimethylsilyltrifluoromethane in presence of a nucleophilic activator for example CsF. Such reactions can be carried out under well-established methods, described for example in Journal of Organic Chemistry, 64(8), 2873-2876; 1999 and a specific example is described in the experimental section.
26) Ketone of formula (XXI) wherein Y5 is hydrogen, CpCgalkyl or CpCghaloalkyl can be prepared by oxidation of alcohols of formula of formula (XX) wherein Y5 is hydrogen, CpCgalkyl or Cp Cghaloalkyl with oxidants for example pyridinium chlorochromate, Dess-Martin periodinane or Swern- type oxidations using well-established methods known to a person skilled in the art and specific examples are described in the experimental section.
Scheme 6
Figure imgf000045_0001
27) Compounds of formula (IX) wherein Y5 is hydrogen, CrC8alkyl, CpCghaloalkyl, or C -
Cgcycloalkyl and Y6 is hydrogen, a halogen, Ci-Qalkyl, Ci-C8haloalkyl, C -C8cycloalkyl or cyano can be prepared through a Horner-Wadsworth-Emmons reaction between carbonyl (XXI) wherein Y5 is hydrogen, CpCgalkyl, CpCghaloalkyl, or C -C8cycloalkyland phosphonate (XXIII) wherein A1 is Cr C4alkyl or
Figure imgf000046_0001
or aryl, Y6 is hydrogen, a halogen, CpCgalkyl, Ci-Cghaloalkyl, or C3- Cgcycloalkyl, G1 is oxygen or sulfur and R is Ci-C4alkoxy or NRlaR2a wherein Rla and R2a are as defined in claim 1. Phosphonates (XXIII) are treated with a strong base for example NaH, KHMDS, tBuOK, or a weaker base DBU with an additional activator such as LiCl or MgC^ in an aprotic solvent for example tetrahydrofuran or dimethoxyethane and then carbonyl (XXI) is added. Such reactions can be carried out under well-established methods, reviewed for example in Organic Reactions 25, 73; 1977 and specific examples are described in the preparation Examples.
Scheme 7
Figure imgf000046_0002
28) Alternatively compounds of formula (IX) Y5 is hydrogen, CpCgalkyl, CpCghaloalkyl, or C3- Cgcycloalkyl and Y6 is hydrogen, CpCgalkyl, CpCghaloalkyl, Q-Cgcycloalkyl or cyano can be formed through a palladium-catalyzed Mizoroki-Heck coupling by reacting compounds of formula (XXII) wherein R31 is a Br or CI with alkenes of formula (XXIV) wherein G1 is oxygen or sulfur and R is Q- C4alkoxy or NRlaR2a wherein Rla and R2a are as defined in claim 1 in presence of a palladium catalyst for example Pd(OAc)2(DTPF) (DTPF: l,l '-bis(ditertbutylphosphino)ferrocene), and a base for example dicyclohexylmethylamine, an additive for example tetrabutylammonium chloride in a polar solvent for example dimethyl acetamide.Such reactions can be carried out under well-established methods, described for example in Org. Process Res. Dev.; 17 (3); 397-405; 2013.
Scheme 8
Figure imgf000046_0003
29) Compounds of formula (IX) wherein Y5 is bromo or chloro, Y6 is hydrogen, Ci-Qalkyl, Cr Cghaloalkyl, Q-Cgcycloalkyl or cyano and G1 is oxygen and R is hydroxy can be prepared by performing a Pinnick oxidation of the corresponding aldehyde (XXV) wherein X is chloro or bromo. Aldehyde (XXV) in a polar solvent for example dimethylsulfoxide or tert-butanol or acetonitrile is treated by aqueous solution sodium chlorite buffered by KH2PO4/K2HPO4 in presence of 2-methyl-2-butene. Such reactions can be carried out under well-established methods, described for example in Tetrahedron; 37; 2091-2096; 1981. Specific examples are described in the experimental section.
30) Aledhydes of formula (XXV) wherein X is bromo or chloro and Y6 is hydrogen, CpCgalkyl, CpCghaloalkyl, C3-C8cycloalkyl or cyano can be obtained by reacting ketones of formula (XXVI)with Vilsmeyer reagent, obtained from reaction of POX3 or COX2 wherein X is chloro or bromo with dimethylformamide using well-established methods known to a person skilled in the art and specific examples are described in the experimental section.
31) Ketones of formula (XXVI) wherein Y6 is hydrogen, CpCgalkyl, CpCghaloalkyl, C3- Cgcycloalkyl or cyano can be obtained by treating ketones of formula (XXI) wherein Y6 is Ci-C9alkyl, Ci-7haloalkylmethyl, Ca-Cgcycloalkylmethyl or cyanomethyl with Ν,Ν-dimethylformamide dimethyl acetal in a polar solvent for example dimethylformamide using well-established methods known to a person skilled in the art and specific examples are described in the experimental section.
Scheme 9
Figure imgf000047_0001
(XXXVII)
32) Compounds of formula (XXVII) wherein R31 is a halogen for example bromo, iodo, chloro with can be made by diazotation of compounds of formula (XXVIII) using NaN02 or alkyl nitrite in presense of an HX where X is CI", Br", OAc" or BF4 " in an aqueous solvent followed by reaction with CuXc wherein Xc is a halogen for example bromo, iodo, chloro. Alternatively KI can be employed when R31 is iodo. Specific examples for compounds of formula (XXVII) wherein R31 is iodo are described in the experimental section
33) Anilines of formula (XXVIII) can be obtained by reduction of compounds of formula (XXXVII) by using a suitable reducing agent as described extensively in Kabalka, G. W.; Varma, R. S., Reduction of Nitro and Nitroso Compounds. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, L, Eds. Pergamon Press: Oxford, 1991 ; Vol. 8, p 363. Suitable reducing agent can be for example iron, magnesium, zinc, tin(II) chloride in protic solvent for example water, ethanol, methanol, acetic acid, aqueous HC1. Alternatively the reduction can be carried using a transition metal catalyst for taken from Pd, Pt, Ni, such as Raney-nickel or palladium on charcoal in the presence of hydrogen pressure, formic acid or ammonium formate. Examples of such methods using Raney-nickel are described in the preparation Examples. Scheme 10
Figure imgf000048_0001
(XXXI)
34) Compounds of formula (XXVII) wherein Y1 is oxygen and R31 is nitro, cyano, chloro, bromo, or C(0)R' wherein R' is Ci-C4alkyl or Ci-Ci5alkoxy, can be made by reacting compounds of formula (XXX) wherein R is hydrogen or trialkylsilyl for example trimethylsilyl with a ketone of formula (XXIX) wherein Y1 is oxygen and R3 and R4 are as defined in claim 1 in presence of an activator such as a fluoride source for example tetrabutylammonium fluoride in presence of a base for example
diisopropylethylamine in an aprotic solvent such tetrahydrofuran following conditions described in J. Org. Chem. 70, 3727-3729; 2005. Specific examples are described in the experimental section
35) Alternatively compounds of formula (XXVII) wherein Y1 is oxygen and R31 nitro, cyano, chloro, bromo, or C(0)R' wherein R' is Ci-C4alkyl or Ci-Ci5alkoxy, can be made by reacting compounds of formula (XXXI) wherein Y1 is OH in presence of a base for example diisopropylethylamine in an solvent such tetrahydrofuran. Such reactions can be carried out using condition, described in J. Org. Chem. 70, 3727-3729; 2005.
36) Compounds of formula (XXXI) wherein Y1 is OH and R31 nitro, cyano, chloro, bromo, or C(0)R' wherein R' is Ci-C4alkyl or Ci-Ci5alkoxy, can be made by reacting compounds of formula (XXX) wherein R is hydrogen or trialkylsilyl for example trimethylsilyl with a compound of formula (XXIX) wherein Y1 is oxygen in presence of catalytic amount an activator such as a fluoride source for example tetrabutylammonium fluoride in an aprotic solvent such tetrahydrofuran. Such reactions can be carried out using condition, described in J. Org. Chem. 70, 3727-3729; 2005 and J. Org. Chem. 51 , 3694; 1986.
Scheme 11
Figure imgf000048_0002
37) Compounds of formula (XXX) wherein R31 nitro, cyano, chloro or bromo, can be made by reacting a compound of formula (XXXIII) with an organometallic reagent of formula (XXXII) wherein R is H or trialkylsilyl such as an orgnomagnesium for example trimethylsilylmethyl magnesium chloride followed by oxidation with a single electron oxidant such as 2,3-dichloro-5,6-dicyano-l ,4-benzoquinone following conditions described in J. Org. Chem. 51 , 3694; 1986. Scheme 12
Figure imgf000049_0001
38) Alternatively compounds of formula (XXX) wherein R31 is nitro, cyano, chloro, bromo or C(0)R' wherein R' is Ci-C4alkyl or Ci-Ci5alkoxy and R is hydrogen can be prepared by oxidation of compounds of formula (XXXIV) using an oxidant for example Oxone®, sodium perborate, potassium permanganate. Some of these methods are described in the preparation Examples.
Scheme 13
Figure imgf000049_0002
(XXXVI) (XXXV) (XXVII)
39) Alternatively compounds of formula (XXVII) wherein Y1 is oxygen and R31 is nitro, cyano, chloro, or C(0)R' wherein R' is Ci-Ci5alkoxy can be prepared by coupling compounds of formula (XXXV) wherein Y1 is OH and Xc is halogen for example bromo or iodo in presence of a transition metal catalyst such palladium or copper for example a copper(I) halide and in presence of a ligand for example 8-quinolinol with a base such as alkali metal carbonate or alkali metal hydroxide or a alkali metal alkoxide for example Cs2C03 in a aprotic solvent such as toluene.
40) Compounds of formula (XXXV) wherein Y1 is OH and R31 is nitro, cyano, chloro or C(0)R' wherein R' is CpCi5alkoxy can be prepared by reaction compounds of formula (XXXVI) with a strong base such lithium amide or alkali metal hexamethyldisilazide for example lithium diisopropyl amide followed by addition of ketone (XXIX) wherein Y1 is oxygen.
The compounds of formula (I) can be used to combat and control infestations of insect pests such as Lepidoptera, Diptera, Hemiptera, Thysanoptera, Orthoptera, Dictyoptera, Coleoptera, Siphonaptera, Hymenoptera and Isoptera and also other invertebrate pests, for example, acarine, nematode and mollusc pests. Insects, acarines, nematodes and molluscs are hereinafter collectively referred to as pests. The pests which may be combated and controlled by the use of the compounsd of the invention include those pests associated with agriculture (which term includes the growing of crops for food and fiber products), horticulture and animal husbandry, companion animals, forestry and the storage of products of vegetable origin (such as fruit, grain and timber); those pests associated with the damage of man-made structures and the transmission of diseases of man and animals; and also nuisance pests (such as flies). The compounds of 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. Compositions comprising the compound of formula I may be used on ornamental garden plants (e.g. flowers, shrubs, broad-leaved trees or evergreens), e.g. to control aphids, whitefly, scales, meelybug, beetles and caterpillars. Compositions comprising the compound of formula I may be used on garden plants (e.g. flowers, shrubs, broad-leaved trees or evergreens), on indoor plants (e.g. flowers and shrubs) and on indoor pest e.g. to control aphids, whitefly, scales, meelybug, beetles and caterpillars.
Furthermore, the compounds of the invention may be effective against harmful insects, without substantially imposing any harmful side effects to cultivated plants. Application of the compounds of the invention may increase the harvest yields, and may improve the quality of the harvested material. The compounds of the invention may have favourable properties with respect to amount appled, residue formulation, selectivity, toxicity, production methodology, high activity, wide spectrum of control, safety, control of resistant organisms, e.g. pests that are resistant to organic phosphorus agents and/or carbamate agents.
Examples of pest species which may be controlled by the compounds of formula (I) include: coleopterans, for example, Callosobruchus chinensis, Sitophilus zeamais, Tribolium castaneum,
Epilachna vigintioctomaculata, Agriotes fuscicollis, Anomala rufocuprea, Leptinotarsa decemlineata, Diabrotica spp., Monochamus alternatus, Lissorhoptrus oryzophilus, Lyctus bruneus, Aulacophora femoralis; lepidopterans, for example, Lymantria dispar, Malacosoma neustria), Pieris rapae,
Spodoptera litura, Mamestra brassicae, Chilo suppressalis), Pyrausta nubilalis, Ephestia cautella, Adoxophyes orana, Carpocapsa pomonella, Agrotisfucosa, Galleria mellonella, Plutella maculipennis, Heliothis virescens, Phyllocnistis citrella; hemipterans, for example, Nephotettix cincticeps, Nilaparvata lugens, Pseudococcus comstocki, Unaspis yanonensis, Myzus persicas, Aphis pomi, Aphis gossypii, Rhopalosiphum pseudobrassicas, Stephanitis nashi, Nezara spp., Trialeurodes vaporariorm, Psylla spp.; thysanopterans , for example, Thrips palmi, Franklinella occidental; orthopterans, for example, Blatella germanica, Periplaneta americana, Gryllotalpa Africana, Locusta migratoria migratoriodes; isopterans, for example, Reticulitermes speratus, Coptotermes formosanus; dipterans, for example, Musca domestica, Aedes aegypti, Hylemia platura, Culex pipiens, Anopheles sinensis, Culex tritaeniorhynchus, Liriomyza trifolii; acari, for example, Tetranychus cinnabarinus, Tetranychus urticae, Panonychus citri, Aculops pelekassi, Tarsonemus spp. ; nematodes, for example, Meloidogyne incognita, Bursaphelenchus lignicolus Mamiya et Kiyohara, Aphelenchoides besseyi, Heterodera glycines, Pratylenchus spp..
Examples of further pest species which may be controlled by the compounds of formula (I) include: from the order of the Anoplura (Phthiraptera), for example, Damalinia spp., Haematopinus spp., Linognathus spp., Pediculus spp., Trichodectes spp.; from the class of the Arachnida, for example, Acarus siro, Aceria sheldoni, Aculops spp., Aculus spp., Amblyomma spp., Argas spp., Boophilus spp., Brevipalpus spp., Bryobia praetiosa, Chorioptes spp., Dermanyssus gallinae, Eotetranychus spp., Epitrimerus pyri, Eutetranychus spp., Eriophyes spp., Hemitarsonemus spp., Hyalomma spp., Ixodes spp., Latrodectus mactans, Metatetranychus spp., Oligonychus spp., Ornithodoros spp., Panonychus spp., Phyllocoptruta oleivora, Polyphagotarsonemus latus, Psoroptes spp., Rhipicephalus spp., Rhizoglyphus spp., Sarcoptes spp., Scorpio maurus, Stenotarsonemus spp., Tarsonemus spp., Tetranychus spp., Vasates lycopersici; from the class of the Bivalva, for example, Dreissena spp.; from the order of the Chilopoda, for example, Geophilus spp., Scutigera spp.; from the order of the Coleoptera, for example,
Acanthoscehdes obtectus, Adoretus spp., Agelastica alni, Agriotes spp., Amphimallon solstitialis, Anobium punctatum, Anoplophora spp., Anthonomus spp., Anthrenus spp., Apogonia spp., Atomaria spp.,
Attagenus spp., Bruchidius obtectus, Bruchus spp., Ceuthorhynchus spp., Cleonus mendicus, Conoderus spp., Cosmopolites spp., Costelytra zealandica, Curculio spp., Cryptorhynchus lapathi, Dermestes spp., Diabrotica spp., Epilachna spp., Faustinus cubae, Gibbium psylloides, Heteronychus arator,
Hylamorpha elegans, Hylotrupes bajulus, Hypera postica, Hypothenemus spp., Lachnosterna
consanguinea, Leptinotarsa decemlineata, Lissorhoptrus oryzophilus, Lixus spp., Lyctus spp., Meligethes aeneus, Melolontha melolontha, Migdolus spp., Monochamus spp., Naupactus xanthographus, Niptus hololeucus, Oryctes rhinoceros, Oryzaephilus surinamensis, Otiorrhynchus sulcatus, Oxycetonia jucunda, Phaedon cochleariae, Phyllophaga spp., Popillia japonica, Premnotrypes spp., Psylliodes chrysocephala, Ptinus spp., Rhizobius ventralis, Rhizopertha dominica, Sitophilus spp., Sphenophorus spp., Sternechus spp., Symphyletes spp., Tenebrio molitor, Tribolium spp., Trogoderma spp., Tychius spp., Xylotrechus spp., Zabrus spp.; from the order of the Collembola, for example, Onychiurus armatus; from the order of the Dermaptera, for example, Forficula auricularia; from the order of the Diplopoda, for example, Blaniulus guttulatus; from the order of the Diptera, for example, Aedes spp., Anopheles spp., Bibio hortulanus, Calliphora erythrocephala, Ceratitis capitata, Chrysomyia spp., Cochliomyia spp.,
Cordylobia anthropophaga, Culex spp., Cuterebra spp., Dacus oleae, Dermatobia hominis, Drosophila spp., Fannia spp., Gastrophilus spp., Hylemyia spp., Hyppobosca spp., Hypoderma spp., Liriomyza spp., Lucilia spp., Musca spp., Nezara spp., Oestrus spp., Oscinella frit, Pegomyia hyoscyami, Phorbia spp., Stomoxys spp., Tab anus spp., Tannia spp., Tipula paludosa, Wohlfahrtia spp.; from the class of the Gastropoda, for example, Arion spp., Biomphalaria spp., Bulinus spp., Deroceras spp., Galba spp., Lymnaea spp., Oncomelania spp., Succinea spp.; from the class of the helminths, for example,
Ancylostoma duodenale, Ancylostoma ceylanicum, Acylostoma braziliensis, Ancylostoma spp., Ascaris lubricoides, Ascaris spp., Brugia malayi, Brugia timori, Bunostomum spp., Chabertia spp., Clonorchis spp., Cooperia spp., Dicrocoelium spp, Dictyocaulus filaria, Diphyllobothrium latum, Dracunculus medinensis, Echinococcus granulosus, Echinococcus multilocularis, Enterobius vermicularis, Faciola spp., Haemonchus spp., Heterakis spp., Hymenolepis nana, Hyostrongulus spp., Loa Loa, Nematodirus spp., Oesophagostomum spp., Opisthorchis spp., Onchocerca volvulus, Ostertagia spp., Paragonimus spp., Schistosomen spp., Strongyloides fuelleborni, Strongyloides stercoralis, Stronyloides spp., Taenia saginata, Taenia solium, Trichinella spiralis, Trichinella nativa, Trichinella britovi, Trichinella nelsoni, Trichinella pseudopsiralis, Trichostrongulus spp., Trichuris trichuria, Wuchereria bancrofti; ft may be furthermore possible to control protozoa, such as Eimeria; from the order of the Heteroptera, for example, Anasa tristis, Antestiopsis spp., Blissus spp., Calocoris spp., Campylomma livida, Cavelerius spp., Cimex spp., Creontiades dilutus, Dasynus piperis, Dichelops furcatus, Diconocoris hewetti, Dysdercus spp., Euschistus spp., Eurygaster spp., Heliopeltis spp., Horcias nobilellus, Leptocorisa spp., Leptoglossus phyllopus, Lygus spp., Macropes excavatus, Miridae, Nezara spp., Oebalus spp., Pentomidae, Piesma quadrata, Piezodorus spp., Psallus seriatus, Pseudacysta persea, Rhodnius spp., Sahlbergella singularis, Scotinophora spp., Stephanitis nashi, Tibraca spp., Triatoma spp.; from the order of the Homoptera, for example, Acyrthosipon spp., Aeneolamia spp., Agonoscena spp., Aleurodes spp., Aleurolobus barodensis, Aleurothrixus spp., Amrasca spp., Anuraphis cardui, Aonidiella spp., Aphanostigma piri, Aphis spp.,
Arboridia apicalis, Aspidiella spp., Aspidiotus spp., Atanus spp., Aulacorthum solani, Bemisia spp., Brachycaudus helichrysii, Brachycolus spp., Brevicoryne brassicae, Calligypona marginata,
Carneocephala fulgida, Ceratovacuna lanigera, Cercopidae, Ceroplastes spp., Chaetosiphon fragaefolii, Chionaspis tegalensis, Chlorita onukii, Chromaphis juglandicola, Chrysomphalus ficus, Cicadulina mbila, Coccomytilus halli, Coccus spp., Cryptomyzus ribis, Dalbulus spp., Dialeurodes spp., Diaphorina spp., Diaspis spp., Doralis spp., Drosicha spp., Dysaphis spp., Dysmicoccus spp., Empoasca spp., Eriosoma spp., Erythroneura spp., Euscelis bilobatus, Geococcus coffeae, Homalodisca coagulata, Hyalopterus arundinis, leery a spp., Idiocerus spp., Idioscopus spp., Laodelphax striatellus, Lecanium spp., Lepidosaphes spp., Lipaphis erysimi, Macrosiphum spp., Mahanarva fimbriolata, Melanaphis sacchari, Mete alfiella spp., Metopolophium dirhodum, Monellia costalis, Monelliopsis pecanis, Myzus spp., Nasonovia ribisnigri, Nephotettix spp., Nilaparvata lugens, Oncometopia spp., Orthezia praelonga, Parabemisia myricae, Paratrioza spp., Parlatoria spp., Pemphigus spp., Peregrinus maidis, Phenacoccus spp., Phloeomyzus passerinii, Phorodon humuli, Phylloxera spp., Pinnaspis aspidistrae, Planococcus spp., Protopulvinaria pyriformis, Pseudaulacaspis pentagona, Pseudococcus spp., Psylla spp.,
Pteromalus spp., Pyrilla spp., Quadr aspidiotus spp., Quesada gigas, Rastrococcus spp., Rhopalosiphum spp., Saissetia spp., Scaphoides titanus, Schizaphis graminum, Selenaspidus articulatus, Sogata spp., Sogatella furcifera, Sogatodes spp., Stictocephala festina, Tenalaphara malayensis, Tinocallis caryaefoliae, Tomaspis spp., Toxoptera spp., Trialeurodes vaporariorum, Trioza spp., Typhlocyba spp., Unaspis spp., Viteus vitifolii; from the order of the Hymenoptera, for example, Diprion spp., Hoplocampa spp., Lasius spp., Mono- morium pharaonis, Vespa spp.; from the order of the Isopoda, for example, Armadillidium vulgar e, Oniscus asellus, Porcellio scaber; from the order of the Isoptera, for example, Reticulitermes spp., Odontotermes spp.; from the order of the Lepidoptera, for example, Acronicta major, Aedia leucomelas, Agrotis spp., Alabama argillacea, Anticarsia spp., Barathra brassicae, Bucculatrix thurberiella, Bupalus piniarius, Cacoecia podana, Capua reticulana, Carpocapsa pomonella,
Cheimatobia brumata, Chilo spp., Choristoneura fumiferana, Clysia ambiguella, Cnaphalocerus spp., Earias insulana, Ephestia kuehniella, Euproctis chrysorrhoea, Euxoa spp., Feltia spp., Galleria mellonella, Helicoverpa spp., Heliothis spp., Hofinannophila pseudospretella, Homona magnanima, Hyponomeuta padella, Laphygma spp., Lithocolletis blancardella, Lithophane antennata, Loxagrotis albicosta, Lymantria spp., Malacosoma neustria, Mamestra brassicae, Mocis repanda, Mythimna separata, Oria spp., Oulema oryzae, Panolis flammea, Pectinophora gossypiella, Phyllocnistis citrella, Pier is spp., Plutella xylostella, Prodenia spp., Pseudaletia spp., Pseudoplusia includens, Pyrausta nubilalis, Spodoptera spp., Thermesia gemmatalis, Tinea pellionella, Tineola bisselliella, Tortrix viridana, Trichoplusia spp.; from the order of the Orthoptera, for example, Acheta domesticus, Blatta orientalis, Blattella germanica, Gryllotalpa spp., Leucophaea maderae, Locus ta spp., Melanoplus spp., Periplaneta americana, Schistocerca gregaria; from the order of the Siphonaptera, for example, Ceratophyllus spp., Xenopsylla cheopis. From the order of the Symphyla, for example, Scutigerella immaculata; from the order of the Thysanoptera, for example, Baliothrips biformis, Enneothrips flavens, Frankliniella spp., Heliothrips spp., Hercinothrips femoralis, Kakothrips spp., Rhipiphorothrips cruentatus, Scirtothrips spp.,
Taeniothrips cardamoni, Thrips spp.; from the order of the Thysanura, for example, Lepisma saccharina. The phytoparasitic nematodes include, for example, Anguina spp., Aphelenchoides spp., Belonoaimus spp., Bursaphelenchus spp., Ditylenchus dipsaci, Globodera spp., Heliocotylenchus spp., Heterodera spp., Longidorus spp., Meloidogyne spp., Pratylenchus spp., Radopholus similis, Rotylenchus spp.,
Trichodorus spp., Tylenchorhynchus spp., Tylenchulus spp., Tylenchulus semipenetrans, Xiphinema spp.
In particular, the compounds of the invention may be used to control the following pest spcies: Myzus persicae (aphid), Aphis gossypii (aphid), Aphis fabae (aphid), Lygus spp. (capsids), Dysdercus spp. (capsids), Nilaparvata lugens (planthopper), Nephotettixc incticeps (leafhopper), Nezara spp. (stinkbugs), Euschistus spp. (stinkbugs), Leptocorisa spp. (stinkbugs), Frankliniellaoccidentalis (thrip), Thrips spp. (thrips), Leptinotarsadecemlineata (Colorado potato beetle), Anthonomusgrandis (boll weevil), Aonidiella spp. (scale insects), Trialeurodes spp. (white flies), Bemisia tabaci (white fly), Ostrinianubilalis (European corn borer), Spodopteralittoralis (cotton leafworm), Heliothisvirescens (tobacco budworm), Helicoverpaarmigera (cotton bollworm), Helicoverpazea (cotton bollworm), Sylepta derogata (cotton leaf roller), Pierisbrassicae (white butterfly), Plutellaxylostella (diamond back moth), Agrotis spp. (cutworms), Chilosuppressalis (rice stem borer), Locustamigratoria (locust),
Chortiocetesterminifera (locust), Diabrotica spp. (rootworms), Panonychusulmi (European red mite), Panonychuscitri (citrus red mite), Tetranychusurticae (two-spotted spider mite),
Tetranychuscinnabarinus (carmine spider mite), Phyllocoptrutaoleivora (citrus rust mite),
Polyphagotarsonemuslatus (broad mite), Brevipalpus spp. (flat mites), Boophilus microplus (cattle tick), Dermacentorvariabilis (American dog tick), Ctenocephalidesfelis (cat flea), Liriomyza spp. (leafminer), Muscadomestica (housefly), Aedesaegypti (mosquito), Anopheles spp. (mosquitoes), Culex spp.
