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WO2000049001A2 - Phenoxy-, phenylthio-, phenylamino-, benzyloxy-, benzylthio- or benzylaminopyrimidine insectidices and acaricides - Google Patents

Phenoxy-, phenylthio-, phenylamino-, benzyloxy-, benzylthio- or benzylaminopyrimidine insectidices and acaricides Download PDF

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Publication number
WO2000049001A2
WO2000049001A2 PCT/US2000/003180 US0003180W WO0049001A2 WO 2000049001 A2 WO2000049001 A2 WO 2000049001A2 US 0003180 W US0003180 W US 0003180W WO 0049001 A2 WO0049001 A2 WO 0049001A2
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independently
alkyl
haloalkyl
fluoro
trifluoromethyl
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PCT/US2000/003180
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French (fr)
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WO2000049001A3 (en
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Thomas Martin Stevenson
Thomas Paul Selby
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E.I. Du Pont De Nemours And Company
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Publication of WO2000049001A3 publication Critical patent/WO2000049001A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/38—One sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/56—One oxygen atom and one sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention relates to certain phenoxypyrimidines, their N-oxides, agriculturally suitable salts and compositions, and methods of their use as arthropodicides in both agronomic and nonagronomic environments.
  • arthropod pests The control of arthropod pests is extremely important in achieving high crop efficiency. Arthropod damage to growing and stored agronomic crops can cause significant reduction in productivity and thereby result in increased costs to the consumer. The control of arthropod pests in forestry, greenhouse crops, ornamentals, nursery crops, stored food and fiber products, livestock, household, and public and animal health is also important. Many products are commercially available for these purposes, but the need continues for new compounds which are more effective, less costly, less toxic, environmentally safer or have different modes of action.
  • 4,6-Diphenoxypyrimidines (Q is O in the formula below) are disclosed in US Patent 5,707,995 as insecticides and acaricides.
  • 4-Anilino-6-phenoxypyrimidines (Q is ⁇ H in the formula below) are disclosed (WO 98/12184 and WO 98/54154) as insecticides and acaricides.
  • JP99/269154 discloses phenoxypyrimidines wherein Q in the formula below can be certain nitrogen-containing groups.
  • This invention is directed to compounds of Formula I, including all geometric and stereoisomers, N-oxides, and agriculturally suitable salts thereof, agricultural compositions containing them and their use as arthropodicides:
  • Q 1 is O, S, NR 17 , OCR 18 R 19 , or NR 17 CR 18 R 19 ; wherein when Q 1 is OCR 18 R 19 or
  • Q 1 is attached to the pyrimidine through the O or N atom respectively;
  • Q 2 is S, CR3R4, OCR 18 R 19 , SCRl 8 R 19 or NR 17 CR 18 R 19 ; wherein when Q 2 is
  • Jl j2 X, Y and Z are each independently N or CR 22 ;
  • R 1 and R 2 are each independently H, C1-C4 alkyl, halogen, NR 7 R 8 , C1-C4 alkoxy,
  • R 3 and R 4 are each independently H, halogen, hydroxy, C1-C 4 alkyl, C1-C4 alkoxy, Cj-C4 haloalkyl or cyano; or R 3 and R 4 are taken together with the attached carbon to make a carbonyl; each R 5 is independently H, halogen, C1-C 4 alkyl, C1-C4 haloalkoxy, C1-C4 haloalkyl,
  • each R 6 and each R 22 is independently H, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C r C 4 haloalkoxy, C r C 4 alkoxy, NR 17 or S(O) n R 9 ;
  • R 7 and R 8 are each independently H, C1-C4 alkyl, C3-C 6 alkenyl, C 3 -C 6 alkynyl,
  • each R 9 is independently C1-C4 alkyl or C1-C4 haloalkyl
  • each R 10 is independently Cj-Cg alkyl, phenyl optionally substituted by R 6 , C1-C6 haloalkyl, CO 2 R 14 , C r C 6 alkoxyalkyl, C 2 -C 4 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 cyanoalkyl or NR 15 R 16 ;
  • R 11 and R 12 are each independently C1-C6 alkyl, Ci-Cg haloalkyl, C 2 -C6 alkenyl or
  • alkyl used either alone or in compound words such as “alkylthio” or “haloalkyl” includes straight-chain or branched alkyl, such as methyl, ethyl, «-propyl, t-propyl, or the different butyl, pentyl or hexyl isomers.
  • Alkenyl includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers.
  • Alkenyl also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl.
  • Alkynyl includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers.
  • Alkynyl can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl.
  • Alkoxy includes, for example, methoxy, ethoxy, «-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers.
  • Alkoxyalkyl denotes alkoxy substitution on alkyl.
  • alkoxyalkyl include CH 3 OCH 2 , CH 3 OCH 2 CH 2 , CH 3 CH 2 OCH 2 , CH 3 CH 2 CH 2 CH 2 OCH 2 and CH 3 CH 2 OCH 2 CH 2 .
  • Cyanoalkyl denotes an alkyl group substituted with one cyano group. Examples of “cyanoalkyl” include NCCH 2 , NCCH 2 CH 2 and CH 3 CH(CN)CH 2 .
  • halogen either alone or in compound words such as “haloalkyl”, includes fluorine, chlorine, bromine or iodine.
  • haloalkyl when used in compound words such as "haloalkyl", said alkyl may be partially or fully substituted with halogen atoms which may be the same or different.
  • haloalkyl include F 3 C, C1CH 2 , CF 3 CH 2 and CF 3 CC1 2 .
  • haloalkoxy is defined analogously to the term “haloalkyl”.
  • C1-C4 alkyl designates methyl, ethyl, «-propyl, t-propyl, or the different butyl isomers.
  • a compound of Formula I when a compound of Formula I is comprised of one or more heterocyclic rings, all substituents are attached to these rings through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.
  • substituents When a compound is substituted with a substituent bearing a subscript that indicates the number of said substituents can exceed 1, said substituents (when they exceed 1) are independently selected from the group of defined substituents. Further, when the subscript indicates a range, e.g. (R)i_ j , then the number of substituents may be selected from the integers between i and j inclusive.
  • substituents When a group contains a substituent which can be hydrogen, for example R 1 or R 6 , then, when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted.
  • nitrogen containing heterocycles can form N-oxides since the nitrogen requires an available lone pair for oxidation to the oxide; one skilled in the art will recognize those nitrogen containing heterocycles which can form N-oxides.
  • nitrogen containing heterocycles which can form N-oxides.
  • tertiary amines can form N-oxides.
  • N-oxides of heterocycles and tertiary amines are very well known by one skilled in the art including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethydioxirane.
  • MCPBA peroxy acids
  • alkyl hydroperoxides such as t-butyl hydroperoxide
  • sodium perborate sodium perborate
  • dioxiranes such as dimethydioxirane
  • Stereoisomers of this invention can exist as one or more stereoisomers.
  • the various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers.
  • one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s).
  • the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers.
  • the present invention comprises compounds selected from Formula I, N-oxides and agriculturally suitable salts thereof.
  • the compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form.
  • the salts of the compounds of the invention 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.
  • 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 salts of the compounds of the invention also include those formed with organic bases (e.g., pyridine, ammonia, or triethylamine) or inorganic bases (e.g., hydrides, hydroxides, or carbonates of sodium, potassium, lithium, calcium, magnesium or barium) when the compound contains an acidic group such as a carboxylic acid or phenol.
  • organic bases e.g., pyridine, ammonia, or triethylamine
  • inorganic bases e.g., hydrides, hydroxides, or carbonates of sodium, potassium, lithium, calcium, magnesium or barium
  • an acidic group such as a carboxylic acid or phenol.
  • compounds of Formula Ie including all geometric and stereoisomers, N-oxides, and agriculturally suitable salts thereof, agricultural compositions containing them and their use as arthropodicides:
  • Q is O, S or ⁇ R 17 ;
  • R 1 and R 2 are each independently H, C1-C4 alkyl, halogen, ⁇ R 7 R 8 , C 1-C4 alkoxy,
  • R 3 and R 4 are each independently H, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl or cyano; or R 3 and R 4 are taken together with the attached carbon to make a carbonyl; each R 5 is independently halogen, C1-C 4 alkyl, C1-C4 haloalkoxy, C1-C4 haloalkyl,
  • each R 6 is independently H, halogen, cyano, C 1 -C4 alkyl, C J -C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, or S(O) n R 9 ;
  • R 7 and R 8 are each independently H, C1-C4 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl,
  • each R 9 is independently C1-C4 alkyl or C1-C4 haloalkyl
  • each R 10 is independently Ci-Cg alkyl, phenyl optionally substituted by R 6 , C j -Cg haloalkyl, CO 2 R 14 , C r C 6 alkoxyalkyl, C 2 -C 4 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 cyanoalkyl or NR 15 R 16 ;
  • R 1 1 and R 12 are each independently Ci-Cg alkyl, Ci-Cg haloalkyl, C 2 -C6 alkenyl or
  • R 13 and R 17 are each independently C r C 4 alkyl, H, COR 10 or CO 2 R ⁇ ; each R 14 is independently C1-C4 alkyl; each R 15 is independently H, C1-C4 alkyl, C1-C4 alkoxy or phenyl optionally substituted by R 6 ; each R 16 is independently H or C1-C 4 alkyl; n is 0-2; p is 0-4; J is J 1 or J 2 ; Ji IS
  • X, Y and Z are each independently N or CR 6 .