(mosquitoes), Lucillia spp. (blowflies), Blattellagermanica (cockroach), Periplanetaamericana
(cockroach), Blattaorientalis (cockroach), termites of the Mastotermitidae (for example Mastotermes spp.), the Kalotermitidae (for example Neotermes spp.), the Rhinotermitidae (for example
Coptotermesformosanus, Reticulitermes flavipes, R. speratu, R. virginicus, R. hesperus, and R.
santonensis) and the Termitidae (for example Globitermessulfureus), Solenopsisgeminata (fire ant), Monomoriumpharaonis (pharaoh's ant), Damalinia spp. and Linognathus spp. (biting and sucking lice), Meloidogyne spp. (root knot nematodes), Globodera spp. and Heterodera spp. (cyst nematodes),
Pratylenchus spp. (lesion nematodes), Rhodopholus spp. (banana burrowing nematodes), Tylenchulus spp. (citrus nematodes), Haemonchus contortus (barber pole worm), Caenorhabditis e/eg «s(vinegar eelworm), Trichostrongylus spp. (gastro intestinal nematodes) and Deroceras reticulatum (slug).
The compound of formula I may be used for pest control on various plants, including soybean (e.g. in some cases 10-70g/ha), corn (e.g. in some cases 10-70g/ha), sugarcane (e.g. in some cases 20- 200g/ha), alfalfa (e.g. in some cases 10-70g/ha), brassicas (e.g. in some cases 10-50g/ha), oilseed rape (e.g. canola) (e.g. in some cases 20-70g/ha), potatoes (including sweet potatoes) (e.g. in some cases 10- 70g/ha), cotton (e.g. in some cases 10-70g/ha), rice (e.g. in some cases 10-70g/ha), coffee (e.g. in some cases 30-150g/ha), citrus (e.g. in some cases 60-200g/ha), almonds (e.g. in some cases 40-180g/ha), fruiting vegetables, cucurbits and pulses (e.g. tomatoes, pepper, chili, eggplant, cucumber, squash etc.)
(e.g. in some cases 10-80g/ha), tea (e.g. in some cases 20-150g/ha), bulb vegetables (e.g. onion, leek etc.) (e.g. in some cases 30-90g/ha), grapes (e.g. in some cases 30-180g/ha), pome fruit (e.g. apples, pears etc.) (e.g. in some cases 30-180g/ha), and stone fruit (e.g. pears, plums etc.) (e.g. in some cases 30-180g/ha).
The compounds of the invention may be used for pest control on various plants, including soybean, corn, sugarcane, alfalfa, brassicas, oilseed rape (e.g. canola), potatoes (including sweet potatoes), cotton, rice, coffee, citrus, almonds, fruiting vegetables, cucurbits and pulses (e.g. tomatoes, pepper, chili, eggplant, cucumber, squash etc.), tea, bulb vegetables (e.g. onion, leek etc.), grapes, pome fruit (e.g.
apples, pears etc.), stone fruit (e.g. pears, plums etc.), and cereals.
The compounds of the invention may be used on soybean to control, for example, Elasmopalpus lignosellus, Diloboderus abderus, Diabrotica speciosa, Trialeurodes spp., Bemisia spp., aphids,
Sternechus subsignatus, Formicidae, Agrotis ypsilon, Julus spp., Murgantia spp., Halyomorpha spp., Thyanta spp., Megascelis ssp., Procornitermes ssp., Gryllotalpidae, Nezara viridula, Piezodorus spp., Acrosternum spp., Neomegalotomus spp., Cerotoma trifurcata, Popillia japonica, Edessa spp., Liogenys fuscus, Euschistus heros, stalk borer, Scaptocoris castanea, phyllophaga spp., Migdolus spp.,
Pseudoplusia includens, Anticarsia gemmatalis, Epinotia spp., Rachiplusia spp., Spodoptera spp., Bemisia tabaci, Tetranychus spp., Agriotes spp., Euschistus spp.. The compounds of the invention are preferably used on soybean to control Diloboderus abderus, Diabrotica speciosa, Trialeurodes spp., Bemisia spp., Nezara viridula, Piezodorus spp., Acrosternum spp., Cerotoma trifurcata, Popillia japonica, Euschistus heros, Scaptocoris castanea, phyllophaga spp., Migdolus spp., Agriotes spp., Euschistus spp..
The compounds of the invention may be used on corn to control, for example, Euschistus heros, Euschistus spp., Dichelops furcatus, Diloboderus abderus, Thyanta spp., Elasmopalpus lignosellus, Halyomorpha spp., Spodoptera frugiperda, Nezara viridula, Cerotoma trifurcata, Popillia japonica, Agrotis ypsilon, Diabrotica speciosa, aphids, Heteroptera, Procornitermes spp., Scaptocoris castanea, Formicidae, Julus ssp., Dalbulus maidis, Diabrotica virgifera, Diabrotica spp., Mocis latipes, Bemisia tabaci, heliothis spp., Tetranychus spp., thrips spp., phyllophaga spp., Migdolus spp., scaptocoris spp., Liogenys fuscus, Spodoptera spp., Ostrinia spp., Sesamia spp., wireworms, Agriotes spp., Halotydeus destructor. The compounds of the invention are preferably used on corn to control Euschistus heros, Euschistus spp., Dichelops furcatus, Diloboderus abderus, Nezara viridula, Cerotoma trifurcata, Popillia japonica, Diabrotica speciosa, Diabrotica virgifera, Diabrotica spp., Tetranychus spp., Thrips spp., Phyllophaga spp., Migdolus spp., Scaptocoris spp., Agriotes spp..
The compounds of the invention may be used on sugar cane to control, for example,
Sphenophorus spp., termites, Migdolus spp., Diloboderus spp., Telchin licus, Diatrea saccharalis, Mahanarva spp., Mealybugs.
The compounds of the invention may be used on alfalfa to control, for example, Hypera brunneipennis, Hypera postica, Colias eurytheme, Collops spp., Empoasca solana, Epitrix spp., Geocoris spp., Lygus hesperus, Lygus lineolaris, Spissistilus spp., Spodoptera spp., Aphids, Trichoplusia ni. The compounds of the invention are preferably used on alfalfa to control Hypera brunneipennis, Hypera postica, Empoasca solana, Epitrix spp., Lygus hesperus, Lygus lineolaris, Trichoplusia ni.
The compounds of the invention may be used on brassicas to control, for example, Plutella xylostella, Pieris spp.,Mamestra spp.,Plusia spp., Trichoplusia ni, Phyllotreta spp.,Spodoptera
spp., Empoasca spp., thrips spp., Delia spp., Murgantia spp., Trialeurodes spp., Bemisia spp., Microtheca spp., Aphids. The compounds of the invention are preferably used on brassicas to control Plutella xylostella, Pieris spp., Plusia spp., Trichoplusia ni, Phyllotreta spp., Thrips spp..
The compounds of the invention may be used on oil seed rape, e.g. canola, to control, for example, Meligethes spp., Ceutorhynchus napi, Halotydeus destructor, Psylloides spp..
The compounds of the invention may be used on potatoes, including sweet potatoes, to control, for example, Empoasca spp.,Leptinotarsa spp.,Diabrotica speciosa, Phthorimaea spp.,Paratrioza spp.,Maladera matrida, Agriotes spp., Aphids, wireworms. The compounds of the invention are preferably used on potatoes, including sweet potatoes, to control Empoasca spp.,Leptinotarsa
spp.,Diabrotica speciosa, Phthorimaea spp.,Paratrioza spp., Agriotes spp..
The compounds of the invention may be used on cotton to control, for example, Anthonomus grandis, Pectinophora spp.,heliothis spp.,Spodoptera spp.,Tetranychus spp., Empoasca spp., Thrips spp., Bemisia tabaci, Trialeurodes spp., Aphids, Lygus spp., phyllophaga spp., Scaptocoris spp., Austroasca viridigrisea, Creontiades spp., Nezara spp.,Piezodorus spp., Halotydeus destructor, Oxycaraenus hyalinipennis, Dysdercus cingulatus. The compounds of the invention are preferably used on cotton to control Anthonomus grandis, Tetranychus spp., Empoasca spp., thrips spp., Lygus spp., phyllophaga spp., Scaptocoris spp..
The compounds of the invention may be used on rice to control, for example, Leptocorisa spp.,Cnaphalocrosis spp., Chilo spp.,Scirpophaga spp.,Lissorhoptrus spp., Oebalus pugnax, Scotinophara spp., Nephotettix malayanus, Nephotettix nigropictus, Nephotettix parvus, Nephottetix virescens,
Nephotettix spp., Mealybugs, Sogatella furcifera, Nilaparvata lugens, Orseolia spp., Cnaphalocrocis medinalis, Marasmia spp., Stenchaetothrips biformis, Thrips spp., Hydrellia philippina, Grasshoppers, Pomacea canaliculata, Scirpophaga innotata, Chilo suppressalis, Chilo auricilius, Chilo polychrysus, Sesamia inferens, Laodelphax striatellus, Nymphula depunctalis, Oulema oryzae, Stinkbugs.The compounds of the invention are preferably used on rice to control Leptocorisa spp.,Lissorhoptrus spp.,Oebalus pugnax, Nephotettix malayanus, Nephotettix nigropictus, Nephotettix parvus, Nephottetix virescens, Nephotettix spp., Sogatella furcifera, Stenchaetothrips biformis, Thrips spp., Hydrellia philippina, Grasshoppers, Pomacea canaliculata, Scirpophaga innotata, Chilo suppressalis, Chilo polychrysus, Oulema oryzae.
The compounds of the invention may be used on coffee to control, for example, Hypothenemus Hampei, Perileucoptera Cojfeella, Tetranychus spp.,Brevipalpus spp., Mealybugs. The compounds of the invention are preferably used on coffee to control Hypothenemus Hampei, Perileucoptera Coffeella.
The compounds of the invention may be used on citrus to control, for example, Panonychus citri, Phyllocoptruta oleivora, Brevipalpus spp.,Diaphorina citri, Scirtothrips spp., Thrips spp., Unaspis spp.,Ceratitis capitata, Phyllocnistis spp., Aphids, Hardscales, Softscales, Mealybugs.The compounds of the invention are preferably used on citrus to control Panonychus citri, Phyllocoptruta oleivora,
Brevipalpus spp., Diaphorina citri, Scirtothrips spp., thrips spp., Phyllocnistis spp..
The compounds of the invention may be used on almonds to control, for example, Amyelois transitella, Tetranychus spp..
The compounds of the invention may be used on fruiting vegetables, cucurbits and pulses, including tomatoes, pepper, chili, eggplant, cucumber, squash etc., to control, for example, Thrips spp., Tetranychus spp.,Polyphagotarsonemus spp.,Aculops spp.,Empoasca spp.,Spodoptera spp.,heliothis spp.,Tuta absoluta, Liriomyza spp.,Bemisia tabaci, Trialeurodes spp., Aphids, Paratrioza
spp.,Frankliniella occidentalis, Frankliniella spp.,Anthonomus spp.,Phyllotreta spp.,Amrasca
spp.,Epilachna spp.,Halyomorpha spp., Scirtothrips spp.,Leucinodes spp.,Neoleucinodes spp. Maruca spp., Fruit flies, Stinkbugs, Lepidopteras, Coleopteras. The compounds of the invention are preferably used on fruiting vegetables, cucurbits and pulses, including tomatoes, pepper, chili, eggplant, cucumber, squash etc., to control Thrips spp., Tetranychus spp., Polyphagotarsonemus spp., Aculops spp., Empoasca spp., Spodoptera spp., heliothis spp., Tuta absoluta, Liriomyza spp., Paratrioza spp., Frankliniella occidentalis, Frankliniella spp., Amrasca spp., Scirtothrips spp., Leucinodes spp., Neoleucinodes spp..
The compounds of the invention may be used on tea to control, for example, Pseudaulacaspis spp., Empoasca spp., Scirtothrips spp.,Caloptilia theivora, Tetranychus spp..The compounds of the invention are preferably used on tea to control Empoasca spp., Scirtothrips spp..
The compounds of the invention may be used on bulb vegetables, including onion, leek etc. to control, for example, Thrips spp., Spodoptera spp., heliothis spp.. The compounds of the invention are preferably used on bulb vegetables, including onion, leek etc. to control Thrips spp..
The compounds of the invention may be used on grapes to control, for example, Empoasca spp.,Lobesia spp.,Eupoecilia ambiguella,Frankliniella spp., Thrips spp., Tetranychus
spp.,Rhipiphorothrips Cruentatus, Eotetranychus Willamettei, Erythroneura Elegantula, Scaphoides spp.,Scelodonta strigicollis, Mealybugs. The compounds of the invention are preferably used on grapes to control Frankliniella spp., Thrips spp., Tetranychus spp., Rhipiphorothrips Cruentatus, Scaphoides spp..
The compounds of the invention may be used on pome fruit, including apples, pears etc., to control, for example, Cacopsylla spp.,Psylla spp., Panonychus ulmi, Cydia pomonella, Lepidopteras, Aphids, Hardscales, Softscales. The compounds of the invention are preferably used on pome fruit, including apples, pears etc., to control Cacopsylla spp., Psylla spp., Panonychus ulmi.
The compounds of the invention may be used on stone fruit to control, for example, Grapholita molesta, Scirtothrips spp., Thrips spp., Frankliniella spp., Tetranychus spp., Aphids, Hardscales, Softscales, Mealybugs. The compounds of the invention are preferably used on stone fruit to control Scirtothrips spp., Thrips spp., Frankliniella spp., Tetranychus spp..
The compounds of the invention may be used on cereals to control, for example, Aphids,
Stinkbugs, earthmites, Eurygaster integriceps, Zabrus tenebrioides, Anisoplia austriaca, Chaetocnema aridula, Phyllotreta spp., Oulema melanopus, Oscinella spp., Delia spp., Mayetiola spp., Contarinia spp.,
Cephus spp., Steneotarsonemus spp., Apamea spp..
In another embodiment compounds of formula I and mixtures of the invention may be used on rice to control Baliothrips biformis (Thrips), Chilo spp. (e.g. Chilo polychrysus (Dark headed striped borer), Chilo suppressalis (Rice stemborer), Chilo indicus (Paddy stem borer), Chilo polychrysus (Dark- headed rice borer), Chilo suppressalis (Stripe stem borer)), Cnaphalocrocis medinalis (Rice leaf folder), Dicladispa armigera (Hispa), Hydrellia philipina (Rice whorl-maggot), Laodelphax spp. (Smaller brown planthopper) (e.g. Laodelphax striatellus ), Lema oryzae (Rice leafbeetle), Leptocorsia acuta (Rice bug), Leptocorsia oratorius (rice bug), Lissorhoptrus oryzophilus (rice water weevil), Mythemina separata (armyworm), Nephottetix spp. (Green leafhopper ) (e.g. Nephotettix cincticeps, Nephotettix malayanus, Nephotettix nigropictus, Nephotettix parvus, Nephottetix virescens), Nilaparvata lugens (Brown
Planthopper), Nymphula depunctalis (Rice caseworm), Orseolia oryzae (Rice Gall midge), Oulema oryzae (Rice leafbeetle), Scirpophaga incertulas (Yellow Stemborer), Scirpophaga innotata (White Stemborer), Scotinophara coarctata (Rice black bug), Sogaella frucifera (White-backed planthopper), Steneotarsonemus spinki.
The compounds of the invention may be used to control animal housing pests including: Ants, Bedbugs (adult), Bees, Beetles, Boxelder Bugs, Carpenter Bees, Carpet Beetles, Centipedes, Cigarette, Beetles, Clover Mites, Cockroaches, Confused Flour Beetle, Crickets, Earwigs, Firebrats, Fleas, Flies, Lesser Grain Borers, Millipedes, Mosquitoes, Red Flour Beetles, Rice Weevils, Saw-toothed Grain Beetles, Silverfish, Sowbugs, Spiders, Termites, Ticks, Wasps, Cockroaches, Crickets, Flies, Litter Beetles (such as Darkling, Hide, and Carrion), Mosquitoes, Pillbugs, Scorpions, Spiders, Spider Mites (Twospotted, Spruce), Ticks.
The compounds of the invention may be used to control ornamental pests including: Ants (Including Imported fire ants), Armyworms, Azalea caterpillars, Aphids, Bagworms, Black vine weevils (adult), Boxelder bugs, Budworms, California oakworms, Cankerworms, Cockroaches, Crickets, Cutworms, Eastern tent caterpillars, Elm leaf beetles, European sawflies, Fall webworms, Flea beetles, Forest tent caterpillars, Gypsy moth larvae, Japanese beetles (adults), June beetles (adults), Lace bugs, Leaf-feeding caterpillars, Leafhoppers, Leafminers (adults), Leaf rollers, Leaf skeletonizers, Midges, Mosquitoes, Oleander moth larvae, Pillbugs, Pine sawflies, Pine shoot beetles, Pinetip moths, Plant bugs, Root weevils, Sawflies, Scale insects (crawlers), Spiders, Spittlebugs, Striped beetles, Striped oakworms, Thrips, Tip moths, Tussock moth larvae, Wasps, Broadmites, Brown softscales, California redscales (crawlers), Clover mites, Mealybugs, Pineneedlescales (crawlers), Spider mites, Whiteflies
The compounds of the invention may be used to control turf pests including: Ants (Including Imported fire ants, Armyworms, Centipedes, Crickets, Cutworms, Earwigs, Fleas (adult), Grasshoppers, Japanese beetles (adult), Millipedes, Mites, Mosquitoes (adult), Pillbugs, Sod webworms, Sow bugs, Ticks (including species which transmit Lyme disease), Bluegrass billbugs (adult), Black turfgrass ataenius (adult), Chiggers, Fleas (adult), Grubs (suppression), Hyperodes weevils (adult), Mole crickets (nymphs and young adults), Mole Crickets (mature adults), Chinch Bugs. The compounds of formula (I) and mixture of the invention, in particular those in the tables above, may be used for soil applications, including as a seed application, to target at least the following: sucking pests such as aphids, thrips, brown plant hopper (e.g. on rice), sting bugs, white flies (e.g. on cotton and vegetables), mites; on soil pests such as corn root worm, wireworms, white grubs, zabrus, termites (e.g. on sugar cane, soy, pasture), maggots, cabbage root fly, red legged earth mite; on lepidoptera, such as spodoptera, cutworms, elasmoplpus,plutella (e.g. brassica), stem borers, leaf miners, flea beetle,
Sternechus; on nematicides, such as Heterodera glycines (e.g. on soybean), Pratylenchus brachyurus (e.g. on corn), P. zeae (e.g. oncorn), P. penetrans (e.g. on corn), Meloidogyne incognita (e.g. on vegetables), Heterodera schachtii (e.g. on sugar beet), Rotylenchus reniformis (e.g. on cotton), Heterodera avenae (e.g. on cereals), Pratylenchus neglectus (e.g. on cereals), thornei (e.g. on cereals).
The compounds of formula (I) and mixture of the invention, in particular those in the tables above may be used for seed applications at least on the following: soil grubs for corn, soybeans, sugarcane: Migdolus spp; Phyllophaga spp.; Diloboderus spp; Cyclocephala spp; Lyogenys fuscus; sugarcane weevils: Sphenophorus levis & Metamasius hemipterus; termites for soybeans, sugarcane, pasture, others: Heterotermes tenuis; Heterotermes longiceps; Cornitermes cumulans; Procornitermes triacifer;
Neocapritermes opacus; Neocapritermes parvus;com root worms for corn and potatoes: Diabrotica spp., seed Maggot: Delia platura; soil stinkbugs: Scaptocoris castanea; wireworms: Agriotes spp; Athous spp Hipnodes bicolor; Ctenicera destructor; Limonius canu; Limonius californicus; rice water weevil;
Lissorhoptrus oryzophilus; Red Legged earth mites: Halotydeus destructor.
The invention therefore provides a method of combating and/or controlling an animal pest, e.g. an invertebrate animal pest, which comprises applying to the pest, to a locus of the pest, or to a plant susceptible to attack by the pest a pesticidally effective amount of a compound of formula (I). In particular, the invention provides a method of combating and/or controlling insects, acarines, nematodes or molluscs which comprises applying an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I), or a composition containing a compound of formula (I), to a pest, a locus of pest, preferably a plant, or to a plant susceptible to attack by a pest, The compounds of formula (I) are preferably used against insects, acarines or nematodes.
The term "plant" as used herein includes seedlings, bushes and trees. Crops are to be understood as also including those crops which have been rendered tolerant to herbicides or classes of herbicides (e.g. ALS-, GS-, EPSPS-, PPO- and HPPD-inhibitors) by conventional methods of breeding or by genetic engineering. An example of a crop that has been rendered tolerant to imidazolinones, e.g. imazamox, by conventional methods of breeding is Clearfield® summer rape (canola). Examples of crops that have been rendered tolerant to herbicides by genetic engineering methods include e.g. glyphosate- and glufosinate- resistant maize varieties commercially available under the trade names RoundupReady® and
LibertyLink®.
The compounds of the invention may be applied to plant parts. Plant parts are to be understood as meaning all parts and organs of plants above and below the ground, such as shoot, leaf, flower and root, examples which may be mentioned being leaves, needles, stalks, stems, flowers, fruit bodies, fruits, seeds, roots, tubers and rhizomes. The plant parts also include harvested material, and vegetative and generative propagation material, for example cuttings, tubers, rhizomes, offshoots and seeds. Treatment according to the invention of the plants and plant parts with the active compounds is carried out directly or by allowing the compounds to act on their surroundings, habitat or storage space by the customary treatment methods, for example by immersion, spraying, evaporation, fogging, scattering, painting on, injecting and, in the case of propagation material, in particular in the case of seed, also by applying one or more coats.
Compounds of formula I may be used on transgenic plants (including cultivars) obtained by genetic engineering methods and/or by conventional methods. These are understood as meaning plants having novel properties ("traits") which have been obtained by conventional breeding, by mutagenesis or by recombinant DNA techniques. Depending on the plant species or plant cultivars, their location and growth conditions (soils, climate, vegetation period, diet), the treatment according to the invention may also result in superadditive "synergistic") effects.
Thus, for example, reduced application rates and/or a widening of the activity spectrum and/or an increase in the activity of the substances and compositions which can be used according to the invention, better plant growth, increased tolerance to high or low temperatures, increased tolerance to drought or to water or soil salt content, increased flowering performance, easier harvesting, accelerated maturation, higher harvest yields, higher quality and/or a higher nutritional value of the harvested products, better storage stability and/or processability of the harvested products are possible, which exceed the effects which were actually to be expected.
The preferred transgenic plants or plant cultivars which are to be treated according to the invention include all plants which, by virtue of the genetic modification, received genetic material which imparts particularly advantageous, useful traits to these plants. Examples of such traits are better plant growth, increased tolerance to high or low temperatures, increased tolerance to drought or to water or soil salt content, increased flowering performance, easier harvesting, accelerated maturation, higher harvest yields, higher quality and/or a higher nutritional value of the harvested products, better storage stability and/or processability of the harvested products.
Further and particularly emphasized examples of such traits are a better defence of the plants against animal and microbial pests, such as against insects, mites, phytopathogenic fungi, bacteria and/or viruses, and also increased tolerance of the plants to certain herbicidally active compounds.
Examples of transgenic plants which may be mentioned are the important crop plants, such as cereals (wheat, rice), maize, soybean, potatoes, sugar beet, tomatoes, peas and other vegetable varieties, cotton, tobacco, oilseed rape and also fruit plants (with the fruits apples, pears, citrus fruits and grapes).
Compounds of formula I may be used on transgenic plants that are capable of producing one or more pesticidal proteins which confer upon the transgenic plant tolerance or resistance to harmful pests, e.g. insect pests, nematode pests and the like. Such pesticidal proteins include, without limitation, Cry proteins from Bacillus thuringiensis CrylAb, CrylAc, CrylF, Cry2Ab, Cry2Ae, Cry3A, Cry3Bb, or Cry9C; engineered proteins such as modified Cry3A ( US Patent 7,030,295) or CrylA.105; or vegetative insecticidal proteins such as Vipl, Vip2 or Vip3. A full list of Bt Cry proteins and VIPs useful in the invention can be found on the worldwide web at Bacillus thuringiensis Toxin Nomenclature Database maintained by the University of Sussex (see also, Crickmore et al. (1998) Microbiol. Mol. Biol. Rev. 62:807-813). Other pesticidal proteins useful in the invention include proteins of bacteria colonizing nematodes, e.g. Photorhabdus spp. or Xenorhabdus spp.; toxins produced by animals, such as scorpion toxins, arachnid toxins, wasp toxins, or other insect-specific neurotoxins; toxins produced by fungi, such Streptomycetes toxins, plant lectins, such as pea or barley lectins; agglutinins; proteinase inhibitors, such as trypsin inhibitors, serine protease inhibitors, patatin, cystatin or papain inhibitors; ribosome- inactivating proteins (RIP), such as ricin, maize-RIP, abrin, luffin, saporin or bryodin; steroid metabolism enzymes, such as 3-hydroxysteroid oxidase, ecdysteroid-IDP-glycosyl-transferase, cholesterol oxidases, ecdysone inhibitors or HMG-CoA-reductase; ion channel blockers, such as blockers of sodium or calcium channels; juvenile hormone esterase; diuretic hormone receptors (helicokinin receptors); stilben synthase, bibenzyl synthase, chitinases or glucanases. Further examples of such pesticidal proteins or transgenic plants capable of synthesizing such proteins are disclosed, e.g., in EP-A 374753, WO 93/007278, WO 95/34656, EP-A 427529, EP-A 451878, WO 03/18810 and WO 03/52073. The methods for producing such transgenic plants are generally known to the person skilled in the art and some of which are commercially available such as Agrisure®CB (corn producing Cryl Ab), Agrisure®RW (corn producing mCry3A), Agrisure® Viptera (corn hybrids producing Vip3Aa); Agrisure300GT (corn hybrids producing Cryl Ab and mCry3A); YieldGard® (corn hybrids producing the Cryl Ab protein), YieldGard® Plus (corn hybrids producing CrylAb and Cry3Bbl), Genuity® SmartStax® (corn hybrids with CrylA.105, Cry2Ab2, CrylF, Cry34/35, Cry3Bb); Herculex® I (corn hybrids producing CrylFa) and Herculex®RW (corn hybrids producing Cry34Abl, Cry35Abl and the enzyme Phosphinothricin-N-Acetyltransferase [PAT]); NuCOTN®33B (cotton cultivars producing CrylAc), Bollgard®I (cotton cultivars producing CrylAc), Bollgard®II (cotton cultivars producing CrylAc and Cry2Ab2) and VIPCOT® (cotton cultivars producing a Vip3Aa). Soybean Cyst Nematode resistance soybean (SCN® - Syngenta) and soybean with Aphid resistant trait (AMT®) are also of interest.