  • Q 1 is O, S, ⁇ R 17 , OCR 18 R 19 , or ⁇ R 17 CR 18 R 19 ; wherein when Q 1 is OCR 18 R 19 or NR 17 CR 18 R 19 , then Q 1 is attached to the pyrimidine through the O or N atom respectively;
  • Q 2 is S, CR 3 R 4 , OCR 18 R 19 , SCR 18 R 19 or NR 17 CR 18 R 19 ; wherein when Q 2 is OCR 18 R 19 , SCR 18 R 19 or NRl 7 CRl 8 Rl then Q 2 is attached to the pyrimidine through the O, S or N atom respectively;
  • J is
  • X, Y and Z are each independently N or CR 22 ;
  • R 1 and R 2 are each independently H, C1-C4 alkyl, halogen, NR 7 R 8 , C1-C4 alkoxy, Ci-
  • R 3 and R 4 are each independently H, halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl or cyano; or R 3 and R 4 are taken together with the attached carbon to make a carbonyl; each R 5 is independently H, halogen, C1-C4 alkyl, C1-C4 haloalkoxy, C1-C4 haloalkyl,
  • each R 6 and each R 22 is independently H, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C r C 4 haloalkoxy, C r C 4 alkoxy, NR 17 or S(O) n R 9 ;
  • R 7 and R 8 are each independently H, C1-C 4 alkyl, C 3 -Cg alkenyl, C 3 -Cg alkynyl,
  • each R 9 is independently C1-C 4 alkyl or C 1 -C4 haloalkyl; each R 10 is independently C1-C6 alkyl, phenyl optionally substituted by R 6 , C1-C6 haloalkyl, CO 2 R 14 , C r C 6 alkoxyalkyl, C 2 -C 4 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 cyanoalkyl or NR 15 R 16 ; R 1 J and R 12 are each independently C j-Cg alkyl, C 1-C6 haloalkyl, C 2 -Cg alkenyl or
  • R 13 and R 17 are each independently C r C 4 alkyl, H, COR 10 or CO 2 R ⁇ ; each R 14 is independently C1-C4 alkyl; each R 15 is independently H, C1-C 4 alkyl, C 1 -C4 alkoxy or phenyl optionally substituted by R 6 ; R 16 and R 19 are each independently H or C1-C4 alkyl; each R 18 is independently H, C ] -C 6 alkyl, C ⁇ -C 6 haloalkyl, C -C 6 alkenyl, C 2 -C 6 alkynyl, or cyano; n is 0-2; p is 0-4; and q is 0-4.
  • Preferred compounds for reasons of better activity and/or ease of synthesis are: Preferred 1. Compounds of Formula I above, N-oxides and agriculturally suitable salts thereof, wherein: J is J 1 ;
  • R 1 and R 2 are H;
  • R 5 is C r C 2 haloalkyl; each R 6 and each R 22 is halogen; and
  • R 3 and R 4 are either each H or taken together with the attached carbon as a carbonyl.
  • Preferred 2. Compounds of Formula I above, N-oxides and agriculturally suitable salts thereof, wherein: J is J 2 ;
  • R 1 and R 2 are H; R 5 is C, to C 2 haloalkyl; each R 6 and each R 22 is halogen; R 3 and R 4 are each H; and Y is ⁇ , X is CH and Z is CR 22 .
  • Most preferred are compounds of Preferred 1 selected from the group: 4-[4-fluoro-3-(trifluoromethyl)phenoxy]-6-[[4-fluoro-3-
  • This invention also relates to arthropodicidal compositions comprising arthropodicidally effective amounts of the compounds of the invention and at least one of a surfactant, a solid diluent or a liquid diluent.
  • a surfactant a solid diluent or a liquid diluent.
  • the preferred compositions of the present invention are those which comprise the above preferred compounds.
  • This invention also relates to a method for controlling arthropods comprising contacting the arthropods or their environment with an arthropodicidally effective amount of the compounds of the invention (e.g., as a composition described herein).
  • the preferred methods of use are those involving the above preferred compounds.
  • the compounds of Formula I can be prepared by one or more of the following methods and variations as described in Schemes 1-10.
  • the definitions of J, Q 1 , Q 2 , R 1 through R 22 , X, Y, Z, n and p in the compounds of Formulae 1-15 below are as defined above in the Summary of the Invention.
  • Compounds of Formulae la-Id are various subsets of the compounds of Formula I, and all substituents for Formulae la-Id are as defined above for Formula I.
  • Scheme 1 illustrates the preparation of compounds of Formula I by displacement of a pyrimidine of Formula 2 with a nucleophile of Formula 3 in the presence of a base.
  • Preferred acid acceptors include alkali carbonates, hydroxides and hydrides with potassium carbonate being the most preferred acid acceptor.
  • Many solvents are acceptable such as acetone, methylethylketone, acetonitrile, dimethylformamide, dimethylacetamide, and dimethylsulfoxide. In some instances aqueous solvents or lower alcohols may be used.
  • the reaction may be run at temperatures from 0 to 150 °C with temperatures from 20 to 80 °C being preferred.
  • reaction may also be run in acidic media such as aqueous mineral acids or homogeneous mixtures of aqueous acids with miscible organic solvents.
  • acidic media such as aqueous mineral acids or homogeneous mixtures of aqueous acids with miscible organic solvents.
  • a preferred method for using anilines is to carry out the reaction in aqueous acetone containing hydrochloric acid.
  • L is halogen or Q 1 is O, S, NR 1 7 or OCR 1 8 R 19 S0 2 (C ⁇ -C 4 alkyl)
  • compounds of Formula 2a can be readily prepared by the coupling of a zinc species of Formula 4 with a halogenopyrimidine of Formula 5.
  • the coupling reaction can be catalyzed by either nickel or palladium complexes.
  • the preferred complexes for this transformation are tetrakis(triphenylphosphine)palladium and dichloro-bis(triphenylphosphine)palladium.
  • the catalyst may be present in an amount from 0.5-10% relative to the pyrimidine and zinc reagent.
  • the reaction may be run in a variety of solvents with aprotic solvents such as acetonitrile, dimethylformamide, and tetrahydrofuran being preferred.
  • aprotic solvents such as acetonitrile, dimethylformamide, and tetrahydrofuran being preferred.
  • the reaction depending upon the substituents on the pyrimidine ring, may be done at temperatures ranging from 20 to 120 °C.
  • Compounds of Formula 5 are generally commercially available or can be made by known methods (see D. J. Brown in The Pyrimidines in E. C. Taylor, editor, The Chemistry of Heterocyclic Compounds, Vol 16, 1957,: Supplement 1, 1967 and Supplement II, 1985; Wiley, New York).
  • Each L 1 is independently halogen
  • Scheme 3 illustrates the synthesis of zinc reagents of Formula 4 from halogenated methylbenzenes of Formula 6.
  • the substituted halide of Formula 6 is reacted with activated zinc (see Jubert and Knochel, J. Org, Chem. 1992,. 57, p 5425 and Knochel et. al., Tetrahedron 1998, 54, p 8275) in a suitable solvent such as tetrahydrofuran, acetonitrile, NN-dimethylformamide, dimethoxy ethane or other aprotic solvent. Reaction temperatures may range from 0 to 80 °C.
  • L 1 is halogen
  • This reaction is carried out in the presence of a strong base such as an alkali hydride, preferrably sodium hydride, in solvents such as dichloromethane, dioxane, tetrahydrofuran, benzene, toluene or other aprotic solvent.
  • the reaction may be carried out at temperatures between 0 and 120 °C.
  • a wide variety of azolium salts catalyze this transformation and a number are described by Miyashita (Heterocycles, 1996, 43, 509-512 and references cited therein).
  • a preferred catalyst is 1,3-dimethylimidazolium iodide which may be present in a 10 to 100% catalyst load.
  • Each L is independently halogen
  • compounds of Formula 2c may be prepared by the reaction of a pyrimidine of Formula 9 with a heterocycle of Formula 10 in the presence of an acid acceptor.
  • acid acceptors are alkali carbonates, hydroxides and hydrides with potassium carbonate being the most preferred acid acceptor.
  • Many solvents are useful such as acetone, methylethylketone, acetonitrile, dimethylformamide, dimethylacetamide, and dimethylsulfoxide. In some instances aqueous solvents or lower alcohols may be used.
  • the reaction may be run at temperatures from 0 to 150 °C with temperatures from 20 to 80 °C being preferred.
  • Pyrimidines of Formula 9 may be prepared according to Scheme 6.
  • Preferred halogenating agents include bromine, N-bromosuccinimide, sulfuryl chloride, and N-chlorosuccinimide.
  • the preferred solvents are lower carboxylic acids such as acetic acid.
  • Polar aprotic solvents such as dimethylformamide are preferred in reactions involving N-halosuccinimides.
  • the halogenation may be carried out at temperatures ranging from 20 to 120 °C.
  • 11 L is halogen or S0 2 C ⁇ -C4alkyl
  • Met is Mg, Li, Zn, Sn
  • Each L 1 is independently halogen
  • compounds of Formula lb may be synthesized by reduction of nitropyrimidines of Formula lb (compounds of Formula I in which R 1 is NO 2 .)
  • the reduction of nitro groups to amines is well known in the art and can be accomplished by many reagents and techniques as illustrated by Larock, Comprehensive Organic Transformations, VCH, 1989, p 411 to 417 and March Advanced Organic Chemistry, Wiley, 1992, 1216-18 and 1232-33.
  • the preferred technique is catalytic hydrogenation using palladium on carbon or platinum oxide as catalyst.
  • ethers, amides, alcohols and esters can be used as solvents in this process with tetrahydrofuran or ethyl acetate being preferred.
  • This transformation can be carried out at temperatures from 0 to 100 °C, with 20-30 °C being preferred, under 1-100 atmospheres of hydrogen.
  • Another useful method is to use tin (II) chloride as the reductant in ethyl acetate or ethanol as solvent. This reaction can be carried out at temperatures between 0 and 80 °C.
  • R 1 is N0 2 *" RMs NH 2
  • Compounds of Formula Ic (compounds of Formula I in which R 1 is NR 7 R 8 ) can be made as indicated in Scheme 9.
  • Compounds of Formula lb may be alkylated, acylated or sulfonylated by alkyl halides, acyl halides or sulfonyl halides of Formula 13, respectively, in the presence of an acid acceptor.
  • the reaction may be carried out with an excess of the compound of Formula 13 to yield compounds of Formula Id where R 7 and R 8 are the same. It also may be carried out in a stepwise manner to yield first a compound of Formula Ic in which R 1 is NR 7 R 8 , R 8 is hydrogen, and R 7 is other than hydrogen.
  • a second compound of Formula 14 may be reacted to yield the compound of Formula Id where R 1 is NR 7 R 8 and both R 7 and R 8 are other than hydrogen.
  • Preferred acid acceptors are tertiary amines, alkali carbonates, hydroxides and hydrides with potassium carbonate and triethylamine being the most preferred acid acceptors.
  • Many solvents are acceptable such as acetone, methyl ethylketone, acetonitrile, dimethylformamide, dimethylacetamide, and dimethylsulfoxide. In some instances aqueous solvents or lower alcohols may be used.
  • the reaction may be run at temperatures from 0 to 150 °C with temperatures from 20 to 80 °C being preferred.
  • L 1 R ] is NR 7 R 8
  • Scheme 10 illustrates the preparation of compounds of Formula 2d by displacement of a pyrimidine of Formula 5a with a nucleophile of Formula 15 in the presence of a base.
  • Pyrimidines of Formula 5a in which L is a halogen or sulfone react with nucleophiles of Formula 15 in the presence of a variety of acid acceptors and in a variety of solvents to give the desired compounds of Formula 2d.
  • Preferred acid acceptors include alkali carbonates, hydroxides, alkoxides and hydrides with potassium carbonate being the most preferred acid acceptor.
  • Organic tertiary amines such as triethylamine are also acceptable bases for this reaction.
  • solvents are acceptable such as acetone, methylethylketone, acetonitrile, dimethylformamide, dimethylacetamide, and dimethylsulfoxide. In some instances aqueous solvents or lower alcohols may be used.
  • the reaction may be run at temperatures from 0 to 150 °C with temperatures from 20 to 80 °C being preferred.
  • the preferred bases are alkali hydrides such as sodium hydride or alkali alkoxides such as potassium t-butoxide. In these cases solvents such as dimethylformamide, dimethylacetamide, and tetrahydrofuran are preferred.
  • Q 2 is NR 17 CR 18 R 19 the preferred bases are tertiary amines with triethylamine being the most preferred.
  • Q 2 is S, OCR 1 8 R 19 , NR 17 CR 1 8 R 19 or SCR 1 8 R 19
  • the zinc was allowed to settle and the supernatant amount was drawn into a syringe and transferred to a solution of 4,6-dichloropyrimidine (1.49 g, 10 mmol) and dichloro-bis(triphenylphosphine)palladium (100 mg, 0.14 mmol) dissolved in tetrahydrofuran (10 mL).
  • the reaction mixture was heated at reflux for 3 hours and allowed to stir at 25 °C overnight.
  • the mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 X 50 mL). The combined extracts were dried over magnesium sulfate.
  • Step B Preparation of 4-rr4-fluoro-3-(trifluoromethyl)phenyl1methyl1-6-[ " 3-
  • Step A Preparation of (6-chloro-4-pyrimidinyl [3 -(trifluoromethyl phenyllmethanone A solution of 4,6-dichloropyrimidine (3.3 g, 21.4 mmol),
  • Step B Preparation of [ " 6-r3-(trifluoromethyl)phenoxy -4-pyrimidinyl][3-
  • Zinc powder (6.5 g, 100 mmol) in tetrahydrofuran (50 mL) was treated with dibromoethane (3 drops) and heated briefly to reflux. Upon cooling trimethylsilyl chloride (3 drops) was added and the mixture was heated at reflux briefly. After the mixture had cooled to 45 °C 4-fluoro-3-trifluoromethylbenzyl bromide (5.23 g, 20 mmol) dissolved in tetrahydrofuran (10 mL) was added dropwise. The addition caused an exotherm to reflux. After heating for 1 h at reflux the reaction was cooled to room temperature. The excess zinc was removed by centrifugation under an inert atmosphere.
  • step A The compound of step A (0.65 g, 1.3 mmol) and 4-fluoro-3-trifluoromethylphenol (0.27 g, 1.5 mmol) were dissolved in tetrahydrofuran (15 mL) and treated with resin-supported l,5,7-triazabicyclo[4.4.0]-dec-5-ene (Fluka, 2.2 mmol/g, 1.5 g, 3.3 mmol). After stirring at 25 °C for 16 h the mixture was filtered and the solvent removed under reduced pressure. The residue was suspended in acetic acid (3 mL) and water (15 mL). The mixture was heated to 50 °C and iron powder 0.3 g was added. The mixture was heated at near reflux for 3 hours and then filtered through celite.
  • Step B Preparation of 4-[4-fluoro-3-(trifluoromethyl)phenoxy "
  • dichloromethane 50 mL
  • m-chloroperbenzoic acid 64%>, 6.4 g, 24 mmol
  • the organic layer was diluted with dichloromethane (100 mL) and washed with saturated aqueous NaHCO 3 solution (200 mL). The organic layer was dried over magnesium sulfate and evaporated to give the titled compound of step B (2.3 g).
  • Step C Preparation of 4- (4-chlorophenyl)methyllthio]-6- 4-fluoro-3-(trifluoro- methyl)phenoxy]pyrimidine
  • the compound of Step B (0.67 g, 2 mmol) was dissolved in dimethylformamide (5 mL) and treated with 4-chlorobenzylmercaptan (0.32 g, 1.8 mmol) and potassium carbonate (0.7 g, 5 mmol).
  • CR 3 R 4 is CO. O 1 is 0,
  • CR 3 R 4 is CO.
  • O 1 is NH.
  • CR 3 R 4 is CO.
  • O 1 is S.
  • R 22 is 4-F.
  • R 6 is 4-F, Z R 8 Z R 8 Z R 8 EZ R 8
  • B is CH 2 .
  • R 22 is 4-F.
  • R 6 is 4-Cl.
  • O 1 is O.
  • Y is N.
  • X is CH.
  • Z is CR 22 , ⁇ 5a R22 R6 R 5a R22 R6 R5a R22 R6
  • O 1 is NH.
  • Y is N.
  • X is CH, Z is CR 22 ,
  • O 1 is O.
  • Y is CR 22 .
  • X is CH.
  • Z is N,
  • Y is CR 22 .
  • X is CH, Z is -N.
  • O 1 is O.
  • Y is N.
  • X is CR 22 .
  • Z is N
  • O 1 is NH.
  • Y is N.
  • X is CR 22 .
  • Z is T
  • O 1 is O Y is CH.
  • X is CH.
  • Z is CR 22
  • R 5a R22 R6 R 5a R 22 R6 R5a R22 R6 CF 3 H 4-F CF 3 CF 2 H 4-F CF 2 H H 4-F CF 3 H H CF 3 CF 2 H H CF 2 H H H CF 3 H 4-Cl CF 3 CF 2 H 4-Cl CF 2 H H 4-Cl CF 3 H 4-N0 2 CF 3 CF 2 H 4-N0 2 CF 2 H H 4-N0 2 CF 3 H 4-Br CF 3 CF 2 H 4-Br CF 2 H H H 4-Br CF 3 Cl 4-F CF 3 CF 2 Cl 4-F CF 3 Cl H CF 3 CF 2 Cl H CF 2 H Cl H
  • Compounds of this invention will generally be used as a Formulation or composition with an agriculturally suitable carrier comprising at least one of a liquid diluent, a solid diluent or a surfactant.
  • the Formulation or composition ingredients are selected to be consistent with the physical properties of the active ingredient, mode of application and environmental factors such as soil type, moisture and temperature.
  • Useful Formulations include liquids such as solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions and/or suspoemulsions) and the like which optionally can be thickened into gels.
  • Useful Formulations further include solids such as dusts, powders, granules, pellets, tablets, films, and the like which can be water-dispersible ("wettable") or water-soluble.
  • the active ingredient can be (micro)encapsulated and further formed into a suspension or solid Formulation; alternatively the entire Formulation of active ingredient can be encapsulated (or "overcoated”). Encapsulation can control or delay release of the active ingredient.
  • Sprayable Formulations can be extended in suitable media and used at spray volumes from about one to several hundred liters per hectare. High-strength compositions are primarily used as intermediates for further Formulation.
  • Formulations will typically contain effective amounts of active ingredient, diluent and surfactant within the following approximate ranges which add up to 100 percent by weight.
  • Typical solid diluents are described in Watkins, et al, Handbook of Insecticide Dust Diluents and Carriers, 2nd Ed., Dorland Books, Caldwell, New Jersey. Typical liquid diluents are described in Marsden, Solvents Guide, 2nd Ed., Interscience, New York, 1950. McCutcheon 's Detergents and Emulsi ⁇ ers Annual, Allured Publ. Corp., Ridgewood, New Jersey, as well as Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964, list surfactants and recommended uses. All Formulations can contain minor amounts of additives to reduce foam, caking, corrosion, microbiological growth and the like, or thickeners to increase viscosity.