Further examples of such transgenic crops are:
1. Btll Maize from Syngenta Seeds SAS, Chemin de l'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 CryIA(b) toxin. Btl 1 maize also transgenically expresses the enzyme PAT to achieve tolerance to the herbicide glufosinate ammonium.
2. Btl 76 Maize from Syngenta Seeds SAS, Chemin de l'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 CryLA(b) toxin. Btl 76 maize also transgenically expresses the enzyme PAT to achieve tolerance to the herbicide glufosinate ammonium.
3. MIR604 Maize from Syngenta Seeds SAS, Chemin de l'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 CrylllA toxin. This toxin is Cry3A055 modified by insertion of a cathepsin-D- protease recognition sequence. The preparation of such transgenic maize plants is described in WO 03/018810.
4. MON 863 Maize from Monsanto Europe S.A. 270-272 Avenue de Tervuren, B-l 150 Brussels, Belgium, registration number C/DE/02/9. MON 863 expresses a CryIIIB(bl) toxin and has resistance to certain Coleoptera insects.
5. IPC 531 Cotton from Monsanto Europe S.A. 270-272 Avenue de Tervuren, B-l 150 Brussels, Belgium, registration number C/ES/96/02.
6. 1507 Maize from Pioneer Overseas Corporation, Avenue Tedesco, 7 B-l 160 Brussels, Belgium, registration number C/NL/00/10. Genetically modified maize for the expression of the protein Cry IF 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-l 150 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 χ 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 CryIA(b) toxin obtained from Bacillus thuringiensis subsp.kurstaki which brings about tolerance to certain Lepidoptera, include the European corn borer.
Further examples of transgenic plants, and of very high interest, are those carrying traits conferring resistance to 2.4D (e.g. Enlist®) (e.g. WO 2011066384), glyphosate (e.g. Roundup Ready®, Roundup Ready 2 Yield®), sulfonylurea (e.g. STS®), glufosinate (e.g. Liberty Link®, Ignite®), Dicamba (Monsanto), HPPD tolerance (e.g. isoxaflutole herbicide) (Bayer CropScience, Syngenta). Double or triple stacks of any of the traits described here are also of interest, including glyphosate and sulfonyl-urea tolerance ((e.g. Optimum GAT®), plants stacked with STS® and Roundup Ready® or plants stacked with STS® and Roundup Ready 2 Yield®), dicamba and glyphosate tolerance (Monsanto). Of particular interest are soybean plants carrying trains conferring resistance to 2.4D (e.g. Enlist®), glyphosate (e.g. Roundup Ready®, Roundup Ready 2 Yield®), sulfonylurea (e.g. STS®), glufosinate (e.g. Liberty Link®, Ignite®), Dicamba (Monsanto) HPPD tolerance (e.g. isoxaflutole herbicide) (Bayer CropScience, Syngenta). Double or triple stack in soybean plants of any of the traits described here are also of interest, including glyphosate and sulfonyl-urea tolerance (e.g. Optimum GAT®, plants stacked with STS® and Roundup Ready® or Roundup Ready 2 Yield®), dicamba and glyphosate tolerance (Monsanto).
Transgenic crops of insect-resistant plants are also described in BATS (Zentrum fur Biosicherheit und Nachhaltigkeit, Zentrum BATS, Clarastrasse 13, 4058 Basel, Switzerland) Report 2003,
(http://bats.ch).
Examples of cotton transgenic events include MON 531 / 757 / 1076 (Bollgard I ® - Monsanto), MON1445 (Roundup ready cotton ®- Monsanto), MON531 x MON1445 (Bollgard I + RR ®- Monsanto), MON15985 (Genuity Bollgard II cotton ®- Monsanto), MON88913 (Genuity RR FLEX cotton ®- Monsanto), MON15985 x MON1445 (Genuity Bollgard II + RR FELX cotton ®- Monsanto),
MON15983 x MON88913 (Genuity Bollgard II + RR FLEX cotton ® - Monsanto), MON15985
(FibreMax Bollgard II Cotton ® - Monsanto), LL25 (FibreMax LL cotton ® - BCS Stoneville), GHB614 (FibreMax GlyTol cotton ®- BCS Stoneville), LL25 x MON15985 (FibreMax LL Bollgard II cotton ® - BCS Stoneville / Monsanto), GHB614 x LL25 (FibreMax LL GlyTol cotton ® - BCS Stoneville), GHB614 x LL25 x MON15985 (FibreMax RR GlyTol Bollgard II cotton ® - BCS Stoneville),
MON88913 x MON15985 (FibreMax LL GlyTol Bollgard II cotton ® - Monsanto), MON88913 (FibreMax RR Flex cotton ® - Monsanto), GHB119 + T304-40 (Twinlink ® - BCS Stoneville), GHB119 + T304-40 x LL25 x GHB614 (Twinlink LL GT ® - BCS Stoneville), 3006-210-23 x 281-24-236 (PhytoGen Widestrike Insect Protection ® - Dow), 3006-210-23 x 281 -24-236 x MON88913 (PhytoGen Widestrike Insect Protection + RR FLEX - ® Dow / Monsanto), 3006-210-23 x 281-24-236 x MON1445 ((PhytoGen Widestrike Insect Protection + RR ® - Dow / Monsanto), MON1445 (PhytoGen Roundup Ready ® - Monsanto), MON88913 (PhytoGen Roundup Ready FLEX ® - Monsanto), COT102 x COT67B (Vipcot ® - Syngenta), COT102 x COT67B x MON88913 (Vipcot RR FLEX ® - Syngenta / Monsanto), 281-24-236 (Dow), 3006-210-23 (Dow), COT102 (Syngenta), COT67B (Syngenta), T304-40 (BCS Stoneville).
Examples of Soy transgenic events include MON87701 x MON89788 (Genuity Roundup ready 2 Yield soybeans® - Monsanto), MON89788 (Roundup Ready2Yield®, RR2Y® - Monsanto), MON87708 (Monsanto), 40-3-2 (Roundup Ready®, RRl® - Monsanto), MON87701 (Monsanto), DAS-68416 (Enlist Weed Control System® - Dow), DP356043 (Optimum GAT® - Pioneer), A5547-127 (LibertyLink soybean® - Bayercropscience), A2704-12 (Bayercropscience), GU262 (Bayercropscience), W62 W98 (Bayercropscience), CRV127 (Cultivance® - BASF / EMBRAPA) SYHT0H2 (WO2012/082548).
Examples of Maize transgenic events include T25 (LibertyLink®, LL® - Bayerscropscience), DHT-1 (Dow), TC1507 (Herculex I® - Dow), DAS59122-7 (Herculex RW® - Dow), TC1507 + DAS59122-7 - Herculex Xtra® - Dow), TC1507 x DAS-59122-7 x NK603 (Herculex Xtra + RR® - Dow), TC1507 x DAS-59122- x MON88017 x MON89034 (Genuity Smartstax corn®, Genuity
Smartstax RIB complete® - Monsanto / Dow), MON89034 x NK603 (Genuity VT double PRO® - Monsanto), MON89034 + MON88017 (Genuity VT Triple PRO® - Monsanto), NK603 (Roundup Ready 2®, RR2® - Monsanto), MON810 (YieldGard BT®, Yieldgard cornborer® - Monsanto), MON810 x NK603 (YieldGard cornborer RR Corn 2® - Monasnto), MON810 x MON863 (YieldGard Plus® - Monsanto), MON863 x MON810 x NK603 (YieldGard Plus + RR Corn2® / YieldGard RR Maize® - Monsanto), MON863 x NK603 (YieldGard Rotworm + RR Corn 2® - Monsanto), MON863 (YieldBard RW® - Monsanto), MON89034 (YieldGard RW® - Monsanto), MON88017 (YieldGard VT RW® - Monsanto), MON810 + MON88017 (YieldGard VT Triple® - Monsanto), MON88017 + MON89034 (YieldGard VT Triple Pro® - Monsanto), Btl 1 + MIR604 + GA21 (Agrisure 3000® - Syngenta), Btl 1 + TC1507 + MIR604 + 5307 + GA21 (Syngenta), Btl 1 + TC1507 + MIR604 + DAS59122 + GA21 (Agrisure 3122® - Syngenta), BT11 (Agrisure CB® - Syngenta), GA21 - (Agrisure GT® - Syngenta), MIR604 (Agrisure RW® - Syngenta), Btl 1 + MIR162 (Agrisure TL VIP® - Syngenta), BT11 + MIR162 + GA21 (Agrisure Viptra 3110® - Syngenta), BT11 + MIR162 + MIR604 (Agrisure TM 3100® -
Syngenta), Event3272 + BT11 + MIR604 + GA21 (Syngenta), BT11 + MIR1692 + MIR604 + GA21 (Agrisure Viptera 3111® - Syngenta), BT11 + MIR 162 + TC1507 + GA21 (Agrisure Viptera 3220® - Syngenta), BT11 + MIR162 + TC1507 + MIR604 + 5307 + GA21 (Agrisure Viptera 3222® - Syngenta), MIR162 (Syngenta), BT11 + GA21 + MIR162 + MIR604 + 5307 (Syngenta), 5307 (Syngenta).
In order to apply a compound of formula (I) as an insecticide, acaricide, nematicide or molluscicide to a pest, a locus of pest, or to a plant susceptible to attack by a pest, a compound of formula (I) is usually formulated into a composition which includes, in addition to the compound of formula (I), a suitable inert diluent or carrier and, optionally, a surface active agent (SFA). SFAs are chemicals which are able to modify the properties of an interface (for example, liquid/solid, liquid/air or liquid/liquid interfaces) by lowering the interfacial tension and thereby leading to changes in other properties (for example dispersion, emulsification and wetting). It is preferred that all compositions (both solid and liquid formulations) comprise, by weight, 0.0001 to 95%, more preferably 1 to 85%, for example 5 to 60%, of a compound of formula (I). The composition is generally used for the control of pests such that a compound of formula (I) is applied at a rate of from O.lg to 10kg per hectare, preferably from lg to 6kg per hectare, more preferably from lg to 1kg per hectare.
When used in a seed dressing, a compound of formula (I) is generally used at a rate of 0.000 lg to lOg (for example O.OOlg or 0.05g), preferably 0.005g to lOg, more preferably 0.005g to 4g, per kilogram of seed.
In another aspect the present invention provides a composition comprising a pesticidally effective amount of a compound of formula (I), in particular an insecticidal, acaricidal, nematicidal or
molluscicidal composition comprising an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I) and a suitable carrier or diluent therefor. The composition is preferably an insecticidal, acaricidal, nematicidal or molluscicidal composition.
The compositions can be chosen from a number of formulation types, including dustable powders (DP), soluble powders (SP), water soluble granules (SG), water dispersible granules (WG), wettable powders (WP), granules (GR) (slow or fast release), soluble concentrates (SL), oil miscible liquids (OL), ultra low volume liquids (UL), emulsifiable concentrates (EC), dispersible concentrates (DC), emulsions (both oil in water (EW) and water in oil (EO)), micro -emulsions (ME), suspension concentrates (SC), aerosols, fogging/smoke formulations, capsule suspensions (CS) and seed treatment formulations. The formulation type chosen in any instance will depend upon the particular purpose envisaged and the physical, chemical and biological properties of the compound of formula (I).
Dustable powders (DP) may be prepared by mixing a compound of formula (I) with one or more solid diluents (for example natural clays, kaolin, pyrophyllite, bentonite, alumina, montmorillonite, kieselguhr, chalk, diatomaceous earths, calcium phosphates, calcium and magnesium carbonates, sulfur, lime, flours, talc and other organic and inorganic solid carriers) and mechanically grinding the mixture to a fine powder. Soluble powders (SP) may be prepared by mixing a compound of formula (I) with one or more water-soluble inorganic salts (such as sodium bicarbonate, sodium carbonate or magnesium sulfate) or one or more water-soluble organic solids (such as a polysaccharide) and, optionally, one or more wetting agents, one or more dispersing agents or a mixture of said agents to improve water
dispersibility/solubility. The mixture is then ground to a fine powder. Similar compositions may also be granulated to form water soluble granules (SG).
Wettable powders (WP) may be prepared by mixing a compound of formula (I) with one or more solid diluents or carriers, one or more wetting agents and, preferably, one or more dispersing agents and, optionally, one or more suspending agents to facilitate the dispersion in liquids. The mixture is then ground to a fine powder. Similar compositions may also be granulated to form water dispersible granules (WG).
Granules (GR) may be formed either by granulating a mixture of a compound of formula (I) and one or more powdered solid diluents or carriers, or from pre-formed blank granules by absorbing a compound of formula (I) (or a solution thereof, in a suitable agent) in a porous granular material (such as pumice, attapulgite clays, fuller's earth, kieselguhr, diatomaceous earths or ground corn cobs) or by adsorbing a compound of formula (I) (or a solution thereof, in a suitable agent) on to a hard core material (such as sands, silicates, mineral carbonates, sulfates or phosphates) and drying if necessary. Agents which are commonly used to aid absorption or adsorption include solvents (such as aliphatic and aromatic petroleum solvents, alcohols, ethers, ketones and esters) and sticking agents (such as polyvinyl acetates, polyvinyl alcohols, dextrins, sugars and vegetable oils). One or more other additives may also be included in granules (for example an emulsifying agent, wetting agent or dispersing agent).
Dispersible Concentrates (DC) may be prepared by dissolving a compound of formula (I) in water or an organic solvent, such as a ketone, alcohol or glycol ether. These solutions may contain a surface active agent (for example to improve water dilution or prevent crystallization in a spray tank).
Emulsifiable concentrates (EC) or oil-in-water emulsions (EW) may be prepared by dissolving a compound of formula (I) in an organic solvent (optionally containing one or more wetting agents, one or more emulsifying agents or a mixture of said agents). Suitable organic solvents for use in ECs include aromatic hydrocarbons (such as alkylbenzenes or alkylnaphthalenes, exemplified by SOLVESSO 100, SOLVESSO 150 and SOLVESSO 200; SOLVESSO is a Registered Trade Mark), ketones (such as cyclohexanone or methylcyclohexanone) and alcohols (such as benzyl alcohol, furfuryl alcohol or butanol), N-alkylpyrrolidones (such as N-methylpyrrolidone or N-octylpyrrolidone), dimethyl amides of fatty acids (such as C8-Ci0 fatty acid dimethylamide) and chlorinated hydrocarbons. An EC product may spontaneously emulsify on addition to water, to produce an emulsion with sufficient stability to allow spray application through appropriate equipment. Preparation of an EW involves obtaining a compound of formula (I) either as a liquid (if it is not a liquid at room temperature, it may be melted at a reasonable temperature, typically below 70°C) or in solution (by dissolving it in an appropriate solvent) and then emulsifiying the resultant liquid or solution into water containing one or more SFAs, under high shear, to produce an emulsion. Suitable solvents for use in EWs include vegetable oils, chlorinated hydrocarbons (such as chlorobenzenes), aromatic solvents (such as alkylbenzenes or alkylnaphthalenes) and other appropriate organic solvents which have a low solubility in water.
Microemulsions (ME) may be prepared by mixing water with a blend of one or more solvents with one or more SFAs, to produce spontaneously a thermodynamically stable isotropic liquid formulation. A compound of formula (I) is present initially in either the water or the solvent/SFA blend. Suitable solvents for use in MEs include those hereinbefore described for use in ECs or in EWs. An ME may be either an oil-in-water or a water-in-oil system (which system is present may be determined by conductivity measurements) and may be suitable for mixing water-soluble and oil-soluble pesticides in the same formulation. An ME is suitable for dilution into water, either remaining as a microemulsion or forming a conventional oil-in-water emulsion.
Suspension concentrates (SC) may comprise aqueous or non-aqueous suspensions of finely divided insoluble solid particles of a compound of formula (I). SCs may be prepared by ball or bead milling the solid compound of formula (I) in a suitable medium, optionally with one or more dispersing agents, to produce a fine particle suspension of the compound. One or more wetting agents may be included in the composition and a suspending agent may be included to reduce the rate at which the particles settle. Alternatively, a compound of formula (I) may be dry milled and added to water, containing agents hereinbefore described, to produce the desired end product.
Aerosol formulations comprise a compound of formula (I) and a suitable propellant (for example ^-butane). A compound of formula (I) may also be dissolved or dispersed in a suitable medium (for example water or a water miscible liquid, such as «-propanol) to provide compositions for use in non- pressurized, hand-actuated spray pumps.
A compound of formula (I) may be mixed in the dry state with a pyrotechnic mixture to form a composition suitable for generating, in an enclosed space, a smoke containing the compound.
Capsule suspensions (CS) may be prepared in a manner similar to the preparation of EW formulations but with an additional polymerization stage such that an aqueous dispersion of oil droplets is obtained, in which each oil droplet is encapsulated by a polymeric shell and contains a compound of formula (I) and, optionally, a carrier or diluent therefor. The polymeric shell may be produced by either an interfacial polycondensation reaction or by a coacervation procedure. The compositions may provide for controlled release of the compound of formula (I) and they may be used for seed treatment. A compound of formula (I) may also be formulated in a biodegradable polymeric matrix to provide a slow, controlled release of the compound.
A composition may include one or more additives to improve the biological performance of the composition (for example by improving wetting, retention or distribution on surfaces; resistance to rain on treated surfaces; or uptake or mobility of a compound of formula (I)). Such additives include surface active agents, spray additives based on oils, for example certain mineral oils or natural plant oils (such as soy bean and rape seed oil), and blends of these with other bio-enhancing adjuvants (ingredients which may aid or modify the action of a compound of formula (I)). A compound of formula (I) may also be formulated for use as a seed treatment, for example as a powder composition, including a powder for dry seed treatment (DS), a water soluble powder (SS) or a water dispersible powder for slurry treatment (WS), or as a liquid composition, including a flowable concentrate (FS), a solution (LS) or a capsule suspension (CS). The preparations of DS, SS, WS, FS and LS compositions are very similar to those of, respectively, DP, SP, WP, SC and DC compositions described above. Compositions for treating seed may include an agent for assisting the adhesion of the composition to the seed (for example a mineral oil or a film-forming barrier).
Wetting agents, dispersing agents and emulsifying agents may be surface SFAs of the cationic, anionic, amphoteric or non-ionic type.
Suitable SFAs of the cationic type include quaternary ammonium compounds (for example cetyltrimethyl ammonium bromide), imidazolines and amine salts.
Suitable anionic SFAs include alkali metals salts of fatty acids, salts of aliphatic monoesters of sulfuric acid (for example sodium lauryl sulfate), salts of sulfonated aromatic compounds (for example sodium dodecylbenzenesulfonate, calcium dodecylbenzenesulfonate, butylnaphthalene sulfonate and mixtures of sodium di-isopropyl- and tri-isopropyl-naphthalene sulfonates), ether sulfates, alcohol ether sulfates (for example sodium laureth-3 -sulfate), ether carboxylates (for example sodium laureth-3- carboxylate), phosphate esters (products from the reaction between one or more fatty alcohols and phosphoric acid (predominately mono-esters) or phosphorus pentoxide (predominately di-esters), for example the reaction between lauryl alcohol and tetraphosphoric acid; additionally these products may be ethoxylated), sulfosuccinamates, paraffin or olefine sulfonates, taurates and lignosulfonates.
Suitable SFAs of the amphoteric type include betaines, propionates and glycinates.
Suitable SFAs of the non-ionic type include condensation products of alkylene oxides, such as ethylene oxide, propylene oxide, butylene oxide or mixtures thereof, with fatty alcohols (such as oleyl alcohol or cetyl alcohol) or with alkylphenols (such as octylphenol, nonylphenol or octylcresol); partial esters derived from long chain fatty acids or hexitol anhydrides; condensation products of said partial esters with ethylene oxide; block polymers (comprising ethylene oxide and propylene oxide);
alkanolamides; simple esters (for example fatty acid polyethylene glycol esters); amine oxides (for example lauryl dimethyl amine oxide); and lecithins.
Suitable suspending agents include hydrophilic colloids (such as polysaccharides,
polyvinylpyrrolidone or sodium carboxymethylcellulose) and swelling clays (such as bentonite or attapulgite).
A compound of formula (I) may be applied by any of the known means of applying pesticidal compounds. For example, it may be applied, formulated or unformulated, to the pests or to a locus of the pests (such as a habitat of the pests, or a growing plant liable to infestation by the pests) or to any part of the plant, including the foliage, stems, branches or roots, to the seed before it is planted or to other media in which plants are growing or are to be planted (such as soil surrounding the roots, the soil generally, paddy water or hydroponic culture systems), directly or it may be sprayed on, dusted on, applied by dipping, applied as a cream or paste formulation, applied as a vapor or applied through distribution or incorporation of a composition (such as a granular composition or a composition packed in a water- soluble bag) in soil or an aqueous environment.
A compound of formula (I) may also be injected into plants or sprayed onto vegetation using electrodynamic spraying techniques or other low volume methods, or applied by land or aerial irrigation systems.
Compositions for use as aqueous preparations (aqueous solutions or dispersions) are generally supplied in the form of a concentrate containing a high proportion of the active ingredient, the concentrate being added to water before use. These concentrates, which may include DCs, SCs, ECs, EWs, MEs, SGs, SPs, WPs, WGs and CSs, are often required to withstand storage for prolonged periods and, after such storage, to be capable of addition to water to form aqueous preparations which remain homogeneous for a sufficient time to enable them to be applied by conventional spray equipment. Such aqueous preparations may contain varying amounts of a compound of formula (I) (for example 0.0001 to 10%, by weight) depending upon the purpose for which they are to be used.
A compound of formula (I) may be used in mixtures with fertilizers (for example nitrogen-, potassium- or phosphorus-containing fertilizers). Suitable formulation types include granules of fertilizer. The mixtures preferably contain up to 25% by weight of the compound of formula (I).
The invention therefore also provides a fertilizer composition comprising a fertilizer and a compound of formula (I).
The compositions of this invention may contain other compounds having biological activity, for example micronutrients or compounds having fungicidal activity or which possess plant growth regulating, herbicidal, insecticidal, nematicidal or acaricidal activity.
The compound of formula (I) may be the sole active ingredient of the composition or it may be admixed with one or more additional active ingredients such as a pesticide, e.g. a insecticide, fungicide or herbicide, or a synergist or plant growth regulator where appropriate. An additional active ingredient may provide a composition having a broader spectrum of activity or increased persistence at a locus; synergize the activity or complement the activity (for example by increasing the speed of effect or overcoming repellency) of the compound of formula (I); or help to overcome or prevent the development of resistance to individual components. The particular additional active ingredient will depend upon the intended utility of the composition.
Examples of suitable pesticides include the following
a) Pyrethroids, such as permethrin, cypermethrin, fenvalerate, esfenvalerate, deltamethrin, cyhalothrin (in particular lambda-cyhalothrin and gamma cyhalothrin), bifenthrin, fenpropathrin, cyfluthrin, tefluthrin, fish safe pyrethroids (for example ethofenprox), natural pyrethrin, tetramethrin, S-bioallethrin, fenfluthrin, prallethrin, acrinathirin, etofenprox or
5-benzyl-3-furylmethyl-(E)-(lR,3S)-2,2-dimethyl- 3-(2-oxothiolan-3-ylidenemethyl)cyclopropane carboxylate;
b) Organophosphates, such as profenofos, sulprofos, acephate, methyl parathion, azinphos-methyl, demeton-s-methy 1, heptenophos, thiometon, fenamiphos, monocrotophos, profenofos, triazophos, methamidophos, dimethoate, phosphamidon, malathion, chlorpynfos, phosalone, terbufos, fensulfothion, fonofos, phorate, phoxim, pirimiphos-methyl, pirimiphos-ethyl, fenitrothion, fosthiazate or diazinon; c) Carbamates (including aryl carbamates), such as pirimicarb, triazamate, cloethocarb, carbofuran, furathiocarb, ethiofencarb, aldicarb, thiofurox, carbosulfan, bendiocarb, fenobucarb, propoxur, methomyl or oxamyl;
d) Benzoyl ureas, such as diflubenzuron, triflumuron, hexaflumuron, flufenoxuron, diafenthiuron, lufeneron, novaluron, noviflumuron or chlorfluazuron;
e) Organic tin compounds, such as cyhexatin, fenbutatin oxide or azocyclotin;
f) Pyrazoles, such as tebufenpyrad, tolfenpyrad, ethiprole, pyriprole, fipronil, and fenpyroximate;
g) Macrolides, such as avermectins or milbemycins, for example abamectin, emamectin benzoate, ivermectin, milbemycin, spinosad, azadirachtin, milbemectin, lepimectin or spinetoram;
h) Hormones or pheromones;
i) Organochlorine compounds, such as endosulfan (in particular alpha-endosulfan), benzene hexachloride, DDT, chlordane or dieldrin;
j) Amidines, such as chlordimeform or amitraz;
k) Fumigant agents, such as chloropicrin, dichloropropane, methyl bromide or metam;
1) Neonicotinoid compounds, such as imidacloprid, thiacloprid, acetamiprid, nitenpyram, dinotefuran, thiamethoxam, clothianidin, or nithiazine;
m) Diacylhydrazines, such as tebufenozide, chromafenozide or methoxyfenozide;
n) Diphenyl ethers, such as diofenolan or pyriproxifen;
o) Pyrazolines such as Indoxacarb or metaflumizone;
p) Ketoenols, such as Spirotetramat, spirodiclofen or spiromesifen;
q) Diamides, such as flubendiamide, chlorantraniliprole (Rynaxypyr®) or cyantraniliprole;
r) Essential oils such as Bugoil® - (Plantlmpact); or
s) a comopund selected from buprofezine, flonicamid, acequinocy 1, bifenazate, cyenopyrafen, cyflumetofen, etoxazole, flometoquin, fluacrypynm, fluensulfone, flufenerim, flupyradifuone, harpin, iodomethane, dodecadienol, pyridaben, pyridalyl, pyrimidifen, flupyradifurone,4-[(6-Chloro-pyridin-3- ylmethyl)-(2,2-difluoro-ethyl)-amino]-5H-furan-2-one (DE 102006015467), CAS: 915972-17-7
(WO 2006129714; WO2011/147953; WO2011/147952), CAS: 26914-55-8 (WO 2007020986), chlorfenapyr, pymetrozine, sulfoxaflor and pyrifluqinazon.
In addition to the major chemical classes of pesticide listed above, other pesticides having particular targets may be employed in the composition, if appropriate for the intended utility of the composition. For instance, selective insecticides for particular crops, for example stemborer specific insecticide (combinations such as cartap ) or hopper specific insecticides (combinations such as buprofezin ) for use in rice may be employed. Alternatively insecticides or acaricides specific for particular insect species/stages may also be included in the compositions (for example acaricidal ovo-larvicides, to give combinations such as clofentezine, flubenzimine, hexythiazox or tetradifon; acaricidal motilicides, to give combinations such as dicofol or propargite; acaricides, to give combinations such as bromopropylate or chlorobenzilate; or growth regulators, such as hydramethylnon, cyromazine, methoprene, chlorfluazuron or diflubenzuron ).
Examples of fungicidal compounds and combinations which may be included in the composition of the invention are (E)-N-methyl-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxy-iminoacetamide (SSF-129), 4-bromo-2-cyano-N,N-dimethyl-6-trifluoromethylbenzimidazole-l -sulfonamide,
a-[N-(3-chloro-2,6-xylyl)-2-methoxyacetamido]-y-butyrolactone, 4-chloro-2-cyano-N,N-dimethyl-5-p- tolylimidazole- 1 -sulfonamide (IKF-916, cyamidazosulfamid), 3 -5 -dichloro-N-(3 -chloro- 1 -ethyl- 1 -methyl-
2- oxopropyl)-4-methylbenzamide (RH-7281 , zoxamide),N-allyl-4,5,-dimethyl-2-trimethylsilylthiophene-
3- carboxamide (MON65500),N-(1 -cyano-1 ,2-dimethylpropyl)-2-(2,4-dichlorophenoxy)propionamide (AC382042),N-(2-methoxy-5-pyridyl)-cyclopropane carboxamide, acibenzolar (CGA245704) (e.g.
acibenzolar-S-methyl), alanycarb, aldimorph, anilazine, azaconazole, azoxystrobin, benalaxyl, benomyl, benthiavalicarb, biloxazol, bitertanol, bixafen, blasticidin S, boscalid, bromuconazole, bupirimate, captafol, captan, carbendazim, carbendazim , chlorhydrate, carboxin, carpropamid, carvone, CGA41396, CGA41397, chinomethionate, chlorothalonil, chlorozolinate, clozylacon, copper containing compounds to give combintations such as copper oxychloride, copper oxyquinolate, copper sulfate, copper tallate and Bordeaux mixture, cyclufenamid, cymoxanil, cyproconazole, cyprodinil, debacarb, di-2-pyridyl disulfide 1,1 '-dioxide, dichlofluanid, diclomezine, dicloran, diethofencarb, difenoconazole, difenzoquat, diflumetorim,C>,C>-di-iso-propyl-S-benzyl thiophosphate, dimefluazole, dimetconazole, dimethomorph, dimethirimol, diniconazole, dinocap, dithianon, dodecyl dimethyl ammonium chloride, dodemorph, dodine, doguadine, edifenphos, epoxiconazole, ethirimo 1, ethyl-(Z)-N-benzyl-N-([methyl(methyl- thioethylideneaminooxycarbonyl)amino]thio)-P-alaninate, etridiazole, famoxadone, fenamidone
(RPA407213), fenarimol, fenbuconazole, fenfuram, fenhexamid (KBR2738), fenpiclonil, fenpropidin, fenpropimorph, fentin acetate, fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil, flumetover, fluopyram, fluoxastrobin, fluoroimide, fluquinconazole, flusilazole, flutolanil, flutriafol, fluxapyroxad, folpet, fuberidazole, furalaxyl, furametpyr, guazatine, hexaconazole, hydroxyisoxazole, hymexazole, imazalil, imibenconazole, iminoctadine, iminoctadine triacetate, ipconazole, iprobenfos, iprodione, iprovalicarb (SZX0722), isopropanyl butyl carbamate, isoprothiolane, isopyrazam, kasugamycin, kresoxim-methyl, LY186054, LY211795, LY248908, mancozeb, mandipropamid, maneb, mefenoxam, metalaxyl, mepanipyrim, mepronil, metalaxyl, metconazole, metiram, metiram-zinc, metominostrobin, myclobutanil, neoasozin, nickel dimethyldithiocarbamate, nitrothal- sopropyl, nuarimol,
ofurace,organomercury compounds, oxadixyl, oxasulfuron, oxolinic acid, oxpoconazole, oxycarboxin, pefurazoate, penconazole, pencycuron, penflufen, penthiopyrad, phenazin oxide, phosetyl-Al, phosphorus acids, phthalide, picoxystrobin (ZA1963), polyoxinD, polyram, probenazole, prochloraz, procymidone, propamocarb, propiconazole, propineb, propionic acid, prothioconazole, pyrazophos, pyrifenox, pyrimethanil, pyraclostrobin, pyroquilon, pyroxyfur, pyrrolnitrin, quaternary ammonium compounds, quinomethionate, quinoxyfen, quintozene, sedaxane, sipconazole (F-155), sodium pentachlorophenate, spiroxamine, streptomycin, sulfur, tebuconazole, tecloftalam, tecnazene, tetraconazole, thiabendazole, thifluzamid, 2-(thiocyanomethylthio)benzothiazole, thiophanate -methyl, thiram, timibenconazole, tolclofos-methyl, tolylfluanid, triadimefon, triadimenol, triazbutil, triazoxide, tricyclazole, tridemorph, trifloxystrobin (CGA279202), triforine, triflumizole, triticonazole, validamycin A, vapam, vinclozolin, zineb and ziram, N-[9-(dichloromethylene)-l,2,3,4-tetrahydro-l,4-methanonaphthalen-5-yl]-3- (difluoromethyl)-l -methyl-lH-pyrazole-4-carboxamide [1072957-71 -1], l-methyl-3-difluoromethyl-lH- pyrazole-4-carboxylic acid (2-dichloromethylene-3-ethyl-l-methyl-indan-4-yl)-amide, and l-methyl-3- difluoromethyl-4H-pyrazole-4-carboxylic acid [2-(2,4-dichloro-phenyl)-2-methoxy-l-methyl-ethyl]- amide .
The active ingredients combinations described above comprising a compound selected of the invention, in particulary from Tables 1 to 179and an active ingredient as described above are preferably combined in a mixing ratio of from 100: 1 to 1 :6000, especially from 50: 1 to 1 :50, more especially in a ratio of from 20:1 to 1 :20, even more especially from 10: 1 to 1 : 10, very especially from 5: 1 and 1 :5, special preference being given to a ratio of from 2: 1 to 1 :2, and a ratio of from 4: 1 to 2: 1 being likewise preferred, above all in a ratio of 1 : 1, or 5:1, or 5:2, or 5:3, or 5:4, or 4: 1, or 4:2, or 4:3, or 3: 1, or 3:2, or 2:1, or 1 :5, or 2:5, or 3:5, or 4:5, or 1 :4, or 2:4, or 3:4, or 1 :3, or 2:3, or 1 :2, or 1 :600, or 1 :300, or 1 : 150, or 1 :35, or 2:35, or 4:35, or 1 :75, or 2:75, or 4:75, or 1 :6000, or 1 :3000, or 1 : 1500, or 1 :350, or 2:350, or 4:350, or 1 :750, or 2:750, or 4:750. Those mixing ratios are understood to include, on the one hand, ratios by weight and also, on other hand, molar ratios.
In addition, biological agents may be included in the composition of the invention e.g.Baciullus species such as Bacillus firmus, Bacillus cereus, Bacillus subtilis, and Pasteuria species such as Pasteuria penetrans and Pasteuria nishizawae. A suitable Bacillus firmus strain is strain CNCM 1-1582 which is commercially available as BioNem™. A suitable Bacillus cereus strain is strain CNCM 1-1562. Of both Bacillus strains more details can be found in US 6,406,690. Other biological organisms that may be included in the compositions of the invention are bacteria such as Streptomyces spp. such as S. avermitilis, and fungi such as Pochonia spp. such as P. chlamydosporia. Also of interest are Metarhizium spp. such as M. anisopliae; Pochonia spp. such as P. chlamydosporia.
The compounds of formula (I) may be mixed with soil, peat or other rooting media for the protection of plants against seed-borne, soil-borne or foliar fungal diseases.
Examples of suitable synergists for use in the compositions include piperonyl butoxide, sesamex, safroxan and dodecyl imidazole.
Suitable herbicides and plant-growth regulators for inclusion in the compositions will depend upon the intended target and the effect required.
An example of a rice selective herbicide which may be included is propanil. An example of a plant growth regulator for use in cotton is ΡΓΧ™.
Some mixtures may comprise active ingredients which have significantly different physical, chemical or biological properties such that they do not easily lend themselves to the same conventional formulation type. In these circumstances other formulation types may be prepared. For example, where one active ingredient is a water insoluble solid and the other a water insoluble liquid, it may nevertheless be possible to disperse each active ingredient in the same continuous aqueous phase by dispersing the solid active ingredient as a suspension (using a preparation analogous to that of an SC) but dispersing the liquid active ingredient as an emulsion (using a preparation analogous to that of an EW). The resultant composition is a suspoemulsion (SE) formulation.
The compounds of the invention are also useful in the field of animal health, e.g. they may be used against parasitic invertebrate pests, more preferably against parasitic invertebrate pests in or on an animal. Examples of pests include nematodes, trematodes, cestodes, flies, mites, tricks, lice, fleas, true bugs and maggots. The animal may be a non-human animal, e.g. an animal associated with agriculture, e.g. a cow, a pig, a sheep, a goat, a horse, or a donkey, or a companion animal, e.g. a dog or a cat.
In a further aspect the invention provides a compound of the invention for use in a method of therapeutic treatment.
In a further aspect the invention relates to a method of controlling parasitic invertebrate pests in or on an animal comprising administering a pesticidally effective amount of a compound of the invention. The administration may be for example oral administration, parenteral administration or external administration, e.g. to the surface of the animal body. In a further aspect the invention relates to a compound of the invention for controlling parasitic invertebrate pests in or on an animal. In a further aspect the invention relates to use of a compound of the invention in the manufacture of a medicament for controlling parasitic invertebrate pests in or on an animal
In a further aspect, the invention relates to a method of controlling parasitic invertebrate pests comprising administering a pesticidally effective amount of a compound of the invention to the environment in which an animal resides.
In a further aspect the invention relates to a method of protecting an animal from a parasitic invertebrate pest comprising administering to the animal a pesticidally effective amount of a compound of the invention. In a further aspect the invention relates to a compound of the invention for use in protecting an animal from a parasitic invertebrate pest. In a further aspect the invention relates to use of a compound of the invention in the manufacture of a medicament for protecting an animal from a parasitic invertebrate pest.
In a further aspect the invention provides a method of treating an animal suffering from a parasitic invertebrate pest comprising administering to the animal a pesticidally effective amount of a compound of the invention. In a further aspect the invention relates to a compound of the invention for use in treating an animal suffering from a parasitic invertebrate pest. In a further aspect the invention relates to use of a compound of the invention in the manufacture of a medicament for treating an animal suffering from a parasitic invertebrate pest.
In a further aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically suitable excipient.
The compounds of the invention may be used alone or in combination with one or more other biologically active ingredients. In one aspect the invention provides a combination product comprising a pesticidally effective amount of a component A and a pesticidally effective amount of component B wherein component A is a compound of the invention and component B is a compound as described below.
The compounds of the invention may 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 EP- 357460, EP -444964 and EP-594291.
Additional anthelmintic agents include semisynthetic and biosynthetic avermectin/milbemycin derivatives such as those described in US-5015630, WO-9415944 and WO-9522552. 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 US-5478855, US- 4639771 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 WO-9615121 and also with anthelmintic active cyclic depsipeptides such as those described in WO-9611945, WO-9319053, WO- 9325543, EP-626375, EP-382173, WO-9419334, EP-382173, and EP-503538.
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 International Patent Application Publication Numbers W095/19363 or WO04/72086, 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, cycloprotbrin, 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, Buprofezine 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.
Fungicides: acibenzolar, aldimorph, ampropylfos, andoprim, azaconazole, azoxystrobin, benalaxyl, benomyl, bialaphos, blasticidin-S, Bordeaux mixture, bromuconazole, bupirimate,
carpropamid, captafol, captan, carbendazim, chlorfenazole, chloroneb, chloropicrin, chlorothalonil, chlozolinate, copper oxychloride, copper salts, cyflufenamid, cymoxanil, cyproconazole, cyprodinil, cyprofuram, RH-7281, diclocymet, diclobutrazole, diclomezine, dicloran, difenoconazole, RP -407213, dimethomorph, domoxystrobin, diniconazole, diniconazole-M, dodine, edifenphos, epoxiconazole, famoxadone, fenamidone, fenarimol, fenbuconazole, fencaramid, fenpiclonil, fenpropidin, fenpropimorph, fentin acetate, fluazinam, fludioxonil, flumetover, flumorf/flumorlin, fentin hydroxide, fluoxastrobin, fluquinconazole, flusilazole, flutolanil, flutriafol, folpet, fosetyl- aluminium, furalaxyl, furametapyr, hexaconazole, ipconazole, iprobenfos, iprodione, isoprothiolane, kasugamycin, krsoxim-methyl, mancozeb, maneb, mefenoxam, mepronil, metalaxyl, metconazole, metominostrobin/fenominostrobin, metrafenone, myclobutanil, neo-asozin, nicobifen, orysastrobin, oxadixyl, penconazole, pencycuron, probenazole, prochloraz, propamocarb, propioconazole, proquinazid, prothioconazole, pyrifenox, pyraclostrobin, pyrimethanil, pyroquilon, quinoxyfen, spiroxamine, sulfur, tebuconazole, tetrconazole, thiabendazole, thifluzamide, thiophanate -methyl, thiram, tiadinil, triadimefon, triadimenol, tricyclazole, trifloxystrobin, triticonazole, validamycin, vinclozin.
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.
When used in combination with other active ingredients, the compounds of the invention are preferably used in combination with the following: imidacloprid, enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, fipronil, ivermectin, omeprazole, tiamulin, benazepril, milbemycin, cyromazine, thiamethoxam, pyriprole, deltamethrin, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, metaflumizone, moxidectin, methoprene (including S-methoprene), clorsulon, pyrantel, amitraz, triclabendazole, avermectin, abamectin, emamectin, eprinomectin, doramectin, selamectin, nemadectin, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, tetramisole, levamisole, pyrantel pamoate, oxantel, morantel, triclabendazole, epsiprantel, fipronil, lufenuron, ecdysone or tebufenozide; more preferably, enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, omeprazole, tiamulin, benazepril, pyriprole, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, moxidectin, clorsulon, pyrantel, eprinomectin, doramectin, selamectin, nemadectin, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, tetramisole, levamisole, pyrantel pamoate, oxantel, morantel, triclabendazole, epsiprantel, lufenuron or ecdysone; even more preferably enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, omeprazole, tiamulin, benazepril, pyriprole, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, moxidectin, clorsulon or pyrantel.
Examples of ratios of the compound of formula I to any mixing partner described herein include 100: 1 to 1 :6000, 50: 1 to 1 :50, 20: 1 to 1 :20, even more especially from 10:1 to 1 :10, 5: 1 to 1 :5, 2: 1 to 1 :2, 4:1 to 2:1, 1 : 1, or 5: 1, or 5:2, or 5:3, or 5:4, or 4: 1, or 4:2, or 4:3, or 3: 1, or 3:2, or 2: 1, or 1 :5, or 2:5, or 3:5, or 4:5, or 1 :4, or 2:4, or 3:4, or 1 :3, or 2:3, or 1 :2, or 1 :600, or 1 :300, or 1 : 150, or 1 :35, or 2:35, or 4:35, or 1 :75, or 2:75, or 4:75, or 1 :6000, or 1 :3000, or 1 : 1500, or 1 :350, or 2:350, or 4:350, or 1 :750, or 2:750, or 4:750. Those mixing ratios are understood to include, on the one hand, ratios by weight and also, on other hand, molar ratios.
Of particular note is a combination where the additional active ingredient has a different site of action from the compound of formula I. In certain instances, a combination with at least one other parasitic invertebrate pest control active ingredient having a similar spectrum of control but a different site of action will be particularly advantageous for resistance management. Thus, a combination product of the invention may comprise a pesticidally effective amount of a compound of formula I and pesticidally effective amount of at least one additional parasitic invertebrate pest control active ingredient having a similar spectrum of control but a different site of action.
One skilled in the art recognizes that because in the environment and under physiological conditions salts of chemical compounds are in equilibrium with their corresponding non salt forms, salts share the biological utility of the non salt forms.
Thus a wide variety of salts of compounds of the invention (and active ingredients used in combination with the active ingredients of the invention) may be useful for control of invertebrate pests and animal parasites. Salts include acid-addition salts with inorganic or organic acids such as
hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids.
The compounds of the invention also include N-oxides. Accordingly, the invention comprises combinations of compounds of the invention including N-oxides and salts thereof and an additional active ingredient including N-oxides and salts thereof.
The compositions for use in animal health may also contain formulation auxiliaries and additives, known to those skilled in the art as formulation aids (some of which may be considered to also function as solid diluents, liquid diluents or surfactants). Such formulation auxiliaries and additives may control: pH (buffers), foaming during processing (antifoams such polyorganosiloxanes), sedimentation of active ingredients (suspending agents), viscosity (thixotropic thickeners), in-container microbial growth
(antimicrobials), product freezing (antifreezes), color (dyes/pigment dispersions), wash-off (film formers or stickers), evaporation (evaporation retardants), and other formulation attributes. Film formers include, for example, polyvinyl acetates, polyvinyl acetate copolymers, polyvinylpyrrolidone -vinyl acetate copolymer, polyvinyl alcohols, polyvinyl alcohol copolymers and waxes. Examples of formulation auxiliaries and additives include those listed in McCutcheon 's Volume 2: Functional Materials, annual International and North American editions published by McCutcheon's Division, The Manufacturing Confectioner Publishing Co.; and PCT Publication WO 03/024222.
The compounds of the invention can be applied without other adjuvants, but most often application will be of a formulation comprising one or more active ingredients with suitable carriers, diluents, and surfactants and possibly in combination with a food depending on the contemplated end use. One method of application involves spraying a water dispersion or refined oil solution of the combination products. Compositions with spray oils, spray oil concentrations, spreader stickers, adjuvants, other solvents, and synergists such as piperonyl butoxide often enhance compound efficacy. Such sprays can be applied from spray containers such as a can, a bottle or other container, either by means of a pump or by releasing it from a pressurized container, e.g., a pressurized aerosol spray can. Such spray compositions can take various forms, for example, sprays, mists, foams, fumes or fog. Such spray compositions thus can further comprise propellants, foaming agents, etc. as the case may be. Of note is a spray composition comprising a pesticidally effective amount of a compound of the invention and a carrier. One embodiment of such a spray composition comprises a pesticidally effective amount of a compound of the invention and a propellant. Representative propellants include, but are not limited to, methane, ethane, propane, butane, isobutane, butene, pentane, isopentane, neopentane, pentene, hydrofluorocarbons, chlorofluorocarbons, dimethyl ether, and mixtures of the foregoing. Of note is a spray composition (and a method utilizing such a spray composition dispensed from a spray container) used to control at least one parasitic invertebrate pest selected from the group consisting of mosquitoes, black flies, stable flies, deer flies, horse flies, wasps, yellow jackets, hornets, ticks, spiders, ants, gnats, and the like, including individually or in combinations.
The controlling of animal parasites includes controlling external parasites that are parasitic to the surface of the body of the host animal (e.g., shoulders, armpits, abdomen, inner part of the thighs) and internal parasites that are parasitic to the inside of the body of the host animal (e.g., stomach, intestine, lung, veins, under the skin, lymphatic tissue). External parasitic or disease transmitting pests include, for example, chiggers, ticks, lice, mosquitoes, flies, mites and fleas. Internal parasites include heartworms, hookworms and helminths. The compounds of the invention may be particularly suitable for combating external parasitic pests. The compounds of the invention may be suitable for systemic and/or non- systemic control of infestation or infection by parasites on animals.
The compounds of the invention may be suitable for combating parasitic invertebrate pests that infest animal subjects including those in the wild, livestock and agricultural working animals. Livestock is the term used to refer (singularly or plurally) to a domesticated animal intentionally reared in an agricultural setting to make produce such as food or fiber, or for its labor; examples of livestock include cattle, sheep, goats, horses, pigs, donkeys, camels, buffalo, rabbits, hens, turkeys, ducks and geese (e.g., raised for meat, milk, butter, eggs, fur, leather, feathers and/or wool), cultured fish, honeybees. By combating parasites, fatalities and performance reduction (in terms of meat, milk, wool, skins, eggs, etc.) are reduced, so that applying the compounds of the invention allows more economic and simple husbandry of animals.
By controlling these pests it is intended to reduce deaths and improve performance (in the case of meat, milk, wool, hides, eggs, honey and the like) and health of the host animal. Also, controlling parasites may help to prevent the transmittance of infectious agents, the term "controlling" referring to the veterinary field, meaning that the active compounds are effective in reducing the incidence of the respective parasite in an animal infected with such parasites to innocuous levels, e.g. the active compound is effective in killing the respective parasite, inhibiting its growth, or inhibiting its proliferation.
The compounds of the invention may be suitable for combating parasitic invertebrate pests that infest companion animals and pets (e.g., dogs, cats, pet birds and aquarium fish), research and experimental animals (e.g., hamsters, guinea pigs, rats and mice), as well as animals raised for/in zoos, wild habitats and/or circuses.
In an embodiment of this invention, the animal is preferably a vertebrate, and more preferably a mammal, avian or fish. In a particular embodiment, the animal subject is a mammal (including great apes, such as humans). Other mammalian subjects include primates (e.g., monkeys), bovine (e.g., cattle or dairy cows), porcine (e.g., hogs or pigs), ovine (e.g., goats or sheep), equine (e.g., horses), canine (e.g., dogs), feline (e.g., house cats), camels, deer, donkeys, buffalos, antelopes, rabbits, and rodents (e.g., guinea pigs, squirrels, rats, mice, gerbils, and hamsters). Avians include Anatidae (swans, ducks and geese),
Columbidae (e.g., doves and pigeons), Phasianidae (e.g., partridges, grouse and turkeys), Thesienidae (e.g., domestic chickens), Psittacines (e.g., parakeets, macaws, and parrots), game birds, and ratites (e.g., ostriches).
Birds treated or protected by the compounds of the invention can be associated with either commercial or noncommercial aviculture. These include Anatidae, such as swans, geese, and ducks, Columbidae, such as doves and domestic pigeons, Phasianidae, such as partridge, grouse and turkeys, Thesienidae, such as domestic chickens, and Psittacines, such as parakeets, macaws and parrots raised for the pet or collector market, among others.
For purposes of the present invention, the term "fish" is understood to include without limitation, the Teleosti grouping of fish, i.e., teleosts. Both the Salmoniformes order (which includes the Salmonidae family) and the Perciformes order (which includes the Centrarchidae family) are contained within the Teleosti grouping. Examples of potential fish recipients include the Salmonidae, Serranidae, Sparidae, Cichlidae, and Centrarchidae, among others.
Other animals are also contemplated to benefit from the inventive methods, including marsupials (such as kangaroos), reptiles (such as farmed turtles), and other economically important domestic animals for which the inventive methods are safe and effective in treating or preventing parasite infection or infestation.
Examples of parasitic invertebrate pests controlled by administering a pesticidally effective amount of the compounds of the invention to an animal to be protected include ectoparasites (arthropods, acarines, etc.) and endoparasites (helminths, e.g., nematodes, trematodes, cestodes, acanthocephalans, etc. and protozoae, such as coccidia).
The disease or group of diseases described generally as helminthiasis is due to infection of an animal host with parasitic worms known as helminths. The term 'helminths' is meant to include nematodes, trematodes, cestodes and acanthocephalans. Helminthiasis is a prevalent and serious economic problem with domesticated animals such as swine, sheep, horses, cattle, goats, dogs, cats and poultry.
Among the helminths, the group of worms described as nematodes causes widespread and at times serious infection in various species of animals.
Nematodes that are contemplated to be treated by the compounds of the invention include, without limitation, the following genera: Acanthocheilonema, Aelurostrongylus , Ancylostoma, Angiostrongylus, Ascaridia, Ascaris, Brugia, Bunostomum, Capillaria, Chabertia, Cooperia, Crenosoma,
Dictyocaulus, Dioctophyme, Dipetalonema, Diphyllobothrium, Dirofilaria, Dracunculus, Enterobius, Filaroides, Haemonchus, Heterakis, Lagochilascaris, Loa, Mansonella, Muellerius, Necator,
Nematodirus, Oesophagostomum, Ostertagia, Oxyuris, Parafilaria, Parascaris, Physaloptera,
Protostrongylus, Setaria, Spirocerca, Stephanofilaria, Strongyloides , Strongylus, Thelazia, Toxascaris, Toxocara, Trichinella, Trichonema, Trichostrongylus, Trichuris, Uncinaria and Wuchereria.