  • Surfactants include, for example, polyethoxylated alcohols, polyethoxylated alkylphenols, polyethoxylated sorbitan fatty acid esters, dialkyl sulfosuccinates, alkyl sulfates, alkylbenzene sulfonates, organosilicones, N,N-dialkyltaurates, lignin sulfonates, naphthalene sulfonate formaldehyde condensates, polycarboxylates, and polyoxyethylene/polyoxypropylene block copolymers.
  • Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, starch, sugar, silica, talc, diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate, and sodium sulfate.
  • Liquid diluents include, for example, water, N,N-dimethylformamide, dimethyl sulfoxide, N-alkylpyrrolidone, ethylene glycol, polypropylene glycol, paraffins, alkylbenzenes, alkylnaphthalenes, oils of olive, castor, linseed, rung, sesame, corn, peanut, cotton-seed, soybean, rape-seed and coconut, fatty acid esters, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy-4-methyl-2-pentanone, and alcohols such as methanol, cyclohexanol, decanol and tetrahydrofurfuryl alcohol.
  • Solutions can be prepared by simply mixing the ingredients. Dusts and powders can be prepared by blending and, usually, grinding as in a hammer mill or fluid-energy mill. Suspensions are usually prepared by wet-milling; see, for example, U.S. 3,060,084. Granules and pellets can be prepared by spraying the active material upon preformed granular carriers or by agglomeration techniques. See Browning, "Agglomeration", Chemical Engineering, December 4, 1967, pp 147-48, Perry's Chemical Engineer 's Handbook, 4th Ed., McGraw-Hill, New York, 1963, pages 8-57 and following, and WO 91/13546. Pellets can be prepared as described in U.S.
  • Water-dispersible and water-soluble granules can be prepared as taught in U.S. 4,144,050, U.S. 3,920,442 and DE 3,246,493. Tablets can be prepared as taught in U.S. 5,180,587, U.S. 5,232,701 and U.S. 5,208,030. Films can be prepared as taught in GB 2,095,558 and U.S. 3,299,566.
  • Compound 7 65.0% dodecylphenol polyethylene glycol ether 2.0% sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0% montmorillonite (calcined) 23.0%.
  • Compound 7 25.0% anhydrous sodium sulfate 10.0% crude calcium ligninsulfonate 5.0% sodium alkylnaphthalenesulfonate 1.0% calcium/magnesium bentonite 59.0%
  • Emulsifiable Concentrate Compound 7 20.0% blend of oil soluble sulfonates and polyoxyethylene ethers 10.0% isophorone 70.0%.
  • the compounds of this invention exhibit activity against a wide spectrum of foliar-feeding, fruit-feeding, stem or root feeding, seed-feeding, aquatic and soil-inhabiting arthropods (term “arthropods” includes insects, mites and nematodes) which are pests of growing and stored agronomic crops, forestry, greenhouse crops, ornamentals, nursery crops, stored food and fiber products, livestock, household, and public and animal health. Those skilled in the art will appreciate that not all compounds are equally effective against all growth stages of all pests.
  • all of the compounds of this invention display activity against pests that include: eggs, larvae and adults of the Order Lepidoptera; eggs, foliar-feeding, fruit-feeding, root-feeding, seed-feeding larvae and adults of the Order Coleoptera; eggs, immatures and adults of the Orders Hemiptera and Homoptera; eggs, larvae, nymphs and adults of the Order Acari; eggs, immatures and adults of the Orders Thysanoptera, Orthoptera and Dermaptera; eggs, immatures and adults of the Order Diptera; and eggs, juveniles and adults of the Phylum Nematoda.
  • the compounds of this invention are also active against pests of the Orders Hymenoptera, Isoptera, Siphonaptera, Blattaria, Thysanura and Psocoptera; pests belonging to the Class Arachnida and Phylum Platyhelminthes.
  • the compounds are active against southern corn rootworm (Diabrotica undecimpunctata howardi), aster leafhopper (Mascrosteles fascifrons), boll weevil (Anthonomus grandis), two-spotted spider mite (Tetranychus urticae), fall armyworm (Spodoptera frugiperda), black bean aphid (Aphis fabae), green peach aphid (Myzus persica), cotton aphid (Aphis gossypii), Russian wheat aphid (Diuraphis noxia), English grain aphid (Sitobion avenae), tobacco budworm (Heliothis virescens), rice water weevil (Lissorhoptrus oryzophilus), rice leaf beetle (Oulema oryzae), whitebacked planthopper (Sogatella furcifera), green leafhopper (Nephotettix cincticeps), brown planthopper (
  • Tetranychidae including Tetranychus urticae, Tetranychus cinnabarinus, Tetranychus mcdanieli, Tetranychus pacificus, Tetranychus turkestani,
  • Compounds of this invention can also be mixed with one or more other insecticides, fungicides, nematocides, bactericides, acaricides, growth regulators, chemosterilants, semiochemicals, repellents, attractants, pheromones, feeding stimulants or other biologically active compounds to form a multi-component pesticide giving an even broader spectrum of agricultural protection.
  • insecticides such as abamectin, acephate, azinphos-methyl, bifenthrin, buprofezin, carbofuran, chlorfenapyr, chlorpyrifos, chlorpyrifos-methyl, cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, deltamethrin, diafenthiuron, diazinon, diflubenzuron, dimethoate, esfenvalerate, fenoxycarb, fenpropathrin, fenvalerate, fipronil, flucythrinate, tau-fluvalinate, fonophos, imidacloprid, isofenphos, malathion, metaldehyde, methamidophos, methidathion, methomyl, methoprene
  • insecticides such as abamectin, acep
  • Arthropod pests are controlled and protection of agronomic, horticultural and specialty crops, animal and human health is achieved by applying one or more of the compounds of this invention, in an effective amount, to the environment of the pests including the agronomic and/or nonagronomic locus of infestation, to the area to be protected, or directly on the pests to be controlled.
  • the present invention further comprises a method for the control of foliar and soil inhabiting arthropods and nematode pests and protection of agronomic and/or nonagronomic crops, comprising applying one or more of the compounds of the invention, or compositions containing at least one such compound, in an effective amount, to the environment of the pests including the agronomic and/or nonagronomic locus of infestation, to the area to be protected, or directly on the pests to be controlled.
  • a preferred method of application is by spraying.
  • granular formulations of these compounds can be applied to the plant foliage or the soil.
  • Other methods of application include direct and residual sprays, aerial sprays, seed coats, microencapsulations, systemic uptake, baits, eartags, boluses, foggers, fumigants, aerosols, dusts and many others.
  • the compounds can be incorporated into baits that are consumed by the arthropods or in devices such as traps and the like.
  • the compounds of this invention can be applied in their pure state, but most often application will be of a formulation comprising one or more compounds with suitable carriers, diluents, and surfactants and possibly in combination with a food depending on the contemplated end use.
  • a preferred method of application involves spraying a water dispersion or refined oil solution of the compounds. Combinations with spray oils, spray oil concentrates, spreader stickers, adjuvants, other solvents, and synergists such as piperonyl butoxide often enhance compound efficacy.
  • the rate of application required for effective control will depend on such factors as the species of arthropod 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. Under normal circumstances, application rates of about 0.01 to 2 kg of active ingredient per hectare are sufficient to control pests in agronomic ecosystems, but as little as 0.001 kg/hectare may be sufficient or as much as 8 kg hectare may be required. For nonagronomic applications, effective use rates will range from about 1.0 to 50 mg/square meter but as little as 0.1 mg/square meter may be sufficient or as much as 150 mg/square meter may be required.
  • Test A demonstrates the control efficacy of compounds of this invention on specific pests.
  • Control efficacy represents inhibition of arthropod development (including mortality) that causes significantly reduced feeding.
  • the pest control protection afforded by the compounds is not limited, however, to this species. See Index Tables A-B for compound descriptions.
  • the abbreviation “Ex.” stands for “Example” and is followed by a number indicating in which example the compound is prepared.
  • Two-Spotted Spider Mite Pieces of kidney bean leaves each approximately 6.5 cm 2 (1 square inch) in area, that had been infested on the undersides with 25 to 30 adult mites (Tetranychus urticae), were sprayed with their undersides facing up on a hydraulic sprayer with a solution of the test compound in 75:25 acetone-distilled water solvent. Spraying was accomplished by passing the leaves, on a conveyor belt, directly beneath a flat fan hydraulic nozzle which discharged the spray at a rate of 0.138 kilograms of active ingredient per hectare (about 0.13 pounds per acre) at 207 kPa (30 p.s.i.).
  • the leaf squares were then placed underside-up on a square of wet cotton in a petri dish and the perimeter of the leaf square was tamped down onto the cotton with forceps so that the mites could not escape onto the untreated leaf surface.
  • the test units were held at 27°C and 50% relative humidity for 48 hours, after which time mortality readings were taken. Of the compounds tested, the following gave mortality levels of 80% or higher: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 35, 37, 39, 40, 41, 42 and 43.
  • TEST B Fall Armyworm Test units each consisting of a H.I. S. (high impact styrene) tray with 16 cells were prepared. Wet filter paper and approximately 8 cm 2 of lima bean leaf was placed into twelve of the cells. A 0.5-cm layer of wheat germ diet was placed into the four remaining cells. Fifteen to twenty third-instar larvae of fall armyworm (Spodoptera frugiperdd) were placed into a 230-n ⁇ L (8-ounce) plastic cup. Solutions of each of the test compounds in 75:25 acetone-distilled water solvent were sprayed into the tray and cup.