Of the above, the most common genera of nematodes infecting the animals referred to above are Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostomum,
Oesophagostomum, Chabertia, Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria, Heterakis, Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris and Parascaris. Certain of these, such as Nematodirus, Cooperia and Oesophagostomum attack primarily the intestinal tract while others, such as Haemonchus and Ostertagia, are more prevalent in the stomach while others such as
Dictyocaulus are found in the lungs. Still other parasites may be located in other tissues such as the heart and blood vessels, subcutaneous and lymphatic tissue and the like.
Trematodes that are contemplated to be treated by the invention and by the inventive methods include, without limitation, the following genera: Alaria, Fasciola, Nanophyetus, Opisthorchis ,
Paragonimus and Schistosoma.
Cestodes that are contemplated to be treated by the invention and by the inventive methods include, without limitation, the following genera: Diphyllobothrium, Diplydium, Spirometra and Taenia.
The most common genera of parasites of the gastrointestinal tract of humans are
Ancylostoma, Necator, Ascaris, Strongy hides, Trichinella, Capillaria, Trichuris and Enterobius. Other medically important genera of parasites which are found in the blood or other tissues and organs outside the gastrointestinal tract are the filarial worms such as Wuchereria, Brugia, Onchocerca and Loa, as well as Dracunculus and extra intestinal stages of the intestinal worms Strongyloides and Trichinella.
Numerous other helminth genera and species are known to the art, and are also contemplated to be treated by the compounds of the invention. These are enumerated in great detail in Textbook of Veterinary Clinical Parasitology, Volume 1, Helminths, E. J. L. Soulsby, F. A. Davis Co., Philadelphia, Pa.; Helminths, Arthropods and Protozoa, (6thEdition of Monnig's Veterinary Helminthology and
Entomology), E. J. L. Soulsby, Williams and Wilkins Co., Baltimore, Md.
The compounds of the invention may be effective against a number of animal ectoparasites (e.g., arthropod ectoparasites of mammals and birds in particular insects such as flies (stinging and licking), parasitic fly larvae, lice, hair lice, bird lice, fleas and the like; or acarids, such as ticks, for examples hard ticks or soft ticks, or mites, such as scab mites, harvest mites, bird mites and the like).
Insect and acarine pests include, e.g., biting insects such as flies and mosquitoes, mites, ticks, lice, fleas, true bugs, parasitic maggots, and the like.
Adult flies include, e.g., the horn fly or Haematobia irritans, the horse fly or Tabanus spp., the stable fly or Stomoxys calcitrans, the black fly or Simulium spp., the deer fly or Chrysops spp., the louse fly or Melophagus ovinus, and the tsetse fly or Glossina spp. Parasitic fly maggots include, e.g., the bot fly (Oestrus ovis and Cuterebra spp.), the blow fly or Phoenicia spp., the screwworm or Cochliomyia hominivorax, the cattle grub or Hypoderma spp., the fleeceworm and the Gastrophilus of horses.
Mosquitoes include, for example, Culex spp., Anopheles spp. and Aedes spp.
Mites include Mesostigmalphatalpha spp. e.g., mesostigmatids such as the chicken mite,
Dermalphanyssus galphallinalphae; itch or scab mites such as Sarcoptidae spp. for example,
Salpharcoptes scalphabiei; mange mites such as Psoroptidae spp. including Chorioptes bovis and Psoroptes ovis; chiggers e.g., Trombiculidae spp. for example the North American chigger,
Trombiculalpha alphalfreddugesi.
Ticks include, e.g., soft-bodied ticks including Argasidae spp. for example Argalphas spp. and Ornithodoros spp.; hard-bodied ticks including Ixodidae spp., for example Rhipicephalphalus sanguineus, Dermacentor variabilis, Dermacentor andersoni, Amblyomma americanum, Ixodes scapularis and other Rhipicephalus spp. (including the former Boophilus genera).
Lice include, e.g., sucking lice, e.g., Menopon spp.
and Bovicola spp.; biting lice, e.g., Haematopinus spp., Linognathus spp. and Solenopotes spp.
Fleas include, e.g., Ctenocephalides spp., such as dog flea (Ctenocephalides canis) and cat flea (Ctenocephalides felis); Xenopsylla spp. such as oriental rat flea (Xenopsylla cheopis); and Pulex spp. such as human flea (Pulex irritans).
True bugs include, e.g., Cimicidae or e.g., the common bed bug (Cimex lectularius); Triatominae spp. including triatomid bugs also known as kissing bugs; for example Rhodnius prolixus and Triatoma spp.
Generally, flies, fleas, lice, mosquitoes, gnats, mites, ticks and helminths cause tremendous losses to the livestock and companion animal sectors. Arthropod parasites also are a nuisance to humans and can vector disease-causing organisms in humans and animals.
Numerous other parasitic invertebrate pests are known to the art, and are also contemplated to be treated by the compounds of the invention. These are enumerated in great detail in Medical and
Veterinary Entomology, D. S. Kettle, John Wiley AND Sons, New York and Toronto; Control of
Arthropod Pests of Livestock: A Review of Technology, R. O. Drummand, J. E. George, and S. E. Kunz, CRC Press, Boca Raton, Fla.
The compounds of the invention may also be effective against ectoparasites, e.g. insects such as flies (stinging and licking), parasitic fly larvae, lice, hair lice, bird lice, fleas and the like; or acarids, such as ticks, for examples hard ticks or soft ticks, or mites, such as scab mites, harvest mites, bird mites and the like. These include e.g. flies such as Haematobia (Lyperosia) irritans (horn fly), Simulium spp.
(blackfly), Glossina spp. (tsetse flies), Hydrotaea irritans (head fly), Musca autumnalis (face fly), Musca domestica (house fly), Morellia simplex (sweat fly), Tabanus spp. (horse fly), Hypoderma bovis,
Hypoderma lineatum, Lucilia sericata, Lucilia cuprina (green blowfly), Calliphora spp. (blowfly), Protophormia spp., Oestrus ovis (nasal botfly), Culicoides spp. (midges), Hippobosca equine,
Gastrophilus intestinalis, Gastrophilus haemorrhoidalis and Gastrophilus nasalis; lice such as Bovicola (Damalinia) bovis, Bovicola equi, Haematopinus asini, Felicola subrostratus, Heterodoxus spiniger, Lignonathus setosus and Trichodectes canis; keds such as Melophagus ovinus; and mites such as
Psoroptes spp., Sarcoptes scabei, Chorioptes bovis, Demodex equi, Cheyletiella spp., Notoedres cati, Trombicula spp. and Otodectes cyanotis (ear mites).
Examples of species of animal health pesets include those from the order of the Anoplurida, for example Haematopinus spp., Linognathus spp., Pediculus spp., Phtirus spp., Solenopotes spp.; particular examples are: Linognathus setosus, Linognathus vituli, Linognathus ovillus, Linognathus oviformis, Linognathus pedalis, Linognathus stenopsis, Haematopinus asini macrocephalus, Haematopinus eurysternus, Haematopinus suis, Pediculus humanus capitis, Pediculus humanus corporis, Phylloera vastatrix, Phthirus pubis, Solenopotes capillatus; from the order of the Mallophagida and the suborders Amblycerina and Ischnocerina, for example Trimenopon spp., Menopon spp., Trinoton spp., Bovicola spp., Werneckiella spp., Lepikentron spp., Damalina spp., Trichodectes spp., Felicola spp.; particular examples are: Bovicola bovis, Bovicola ovis, Bovicola limbata, Damalina bovis, Trichodectes canis, Felicola subrostratus, Bovicola caprae, Lepikentron ovis, Werneckiella equi; from the order of the
Diptera and the suborders Nematocerina and Brachycerina, for example Aedes spp., Anopheles spp., Culex spp., Simulium spp., Eusimulium spp., Phlebotomus spp., Lutzomyia spp., Culicoides spp., Chrysops spp., Odagmia spp., Wilhelmia spp., Hybomitra spp., Atylotus spp., Tabanus spp., Haematopota spp., Philipomyia spp., Br aula spp., Musca spp., Hydrotaea spp., Stomoxys spp., Haematobia spp., Morellia spp., Fannia spp., Glossina spp., Calliphora spp., Lucilia spp., Chrysomyia spp., Wohlfahrtia spp., Sarcophaga spp., Oestrus spp., Hypoderma spp., Gasterophilus spp., Hippobosca spp., Lipoptena spp., Melophagus spp., Rhinoestrus spp., Tipula spp.; particular examples are: Aedes aegypti, Aedes albopictus, Aedes taeniorhynchus, Anopheles gambiae, Anopheles maculipennis, Calliphora
erythrocephala, Chrysozona pluvialis, Culex quinquefasciatus, Culex pipiens, Culex tarsalis, Fannia canicularis, Sarcophaga carnaria, Stomoxys calcitrans, Tipula paludosa, Lucilia cuprina, Lucilia sericata, Simulium reptans, Phlebotomus papatasi, Phlebotomus longipalpis, Odagmia ornata, Wilhelmia equina, Boophthora erythrocephala, Tabanus bromius, Tabanus spodopterus, Tabanus atratus, Tabanus sudeticus, Hybomitra ciurea, Chrysops caecutiens, Chrysops relictus, Haematopota pluvialis,
Haematopota italica, Musca autumnalis, Musca domestica, Haematobia irritans irritans, Haematobia irritans exigua, Haematobia stimulans, Hydrotaea irritans, Hydrotaea albipuncta, Chrysomya chloropyga, Chrysomya bezziana, Oestrus ovis, Hypoderma bovis, Hypoderma lineatum, Przhevalskiana silenus, Dermatobia hominis, Melophagus ovinus, Lipoptena capreoli, Lipoptena cervi, Hippobosca variegata, Hippobosca equina, Gasterophilus intestinalis, Gasterophilus haemorroidalis, Gasterophilus inermis, Gasterophilus nasalis, Gasterophilus nigricornis, Gasterophilus pecorum, Braula coeca; from the order of the Siphonapterida, for example Pulex spp., Ctenocephalides spp., Tunga spp., Xenopsylla spp., Ceratophyllus spp.; particular examples are: Ctenocephalides canis, Ctenocephalides felis, Pulex irritans, Tunga penetrans, Xenopsylla cheopis; from the order of the Heteropterida, for example Cimex spp., Triatoma spp., Rhodnius spp., Panstrongylus spp; from the order of the Blattarida, for example Blatta orientalis, Periplaneta americana, Blattela germanica, Supella spp. (e.g. Suppella longipalpd); from the subclass of the Acari (Acarina) and the orders of the Meta- and Mesostigmata, for example Argas spp., Ornithodorus spp., Otobius spp., Ixodes spp., Amblyomma spp., Rhipicephalus (Boophilus) spp Dermacentor spp., Haemophysalis spp., Hyalomma spp., Dermanyssus spp., Rhipicephalus spp. (the original genus ofmulti host ticks) Ornithonyssus spp., Pneumonyssus spp., Raillietia spp., Pneumonyssus spp., Sternostoma spp., Varroa spp., Acarapis spp.; particular examples are: Argas persicus, Argas reflexus, Ornithodorus moubata, Otobius megnini, Rhipicephalus (Boophilus) microplus, Rhipicephalus (Boophilus) decoloratus, Rhipicephalus (Boophilus) annulatus, Rhipicephalus (Boophilus) calceratus, Hyalomma anatolicum, Hyalomma aegypticum, Hyalomma marginatum, Hyalomma transiens,
Rhipicephalus evertsi, Ixodes ricinus, Ixodes hexagonus, Ixodes canisuga, Ixodes pilosus, Ixodes rubicundus, Ixodes scapularis, Ixodes holocyclus, Haemaphysalis concinna, Haemaphysalis punctata, Haemaphysalis cinnabarina, Haemaphysalis otophila, Haemaphysalis leachi, Haemaphysalis longicorni, Dermacentor marginatus, Dermacentor reticulatus, Dermacentor pictus, Dermacentor albipictus, Dermacentor andersoni, Dermacentor variabilis, Hyalomma mauritanicum, Rhipicephalus sanguineus, Rhipicephalus bursa, Rhipicephalus appendiculatus, Rhipicephalus capensis, Rhipicephalus turanicus, Rhipicephalus zambeziensis, Amblyomma americanum, Amblyomma variegatum, Amblyomma maculatum, Amblyomma hebraeum, Amblyomma cajennense, Dermanyssus gallinae, Ornithonyssus bursa,
Ornithonyssus sylviarum, Varroa jacobsoni; from the order of the Actinedida (Prostigmata) and
Acaridida (Astigmata), for example Acarapis spp., Cheyletiella spp., Ornithocheyletia spp., Myobia spp., Psorergates spp., Demodex spp., Trombicula spp., Listrophorus spp., Acarus spp., Tyrophagus spp., Caloglyphus spp., Hypodectes spp., Pterolichus spp., Psoroptes spp., Chorioptes spp., Otodectes spp., Sarcoptes spp., Notoedres spp., Knemidocoptes spp., Cytodites spp., Laminosioptes spp.; particular examples are: Cheyletiella y as guri, Cheyletiella blakei, Demodex canis, Demodex bovis, Demodex ovis, Demodex caprae, Demodex equi, Demodex caballi, Demodex suis, Neotrombicula autumnalis,
Neotrombicula desaleri, Neoschongastia xerothermobia, Trombicula akamushi, Otodectes cynotis, Notoedres cati, Sarcoptis canis, Sarcoptes bovis, Sarcoptes ovis, Sarcoptes rupicaprae (S. caprae), Sarcoptes equi, Sarcoptes suis, Psoroptes ovis, Psoroptes cuniculi, Psoroptes equi, Chorioptes bovis, Psoergates ovis, Pneumonyssoidic mange, Pneumonyssoides caninum, Acarapis woodi; Gasterophilus spp., Stomoxys spp., Trichodectes spp., Rhodnius spp., Ctenocephalides canis, Cimx lecturius,
Ctenocephalides felis, Lucilia cuprina; examples of acari include Ornithodoros spp., Ixodes spp.,
Boophilus spp..
Treatments of the invention are by conventional means such as by enteral administration in the form of, for example, tablets, capsules, drinks, drenching preparations, granulates, pastes, boli, feed- through procedures, or suppositories; or by parenteral administration, such as, for example, by injection (including intramuscular, subcutaneous, intravenous, intraperitoneal) or implants; or by nasal
administration; or by dermal application in the form of, for example, bathing or dipping, spraying, pouring-on and spotting-on, washing, dusting, and with the aid of active-compound-comprising shaped articles such as collars, ear tags, tail tags, limb bands, halters, marking devices and the like.
When compounds of the invention are applied in combination with an additional biologically active ingredient, they may be administered separately e.g. as separate compositions. In this case, the biologically active ingredients may be administered simultaneously or sequentially. Alternatively, the biologically active ingredients may be components of one composition.
The compounds of the invention may be administered in a controlled release form, for example in subcutaneous or orally adminstered slow release formulations.
Typically a parasiticidal composition according to the present invention comprises a compound of the invention, optionally in combination with an additional biologically active ingredient, or N-oxides or salts thereof, with one or more pharmaceutically or veterinarily acceptable carriers comprising excipients and auxiliaries selected with regard to the intended route of administration (e.g., oral or parenteral administration such as injection) and in accordance with standard practice. In addition, a suitable carrier is selected on the basis of compatibility with the one or more active ingredients in the composition, including such considerations as stability relative to pH and moisture content. Therefore of note are compounds of the invention for protecting an animal from an invertebrate parasitic pest comprising a parasitically effective amount of a compound of the invention, optionally in combination with an additional biologically active ingredient and at least one carrier.
For parenteral administration including intravenous, intramuscular and subcutaneous injection, the compounds of the invention can be formulated in suspension, solution or emulsion in oily or aqueous vehicles, and may contain adjuncts such as suspending, stabilizing and/or dispersing agents.
The compounds of the invention may also be formulated for bolus injection or continuous infusion. Pharmaceutical compositions for injection include aqueous solutions of water-soluble forms of active ingredients (e.g., a salt of an active compound), preferably in physiologically compatible buffers containing other excipients or auxiliaries as are known in the art of pharmaceutical formulation.
Additionally, suspensions of the active compounds may be prepared in a lipophilic vehicle. Suitable lipophilic vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides, or materials such as liposomes.
Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
In addition to the formulations described supra, the compounds of the invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular or subcutaneous injection.
The compounds of the invention may be formulated for this route of administration with suitable polymeric or hydrophobic materials (for instance, in an emulsion with a pharmacologically acceptable oil), with ion exchange resins, or as a sparingly soluble derivative such as, without limitation, a sparingly soluble salt.
For administration by inhalation, the compounds of the invention can be delivered in the form of an aerosol spray using a pressurized pack or a nebulizer and a suitable propellant, e.g., without limitation, dichlorodifluoromethane, tnchlorofluoromethane, dichlorotetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be controlled by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
The compounds of the invention may have favourable pharmacokinetic and pharmacodynamic properties providing systemic availability from oral administration and ingestion. Therefore after ingestion by the animal to be protected, parasiticidally effective concentrations of a compound of the invention in the bloodstream may protect the treated animal from blood-sucking pests such as fleas, ticks and lice. Therefore of note is a composition for protecting an animal from an invertebrate parasite pest in a form for oral administration (i.e. comprising, in addition to a parasiticidally effective amount of a compound of the invention, one or more carriers selected from binders and fillers suitable for oral administration and feed concentrate carriers).
For oral administration in the form of solutions (the most readily available form for absorption), emulsions, suspensions, pastes, gels, capsules, tablets, boluses, powders, granules, rumen-retention and feed/water/lick blocks, the compounds of the invention can be formulated with binders/fillers known in the art to be suitable for oral administration compositions, such as sugars and sugar derivatives (e.g., lactose, sucrose, mannitol, sorbitol), starch (e.g., maize starch, wheat starch, rice starch, potato starch), cellulose and derivatives (e.g., methylcellulose, carboxymethylcellulose, ethylhydroxycellulose), protein derivatives (e.g., zein, gelatin), and synthetic polymers (e.g., polyvinyl alcohol, polyvinylpyrrolidone). If desired, lubricants (e.g., magnesium stearate), disintegrating agents (e.g., cross-linked
polyvinylpyrrolidinone, agar, alginic acid) and dyes or pigments can be added. Pastes and gels often also contain adhesives (e.g., acacia, alginic acid, bentonite, cellulose, xanthan gum, colloidal magnesium aluminum silicate) to aid in keeping the composition in contact with the oral cavity and not being easily ejected.
In one embodiment a composition of the present invention is formulated into a chewable and/or edible product (e.g., a chewable treat or edible tablet). Such a product would ideally have a taste, texture and/or aroma favored by the animal to be protected so as to facilitate oral administration of the compounds of the invention.
If the parasiticidal compositions are in the form of feed concentrates, the carrier is typically selected from high-performance feed, feed cereals or protein concentrates.
Such feed concentrate-containing compositions can, in addition to the parasiticidal active ingredients, comprise additives promoting animal health or growth, improving quality of meat from animals for slaughter or otherwise useful to animal husbandry.
These additives can include, for example, vitamins, antibiotics, chemotherapeutics, bacteriostats, fungistats, coccidiostats and hormones. The compound of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.
The formulations for the method of this invention may include an antioxidant, such asBHT (butylated hydroxytoluene). The antioxidant is generally present in amounts of at 0.1 - 5 percent (wt/vol). Some of the formulations require a solubilizer, such as oleic acid, to dissolve the active agent, particularly if spinosad is included. Common spreading agents used in these pour-on formulations include isopropyl myristate, isopropyl palmitate, caprylic/capric acid esters of saturated
Figure imgf000084_0001
fatty alcohols, oleic acid, oleyl ester, ethyl oleate, triglycerides, silicone oils and dipropylene glycol methyl ether. The pour-on formulations for the method of this invention are prepared according to known techniques. Where the pour-on is a solution, the parasiticide/insecticide is mixed with the carrier or vehicle, using heat and stirring if required. Auxiliary or additional ingredients can be added to the mixture of active agent and carrier, or they can be mixed with the active agent prior to the addition of the carrier. Pour-on
formulations in the form of emulsions or suspensions are similarly prepared using known techniques.
Other delivery systems for relatively hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well-known examples of delivery vehicles or carriers for hydrophobic drugs. In addition, organic solvents such as dimethylsulfoxide may be used, if needed.
The rate of application required for effective parasitic invertebrate pest control (e.g. "pesticidally effective amount") will depend on such factors as the species of parasitic invertebrate pest to be controlled, the pest's life cycle, life stage, its size, location, time of year, host crop or animal, feeding behavior, mating behavior, ambient moisture, temperature, and the like. One skilled in the art can easily determine the pesticidally effective amount necessary for the desired level of parasitic invertebrate pest control.
In general for veterinary use, the compounds of the invention are administered in a pesticidally effective amount to an animal, particularly a homeothermic animal, to be protected from parasitic invertebrate pests.
A pesticidally effective amount is the amount of active ingredient needed to achieve an observable effect diminishing the occurrence or activity of the target parasitic invertebrate pest. One skilled in the art will appreciate that the pesticidally effective dose can vary for the various compounds and compositions useful for the method of the present invention, the desired pesticidal effect and duration, the target parasitic invertebrate pest species, the animal to be protected, the mode of application and the like, and the amount needed to achieve a particular result can be determined through simple
experimentation.
For oral or parenteral administration to animals, a dose of the compositions of the present invention administered at suitable intervals typically ranges from about 0.01 mg/kg to aboutl OO mg/kg, and preferably from about 0.01 mg/kg to about 30 mg/kg of animal body weight.
Suitable intervals for the administration of the compositions of the present invention to animals range from about daily to about yearly. Of note are administration intervals ranging from about weekly to about once every 6 months. Of particular note are monthly adminstration intervals (i.e. administering the compounds to the animal once every month).
The following Examples illustrate, but do not limit, the invention.
The following abbreviations were used in this section: DMF: dimethylformamide; THF:
tetrahydrofuran; EtOAc : ethyl acetate; s = singlet; bs = broad singlet; d = doublet; dd = double doublet; dt = double triplet; t = triplet, tt = triple triplet, q = quartet, sept = septet; m = multiplet; Me = methyl; Et = ethyl; Pr = propyl; Bu = butyl; M.p. = melting point; RT = retention time, [M+H]+ = molecular mass of the molecular cation, [M-H]" = molecular mass of the molecular anion.
The following LC-MS methods were used to characterize the compounds:
Method A
MS ACQUITY SQD Mass Spectrometer from Waters (Single quadrupole mass
spectrometer)
Ionisation method: Electrospray
Polarity: positive ions
Capillary (kV) 3.00, Cone (V) 20.00, Extractor (V) 3.00, Source Temperature (°C)
150, Desolvation Temperature (°C) 400, Cone Gas Flow (L/Hr) 60, Desolvation
Gas Flow (L/Hr) 700
Mass range: 100 to 800 Da
DAD Wavelength range (nm): 210 to 400
LC Method Waters ACQUITY UPLC with the following HPLC gradient conditions
(Solvent A: Water/Methanol 9: 1,0.1% formic acid and Solvent B: Acetonitrile,0.1%
formic acid )
Time (min) A% B% Flow ( ml/min)
0 100 0 0.75
2.5 0 100 0.75
2.8 0 100 0.75
3.0 100 0 0.75
Method B
MS I Shimadzu LCMS-2010EV Mass Spectrometer (Single quadrupole mass
spectrometer)
Ionisation method: Electrospray
Polarity: positive and negative ions
Capillary (kV) 1.50, Extractor (V) 5.00, Source Temperature (°C) 200, Desolvation
Temperature (°C) 250, Cone Gas Flow (L/Hr) 90, Desolvation Gas Flow (L/Hr) 90
Mass range: 50 to 1000 Da
LC-20AD Method Waters ACQUITY UPLC with the following HPLC gradient
conditions
Detector: 254 nm
Diamonsil CI 8(2) 4.6*150 mm 5 μιη
(Solvent A: Water , 0.1% trifluoroacetic acid and Solvent B: Acetonitrile, 0.1%
trifluoroacetic acid)
Time (min) A% B% Flow ( ml/min)
0 90 10 1.00
15.00 0 100 1.00 25.00 0 100 1.00
27.00 90 10 1.00
36.00 90 10 1.00
Example PI : Synthesis of (E)-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihvdrobenzofuran-5^ ylVN-(pyridin-2-ylmethyl¼cr lamide (A5)
Figure imgf000086_0001
Step A: Synthesis of methyl 2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5- carboxylate
Figure imgf000086_0002
At room temperature, tetrabutylammonium fluoride (150ml, 1.0M in THF) was added to a mixture of compound methyl 3-methyl-4-nitrobenzoate (19.5g), compound l -(3,5-dichlorophenyl)-2,2,2- trifluoroethanone (36g) and N, N-diisopropylethylamine (25.8g) in 100ml of THF. After the addition, the reaction mixture was refluxed for 24h. Then, the mixture was poured into waterand extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel to give the title compound (18g).¾ NMR (300Mz, DMSO-d6): δ 3.81 (s, 3H), 3.92 (dd, 2H), 7.21 (d, 1H), 7.69 (s, 2H), 7.791-7.796 (m, 1H), 7.88-7.90 (m, 2H).