  • H.I. S. high impact styrene
  • Spraying was accomplished by passing the tray and cup on a conveyer belt directly beneath a flat fan hydraulic nozzle which discharged the spray at a rate of 0.138 kilograms of active ingredient per hectare (about 0.13 pounds per acre) at 207 kPa (30 p.s.i.).
  • the insects were transferred from the 230-mL cup to the H.I.S. tray (one insect per cell).
  • the trays were covered and held at 27°C and 50% relative humidity for 48 hours, after which time readings were taken on the twelve cells with lima bean leaves. The four remaining cells were read at 6-8 days for delayed toxicity. Of the compounds tested, the following gave control efficacy levels of 80% or greater: 41.
  • test unit consisted of a plastic cup containing 126 +/- 4 grams of sterilized, non-fertilized sassafras (sandy loam) soil.
  • sassafras sandy loam soil.
  • One pre-germinated Pioneer variety 3394 corn seed is placed in a 1 inch depression in the soil and covered.
  • the test unit was watered with 15mL of distilled water and placed in a closed plexiglas box inside a greenhouse operating at 24 degrees centigrade and 36% relative humidity for 4 days at which time it is ready for test.
  • a snug-fitting test unit lid with a small opening at the top was placed on all test units prior to test.
  • Test compounds were formulated at 250 ppm in 20% acetone: 80% water containing 500 ppm Ortho X-77 surfactant. Compounds were applied through the opening in the test unit lid with an atomizer sprayer fitted with a Model 17690- 1/8JJAU nozzle and a spray set-up consisting of a J2850 Fluid Cap and J70 Air Cap (Spray Sytems, Inc.). The sprayer was operated at 12-13psi. For each compound, 2 test units were sprayed with a total of 2 mL each of test solution. After spraying, test units were placed in a ventilated enclosure for 10-15 minutes to dry.
  • Insect Infesting/Evaluation After drying, a thin layer of white quartz sand was poured onto the soil of each test unit to aid in the evaluation of live and dead insects at the conclusion of the test. Each unit was infested with a minimum of 15 nymphs of the corn planthopper, Peregrinus maidis, which were approximately 21 days old. Infested test units were held in a growth chamber operating at 22 degrees centigrade and 50% relative humidity with a 16:8 ligh dark photoperiod. Insect mortality was evaluated at 6 days post-infestation. Moribund insects were counted as dead. Of the compounds tested, the following gave mortality of 80% or greater: 42.

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Abstract

Compounds of Formula (I), and their N-oxides and agriculturally suitable salts, are disclosed which are useful as arthropodicides wherein Q1 is O, S, NR?17, OCR18R19, or NR17CR18R19¿; wherein when Q?1 is OCR18R19 or NR17CR18R19¿, then Q1 is attached to the pyrimidine through the O or N atom respectively; Q2 is S, CR?3R4, OCR18R19, SCR18R19 or NR17CR18R19¿; wherein when Q?2 is OCR18R19, SCR18R19 or NR17CR18R19 then Q2¿ is attached to the pyrimidine through the O, S or N atom respectively; R?1 and R2¿ are each independently H, C¿1?-C4 alkyl, halogen, NR?7R8, C¿1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylthio or nitro; each R5 is independently H, halogen, C¿1?-C4 alkyl, C1-C4 haloalkoxy, C1-C4 haloalkyl, C1-C4 alkoxy, SF5, S(O)nR?9¿, cyano or CO¿2R?11; each R6 and each R22 is independently H, halogen, cyano, C¿1?-C4 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, NR?17¿ or S(O)¿nR?9; p is 0-4; and J, R?3, R4R7, R8, R9, R11, R17, R18, R19¿ and n are as defined in the disclosure. Also disclosed are compositions containing the compounds of Formula (I) and a method for controlling arthropods which involves contacting the arthropods or their environment with an effective amount of a compound of Formula (I).

Description

TITLE PHENOXYPYRIMIDINE INSECTICIDES AND ACARICIDES
BACKGROUND OF THE INVENTION
This invention relates to certain phenoxypyrimidines, their N-oxides, agriculturally suitable salts and compositions, and methods of their use as arthropodicides in both agronomic and nonagronomic environments.
The control of arthropod pests is extremely important in achieving high crop efficiency. Arthropod damage to growing and stored agronomic crops can cause significant reduction in productivity and thereby result in increased costs to the consumer. The control of arthropod pests in forestry, greenhouse crops, ornamentals, nursery crops, stored food and fiber products, livestock, household, and public and animal health is also important. Many products are commercially available for these purposes, but the need continues for new compounds which are more effective, less costly, less toxic, environmentally safer or have different modes of action.
4,6-Diphenoxypyrimidines (Q is O in the formula below) are disclosed in US Patent 5,707,995 as insecticides and acaricides. 4-Anilino-6-phenoxypyrimidines (Q is ΝH in the formula below) are disclosed (WO 98/12184 and WO 98/54154) as insecticides and acaricides. JP99/269154 discloses phenoxypyrimidines wherein Q in the formula below can be certain nitrogen-containing groups.
Figure imgf000003_0001
The phenoxypyrimidines of the present invention are not disclosed in these publications.
SUMMARY OF THE INVENTION This invention is directed to compounds of Formula I, including all geometric and stereoisomers, N-oxides, and agriculturally suitable salts thereof, agricultural compositions containing them and their use as arthropodicides:
Figure imgf000003_0002
wherein
Q1 is O, S, NR17, OCR18R19, or NR17CR18R19; wherein when Q1 is OCR18R19 or
NR17CR18R19, then Q1 is attached to the pyrimidine through the O or N atom respectively; Q2 is S, CR3R4, OCR18R19, SCRl8R19 or NR17CR18R19; wherein when Q2 is
OCR18R19, SCR18Rl9 or NRl7CRl 8Rl then Q2 is attached to the pyrimidine through the O, S or N atom respectively; J is
Figure imgf000004_0001
Jl j2 X, Y and Z are each independently N or CR22;
R1 and R2 are each independently H, C1-C4 alkyl, halogen, NR7R8, C1-C4 alkoxy,
C1-C4 haloalkyl, C1-C4 alkylthio or nitro; R3 and R4 are each independently H, halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, Cj-C4 haloalkyl or cyano; or R3 and R4 are taken together with the attached carbon to make a carbonyl; each R5 is independently H, halogen, C1-C4 alkyl, C1-C4 haloalkoxy, C1-C4 haloalkyl,
CrC4 alkoxy, SF5, S(O)nR9, cyano or CO2Rπ; each R6 and each R22 is independently H, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, CrC4 haloalkoxy, CrC4 alkoxy, NR17 or S(O)nR9; R7 and R8 are each independently H, C1-C4 alkyl, C3-C6 alkenyl, C3-C6 alkynyl,
COR1(>, CO2Rn, CHO, SO2R12 or OR13; each R9 is independently C1-C4 alkyl or C1-C4 haloalkyl; each R10 is independently Cj-Cg alkyl, phenyl optionally substituted by R6, C1-C6 haloalkyl, CO2R14, CrC6 alkoxyalkyl, C2-C4 alkenyl, C2-C6 alkynyl, C2-C6 cyanoalkyl or NR15R16;
R11 and R12 are each independently C1-C6 alkyl, Ci-Cg haloalkyl, C2-C6 alkenyl or
C2-Cg alkynyl; R13 and R17 are each independently CrC4 alkyl, H, COR10 or CO^11; each R14 is independently C1-C4 alkyl; each R15 is independently H, C1-C4 alkyl, Cj-C alkoxy or phenyl optionally substituted by R6; R16 and R19 are each independently H or C1-C4 alkyl; each R18 is independently H, Ci-Cg alkyl, Ci-Cg haloalkyl, C2-C6 alkenyl, C2-Cg alkynyl, or cyano; n is 0-2; p is 0-4; and q is 0-4; provided that when Q2 is NR17CR18R19, then J is J2.
In the above recitations, the term "alkyl", used either alone or in compound words such as "alkylthio" or "haloalkyl" includes straight-chain or branched alkyl, such as methyl, ethyl, «-propyl, t-propyl, or the different butyl, pentyl or hexyl isomers. "Alkenyl" includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers. "Alkenyl" also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl. "Alkynyl" includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers. "Alkynyl" can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl. "Alkoxy" includes, for example, methoxy, ethoxy, «-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers. "Alkoxyalkyl" denotes alkoxy substitution on alkyl. Examples of "alkoxyalkyl" include CH3OCH2, CH3OCH2CH2, CH3CH2OCH2, CH3CH2CH2CH2OCH2 and CH3CH2OCH2CH2. "Cyanoalkyl" denotes an alkyl group substituted with one cyano group. Examples of "cyanoalkyl" include NCCH2, NCCH2CH2 and CH3CH(CN)CH2. The term "halogen", either alone or in compound words such as "haloalkyl", includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as "haloalkyl", said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of "haloalkyl" include F3C, C1CH2, CF3CH2 and CF3CC12. The term "haloalkoxy" is defined analogously to the term "haloalkyl".
The total number of carbon atoms in a substituent group is indicated by the "Cj-C;" prefix where i and j are numbers from 1 to 6. For example, C1-C4 alkyl designates methyl, ethyl, «-propyl, t-propyl, or the different butyl isomers. In the above recitations, when a compound of Formula I is comprised of one or more heterocyclic rings, all substituents are attached to these rings through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.