Step B: Synthesis of (2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)methanol
Figure imgf000086_0003
Compound methyl 2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5- carboxylate (6g) dissolved in 55ml of anhydrous THF was slowly added to lithium aluminium hydride(880mg, 23.1mmol) suspended in 15 ml of anhydrous THF at 0°C . After stirring at room temperature for 5h, the mixture was poured into the ice water and adjusted to PH = 2. The organic phase was extracted with ethyl ether three times. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel to give the title compound (4.8g). 'H NMR (300MZ, CDC13): δ 3.55 (d, 1H), 3.97 (d,lH), 4.61 (s, 2H),
6.97 (d, 1H), 7.20 (d, 2H), 7.39 (t, 1H), 7.51 (s, 2H)
Step C: Synthesis of 2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-carbaldehyde
Figure imgf000087_0001
Pyridinium chlorochromate (6.45g) was added to a solution of compound (2-(3,5-dichlorophenyl)- 2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)methanol (3.62g) in 30ml of CH2C12. After stirring for 2h at room temperature, silica gel (50g) was added to the reaction mixture and filtered. The filtrate was concentrated and purified by column chromatography on silica gel to give the title compound (2.5g). 'H NMR (300Mz, DMSO-d6): δ 3.98 (d, 1H), 4.1 l(d, 1H), 7.32 (d, 1H), 7.70 (s, 2H), 7.77 (s, 1H), 7.85 (d, 2H), 9.87 (s, 1H)
Step D: Synthesis of (E)-ethyl 3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5- yl)acrylate
Figure imgf000087_0002
Triethyl phosphonoacetate (246mg) was slowly added to a mixture of NaH (44mg) in 10ml of anhydrous THF at 0°C under nitrogen. After stirring for 30min, compound 2-(3,5-dichlorophenyl)-2- (trifluoromethyl)-2,3-dihydrobenzofuran-5-carbaldehyde (360mg) was added to the mixture. Then, the reaction mixture was stirred at room temperature for another 2h, poured into diluted hydrochloric acid and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatography on silica gel to give the title compound (280mg). ¾ NMR (300Mz, DMSO-dg): δ 1.22 (t, 3H), 3.83 (d, 1H), 4.00 (d, 1H), 4.11 (q, 2H), 6.49 (d, 1H), 7.14 (d, 1H), 7.57 (d, 1H), 7.62 (s, 1H), 7.68 (s, 3H), 7.76 (s, 1H).
Step E: Synthesis of (E)-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5- yl)acrylic acid
Figure imgf000088_0001
A mixture of compound (£)-ethyl 3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran- 5-yl)acrylate (1.2g) and LiOH (1.18g) in 50ml of THF and 50ml of H20 was stirred at room temperature for 16h. Then, the reaction mixture was poured into diluted hydrochloric acidand extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and
concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give the title compound (0.85g). ¾ NMR (300Mz, DMSO- 6): δ 3.83(d, IH), 4.01 (d, IH), 6.38 (d, IH), 7.14 (d, IH), 7.52 (d, 2H), 7.56 (d, IH), 7.64(s, IH), 7.68 (s, IH), 7.76 (s, IH), 12.25 (br s, IH); ESI-MS: 401(M-H)\
Step F: Synthesis of (E)-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)-N- (pyridin-2-ylmethyl)acrylamide (A5)
Figure imgf000088_0002
A mixture of compound (i^-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5- yl)acrylic acid (200mg), HOBT (68mg), EDC.HC1 (286mg) and Et3N (253mg) in 25ml of THF was stirred at room temperature for 30min. 2-picolylamine(162mg) was added to the mixture. After the mixture was stirred for another 16h, it was concentrated under vacuum to dryness and the residue was purified by column chromatography on silica gel to give the title compound(120mg). ¾ NMR (300Mz, DMSO- 6): δ 3.85 (d, IH), 4.03 (d, IH), 4.46 (d, 2H), 6.62 (d,lH), 7.14 (d,lH), 7.22-7.29 (m, 2H), 7.38- 7.50(m, 3H), 7.67 (s, 2H), 7.71-7.75 (m, IH), 7.76 (m, IH), 8.49 (d, IH), 8.61 (t, IH); ESI-MS:
493(M+H)+, 515(M + Na)+; M.p.: 95 °C ; HPLC: 98.4%.
Example P2: Synthesis of (EN)-N-cyclobutyl-3-(2-(trifluoromethylN)-2-(3-(trifluoromethylN)phenylN)-2,3- dihydrobenzofuran-5 -yDbut-2-enamide (A9)
Figure imgf000088_0003
Step A: Synthesis of 3-Methyl-4-nitrobenzoyl chloride
Figure imgf000089_0001
A mixture of 3-methyl-4-nitrobenzoic acid (100g, 0.55mol) in SOCl2 (500ml) was refluxed for 5h. Then, the excess SOCl2 was removed under reduced pressure to give the crude 3-methyl-4-nitrobenzoyl chloride in almost quantitative yield (119g). The crude 3-methyl-4-nitrobenzoyl chloride was directly used for the next step without further purification.
Step B: Synthesis of 3-Methyl-4-nitrobenzamide
Figure imgf000089_0002
3-Methyl-4-nitrobenzoyl chloride (119g, 0.6mol) was added to NH3.H20 (600ml) at 0°C . Then the mixture was stirred at room temperature for lh. After the addition, the mixture was stirred at the same temperature for lh, then it was poured into ice-water and a yellowish solid generated. After the filtration, the solid was dried in vacuo to give the title compound (85g, 85% yield) as a pale yellow solid.
Step C: Synthesis of 3-Methyl-4-nitrobenzonitrile
Figure imgf000089_0003
To a stirred solution of 3-methyl-4-nitrobenzamide (5g, 28mmol) in 300 ml of toluene was added POCI3 (22g, 140mmol). After the addition, the mixture was refluxed for 24h. Then, the reaction mixture was poured into ice-water and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by recrystallization with ethanol to give the title compound (3.2g, 70% yield).
Step D: Synthesis of 2-(trifluoromethyl)-2-(3-(trifluoromethyl)phenyl)-2,3-dihydrobenzofuran-5- carbonitrile
Figure imgf000089_0004
To a mixture of 3-methyl-4-nitrobenzonitrile (20g, 12.3mmol), 3-trifluoromethyl-2,2,2- trifluoroacetophenone (33g, 13.6mmol) and i-Pr2NEt (32g, 24.6mmol) in 40ml of THF was added TBAF (160g, 61.5mmol) at room temperature. After the addition, the mixture was refluxed for 24h. Then, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel to give the title compound (36 g, 80%yield). ¾ NMR (300Mz, DMSO- 6): δ 3.90 (d, 1H), 4.13 (d, 1H), 7.32 (d, 1H), 7.75-7.79 (m, 3H), 7.88-7.90 (m, 1H), 7.93-8.00 (m, 2H).
Step E: Synthesis of l-(2-(trifluoromethyl)-2-(3-(trifluoromethyl)phenyl)-2,3-dihydrobenzofuran-5- yl)ethanone
Figure imgf000090_0001
To a stirred solution of MeMgBr (300ml, 300mmol) in 200ml of THF was added 2-(trifluoromethyl)-2- (3-(trifluoromethyl)phenyl)-2,3-dihydrobenzofuran-5-carbonitrile (36g, lOOmmol) in 300ml of THF. After the addition, the mixture was stirred at room temperature for 24h. Then, the reaction mixture was poured into ice-water and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel to give the title compound (20g, 53% yield). ¾ NMR (300Mz, DMSO-<i6): δ 2.50 (s, 3H), 3.86 (d, 1H), 4.10 (d, 1H), 7.20 (d, 1H), 7.73-7.78 (m, 1H), 7.84-7.92 (m, 4H), 7.95 (d, 1H).
Step F: Synthesis of (E)-ethyl 3-(2-(trifluoromethyl)-2-(3-(trifluoromethyl)phenyl)-2,3- dihydrobenzofuran-5-yl)but-2-enoate
Figure imgf000090_0002
Triethyl phosphonoacetate (10g, 44.1mmol) was slowly added to a mixture of NaH (2.2g, 88mmol) in dry THF (200ml) at 0°C under nitrogen. After stirring for 30min, a solution of l -(2-(trifluoromethyl)-2-(3- (trifluoromethyl)phenyl)-2,3-dihydrobenzofuran-5-yl) ethanone (10g, 29mmol) in dry THF (100ml) was added to the mixture. The mixture was refluxed for 4h. Then, it was poured into diluted hydrochloric acid and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatography on silica gel to give the title compound (4.5g, 35% yield). ¾ NMR (300Mz, DMSO- 6): δ 1.19 (t, 3H), 2.47
(s, 3H), 3.82 (d, 1H), 4.06 (d, 1H), 4.10 (q, 2H), 6.09 (s, 1H), 7.13 (d, 1H), 7.45-7.49 (m, 1H), 7.54 (s, 1H), 7.74-7.79 (m, 1H),7.86 (d, 1H), 7.94 (s, 1H), 7.97 (d, 1H).
Step G: Synthesis of (E)-3-(2-(trifluoromethyl)-2-(3-(trifluoromethyl)phenyl)-2,3-dihydro-benzofuran-5- yl)but-2-enoic acid
Figure imgf000091_0001
A mixture of (is)-ethyl 3-(2-(trifluoromethyl)-2-(3-(trifluoromethyl)phenyl)-2,3-dihydroben- zofuran-5- yl)but-2-enoate (4.5g, 11.2mmol) and LiOH (1.5g, 56mmol) in THF (25ml) / H20 (5ml) / CH3OH (25ml) was refluxed for 2h. Then, the reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to provide the title compound (3.3g, 71% yield). ¾ NMR (300Mz, DMSO- 6): δ 2.46 (s, 3H), 3.83 (d, 1H), 4.07 (d, 1H), 6.04 (s, 1H), 7.13 (d, 1H), 7.44 (d, 1H), 7.51 (s, 1H), 7.74-7.80 (m, 1H), 7.86 (d, 1H), 7.94 (s, 1H), 7.98 (d, 1H), 12.14 (br s, 1H).
Step H: Synthesis of (i?)-N-cyclobutyl-3-(2-(trifluoromethyl)-2-(3-(trifluoromethyl)phenyl)-2,3- dihydrobenzofuran-5 -yl)but-2-enamide A9)
Figure imgf000091_0002
A mixture of compound (£)-3-(2-(trifluoromethyl)-2-(3-(trifluoromethyl)phenyl)-2,3-dihydro - benzofuran-5-yl)but-2-enoic acid (500mg, 1.3mmol), HOBT (540mg, 4mmol), EDC.HCl (764mg, 4mmol) and Et3N (1.3g, 13mmol) in 20ml of THF was stirred at room temperature for 30min. Cyclobutylamine (400mg, 4mmol) was then added to the mixture. After the mixture was stirred for 16h, it was concentrated under vacuum to dryness and the residue was purified by column chromatography on silica gel to give the title compound (500mg, 77% yield). ¾ NMR (300Mz, DMSO- 6): δ 1.59-1.67 (m, 2H), 1.84-1.90 (m, 2H), 2.16-2.18 (m, 2H), 2.43 (s, 3H), 3.84 (d, 1H), 4.07 (d, 1H), 4.21 -4.29 (m, 1H), 6.10 (s, 1H), 7.13 (d, 1H), 7.36 (d, 1H), 7.43 (s, 1H), 7.75-7.80 (m, 1H), 7.87-7.90 (m, 1H), 7.94 (s, 1H), 7.98-7.01 (m, 1H), 8.20-8.22 (d, 1H); ESI-MS: 470 (M+H)+, 492 (M+Na)+. Example P3: Synthesis of (E)-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihvdrobenzofuran-5- yl -N-(2,2,2-trifluoroethyl acrylamide (Al 0)
Figure imgf000092_0001
A mixture of 3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran -5-yl)acrylic acid (lOOmg, 0.25mmol), HOBT (54mg, 0.4mmol), EDC.HCl (58mg, 0.3mmol) and Et3N (162mg, 1.6mmol) in 10ml of THF was stirred at room temperature for 30min.Trifluoroethylamine (40mg, 0.4mmol) was added to the mixture. After the mixture was stirred for 16h, the mixture was concentrated under vacuum to dryness and the residue was purified by column chromatography on silica gel to give the title compound(103 mg). 'H NMR (300MZ, DMSO- 6): δ 3.87 (d, 1H), 3.94-4.05 (m, 3H), 6.57 (d, 1H), 7.16 (d, 1H), 7.44-7.51 (m, 3H), 7.67 (d, 2H), 7.76 (m, 1H), 8.66 (m, 1H); ESI-MS (-): 482 (M-H)\
Example P4: Synthesis of (£'N)-N-cyclobutyl-3-(2-(3,5-dichlorophenylN)-2-(trifluoromethylN)-2,3- dihydrobenzofuran-5 -ylN)pent-2-enamide (A65)
Figure imgf000092_0002
Step A: Synthesis of l-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)propan- l-ol
Figure imgf000092_0003
To a stirred solution of EtMgBr (42ml, lmol/L) in 42ml of THF was added compound 2-(3,5- dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-carbaldehyde (5.04g) in 42ml of THF. After the addition, the mixture was stirred at room temperature for another 24h. Then, the reaction mixture was poured into ice-water and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gelto give the title compound (3.9 g).¾ NMR (300Mz, CDCI3): δ 0.79(t, 3H), 1.43-1.56(m, 2H), 3.78(d, 1H), 3.96(d, 1H), 4.31 -4.36 (m, 1H), 5.05 (t, 1H), 7.00 (d, 1H), 7.12 ( t, 1H), 7.21 (d, 1H), 7.46(s, 2H), 7.55(s, 1H) Step B: Synthesis of l-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)propan-
1-one
Figure imgf000093_0001
Pyridinium chlorochromate (5.6g, 26.1mmol) was added to a solution of compound 1 -(2-(3,5- dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)propan-l - ol (3.4g) in 50ml of CH2CI2. After stirring for 2h at room temperature, silica gel (50g) was added to the reaction mixture and filtered. The filtrate was concentrated to dryness and the residue was purified by column chromatography on silica gel to give the title compound(2.8 g). 'H-NMR (300MZ,
CDCI3): δ 1.20(t, 3H), 2.93(q, 2H), 3.60(d, 1H), 4.00(d, 1H), 7.04(d, 1H), 7.40(m, 1H), 7.49(s, 2H),
7.85(s, 1H), 7.90(d, 1H); ESI-MS: 389(M + H) +.
Step C: Synthesis of (E)-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)pent- 2-enoic acid
Figure imgf000093_0002
Triethyl phosphonoacetate (1.747g) was slowly added to a suspension of NaH (936mg) in 16 ml of dry THF at 0°C under nitrogen and stirring was continued for 30min. Then, compound l-(2-(3,5- dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)propan-l-one (1.513g) in 16ml of THF was added. After refluxing for another 5h, the reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel to give the title compound (280 mg). ¾ NMR (300Mz,DMSO-d6): δ 0.94 (t, 3H), 3.01 (q, 2H), 3.84 (d, 1H), 4.03 (d, 1H), 5.92 (s, 1H), 7.13 (d, 1H), 7.41 (d, 1H), 7.46 (s, 1H), 7.69 (s, 2H), 7.76(m, 1H), 12.16(br s, 1H); ESI-MS: 429 (M-H)\
Step D: Synthesis of (i?)-N-cyclobutyl-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3- dihydrobenzofuran-5 -yl)pent-2-enamide (A65)
Figure imgf000094_0001
A mixture of compound (E)-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5- yl)pent-2-enoic acid (250 mg), HOBT (79mg), EDC.HC1 (333 mg) and Et3N (293mg) in 25ml of THF was stirred at room temperature for 30min. Then, cyclobutylamine (124 mg) was added to the mixture. After the mixture was stirred for another 16h, it was concentrated under vacuum and the residue was purified by column chromatography on silica gel to give the title compound (180 mg). ¾ NMR (300Mz, DMSO-dg): δ 0.90 (t, 3H),1.58-1.67(m, 2H), 1.83-1.89(m, 2H), 2.16-2.18(m, 2H), 3.03 (q, 2H), 3.85 (d, 1H), 4.03(d, 1H), 4.25 (q, 1H), 5.95 (s, 1H), 7.12 (d, 1H), 7.33 (d, 1H), 7.38 (s, 1H), 7.70 (s, 2H), 7.78 (m, 1H), 8.17 (d, 1H); ESI-MS: 484 (M+H) +, 506 (M + Na)+, 538 (M + MeOH + Na)+; m.p.: 108-110°C ; HPLC: 99.2%.
Example P5: Synthesis of (Z)-3-chloro-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3- dihydrobenzofuran-5 -yl)-N-(2,2 2-trifluoroethyl)acrylamide (Al 2)
Figure imgf000094_0002
Step A: Synthesis of3-methyl-4-nitrobenzoyl chloride
Figure imgf000094_0003
A mixture ofcompound 3-methyl-4-nitrobenzoic acid (36 g) in SOCl2 (100ml) was refluxed for 5h. Then, the excess SOCl2 was removed under reduced pressure to give the title compound (38g) in almost quantitative yield. The title compound was directly used for the next step without further purification.
Step B: Synthesis of 3 -methyl -4-nitrobenzamide
Figure imgf000094_0004
Compound 3-methyl-4-nitrobenzoyl chloride (38g) was added to 200 ml of NH3.H20 at 0°C . Then the mixture was stirred at room temperature for lh. After the addition, the mixture was stirred at the same temperature for another lh, then it was poured into ice-water and a yellowish solid generated. After filtration, the solid was dried under vacuum to give the title compound (36g) as a pale yellow solid.
Step C: Synthesis of 3-methyl-4-nitrobenzonitrile
Figure imgf000095_0001
To a stirred solution of compound 3-methyl-4-nitrobenzamide (5.4g) in 30ml of toluene was added POCl3 (22.8g). After the addition, the mixture was refluxed for 24h. Then, the reaction mixture was poured into ice-water and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by recrystallization with ethanol to give the title compound(20 g) as a pale yellow solid. Ή NMR (300Mz, CDC13): δ 2.64 (s, 3H), 7.66 (d, 2H), 7.67 (s, 1H), 8.03 (d, 1H).
Step D: Synthesis of 2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5- Carbonitrile
Figure imgf000095_0002
To a mixture of compound 3-methyl-4-nitrobenzonitrile (16.2g), compound l-(3,5-dichlorophenyl)-2,2,2- trifluoroethanone (29g) and z-Pr2NEt (25.8g) was added TBAF(150ml, 1.0M in THF) at room
temperature.After the addition, the mixture was refluxed for 24h under nitrogen. Then the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by recrystallization with petroleum ether to give the title compound(18g)as a white solid. ¾ NMR (300Mz, CDC ): δ 3.60(d, 1H), 3.98 (d, 1H), 7.08 (d, 1H), 7.41(s, 1H), 7.46 (m, 3H), 7.55(d, 1H).
Step E: Synthesis of l-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5- yl)ethanone
Figure imgf000095_0003
To a stirred solution of MeMgBr (30 ml, 2.8 M/L in THF) in 30ml of THF was added compound 2-(3,5- dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-carbonitrile (3.57g) in 15ml of THF. After the addition, the mixture was stirred at room temperature for 24 h under nitrogen. Then it was poured into ice-water and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash
chromatography on silica gelto give the title compound (2.2g). Ή NMR (300Mz, CDC¾): δ 2.56(s, 3H), 3.61(d, 1H), 4.01 (d, 1H), 7.06 (d, 1H), 7.42(m, 1H), 7.50 (s, 2H), 7.86 (s, 1H), 7.90 (d, 1H).
Step F: Synthesis of (E)-l-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)-3- (dimethylamino)prop-2-en- 1 -one
Figure imgf000096_0001
A mixture of compound l-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5- yl)ethanone (3.5g) and Ν,Ν-dimethylformamide dimetyl acetal (4.45g) in 25 ml of DMF was refluxed for 3h. Then the solvent was removed under vacuum to give a light brown solid. The crude product was purified by column chromatography on silica gel to give the title compound (3.8g). ¾ NMR (300Mz, CDC13): δ 2.95(s, 3H), 3.1 l(s, 3H), 3.57(d, 1H), 3.98(d, 1H), 5.64(d, 1H), 7.00 (d, 1H), 7.39 (m, 1H), 7.50(s, 2H), 7.81(m, 3H) ; ESI-MS: 430(M + H) +.
Step G: Synthesis of (Z)-3-chloro-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran- 5-yl)acrylaldehyde
Figure imgf000096_0002
A mixture of compound (E)-l -(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)- 3-(dimethylamino)prop-2-en-l-one (1.93g) and ΡΟ(¾(0.8ιη1) in 15 ml of CH2CI2 was refluxed for 3h. The solvent was removed under vacuum. The residue was dissolved in 40ml of water and 40ml of THF. After stirring at room temperature for 24h, the mixture was diluted with water and extracted with ethyl acetate three times. The organic extract was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel to give the title compound (1.3g). 'H NMR (300MZ, CDC13): δ 3.62(d, 1H), 4.02(d, 1H), 6.57(d, 1H), 7.07 (d, 1H),
7.42 (m, 1H), 7.50(s, 2H), 7.61(s,lH), 7.68(d, 1H), 10.17(d, 1H).
Step H: Synthesis of (Z)-3-chloro-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofiiran- 5-yl)acrylic acid
Figure imgf000097_0001
To a stirred mixture of compound (Z)-3-chloro-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3- dihydrobenzofuran-5-yl)acrylaldehyde (350mg) in 10 ml of DMSO was added sodium hydrogen phosphate monohydrate(123mg) in 3ml of water. The reaction mixture was cooled in ice bath at 0°C . Sodium chlorite (225mg) dissolved in 3 ml of water was slowly added to the reaction mixture. After the addition, the ice bath was removed and the reaction mixture was stirred at room temperature for another 6h. Then, it was poured into diluted hydrochloric acid and extracted with ethyl acetate three times. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound (325 mg).'H NMR (300Mz, DMSO-d6): δ 3.86 (d, 1H), 4.05 (d, 1H), 6.67 (s, 1H), 7.18 (d, 1H), 7.68 (m, 4H), 7.79 (s, 1H), 12.64 (br s, 1H); ESI-MS: 435(M-H)\
Step I: Synthesis of (Z)-3-chloro-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran- 5-yl)-N-(2,2,2-trifluoroethyl)acr lamide (A12)
Figure imgf000097_0002
A mixture of compound (Z)-3-chloro-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3- dihydrobenzofuran-5-yl)acrylic acid (250 mg), HOBT (78 mg), EDC.HC1 (327 mg) and Et3N (288mg) in 25ml of THF was stirred at room temperature for 30min.Trifluoroethylamine (170mg, 1.71mmol) was added to the mixture. After stirring for 16h, the mixture was concentrated under vacuum and the residue was purified by column chromatography on silica gel to give the title compound (160mg). Ή NMR (300Mz, CDC13): δ 3.69 (d, 1H), 3.98 (d, 1H), 4.02-4.09(m, 2H), 6.45 (s, 1H), 6.61 (t, 1H), 7.03 (d, 1H), 7.42 (s, 1H), 7.51 (m, 4H); 19F NMR (282Mz, CDC13): δ 39.84 (s, 3F), 48.04 (t, 3F); ESI-MS: 540 (M + Na)+, 572(M + MeOH + Na)+; m.p.: 264-266°C ; HPLC: 99.8%. Example P6: Synthesis of (Z)-3-bromo-N-cvclobu1yl-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2, 3- dihydrobenzofuran-5 -vDacrylamide (A88)
Figure imgf000098_0001
Step A: Synthesis of (Z)-3-bromo-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran- 5-yl)acrylaldehyde
Figure imgf000098_0002
A mixture of compound (i^-l-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)- 3-(dimethylamino)prop-2-en-l -one (215mg) and POBr3(717mg) in 2ml of CH2C12 was refluxed for 3h. Then the solvent was removed under vacuum. The residue was dissolved in 4ml of water and 4 ml of THF and the resulting mixture was stirred at room temperature for another 24h. Then, the mixture was diluted with water and extracted with ethyl acetate three times. The organic extract was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel to give the title compound (160 mg). ¾ NMR (300Mz, CDC13): δ 3.62 (d, 1H), 3.99 (d, 1H), 6.99 (d, 1H), 7.05 (d, 1H), 7.42 (s, 1H), 7.50 (s, 2H), 7.58 (s, 1H), 7.63 (d, 1H), 10.01 (d, 1H).
Step B: Synthesis of (Z)-3-bromo-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3- dihydrobenzofuran-5-yl)acrylic acid
Figure imgf000098_0003
To a stirred mixture of compound (Z)-3-bromo-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3- dihydrobenzofuran-5-yl)acrylaldehyde (120 mg) in 2ml of DMSO was added sodium hydrogen phosphate monohydrate(43mg) in 2ml of water. The reaction mixture was cooled in ice bath at 0 °C . Sodium chlorite (47mg) dissolved in 2ml of water was slowly added to the reaction mixture. After the addition, the ice bath was removed. The reaction mixture was stirred at room temperature for another 6h, poured into diluted hydrochloric acid and extracted with ethyl acetate three times. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound(80 mg). 'H NMR (300Mz, CDC13): δ 3.59 (d, 1H), 3.99 (d, 1H), 6.68 (s, 1H), 7.03 (d, 1H), 7.42 (m, 1H), 7.50 (m, 3H), 7.56 (d, 1H); ESI-MS: 480(M-H)". Step C: Synthesis of (Z)-3-bromo-N-cyclobutyl-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3- dihydrobenzofuran-5 -yl)acrylamide
Figure imgf000099_0001
A mixture of compound (Z)-3-bromo-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3- dihydrobenzofuran-5-yl)acrylic acid (865 mg), HOBT (243 mg), EDC.HC1 (1.031g) and Et3N (9.9g) in 25ml of THF was stirred at room temperature for 30min.Cyclobutylamine (384mg) was then added to the mixture. After the mixture was stirred for 16h, it was concentrated under vacuum to dryness and the residue was purified by column chromatography on silica gel to give the title compound (350 mg). ¾ NMR (300Mz, CDC13): δ 1.74-1.81 (m, 2H), 1.89-2.02 (m, 2H), 2.36-2.46 (m, 2H), 3.57 (d, 1H), 3.97 (d, 1H), 4.51 (m, 1H), 6.29 (d, 1H), 6.53 (s, 1H), 6.99 (d, 1H), 7.41 (m, 2H), 7.45 (d, 1H), 7.49 (m, 2H);19F NM (282Mz, CDC13): δ 39.88 (s, 3F); ESI-MS: 535 (M + H)+, 557 (M + Na)+, 589 (M + MeOH + Na)+; m.p.: 250-252°C ; HPLC: 98.1%.
Example P7: Synthesis of 3-r2-(3,5-dichloro-phenyl)-2-trifluoromethyl-2,3-dihvdro-benzofuran-5-yll- but-2-enoic acid cyclobutylamide (A14)
Figure imgf000099_0002
To a mixture of 3-methyl-4-nitrobenzonitrile (16.2g), l-(3,5-dichloro-phenyl)-2,2,2-trifluoro -ethanone (29g), and i-Pr2NEt (25.8g) was added TBAF(1.0M in THF, 150ml) at room temperature. After the addition, the mixture was refluxed for 24h. Then, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by recrystallization with petroleum ether to give the title compound (18g)as a white solid.'H NMR (300Mz, DMSO- 6): δ 3.96(dd, 2H), 7.28 (d, 1H), 7.67(s, 2H), 7.71-7.76(m, 3H).
Step B: Synthesis of l-[2-(3,5-dichloro-phenyl)-2-trifluoromethyl-2,3-dihydro-benzofuran-5-yl]- ethanone
Figure imgf000100_0001
To a stirred solution of MeMgBr (10ml, 3.0mol/ 1 in THF) in 10ml of THF was added compound 2-(3,5- dichloro-phenyl)-2 rifluoromethyl-2,3-dihydro-benzofuran-5-carbonitrile (3.58g) in 10ml of THF. After the addition, the mixture was stirred at room temperature for 20h. Then, the reaction mixture was poured into ice-water and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash
chromatography on silica gel (EtOAc / PE = 1 / 10 as an eluent) to afford the title compound (3.1 g) . ¾ NMR (300Mz, CDC13): δ 2.55 (s, 3H), 3.79 (dd, 2H), 7.06 (d, 1H), 7.40 (m, 1H), 7.49(s, 2H), 7.85 (s, 1H), 7.90 (d, 1H).
Step C: Synthesis of 3-[2-(3,5-dichloro-phenyl)-2 rifluoromethyl-2,3-dihydro-benzofuran-5-yl]-but-2- enoic acid ethyl ester
Figure imgf000100_0002
To a stirred mixture of NaH (180mg) in 10ml of THF was added triethyl phosphonacetate(l .0g) at 0 °C. After the mixture was stirred for another 30min,l-[2-(3,5-dichloro-phenyl)-2-trifluoromethyl-2,3- dihydro- benzofuran-5-yl]-ethanone (1.12g) in 5ml of THF was slowly added. Then, the resulting mixture was refluxed for another 20 h, poured into ice-water and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (EtOAc / PE = 1 / 50 as an eluent) to afford the title compound (890 mg). ¾ NMR (300Mz, CDC13): δ 1.28 (t, 3H), 2.54 (s, 3H), 3.77 (dd, 2H), 4.22(q, 2H), 6.07 (s, 1H) 6.98 (d, 1H) 7.32-7.39 (m, 3H), 7.51 (s, 2H).
Step D: Synthesis of 3-[2-(3,5-dichloro-phenyl)-2-trifluoromethyl-2,3-dihydro-benzofuran-5-yl]-but-2- enoic acid
Figure imgf000100_0003
A mixture of 3-[2-(3,5-dichloro-phenyl)-2-trifluoromethyl-2,3-dihydro-benzofuran-5-yl] -but-2-enoic acid ethyl ester (890mg) and NaOH (4g) in EtOH (4ml) / H20 (20ml) was refluxed for 5h. Then, the reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate three times The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel to provide the title compound (600 mg). ¾ NMR (300Mz, DMSO- 6): δ 2.43 (s, 3H), 3.91 (dd, 2H), 6.02 (s, 1H) 7.10 (d, 1H), 7.43(d, 1H), 7.47 (s, 1H), 7.68 (s, 2H), 7.76(s, 1H), 12.13 (s, 1H).
Step E: Synthesis of 3-[2-(3,5-Dichloro-phenyl)-2-trifluoromethyl-2,3-dihydro-benzofuran-5-yl]-but-2- enoic acid cyclobutylamide (A14)
Figure imgf000101_0001
A mixture of 3-[2-(3,5-dichloro-phenyl)-2-trifluoromethyl-2,3-dihydro-benzofuran-5- yl]-but-2-enoic acid (158mg), HOBT (67mg), EDC.HC1 (77mg) and Et3N (202mg) in 10ml of THF was stirred at room temperature for 30min. Cyclobutylamine (35mg) was added to the mixture. After the mixture was stirred about 48h, the mixture was concentrated under vacuum to dryness and the residue was purified by column chromatography on silica gel to provide the title compound (120mg). 'H NMR (300Mz, DMSO-<i6): δ 1.59-1.65 (m, 2H), 1.82-1.89 (m, 2H), 2.14-2.18 (m, 2H), 2.41 (s, 3H), 3.92 (dd, 2H), 4.22-4.25 (m, 1H), 6.07 (s, 1H), 7.23 (dd, 2H), 7.40(s, 1H), 7.68 (s, 2H), 7.22 (s, 1H), 8.15 (d,lH).
Example P8: Synthesis of (Z)-N-cvclobutyl-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3- dihydrobenzofuran -5-yl)-4A4-trifluorobut-2-enamide (A64)
Figure imgf000101_0002
Step A: Synthesis of (l-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran- 5-yl) -2,2,2- trifluoroethoxy)trimethylsilane
Figure imgf000101_0003
CsF (152mg, lmmol) was added to a solution of 2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3- dihydrobenzofuran-5-carbaldehyde (3.6g, lOmmol) and TMSCF3 (1.7g, 12mmol) in dry THF (25ml) under nitrogen at room temperature. After the mixture was stirred for 16h, it was concentrated under vacuum to dryness and the residue was purified by column chromatography on silica gel to give the title compound (4.97g). ¾ NMR (300Mz, CDC13): δ 0.11 (d, 9H), 3.61 (d, 1H), 3.95 (d, 1H), 4.85 (q, 1H), 6.99 (d, 1H), 7.25-7.31 (m, 2H), 7.39 (t, 1H), 7.51 (s, 2H). Step B: Synthesis of l -(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5 -yl)-2,2,2- trifluoroethanol
Figure imgf000102_0001
A mixture of (l -(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)-2,2,2- trifluoroethoxy)trimethylsilane (502mg, lmmol) in 10ml of aqueous HC1 (lmol/1) and 10ml of THF was stirred at room temperature for 8h, Then the reaction mixture was poured into brine and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography on silica gel to give the title compound(426 mg). ¾ NMR (300Mz, CDC13): δ 2.46 (br s, 1H), 3.60 (dd, 1H), 3.96 (d, 1H), 4.98 (q, 1H), 7.03 (dd, 1H), 7.31 (s, 1H), 7.35 (s, 1H), 7.40 (s, 1H), 7.50 (s, 2H).
Step C: Synthesis of l -(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran -5-yl)-2,2,2- trifluoroethanone
Figure imgf000102_0002
DMP (509mg, 1.2mmol) was added to a solution of l -(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3- dihydrobenzofuran-5-yl)-2,2,2-trifluoroethanol(430mg, lmmol) in 5ml of CH2C12. The mixture was stirred at room temperature 30min. Then the mixture was filtered and the filtrate was concentrated under vacuum to dryness and the residue was purified by column chromatography on silica gel to give the title compound (360mg). 'H NMR (300MZ, CDC13): δ 3.68 (d, 1H), 4.02 (d, 1H), 7.17 (d, 1H), 7.43 (t, 1H), 7.49 (s, 2H), 7.95 (s, 1H), 8.06 (d, 1H); 19F NMR (EA): δ -70.0 (d, 3F), -79.5 (d, 3F); ESI-MS (-): 427 (M-H)\
Step D: Synthesis of (Z)-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)- 4,4,4-trifluorobut-2-enoic acid
Figure imgf000103_0001
Triethyl phosphonoacetate (448mg, 2mol) was slowly added to a mixture of NaH (160mg, 4mmol) in dry THF (4ml) at 0°C under nitrogen and stirring was continued for 30min. Then, l -(2-(3,5-dichlorophenyl)- 2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)-2,2,2-trifluoroethanone (428mg, lmmol) in 4ml of THF was added to the mixture. The resulting mixture was stirred at room temperature for another 2h. Then, it was poured into diluted hydrochloric acid and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatography on silica gel to give the title compound (296mg). ¾ NMR (300Mz, CDC13): δ 3.61 (d, IH), 3.96 (d, IH), 6.56 (d, IH), 7.02 (d, IH), 7.11-7.15 (m, 2H), 7.41 (t, IH), 7.50 (s, 2H); ESI-MS: 469 (M-H)" .
Step E: Synthesis of (Z)-N-cyclobutyl-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3- dihydrobenzofuran -5-yl)-4,4,4-trifluorobut-2-enamide (A64)
Figure imgf000103_0002
A mixture of (Z)-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3 -dihydrobenzofuran-5-yl) -4,4,4- trifluorobut-2-enoic acid (470mg, lmmol), HOBT (270mg, 2mmol), EDC.HCl (382mg, 2mmol) and Et3N (808mg, 8mmol) in 20ml of THF was stirred at room temperature for 30min. Cyclobutylamine (142mg, 2mmol) was added to the mixture. After the mixture was stirred for 16h, it was concentrated under vacuum to dryness and the residue was purified by column chromatography on silica gel to give the title compound(377 mg). 'H NMR (300MZ, DMSO- 6): δ 1.44-1.70 (m, 4H), 1.94-2.00 (m, 2H), 3.89 (d, IH), 3.99-4.08 (m, 2H), 6.83 (s, IH), 7.17 (s, 2H), 7.21 (s, IH), 7.71 (s, 2H), 7.80 (t, IH), 8.45 (d, IH); ESI- MS: 522 (M-H)".
Example P9: Synthesis of (E)-N-butyl-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3- dihydrobenzofuran-5 -yl)-2-methylacrylamide (A79)
Figure imgf000103_0003
Step A: Synthesis of (E)-ethyl 3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5- yl)-2-methylacrylate
Figure imgf000104_0001
Triethyl 2-phosphonopropionate (357mg) was slowly added to a suspension of NaH (60mg) in 10 ml of dry THF at 0°C under nitrogen. After stirring for 30min, compound 2-(3,5-dichlorophenyl)-2- (trifluoromethyl)-2,3-dihydrobenzofuran-5-carbaldehyde (360mg) was added to the mixture. The reaction mixture was stirred at room temperature for another 2h. Then, it was poured into diluted hydrochloric acid and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel to give the title compound (370mg). ¾ NMR (300Mz, CDC13): δ 1.34 (t, 3H), 2.10 (s, 3H), 3.58 (d, 1H), 4.98 (d, 1H), 4.26 (q, 2H), 7.03 (d, 1H), 7.26 (s, 1H), 7.29 (d, 1H), 7.40 (s, 1H), 7.51 (s, 2H), 7.61 (s, 1H).
Step B: Synthesis of (E)-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)-2- methylacrylic acid
Figure imgf000104_0002
A mixture of compound (E)-ethyl 3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran- 5-yl)-2-methylacrylate (210 mg) and LiOH (198 mg) in 10 ml of THF and 10ml of H20 was stirred at room temperature for 16h. Then, the reaction mixture was poured into diluted hydrochloric acidand extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel to give the title compound (180 mg). ¾ NMR (300Mz, DMSO- 6): δ 1.98 (s, 3H), 3.86 (d, 1H), 4.03 (d, 1H), 7.15 (d, 1H), 7.36 (d, 1H), 7.41 (s, 1H), 7.52 (s, 1H), 7.68 (s, 2H), 7.76 (m, 1H), 12.40(br s, 1H); ESI-MS: 415(M-H)\
Step C: Synthesis of (E)-N-butyl-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran- 5-yl)-2-methylacrylamide (A79)
Figure imgf000105_0001
A mixture of compound (E)-3-(2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)- 2-methylacrylic acid(180 mg), HOBT (61mg), EDC.HC1 (258 mg) and Et3N (228 mg) in 25ml of THF was stirred at room temperature for 30min. «-Butylamine (99 mg) was added to the mixture. After the mixture was stirred for another 16h, it was concentrated under vacuum to dryness and the residue was purified by column chromatography on silica gel to give the title compound (180 mg).'H NMR (300Mz, DMSO- 6): δ 0.86 (t, 3H), 1.23-1.33 (m, 2H), 1.38-1.47 (m, 2H), 1.95(s, 3H), 3.12 (q, 2H), 3.84 (d, 1H), 4.02 (d, 1H), 7.12(d, 2H),7.25(d, 1H), 7.30(s,lH), 7.68 (s, 2H), 7.76 (s, 1H), 7.91(t, 1H); ESI-MS: 472 (M + H) +, 494(M + Na)+, 526 (M + MeOH + Na)+; m.p.: 217-219°C ; HPLC: 98.2%.
Example P10: Synthesis ofN-r(E)-3-r2-(3,5-dichlorophenyD-2-(trifluoromethyD-3H-benzofuran-5- yllallyllcyclopropanecarboxamide (B4) and N-r(ZN)-3-r2-(3,5-dichlorophenylN)-2-(trifluoromethylN)-3H- benzofuran-5 -yllall llcyclopropanecarboxamide (B5)
Figure imgf000105_0002
Step A: Synthesis of 2-[(^-3-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran-5- yl]allyl]isoindoline-l,3-dione and 2-[(^-3-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran-5- yl]allyl]isoindoline-l 3-dione
Figure imgf000105_0003
A mixture of compound 2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran-5-carbaldehyde (2.2g, 6.1mmol), compound 2-(l,3-dioxoisoindolin-2-yl)ethyl-triphenyl-phosphonium bromide (3.17 g, 6.1 mmol), K2C03 (842 mg, 6.1 mmol) and 18-crow-6 (264mg, lmmol) in 80ml of toluene was refluxed for 16h. Then the mixture was cooled to room temperature, poured into water and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to provide 2-[f2)-3- [2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran-5-yl]allyl]isoindoline-l,3-dione (l .Olg, 32% yield) and 2-[(^-3-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran-5-yl]allyl]isoindolin^ dione(725mg, 23% yield). 2-[(^-3-[2-(3,5-dichlorophenyl)-2-(triflu^ ¾
NMR (300Mz, DMSO- 6): δ 3.88 (d, 1H), 4.02 (d, 1H), 4.47 (dd, 2H), 5.54-5.60 (m, 1H), 6.49 (d, J=12Hz, 1H), 7.16 (d, 1H), 7.27 (d, 1H), 7.35 (s, 1H), 7.71 (s, 2H), 7.78-7.88 (m, 5H);
2-[E)-3-[2-(3,5-dichlorophenyl)-2-(trifluoro ¾ NMR (300Mz, DMSO- e): δ 3.80 (d, 1H), 3.93 (d, 1H), 4.31 (d, 2H), 6.13-6.22 (m, 2H), 6.50 (d, J=15.9Hz, 1H), 7.04 (d, 1H), 7.26-7.37 (m, 2H), 7.64-790 (m, 7H).
Step B: Synthesis of N-[(^-3-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran-5- yl]allyl]cyclopropanecarboxamide (B4)
Figure imgf000106_0001
2- [(ΐ^ -3 - [2 -(3 ,5 -dichlorophenyl) -2 -(trifluorome
(257mg, 0.5mmol) and hydrazine hydrate (150mg, 3mmol) in 20ml of methanol was refluxed for 4h. Then, the mixture was cooled to room temperature, filtered and concentrated under reduced pressure to provide the crudeproduct (^-3-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran-5-yl]prop-2- en-1 -amine. The crude product was added to a solution of Et3N (303mg, 3mmol) in 30ml of THF. Then cyclopropanecarboxylic acid chloride (208mg, 2mmol) was added to the mixture at 0 °C . After the addition, the mixture was stirred at the same temperature for 30min. Then, the mixture was poured into water and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to provide product B4 (82mg, 36% yield). Ή NMR (300Mz, DMSO-d6): δ 0.59-0.68 (m, 4H), 1.55-1.60 (m, 1H), 3.77 (d, 1H), 3.83 (s, 2H), 3.96 (d, 1H), 6.06-6.16 (m, 1H), 6.42 (d, J=15.6Hz, 1H), 7.03-7.06 (m, 1H), 7.25 (d, 1H), 7.37 (s, 1H), 7.69 (s, 2H), 7.88 (s, 1H), 8.26 (t, 1H); EI- MS: 455 (M), 386, 1 10, 97, 69, 41.
Step B': N-[(^-3-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran-5- yl]allyl]cyclopropanecarboxamide (B5)
Figure imgf000106_0002
2-[(^-3-[2-(3,5-dichlorophenyl)-2-(trifluorometh^
(290mg, 0.56mmol) and hydrazine hydrate (150mg, 3mmol) in 20ml of methanol was refluxed for 4h. Then, the mixture was cooled to room temperature, filtered and concentrated under reduced pressure to provide the crudeproduct f¾)-3-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran-5-yl]prop-2- en-1 -amine. The crude productwas added to a solution of Et3N (303mg, 3mmol) in 30ml of THF. Then cyclopropanecarboxylic acid chloride (208mg, 2mmol) was added to the mixture at 0°C . After the addition, the mixture was stirred at the same temperature for 30min. Then, the mixture was poured into water and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to provide product B5 (132mg, 52% yield). Ή NMR (300Mz, CDC13): δ 0.73-0.74 (m, 2H), 0.96-0.97 (m, 2H), 1.73-1.75 (m, IH), 3.57 (d, IH), 3.93 (d, IH), 4.16-4.17 (m, 2H), 5.55-5.61 (m, IH), 5.70 (s, IH), 6.47 (d, J=11.7Hz, IH), 6.98 (d, IH), 7.07 (s, 2H), 7.39 (s, IH), 7.50 (s, 2H); ESI-MS(+): 456 (M+H) +, 478 (M+Na+).
Example PI 1 : Synthesis of N-r^i?)-3-r2-(3,5-dichlorophenyD-2-(trifluoromethyD-3H-benzofuran-5-yll-l - methyl-allyll-2-methylsulfanyl-acetamide (B 1 )
Figure imgf000107_0001
Step A: Synthesis of 5-(bromomethyl)-2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran
Figure imgf000107_0002
PBr3(1.36g, 5ml) was added to a solution of [2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran- 5-yl]methanol (3.62g, lOmmol) in 5ml of dichloromethane at room temperature. After the addition, the mixture was stirred at the same temperature for lh. Then, the mixture was poured into water and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to provide 5-(bromomethyl)-2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran(3.99g, 94% yield). 'H NMR (300Mz, DMSO- 6): δ 3.87 (d, IH), 3.99 (d, IH), 4.71 (s, 2H), 7.11 (d, IH), 7.32 (dd, IH), 7.40 (s, IH), 7.69 (d, 2H), 7.77 -7.78(m, IH).
Step B: Synthesis of [2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran-5-yl]methyl-triphenyl- phosphonium bromide
Figure imgf000107_0003
A mixture of 5-(bromomethyl)-2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran (4.25g, lOmmol) and triphenyl phosphine (3.14g, 12mmol) in 50ml of toluene was re fluxed for 16h. Then, the mixture cooled to room temperature, filtered and the filter cake was dried in vacuum to provide [2-(3,5- dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran-5-yl]methyl-triphenylphosphonium bromide (6.3g, 92% yield). ¾ NMR (300Mz, DMSO- 6): δ 3.71 (d, 1H), 3.82 (d, 1H), 5.15 (d, 2H), 6.81 (s, 1H), 6.89 (d, 1H), 6.98 (d, 1H), 7.57-7.81 (m, 15H), 7.86-7.91 (m, 3H); ESI-MS(+): 607 (M+H)+.
Step C: Synthesis of 2-[(Z)-3-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran-5-yl]-l-methyl- allyl]isoindoline-l,3-dione and 2-[(£)-3-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran-5- yl]-l -methyl-all l]isoindoline-l ,3-dione
Figure imgf000108_0001
A mixture of compound [2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran-5-yl]methyl- triphenylphosphonium bromide (11. lg, 16.2mmol), compound 2-(l,3-dioxoisoindolin-2-yl)propanal (3.3g, 16.2mmol), K2C03 (4.5g, 32.4mmol) and 18-crow-6 (528mg, 2mmol) in 150ml of toluene was refluxed for 16h. Then, the mixture was cooled to room temperature, poured into water and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and
concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to provide 2-[f¾)-3-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran-5-yl]-l-methyl- allyl]isoindoline-l,3-dione and(4.04g, 47% yield) and 2-[(¾)-3-[2-(3,5-dichlorophenyl)-2- (trifluoromethyl)-3H-benzofuran-5-yl]-l-methyl-allyl]isoindoline-l,3-dione (3.44g, 40% yield).
2-[(^-3-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran-5-yl]-l -methyl-allyl]isoindolm^ dione:'H NMR (300Mz, DMSO- 6): δ 1.47 (dd, 3H), 3.73-4.02 (m, 1H), 5.23-5.30 (m, 1H), 6.03-6.10 (m, 1H), 6.48 (d, J=l 1.4Hz, 1H), 7.047.14 (m, 2H), 7.18 (s, 1H), 7.69 (s, 2H), 7.77-7.79 (m ,5H).
2-[(^-3-[2-(3,5-dichlorophenyl)-2-(trifluo
dione : 'H NMR (300MZ, DMSO- 6): δ 1.59 (d, 3H), 3.81 (d, 1H), 3.95 (d, 1H), 4.96 (dq, 1H), 6.41-6.57 (m, 2H), 7.06 (d, 1H), 7.26 (d, 1H), 7.40 (s, 1H), 7.67 (s, 2H), 7.77 (s, 1H), 7.85-7.87 (m, 4H).
Step D: Synthesis of (^-4-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran-5-yl]but-3-en-2- amine
Figure imgf000108_0002
A mixture of 2-[(^-3-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran-5-yl]-l-methyl- allyl]isoindo line- 1,3 -dione (3.5g, 6.6mmol) and hydrazine hydrate (1.65g, 33mmol) in 30ml of MeOH was refluxed for 4h. Then the mixture was cooled to room temperature, filtered and concentrated under reduced pressure to provide crude (¾)-4-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran-5- yl]but-3-en-2-amine (2.62g, 99% yield).The crude product was directly used for the next step without further purification.
Step E: Synthesis of N-[(^-3-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran-5-yl]-l- methyl-allyl]-2-methylsulfanyl-acetamide (Bl)
Figure imgf000109_0001
2-(Methylthio)acetyl chloride (248mg, 2mmol) was added to a solution of (¾)-4-[2-(3,5-dichlorophenyl)- 2-(trifluoromethyl)-3H-benzofuran-5-yl]but-3-en-2-amine (401mg, lmmol) and Et3N (303mg, 3mmol) in 20ml of THF at 0°C . After the addition, the mixture was stirred at the same temperature for another 30min. Then, it was poured into water and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to provide product Bl (328mg, 67% yield). ¾ NMR (300Mz, DMSO- e): 51.22 (d, 3H), 2.11 (s, 3H), 3.08 (s, 2H), 3.83 (d, 1H), 3.97 (d, 1H), 4.44 (dq, 1H), 6.16 (dd, 1H), 6.40 (d, J=16.8Hz, 1H), 7.07 (d, 1H), 7.23 (d, 1H), 7.35 (s, 1H), 7.68 (d, 2H), 7.75 (m, 1H), 8.06 (d, 1H); 19F NMR (300Mz, DMSO- 6): δ -74.49 (s, 3F); ESI-MS(+): 544 (M+Na+MeOH)+.
Example P12: Synthesis of N-r(Z)-3-r2-(3,5-dichlorophenyD-2-(trifluoromethyD-3H-benzofuran-5-yll-l - methyl-allyll-2-methylsulfanyl-acetamide B2)
Figure imgf000109_0002
Step A: Synthesis of (^-4-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran-5-yl]but-3-en-2- amine
Figure imgf000109_0003
A mixture of compound 2-[(^-3-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran-5-yl]-l - methyl-allyl]isoindoline-l,3-dione (1.516g, 2.85mmol) and hydrazine hydrate (700mg, 14mmol) in 30ml of MeOH was refluxed for 4h. Then, the mixture was cooled to room temperature, filtered and concentrated under reduced pressure to provide the crude(2)-4-[2-(3,5-dichlorophenyl)-2- (trifluoromethyl)-3H-benzofuran-5-yl]but-3-en-2-amine (1.126g, 97% yield).The crude product was directly used for the next step without further purification. Step B: Synthesis of N-[(^-3-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran-5-yl]-l - methyl-allyl]-2-methylsulfanyl-acetamide (B2)
Figure imgf000110_0001
A mixture of (^-4-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-benzofuran-5-yl]but-3-en-2-amine (300mg, 0.74mmol), HOBT (270mg, 2mmol), PyBop (1.4g, 2mmol), 3,3,3-trifluoropropanoic acid (256mg, 2mmol) and DIPEA (516mg, 4mmol) in 20ml of THF was stirred at room temperature for 16h. Then, the reaction mixture was poured into aqueous NaHC03 and extracted with ethyl acetatethree times. The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give compound B2 (297mg,
78% yield). 'H NMR (300MZ, DMSO-d6): δ 1.17 (d, 3H), 3.22 (q, 2H), 3.88-3.97 (m, 2H), 4.78 (dq, 1H), 5.47 (t, 1H), 6.36 (d, J=11.4Hz, 1H), 7.12 (d, 1H), 7.19 (d, 1H), 7.26 (s, 1H), 7.70 (s, 2H), 7.78 (s, 1H), 8.43 (d, 1H); 19F NMR (300Mz, DMSO- 6): δ -74.43 (d, 3F), -56.62 (t, 3F); ESI-MS(-): 510 (M-H)".
Table A.