When a compound is substituted with a substituent bearing a subscript that indicates the number of said substituents can exceed 1, said substituents (when they exceed 1) are independently selected from the group of defined substituents. Further, when the subscript indicates a range, e.g. (R)i_j, then the number of substituents may be selected from the integers between i and j inclusive. When a group contains a substituent which can be hydrogen, for example R1 or R6, then, when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted.
One skilled in the art will appreciate that not all nitrogen containing heterocycles can form N-oxides since the nitrogen requires an available lone pair for oxidation to the oxide; one skilled in the art will recognize those nitrogen containing heterocycles which can form N-oxides. One skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for the preparation of N-oxides of heterocycles and tertiary amines are very well known by one skilled in the art including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethydioxirane. These methods for the preparation of N-oxides have been extensively described and reviewed in the literature, see for example: T. L. Gilchrist in Comprehensive Organic Synthesis, vol. 1, pp 748-750, S. V. Ley, Ed., Pergamon Press; M. Tisler and B. Stanovnik in Comprehensive Heterocyclic Chemistry, vol. 3, pp 18-20, A. J. Boulton and A. McKillop, Eds., Pergamon Press; M. R. Grimmett and B. R. T. Keene in Advances in Heterocyclic Chemistry, vol. 43, pp 149-161, A. R. Katritzky, Ed., Academic Press; M. Tisler and B. Stanovnik in Advances in Heterocyclic Chemistry, vol. 9, pp 285-291, A. R. Katritzky and A. J. Boulton, Eds., Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk in Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, A. R. Katritzky and A. J. Boulton, Eds., Academic Press.
Compounds of this invention can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. One skilled in the art will appreciate that one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers. Accordingly, the present invention comprises compounds selected from Formula I, N-oxides and agriculturally suitable salts thereof. The compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form.
The salts of the compounds of the invention 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 salts of the compounds of the invention also include those formed with organic bases (e.g., pyridine, ammonia, or triethylamine) or inorganic bases (e.g., hydrides, hydroxides, or carbonates of sodium, potassium, lithium, calcium, magnesium or barium) when the compound contains an acidic group such as a carboxylic acid or phenol. Of note are compounds of Formula Ie, including all geometric and stereoisomers, N-oxides, and agriculturally suitable salts thereof, agricultural compositions containing them and their use as arthropodicides:
Figure imgf000007_0001
wherein
Q is O, S or ΝR17;
R1 and R2 are each independently H, C1-C4 alkyl, halogen, ΝR7R8, C 1-C4 alkoxy,
C1-C4 haloalkyl, C1-C4 alkylthio or nitro; R3 and R4 are each independently H, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl or cyano; or R3 and R4 are taken together with the attached carbon to make a carbonyl; each R5 is independently halogen, C1-C4 alkyl, C1-C4 haloalkoxy, C1-C4 haloalkyl,
CrC4 alkoxy, SF5, S(O)nR9, cyano or CO2Rπ; each R6 is independently H, halogen, cyano, C1-C4 alkyl, CJ-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, or S(O)nR9; R7 and R8 are each independently H, C1-C4 alkyl, C3-C6 alkenyl, C3-C6 alkynyl,
COR10, CO2Rn, CHO, SO2R12 or OR13; each R9 is independently C1-C4 alkyl or C1-C4 haloalkyl; each R10 is independently Ci-Cg alkyl, phenyl optionally substituted by R6, Cj-Cg haloalkyl, CO2R14, CrC6 alkoxyalkyl, C2-C4 alkenyl, C2-C6 alkynyl, C2-C6 cyanoalkyl or NR15R16; R1 1 and R12 are each independently Ci-Cg alkyl, Ci-Cg haloalkyl, C2-C6 alkenyl or
C2-Cg alkynyl; R13 and R17 are each independently CrC4 alkyl, H, COR10 or CO2Rπ; each R14 is independently C1-C4 alkyl; each R15 is independently H, C1-C4 alkyl, C1-C4 alkoxy or phenyl optionally substituted by R6; each R16 is independently H or C1-C4 alkyl; n is 0-2; p is 0-4; J is J1 or J2; Ji IS
Figure imgf000008_0001
J2 IS
Figure imgf000008_0002
X, Y and Z are each independently N or CR6. Also of note are compounds of Formula If, including all geometric and stereoisomers, N-oxides, and agriculturally suitable salts thereof, agricultural compositions containing them and their use as arthropodicides:
Figure imgf000008_0003
If wherein
Q1 is O, S, ΝR17, OCR18R19, or ΝR17CR18R19; wherein when Q1 is OCR18R19 or NR17CR18R19, then Q1 is attached to the pyrimidine through the O or N atom respectively; Q2 is S, CR3R4, OCR18R19, SCR18R19 or NR17CR18R19; wherein when Q2 is OCR18R19, SCR18R19 or NRl7CRl8Rl then Q2 is attached to the pyrimidine through the O, S or N atom respectively; J is
Figure imgf000008_0004
X, Y and Z are each independently N or CR22;
R1 and R2 are each independently H, C1-C4 alkyl, halogen, NR7R8, C1-C4 alkoxy, Ci-
C4 haloalkyl, C1-C4 alkylthio or nitro; R3 and R4 are each independently H, halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl or cyano; or R3 and R4 are taken together with the attached carbon to make a carbonyl; each R5 is independently H, halogen, C1-C4 alkyl, C1-C4 haloalkoxy, C1-C4 haloalkyl,
CrC4 alkoxy, SF5, S(O)nR9, cyano or CO2Rπ; each R6 and each R22 is independently H, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, CrC4 haloalkoxy, CrC4 alkoxy, NR17 or S(O)nR9;
R7 and R8 are each independently H, C1-C4 alkyl, C3-Cg alkenyl, C3-Cg alkynyl,
COR10, CO2Rn, CHO, SO2R12 or OR13; each R9 is independently C1-C4 alkyl or C1-C4 haloalkyl; each R10 is independently C1-C6 alkyl, phenyl optionally substituted by R6, C1-C6 haloalkyl, CO2R14, CrC6 alkoxyalkyl, C2-C4 alkenyl, C2-C6 alkynyl, C2-C6 cyanoalkyl or NR15R16; R1 J and R12 are each independently C j-Cg alkyl, C 1-C6 haloalkyl, C2-Cg alkenyl or
C2-Cg alkynyl; R13 and R17 are each independently CrC4 alkyl, H, COR10 or CO2Rπ; each R14 is independently C1-C4 alkyl; each R15 is independently H, C1-C4 alkyl, C1-C4 alkoxy or phenyl optionally substituted by R6; R16 and R19 are each independently H or C1-C4 alkyl; each R18 is independently H, C]-C6 alkyl, Cι-C6 haloalkyl, C -C6 alkenyl, C2-C6 alkynyl, or cyano; n is 0-2; p is 0-4; and q is 0-4. Preferred compounds for reasons of better activity and/or ease of synthesis are: Preferred 1. Compounds of Formula I above, N-oxides and agriculturally suitable salts thereof, wherein: J is J1;
R1 and R2 are H; R5 is CrC2 haloalkyl; each R6 and each R22 is halogen; and
R3 and R4 are either each H or taken together with the attached carbon as a carbonyl. Preferred 2. Compounds of Formula I above, N-oxides and agriculturally suitable salts thereof, wherein: J is J2;
R1 and R2 are H; R5 is C, to C2 haloalkyl; each R6 and each R22 is halogen; R3 and R4 are each H; and Y is Ν, X is CH and Z is CR22. Most preferred are compounds of Preferred 1 selected from the group: 4-[4-fluoro-3-(trifluoromethyl)phenoxy]-6-[[4-fluoro-3-
(trifluoromethyl)phenyl]methyl]pyrimidine; 4- [4-chloro-3 -(trifluoromethy l)phenoxy] -6- [ [4-fluoro-3 - (trifluoromethyl)phenyl]methyl]pyrimidine;
[6-[4-fluoro-3-(trifluoromethyl)phenoxy]-4-pyrimidinyl][4-fluoro-3- (trifluoromethyl)phenyl]methanone;
4-[4-fluoro-3 -(trifluoromethyl)phenyl]-6- [3 -(trifluoromethyl)- phenyljmethoxypyrimidine;
4- [4-fluoro-3 -(trifluoromethy l)phenoxy] -6- [ [4-fluoro-3 - (trifluoromethyl)phenyl]methyl]-5-pyrimidinamine; 4-[(3 ,4-difluorophenyl)methoxy]-6-[4-fluoro-3-
(trifluoromethyl)phenoxy]pyrimidine and
4-[4-fluoro-3-(trifluoromethyl)phenoxy]- 6-[(4-fluorophenyl)thio]pyrimidine. This invention also relates to arthropodicidal compositions comprising arthropodicidally effective amounts of the compounds of the invention and at least one of a surfactant, a solid diluent or a liquid diluent. The preferred compositions of the present invention are those which comprise the above preferred compounds.
This invention also relates to a method for controlling arthropods comprising contacting the arthropods or their environment with an arthropodicidally effective amount of the compounds of the invention (e.g., as a composition described herein). The preferred methods of use are those involving the above preferred compounds.