Table A provides compounds of formula A
Figure imgf000111_0001
A28 trans 0 C-H C-H C-H Me H H 1-cyclopropylcydoprop-l-yl- CF3 3,5-dichlorophenyl- 2.20 496.41 A
(lS)-3-methyl-l-
A29 trans 0 C-H C-H C-H Me H H (trifluoromethyl)butyl- CF3 3,5-dichlorophenyl- 2.38 554.34 A
A30 trans 0 C-H C-H C-H Me H H (lS)-l-(trifluoromethyl)propyl- CF3 3,5-dichlorophenyl- 2.25 526.31 A
(lS)-2-methyl-l-
A31 trans 0 C-H C-H C-H Me H H (trifluoromethyl)propyl- CF3 3,5-dichlorophenyl- 2.33 540.32 A
(2E)-2-methoxyimino-l,l-dimethyl-
A32 trans 0 C-H C-H C-H Me H H ethyl- CF3 3,5-dichlorophenyl- 2.20 515.35 A
A33 0 C-H C-H C-H CI H H 2-pyridylmethyl- CF3 3,5-dichlorophenyl- 13.92 549(M+Na)+ B 70 - 72
A34 trans 0 C-H C-H C-H Me H H l,l-dimethylbut-2-ynyl- CF3 3,5-dichlorophenyl- 2.21 496.32 A
A35 trans 0 C-H C-H C-H Me H H l,l-dimethylprop-2-ynyl- CF3 3,5-dichlorophenyl- 2.14 482.27 A
A36 trans 0 C-H C-H C-H Me H H (l-methoxy)-2-methylprop-2-yl- CF3 3,5-dichlorophenyl- 2.21 502.34 A
A37 trans 0 C-H C-H C-H Me H H (l-cyano-2-methoxy-l-methyl-ethyl)- CF3 3,5-dichlorophenyl- 2.09 513.33 A
A38 trans 0 C-H C-H C-H Me H H 3-tetrahyd rothiophenyl- CF3 3,5-dichlorophenyl- 2.13 502.25 A
A39 trans 0 C-H C-H C-H Me H H 2-(methylsulfanyl)ethyl- CF3 3,5-dichlorophenyl- 2.09 490.28 A
A40 trans 0 C-H C-H C-H Me H H 2-(methylsulfinyl)ethyl- CF3 3,5-dichlorophenyl- 1.78 506.3 A
A41 trans 0 C-H C-H C-H Me H H (lR,2R,4S)-norbornan-2-yl- CF3 3,5-dichlorophenyl- 2.31 510.35 A
A42 trans 0 C-H C-H C-H Me H H 3-thietanyl- CF3 3,5-dichlorophenyl- 2.11 488.18 A
A43 trans 0 C-H C-H C-H Me H H l-oxothietan-3-yl- CF3 3,5-dichlorophenyl- 1.83 504.28 A
A44 trans 0 C-H C-H C-H Me H H 3-fluorophenyl- CF3 3,5-dichlorophenyl- 2.31 510.39 A
(l,l-dimethyl-2-methylsulfanyl-
A45 trans 0 C-H C-H C-H Me H H ethyl)- CF3 3,5-dichlorophenyl- 2.28 518.33 A
A46 trans 0 C-H C-H C-H Me H H (3-methylthietan-3-yl)- CF3 3,5-dichlorophenyl- 2.21 502.3 A
A47 trans 0 C-H C-H C-H Me H H (2,5-dimethylpyrazol-3-yl)- CF3 3,5-dichlorophenyl- 2.03 510.41 A
A48 trans 0 C-H C-H C-H Me H H 3-pyridyl- CF3 3,5-dichlorophenyl- 1.84 493.25 A
A49 trans 0 C-H C-H C-H Me H H 2-chloropyrid-4-yl- CF3 3,5-dichlorophenyl- 2.11 541.28 A
A50 trans 0 C-H C-H C-H Me H H 4-methoxyphenylmethyl- CF3 3,5-dichlorophenyl- 2.17 536.34 A
A51 trans 0 C-H C-H C-H Me H H phenyleth-2-yl- CF3 3,5-dichlorophenyl- 2.24 520.3 A
A52 trans 0 C-H C-H C-H Me H H 2-fluorophenylmethyl- CF3 3,5-dichlorophenyl- 2.21 524.32 A
A53 trans 0 C-H C-H C-H Me H H 2-tetrahydrofuranyl- CF3 3,5-dichlorophenyl- 2.05 500.33 A
A54 trans 0 C-H C-H C-H Me H H 3,3,3-trifluoropropyl- CF3 3,5-dichlorophenyl- 2.14 512.3 A
A55 trans 0 C-H C-H C-H Me H H allyl- CF3 3,5-dichlorophenyl- 2.07 455.58 A
2-oxo-2-(2,2,2-
A56 trans 0 C-H C-H C-H Me H H trifluoroethylamino)ethyl- CF3 3,5-dichlorophenyl- 1.97 555.54 A
A57 trans 0 C-H C-H C-H Me H H (l-methoxy)prop-2-yl- CF3 3,5-dichlorophenyl- 2.07 488.15 A
A58 trans 0 C-H C-H C-H Me H H cyclobutyl- CF3 3-trifluoromethylphenyl- 17.05 468(M-H)- B 115 - 116
A59 trans 0 N C-H C-H Me H H cyclobutyl- CF3 3-trifluoromethylphenyl- 16.08 471 (M+H)+ B 158 - 160
A60 trans 0 C-H C-H C-H Me Me H cyclobutyl- CF3 3,5-dichlorophenyl- 17.96 484(M+H)+ B 143 - 144
A61 trans 0 C-H C-H C-H H Me H cyclobutyl- CF3 3,5-dichlorophenyl- 17.98 470(M+H)+ B 272 - 273
Figure imgf000113_0001
Table B
Table B provides compounds of formula B
Figure imgf000114_0001
Figure imgf000114_0002
Biological examples
These Examples illustrate the pesticidal/insecticidal properties of compounds of formula (I).
Tests were performed as follows:
Spodoptera littoralis (Egyptian cotton leafworm):
Cotton leaf discs were placed on agar in a 24-well microtiter plate and sprayed with test solutions at an application rate of 200 ppm. After drying, the leaf discs were infested with 5 LI larvae. The samples were checked for mortality, feeding behavior, and growth regulation 3 days after treatment (DAT).
The following compounds gave at least 80% control of Spodoptera littoralis: Al, A2, A7, A9, A10, A12, A13, A14, A15, A16, A18, A19, A22, A23, A27, A28, A30, A33, A35, A37, A38, A41, A42, A43, A45, A46, A48, A49, A52, A53, A54, A55, A57, A58, A59, A61, A62, A63, A64, A65, A66, A67, A68, A69, A70, A71, A73, A75, A76, A77, A80, A81, A82, A83, A86, A88, Bl, B4.
Heliothis virescens (Tobacco budworm):
Eggs (0-24 h old) were placed in 24-well microtiter plate on artificial diet and treated with test solutions at an application rate of 200 ppm (concentration in well 18 ppm) by pipetting. After an incubation period of 4 days, samples were checked for egg mortality, larval mortality, and growth regulation.
The following compounds gave at least 80% control of Heliothis virescens:A2, A5, A7, A8, A9, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, A32, A33, A34, A35, A36, A37, A38, A39, A40, A41, A42, A43, A44, A45, A46, A47, A48, A49, A50, A51, A52, A53, A54, A55, A56, A57, A58, A62, A64, A65, A66, A67, A68, A70, A71, A73, A75, A76, A78, A80, A81, A82, A84, A85, A86, A87, A88, Bl, B3, B4, B5.
Plutella xylostella (Diamond back moth):
24-well microtiter plate (MTP) with artificial diet was treated with test solutions at an application rate of 200 ppm (concentration in well 18 ppm) by pipetting. After drying, the MTP's were infested with L2 larvae (7-12 per well). After an incubation period of 6 days, samples were checked for larval mortality and growth regulation.
The following compounds gave at least 80% control of Plutella xylostella: Al, A2, A5, A6, A7, A8, A9, A12, A13, A14, A15, A16, A17, A18, A21, A22, A23, A24, A25, A27, A28, A30, A32, A33, A35, A36, A37, A38, A39, A40, A41, A42, A43, A44, A45, A46, A47, A48, A49, A50, A51, A52, A53, A54, A55, A56, A57, A58, A61, A62, A64, A65, A66, A67, A68, A69, A70, A71, A72, A73, A75, A76, A79, A80, A81, A82, A84, A85, A86, A88, Bl, B4, B5.
Diabrotica balteata (Corn root worm):
A 24-well microtiter plate (MTP) with artificial diet was treated with test solutions at an application rate of 200 ppm (concentration in well 18 ppm) by pipetting. After drying, the MTP's were infested with L2 larvae (6-10 per well). After an incubation period of 5 days, samples were checked for larval mortality and growth regulation.
The following compounds gave at least 80% control of Diabrotica balteata: A2, A7, A8, A9, A12, A14, A15, A16, A18, A25, A26, A27, A31, A33, A38, A39, A41, A42, A43, A46, A48, A50, A52, A53, A54, A55, A56, A57, A58, A62, A65, A66, A67, A68, A70, A71, A73, A76, A80, A81, A84, A88, Bl, B4.
Myzus persicae (Green peach aphid), systemic test:
Roots of pea seedlings, infested with an aphid population of mixed ages, are placed directly in the test solutions at an application rate of 12.5 ppm. 6 days after introduction, samples are checked for mortality and special effects on the plant.
The following compounds gave at least 80% control of Myzus persicae: A2, A12, A31, A33, A41, A48, A64, A70.
Thrips tabaci (Onion thrips):
Sunflower leaf discs were placed on agar in a 24-well microtiter plate and sprayed with test solutions at an application rate of 200 ppm. After drying, the leaf discs were infested with an thrips population of mixed ages. After an incubation period of 7 days, samples were checked for mortality.
The following compounds gave at least 80% control of Thrips tabaci: A7, A12, A14, A27, A31, A33, A38, A41, A42, A43, A57, A62, A65, A66, A67, A68, A71, A73, A76, A88, Bl, B4.
Tetranychus urticae (Two-spotted spider mite):
Bean leaf discs on agar in 24-well microtiter plates were sprayed with test solutions at an application rate of 200 ppm. After drying, the leaf discs are infested with mite populations of mixed ages. 8 days later, discs are checked for egg mortality, larval mortality, and adult mortality.
The following compounds gave at least 80% control of Tetranychus urticae: A3, A7, A18, A23, A25, A38, A40, A41, A42, A43, A45, A46, A57, A62, Bl .

Claims

Claims
1. A compound of formula I
Figure imgf000117_0001
Q is Ql or Q2
Figure imgf000117_0002
G1 is oxygen or sulfur;
Y1 is oxygen, sulfur or CH2;
2 3 4 5 2 3
Y YJ and Y are each independently C-H, C-R or nitrogen, wherein no more than one of Y , YJ and Y4 is C-R5;
Y5 is hydrogen, halogen, Ci-C8alkyl, Ci-C8haloalkyl, or C3-C8cycloalkyl;
Y6 is hydrogen, halogen, cyano, Ci-C8alkyl, Ci-C8haloalkyl, or C3-C8cycloalkyl;
Rla is hydrogen, CpC8alkyl, Ci-C8alkoxy, Ci-C8alkylcarbonyl, or CpC8alkoxycarbonyl;
Rlb is hydrogen, CpQalkyl, Ci-C8alkylcarbonyl or CpQalkoxycarbonyl;
R2a is CrC8alkyl or Ci-C8alkyl substituted by one to five R7, C2-C8alkenyl or C2-C8alkenyl substituted by one to five R7, C2-C8alkynyl or C2-C8alkynyl substituted by one to five R7, C - Ciocycloalkyl or C3-Ci0cycloalkyl substituted by one to five R8, C3-Ciocycloalkyl-Ci-C4alkylene or C - Ciocycloalkyl-Ci-C4alkylene substituted by one to five R8, aryl-Ci-C4alkylene- or aryl-Ci-C4alkylene- substituted by one to five R9, heterocyclyl-Ci-C4alkylene- or heterocyclyl-Ci-C4alkylene- substituted by one to five R9, aryl or aryl substituted by one to five R9, heterocyclyl or heterocyclyl substituted by one to five R9, Ci-C8alkylaminocarbonyl-Ci-C4alkylene, Ci-C8haloalkylaminocarbonyl-Ci-C4 alkylene, C3- C8cycloalkyl-aminocarbonyl-Ci-C4alkylene, aryl-CH2-aminocarbonyl-Ci-C4alkylene or aryl-CH2- aminocarbonyl-Ci-C4alkylene wherein the aryl is substituted by one to five R9, Ci-C8alkylaminocarbonyl, Ci-C8haloalkylaminocarbonyl, C3-C6cycloalkylaminocarbonyl, Ci-C6alkyl-0-N=CH-, Ci-Cehaloalkyl-O- N=CH-, C1-C6alkyl-0-N=CH-C1-C4alkylene- or C1-C6alkyl-0-N=CH-C1-C4alkylene- substituted by one to five R7, and wherein alkylene groups may be substituted by a fused 3- to 6-membered carbocyclic ring; or Rla and R2a together form a 4- or 5-membered ring fragment containing carbon atoms as ring members, optionally substituted by one to five R9;
R2b is Ci-C8alkyl or Ci-C8alkyl substituted by one to five R7, C2-C8alkenyl or C2-C8alkenyl substituted by one to five R7, C2-C8alkynyl or C2-C8alkynyl substituted by one to five R7, Ci-C8alkoxy- CpC8alkyl or CpC8alkoxy-CpC8alkyl substituted by one to five R7, C3-Ciocycloalkyl or C3-Ciocycloalkyl substituted by one to five R8, C3-Ciocycloalkyl-Ci-C4alkylene or C3-Ciocycloalkyl-Ci-C4alkylene substituted by one to five R8, aryl-Ci-C4alkylene- or aryl-Ci-C4alkylene- substituted by one to five R9, heterocyclyl-Ci-C4alkylene- or heterocyclyl-Ci-C4alkylene- substituted by one to five R9, aryl or aryl substituted by one to five R9, heterocyclyl or heterocyclyl substituted by one to five R9, and wherein alkylene groups may be substituted by a fused 3- to 6-membered carbocyclic ring;
R3 is Ci-Cghaloalkyl;
R4 is aryl or aryl substituted by one to five R10, or heteroaryl or heteroaryl substituted by one to five R10;
each R5 is independently halogen, cyano, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy or Cp C4haloalkoxy;
R a is hydrogen, cyano, CpC8alkyl, CpC8haloalkyl or C3-C8cycloalkyl;
R b is hydrogen, cyano, CrC8alkyl, CpC8haloalkyl or C3-C8cycloalkyl;
or R a and R b together with the carbon atom to which they are attached may form a 3 to 6- membered carbocyclic ring;
each R7 is independently halogen, cyano, nitro, hydroxy, amino, CrC8alkyl, C2-C8alkenyl, C2- C8alkynyl, Ci-C8alkylamino, (CpC8alkyl)2ammo, Ci-C8alkylcarbonylamino, Cp
C8haloalkylcarbonylamino, carbonylamino, (carbonyl)(Ci-C8alkyl)amino, (CpC8alkylcarbonyl)(Cp C8alkyl)amino, (Ci-C8haloalkylcarbonyl)(Ci-C8alkyl)amino, Ci-C8alkoxy, Ci-C8haloalkoxy, C3- Cecycloalkyl, Ci-C8alkylcarbonyl, CpC8alkoxycarbonyl, mercapto, Ci-C8alkylthio, Ci-C8haloalkylthio, Ci-C8alkylsulfinyl, Ci-C8haloalkylsulfinyl, Ci-C8alkylsulfonyl, Ci-C8haloalkylsulfonyl, aryl-Cp
C4alkylthio or aryl-Ci-C4alkylthio wherein the aryl moiety is substituted by one to five R11, or two R7 are together OH-N= or CrC6alkoxy-N- each R8 is independently halogen, cyano, Ci-C8alkyl, Ci-C8haloalkyl, C2-C8alkenyl, C2- C8haloalkenyl, C2-C8alkynyl, C2-C8haloalkynyl, Ci-C8alkoxy, Ci-C8haloalkoxy, C3-C6cycloalkyl or Cp C8akoxycarbonyl;
each R9 is independently halogen, cyano, nitro, Ci-C8alkyl, Ci-C8haloalkyl, Ci-C8cyanoalkyl, C2- C8alkenyl, C2-C8haloalkenyl, C2-C8alkynyl, C2-C8haloalkynyl, C3-Ciocycloalkyl, C3-Ciocycloalkyl-Ci- C4alkylene, hydroxy, Ci-C8alkoxy, Ci-C8haloalkoxy, mercapto, CrC8alkylthio, Ci-C8haloalkylthio, Cp C8alkylsulfinyl, Ci-C8haloalkylsulfinyl, Ci-C8alkylsulfonyl, Ci-C8haloalkylsulfonyl, Cp
C8alkylaminosulfonyl, (Ci-C8alkyl)2aminosulfonyl, Ci-C8alkylcarbonyl, Ci-C8haloalkylcarbonyl, Cp C8alkoxycarbonyl or Ci-C8haloalkoxycarbonyl;
each R10 is independently halogen, cyano, nitro, CrC8alkyl, Ci-C8haloalkyl, C2-C8alkenyl, C2- C8haloalkenyl, C2-C8alkynyl, C2-C8haloalkynyl, hydroxy, Ci-C8alkoxy, Ci-C8haloalkoxy, mercapto, Cp C8alkylthio, Ci-C8haloalkylthio, Ci-C8alkylsulfinyl, Ci-C8haloalkylsulfinyl, Ci-C8alkylsulfonyl, Cp C8haloalkylsulfonyl, Ci-C8alkylcarbonyl or CpC8alkoxycarbonyl;
each R11 is independently halogen, cyano, nitro, CpC4alkyl, CpC4haloalkyl, CpC4alkoxy or Cp C4haloalkoxy; or a salt or N-oxide thereof.
2. A compound according to claim 1, wherein Q is Ql .
3. A compound according to claim 1, wherein Q is Q2.
4. A compound according to any one of claims 1 to 3, wherein Y1 is oxygen.
5. A compound according to any one of claims 1 to 4, wherein G1 is oxygen.
6. A compound according to any one of claims 1 to 5, wherein Y2 is C-H, Y3 and Y4 are C-H or C- R5, wherein no more than one of Y3 and Y4 is C-R5, preferably wherein R5 is halogen, cyano, methyl, halomethyl, methoxy or halomethoxy.
7. A compound according to any one of claims 1 to 6, wherein Y5 is hydrogen, methyl, chloro, bromo or tnfluoromethyl and Y6 is hydrogen or methyl, preferably wherein at least one of Y5 and Y6 is hydrogen.
8. A compound according to any one of claims 1, 2 and 4 to 7, wherein R2a is CpCgalkyl or Q- Cgalkyl substituted by one to five R7, C2-Cgalkenyl or C2-Cgalkenyl substituted by one to five R7, C2- Cgalkynyl or C2-C8alkynyl substituted by one to five R7, C3-Ciocycloalkyl or C3-Ciocycloalkyl substituted by one to five R8, C3-C10cycloalkyl-C(R12)(R13)- or C3-C10cycloalkyl-C(R12)(R13)- wherein the cycloalkyl
8 12 13 12 13
is substituted by one to five R , aryl-C(R )(R )- or aryl-C(R )(R )- wherein the aryl is substituted by
9 12 13 12 13
one to five R , heterocyclyl-C(R )(R )- or heterocyclyl-C(R )(R )- wherein the heterocyclyl is substituted by one to five R9, aryl or aryl substituted by one to five R9, heterocyclyl or heterocyclyl substituted by one to five R9, CrC6alkyl-0-N=CH-, CrC6haloalkyl-0-N=CH-, CrC4alkyl-0-N=CH- C(R12)(R13)-, CrC4haloalkyl-0-N=CH-C(R12)(R13)-, Ci-C4alkylaminocarbonyl-CH2- or Cr
C4haloalkylaminocarbonyl-CH2-;
wherein heterocyclyl is a 4 to 7-membered heterocyclic ring containing one to three heteroatoms independently selected from O, S, SO, S(¾, N, and N(R14) as ring atoms.
wherein aryl is phenyl;
wherein R12 and R13 are independently hydrogen, cyano, halogen, Ci-C4alkyl, Ci-Czihaloalkyl, Cp C4alkoxy, Ci-C4haloalkoxy or C3-C6cycloalkyl;
or R12 and R13 together form a three to six membered carbocycle;
and wherein R14 is hydrogen, oxygen or R9;
or Rla and R2a together form a 4- or 5-membered ring fragment containing carbon atoms as ring members, optionally substituted by one to five R9.
9. A compound according to any one of claims 1 and 3 to 8, wherein R2b is CpCgalkyl or CpCgalkyl substituted by one to five R7, C2-Cgalkenyl or C2-Cgalkenyl substituted by one to five R7, C2-C8alkynyl or C2-C8alkynyl substituted by one to five R7, Ci-Cealkoxy-Ci-Cealkyl or Ci-Cealkoxy-Ci-Cealkyl substituted by one to five R7, C3-Ciocycloalkyl or C3-Ciocycloalkyl substituted by one to five R8, C3- C10cycloalkyl-C(R12)(R13)-or C3-C10cycloalkyl-C(R12)(R13)-substituted by one to five R8, aryl- C(R12)(R13)- or aryl-C(R12)(R13)- substituted by one to five R9, heterocyclyl-C(R12)(R13)- or heterocyclyl-
12 13 9 9
C(R )(R )- substituted by one to five R , aryl or aryl substituted by one to five R , heterocyclyl or heterocyclyl substituted by one to five R9;
wherein aryl is phenyl;
wherein heterocyclyl is a 4- to 7-membered heterocyclic ring containing one to four heteroatoms independently selected from O, S, SO, S02, N and N(R14) as ring atoms;
wherein R12 and R13 are independently hydrogen, cyano, halogen, Ci-C4alkyl, Ci-C4haloalkyl, Cr C4alkoxy, Ci-C4haloalkoxy or C3-C6cycloalkyl; and
wherein R14 is hydrogen, oxygen or R9.
10. A compound according to any one of claims 1 to 9, wherein R3 is chlorodifluoromethyl, difluoromethyl or trifluoromethyl.
11. A compound according to any one of claims 1 to 10, wherein R4 is group A
Figure imgf000120_0001
wherein X2 is C-X4 or nitrogen and X1, X3 and X4 are independently hydrogen, halogen or trihalomethyl, providing that at least one of X1, X3 and X4 is not hydrogen.
A compound of formula Int-I
Figure imgf000120_0002
wherein Y1, Y2, Y3, Y4, Y5, Y6, R1, R3, R4, R a and R b are as defined for compounds of formula I in any one of claims 1 to 11 , or a salt or N-oxide thereof; or
a compound of formula Int-II
Figure imgf000121_0001
wherein R 21 and R 22 are independently CpCgalkylcarbonyl, CpCgalkoxycarbonyl, or R 21 and R 22 together are -C(=0)-(CH2)r-C(=0)- wherein r is 1 to 4, -C(CrC3alkyl)=C-C=(Ci-C3alkyl)C-, or group B
Figure imgf000121_0002
and Y1, Y2, Y3, Y4, Y5, Y6, R3, R4, R a and R b are as defined for compounds of formula I in any one of claims 1 to 11 , or a salt or N-oxide thereof; or
a compound of formula Int-III
Figure imgf000121_0003
wherein R is a leaving group (preferably hydroxy, CrC15alkoxy, CI, F or Br), and Y1, Y2, Y3, Y4, Y5, Y6, G1, R3 and R4 are as defined for compounds of formula I in any one of claims 1 to 11 ,or a salt or N-oxide thereof; or
a compounds of formula Int-IV
Figure imgf000121_0004
wherein Ra is hydroxy, PPh3, Br or CI, and Y1, Y2, Y3, Y4, Y5, R3 and R4 are as defined for compounds of formula I in any one of claims 1 to 11, or a salt or N-oxide thereof; or
a compound of formula Int-V
Figure imgf000121_0005
wherein Y1 is hydroxy, Rb is nitro or halogen, R31is nitro, cyano, fluoro, chloro, bromo, iodo or C(0)R'
2 3 4 5 3 4
wherein R' is hydroxy, CrC15alkoxy or CrC4alkyl, and Y Y\ Y Y\ RJ and R" are as defined for compounds of formula I in any one of claims 1 to 11 , or a salt or N-oxide thereof; or
a compound of formula Int-VI
Figure imgf000122_0001
wherein Y6 is hydrogen, hydroxy, halogen, CpCgalkyl, Ci-C8haloalkyl or C3-C8cycloalkyl and Y1, Y2, Y3, Y4, R3 and R4 are as defined for compounds of formula I in any one of claims 1 to 11 , or a salt or N-oxide thereof; or
a compound of formula Int-VII
Figure imgf000122_0002
wherein Rc is NH2 or R , wherein R32is nitro, cyano, halogen, -C(0)N(R")OR",-C(0)R' or C(0)OR", wherein R' is CrCi5alkoxy or Ci-C4alkyl,and each R" is indepedently Ci-C6alkyl, and Y1, Y2, Y3, Y4, R3 and R4 are as defined for compounds of formula Iin any one of claims 1 to 11 , or a salt or N-oxide thereof; or
a compound of formula Int-VIII
Figure imgf000122_0003
1 2 3 4 6 3 4
wherein X is chloro or bromo and Y , Y , Y , Y , Y , R and R are as defined for compounds of formula I in any one of claims 1 to 11 , or a salt or N-oxide thereof; or
a compound of formula Int-IX
R33
Figure imgf000122_0004
(Int-IX)
wherein each R 3J3J is independently CrC6alkyl and Y 1 , Y2, Y 3J,
Figure imgf000122_0005
Y 6°, R 3J and R 4" are as defined for compounds of formula I in any one of claims 1 to 11 ,or a salt or N-oxide thereof.
13. A method of controlling insects, acarines, nematodes or molluscs which comprises applying to a pest, to a locus of a pest, or to a plant susceptible to attack by a pest an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I) as defined in any one of claims 1 to 11.
14. An insecticidal, acaricidal, nematicidal or molluscicidal composition comprising an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I) as defined in any one of claims 1 to 11 , optionally comprising at least one additional compound having biological activity.
15. A combination product comprising a pesticidally effective amount of a component A and a pesticidally effective amount of component B, wherein component A is a compound of formula (I) as defined in any one of claims 1 to 11 , and compound B is imidacloprid, enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, fipronil, ivermectin, omeprazole, tiamulin, benazepril, milbemycin, cyromazine, thiamethoxam, pyriprole, deltamethrin, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, metaflumizone, moxidectin, methoprene (including S-methoprene), clorsulon, pyrantel, amitraz, triclabendazole, avermectin, abamectin, emamectin, eprinomectin, doramectin, selamectin, nemadectin, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, tetramisole, levamisole, pyrantel pamoate, oxantel, morantel, triclabendazole, epsiprantel, fipronil, lufenuron, ecdysone or tebufenozide.
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