DETAILS OF THE INVENTION The compounds of Formula I can be prepared by one or more of the following methods and variations as described in Schemes 1-10. The definitions of J, Q1, Q2, R1 through R22, X, Y, Z, n and p in the compounds of Formulae 1-15 below are as defined above in the Summary of the Invention. Compounds of Formulae la-Id are various subsets of the compounds of Formula I, and all substituents for Formulae la-Id are as defined above for Formula I. Scheme 1 illustrates the preparation of compounds of Formula I by displacement of a pyrimidine of Formula 2 with a nucleophile of Formula 3 in the presence of a base. Pyrimidines of Formula 2 in which L is a halogen or sulfone react with nucleophiles of Formula 3 in the presence of a variety of acid acceptors and in a variety of solvents to give the desired compounds of Formula I. Preferred acid acceptors include alkali carbonates, hydroxides and hydrides with potassium carbonate being the most preferred acid acceptor. Many solvents are acceptable such as acetone, methylethylketone, acetonitrile, dimethylformamide, dimethylacetamide, and dimethylsulfoxide. In some instances aqueous solvents or lower alcohols may be used. The reaction may be run at temperatures from 0 to 150 °C with temperatures from 20 to 80 °C being preferred. When Q1 is NR17 the reaction may also be run in acidic media such as aqueous mineral acids or homogeneous mixtures of aqueous acids with miscible organic solvents. A preferred method for using anilines (Formula 3 wherein Q1 is NR17) is to carry out the reaction in aqueous acetone containing hydrochloric acid.
Scheme 1
Figure imgf000011_0001
L is halogen or Q1 is O, S, NR1 7 or OCR1 8R19 S02(C ι -C4 alkyl)
As shown in Scheme 2, compounds of Formula 2a (compounds of Formula 2 wherein J is J1 and Q2 is CR3R4) can be readily prepared by the coupling of a zinc species of Formula 4 with a halogenopyrimidine of Formula 5. The coupling reaction can be catalyzed by either nickel or palladium complexes. The preferred complexes for this transformation are tetrakis(triphenylphosphine)palladium and dichloro-bis(triphenylphosphine)palladium. The catalyst may be present in an amount from 0.5-10% relative to the pyrimidine and zinc reagent. The reaction may be run in a variety of solvents with aprotic solvents such as acetonitrile, dimethylformamide, and tetrahydrofuran being preferred. The reaction, depending upon the substituents on the pyrimidine ring, may be done at temperatures ranging from 20 to 120 °C. Compounds of Formula 5 are generally commercially available or can be made by known methods (see D. J. Brown in The Pyrimidines in E. C. Taylor, editor, The Chemistry of Heterocyclic Compounds, Vol 16, 1957,: Supplement 1, 1967 and Supplement II, 1985; Wiley, New York). Scheme 2
Figure imgf000012_0001
2a
Each L1 is independently halogen
Scheme 3 illustrates the synthesis of zinc reagents of Formula 4 from halogenated methylbenzenes of Formula 6. The substituted halide of Formula 6 is reacted with activated zinc (see Jubert and Knochel, J. Org, Chem. 1992,. 57, p 5425 and Knochel et. al., Tetrahedron 1998, 54, p 8275) in a suitable solvent such as tetrahydrofuran, acetonitrile, NN-dimethylformamide, dimethoxy ethane or other aprotic solvent. Reaction temperatures may range from 0 to 80 °C.
Scheme 3
Activated Zn
Figure imgf000012_0002
L1 is halogen
Compounds of Formula 2b (compounds of Formula 2 wherein Q2 is C(=O), J is J1 and L1 is halogen) can be prepared by the condensation of pyrimidines of Formula 5 and aldehydes of Formula 7 in the presence of an imidazolium catalyst of Formula 8 as shown in Scheme 4. This reaction is carried out in the presence of a strong base such as an alkali hydride, preferrably sodium hydride, in solvents such as dichloromethane, dioxane, tetrahydrofuran, benzene, toluene or other aprotic solvent. The reaction may be carried out at temperatures between 0 and 120 °C. A wide variety of azolium salts catalyze this transformation and a number are described by Miyashita (Heterocycles, 1996, 43, 509-512 and references cited therein). A preferred catalyst is 1,3-dimethylimidazolium iodide which may be present in a 10 to 100% catalyst load. Scheme 4
Figure imgf000013_0001
Each L is independently halogen
As shown in Scheme 5, compounds of Formula 2c (compounds of Formula 2 wherein J is J2 and Q2 is CR3R4) may be prepared by the reaction of a pyrimidine of Formula 9 with a heterocycle of Formula 10 in the presence of an acid acceptor. Preferred acid acceptors are alkali carbonates, hydroxides and hydrides with potassium carbonate being the most preferred acid acceptor. Many solvents are useful such as acetone, methylethylketone, acetonitrile, dimethylformamide, dimethylacetamide, and dimethylsulfoxide. In some instances aqueous solvents or lower alcohols may be used. The reaction may be run at temperatures from 0 to 150 °C with temperatures from 20 to 80 °C being preferred.
Scheme 5
L is halogen
L is halogen or SO2C1-C4 alkyl Pyrimidines of Formula 9 may be prepared according to Scheme 6. Treatment of pyrimidines of Formula 11 with a suitable halogenating reagent gives the pyrimidine of Formula 9. Preferred halogenating agents include bromine, N-bromosuccinimide, sulfuryl chloride, and N-chlorosuccinimide. In the case of bromine the preferred solvents are lower carboxylic acids such as acetic acid. Polar aprotic solvents such as dimethylformamide are preferred in reactions involving N-halosuccinimides. The halogenation may be carried out at temperatures ranging from 20 to 120 °C. Scheme 6
Halogenating Reagent
Figure imgf000014_0001
11 L is halogen or S02C \ -C4alkyl
Many compounds of Formula 11 are known in the art and others as illustrated by Scheme 7 can be prepared by the reaction of known organometallic species of Formula 12 with pyrimidines of Formula 5. The coupling reaction can be catalyzed by either nickel or palladium complexes. The preferred complexes for this transformation are tetrakis(triphenylphosphine)palladium and dichloro-bis(triphenylphosphine)palladium. The catalyst may be present in an amount from 0.5-10 % relative to the pyrimidine and zinc reagent. The reaction may be run in a variety of solvents with aprotic solvents such as acetonitrile, dimethylformamide, and tetrahydrofuran being preferred. The reaction depending upon the substituents on the pyrimidine ring may be done at temperatures ranging
Figure imgf000014_0002
Scheme 7
Figure imgf000014_0003
12
Met is Mg, Li, Zn, Sn
Each L1 is independently halogen
As indicated in Scheme 8, compounds of Formula lb (compounds of Formula I in which R1 is NH ) may be synthesized by reduction of nitropyrimidines of Formula lb (compounds of Formula I in which R1 is NO2.) The reduction of nitro groups to amines is well known in the art and can be accomplished by many reagents and techniques as illustrated by Larock, Comprehensive Organic Transformations, VCH, 1989, p 411 to 417 and March Advanced Organic Chemistry, Wiley, 1992, 1216-18 and 1232-33. In the present example the preferred technique is catalytic hydrogenation using palladium on carbon or platinum oxide as catalyst. A wide variety of ethers, amides, alcohols and esters can be used as solvents in this process with tetrahydrofuran or ethyl acetate being preferred. This transformation can be carried out at temperatures from 0 to 100 °C, with 20-30 °C being preferred, under 1-100 atmospheres of hydrogen. Another useful method is to use tin (II) chloride as the reductant in ethyl acetate or ethanol as solvent. This reaction can be carried out at temperatures between 0 and 80 °C.
Scheme 8
Reduction Ia Conditions lb
R1 is N02 *" RMs NH2
Such as SnCl2 or H2/Pd-C or Pt02
Compounds of Formula Ic (compounds of Formula I in which R1 is NR7R8) can be made as indicated in Scheme 9. Compounds of Formula lb may be alkylated, acylated or sulfonylated by alkyl halides, acyl halides or sulfonyl halides of Formula 13, respectively, in the presence of an acid acceptor. The reaction may be carried out with an excess of the compound of Formula 13 to yield compounds of Formula Id where R7 and R8 are the same. It also may be carried out in a stepwise manner to yield first a compound of Formula Ic in which R1 is NR7R8, R8 is hydrogen, and R7 is other than hydrogen. In a second iteration of the process a second compound of Formula 14 may be reacted to yield the compound of Formula Id where R1 is NR7R8 and both R7 and R8 are other than hydrogen. Preferred acid acceptors are tertiary amines, alkali carbonates, hydroxides and hydrides with potassium carbonate and triethylamine being the most preferred acid acceptors. Many solvents are acceptable such as acetone, methyl ethylketone, acetonitrile, dimethylformamide, dimethylacetamide, and dimethylsulfoxide. In some instances aqueous solvents or lower alcohols may be used. The reaction may be run at temperatures from 0 to 150 °C with temperatures from 20 to 80 °C being preferred.
Scheme 9
Acid Acceptor Acid Acceptor lb Ic . Id
R7.L 1 R S NHR? R8.L 1 R] is NR7R8
13 14
(each L is independently halogen)
Scheme 10 illustrates the preparation of compounds of Formula 2d by displacement of a pyrimidine of Formula 5a with a nucleophile of Formula 15 in the presence of a base. Pyrimidines of Formula 5a in which L is a halogen or sulfone react with nucleophiles of Formula 15 in the presence of a variety of acid acceptors and in a variety of solvents to give the desired compounds of Formula 2d. Preferred acid acceptors include alkali carbonates, hydroxides, alkoxides and hydrides with potassium carbonate being the most preferred acid acceptor. Organic tertiary amines such as triethylamine are also acceptable bases for this reaction. Many solvents are acceptable such as acetone, methylethylketone, acetonitrile, dimethylformamide, dimethylacetamide, and dimethylsulfoxide. In some instances aqueous solvents or lower alcohols may be used. The reaction may be run at temperatures from 0 to 150 °C with temperatures from 20 to 80 °C being preferred. When Q2 is OCR18R19 or SCR18R19 the preferred bases are alkali hydrides such as sodium hydride or alkali alkoxides such as potassium t-butoxide. In these cases solvents such as dimethylformamide, dimethylacetamide, and tetrahydrofuran are preferred. When Q2 is NR17CR18R19 the preferred bases are tertiary amines with triethylamine being the most preferred.
Scheme 10
Figure imgf000016_0001
Q2 is S, OCR1 8R19, NR17 CR1 8R19 or SCR1 8R19
It is recognized that some reagents and reaction conditions described above for preparing compounds of Formula I may not be compatible with certain functionalities present in the intermediates. In these instances, the incorporation of protection/deprotection sequences or functional group interconversions into the synthesis will aid in obtaining the desired products. The use and choice of the protecting groups will be apparent to one skilled in chemical synthesis (see, for example, Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). One skilled in the art will recognize that, in some cases, after the introduction of a given reagent as it is depicted in any individual scheme, it may be necessary to perform additional routine synthetic steps not described in detail to complete the synthesis of compounds of Formula I. One skilled in the art will also recognize that it may be necessary to perform a combination of the steps illustrated in the above schemes in an order other than that implied by the particular sequence presented to prepare the compounds of Formula I. One skilled in the art will also recognize that compounds of Formula I and the intermediates described herein can be subjected to various electrophilic, nucleophilic, radical, organometallic, oxidation, and reduction reactions to add substituents or modify existing substituents. Without further elaboration, it is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever. Percentages are by weight except for chromatographic solvent mixtures or where otherwise indicated. Parts and percentages for chromatographic solvent mixtures are by volume unless otherwise indicated. ^H NMR spectra are reported in ppm downfield from tetramethylsilane; s is singlet, d is doublet, t is triplet, q is quartet, m is multiplet, dd is doublet of doublets, dt is doublet of triplets, br s is broad singlet.
EXAMPLE 1
Preparation of 4-|" 4-fluoro-3-(trifluoromethyl)phenyl]methyll-6-f3- (trifluoromethyl)phenoxylpyrimidine
Step A: Preparation of 4-chloro-6-[T4-fluoro-3-
(trifluoromethyl)phenyl]methyl]pyrimidine Zinc powder (1.3 g, 20 mmol) was suspended in tetrahydrofuran (10 mL) and treated with dibromoethane (2 drops) and heated at reflux for 5 minutes. Trimethylsilyl chloride (2 drops) was added and the reaction was heated at reflux for 5 minutes. 4-Fluoro-3- trifluoromethylbenzyl bromide (2.5 g, 10 mmol) in tetrahydrofuran (20 mL) was then added dropwise with a corresponding exotherm slowly to reflux during the addition. The mixture was heated at reflux for 20 minutes more. The zinc was allowed to settle and the supernatant amount was drawn into a syringe and transferred to a solution of 4,6-dichloropyrimidine (1.49 g, 10 mmol) and dichloro-bis(triphenylphosphine)palladium (100 mg, 0.14 mmol) dissolved in tetrahydrofuran (10 mL). The reaction mixture was heated at reflux for 3 hours and allowed to stir at 25 °C overnight. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 X 50 mL). The combined extracts were dried over magnesium sulfate. The residue was subjected to chromatography on silica gel using hexanes/ethyl acetate (9:1) as eluent. Appropriate fractions were pooled to give the titled compound of Step A (0.75 g) as an oil. IH NMR (CDC13), δ 4.2 (s,2H), 7.15-7.25 (m,2H), 7.42-7.55 (m,2H), 8.95 (s,lH).
Step B: Preparation of 4-rr4-fluoro-3-(trifluoromethyl)phenyl1methyl1-6-["3-
("trifluoromethvDphenoxylpyrimidine The title compound of Step A (0.38 g, 1.3 mmol) was dissolved in acetonitrile
(25 mL) and treated with 3 -trifluoromethy lphenol (0.18 g, 1.1 mmol) followed by potassium carbonate (0.7 g, 5 mmol). The mixture was heated at reflux for 6 hours and then filtered. The residue was subjected to chromatography on silica gel using hexanes/ethyl acetate (85:15) as eluent. Appropriate fractions were pooled to give 4-[[4-fluoro-3- (trifluoromethyl)phenyl]methyl]-6-[3-(trifluoromethyl)phenoxy]pyrimidine, a compound of the invention (0.38 g) as an oil. IH NMR (CDC13), δ 4.11 (s,2H), 6.75 (s,lH), 7.18 (t,lH), 7.28-7.38 (m,lH), 7.42 (s,lH), 7.43-7.60 (m,2H), 8.70 (s,lH).
EXAMPLE 2
Preparation of ["6-|"3-(trifluoromethyl)phenoxy1-4-pyrimidinyl][3-
(trifluoromethvDphenyllmethanone
Step A: Preparation of (6-chloro-4-pyrimidinyl [3 -(trifluoromethyl phenyllmethanone A solution of 4,6-dichloropyrimidine (3.3 g, 21.4 mmol),
3 -trifluoromethy lbenzaldehyde (5.0 g, 27.8 mmol), and 1,3-dimethylimidazolium iodide (2.07 g, 9.3 mmol) in dichloromethane (40 mL) was treated with sodium hydride (60% in mineral oil, 1.11 g, 27.8 mmol). The mixture exothermed to reflux after this addition. The mixture was then heated at reflux for 3 hours. The mixture was diluted with dichloromethane (50 mL) and washed with water (50 mL) followed by saturated sodium chloride solution (50 mL). The dichloromethane solution was dried over magnesium sulfate and evaporated under reduced pressure. The residue was stirred with hexanes (50 mL) and filtered. The filtrate was evaporated and subjected to chromatography on silica gel using hexanes/ethyl acetate (85:15) as eluent. Appropriate fractions were pooled and evaporated. The residue was washed with hexanes (10 mL) to give the titled compound of Step A as an oil (0.5 g) lH NMR (CDC13), δ 7.67 (t,lH), 7.95 (d,lH), 8.03 (s,lH), 8.35 (d,lH), 8.45 (s,lH), 9.18 (s, IH).
Step B: Preparation of ["6-r3-(trifluoromethyl)phenoxy -4-pyrimidinyl][3-
(trifluoromethyl)phenyl]methanone The title compound of Step A (0.40 g, 1.4 mmol) was dissolved in acetonitrile (15 mL) and treated with 3 -trifluoromethy lphenol (0.2 g, 1.2 mmol) followed by potassium carbonate (0.59 g, 5 mmol). The mixture was stirred at room temperature overnight. The solid was removed by filtration and the filtrate was evaporated. The residue was subjected to column chromatography on silica gel using hexanes/ethyl acetate (85:15) as eluent to give [6-[3-(trifluoromethyl)phenoxy]-4-pyrimidinyl][3-(trifluoromethyl)phenyl]methanone, a compound of the invention (0.30 g) as an oil. Η NMR (CDC13) δ 7.38-7.45 (m,lH), 7.49 (s,lH), 7.61 (d,3H), 7.62-7.72 (m,lH), 7.90 (d,lH), 8.38 (d,lH), 8.44 (s,lH), 8.92 (s,lH).
EXAMPLE 3
Preparation of N-r4-fluoro-3-(trifluoromethvπphenyl1-6-[f3-(trifluormethyl phenyl]methyll- 4-pyrimidinamine
4-Chloro-6-(3-trifluoromethylbenzyl)pyrimidine (0.65 g, 2.4 mmol), prepared by the same procedure as Example 1, Step A by using 3 -trifluoromethy lbenzyl bromide in place of 4-fluoro-3 -trifluoromethy lbenzyl bromide, was combined with acetone (50 mL) and water (50 mL). 4-Fluoro-3-trifluoromethylaniline (0.42 g, 2.4 mmol) and concentrated hydrochloric acid (0.5 mL) were added and the mixture was heated at reflux for 16 h. The cooled reaction mixture was made basic by the addition of concentrated ammonium hydroxide and concentrated under reduced pressure. The residue was partitioned between diethyl ether (50 mL) and water (50 mL). The organic layer was washed with saturated aqueous sodium chloride solution 50 mL), dried over magnesium sulfate, and concentrated under reduced pressure to provide an oil which upon standing gave the titled compound, a compound of the invention as a solid (0.9 g), m.p. 102-104 °C. H1 NMR (CDC13) δ 4.03 (s,2H), 6.32 (s,lH), 6.78 (s,lH), 7.20 (m,lH), 7.43-7.57 (m,4H), 7.58-7.68 (m,2H), 8.65 (s,lH).
EXAMPLE 4
Preparation of 4-|"4-fluoro-3-(trifluoromethyl)phenyll-6-[3-(trifluoromethyl)- phenyl]methoxypyrimidine Step A: Preparation of 4-chloro-6-[ -(trifluoromethyl1phenyl1methoxypyrimidine
To a solution of 4,6-dichloropyrimidine (2.0 g, 13 mmol) and 3-(trifluoromethyl)- benzyl alcohol (2.0 g, 11 mmol) stirring in 20 mL of tetrahydrofuran, sodium hydride (0.5 g, 60% in oil) was added with foaming. After stirring at room temperature overnight, the reaction mixture was partitioned between 100 ml, of ethyl acetate and 30 mL of water. The separated organic layer was washed twice with water and brine, dried over magnesium sulfate, and evaporated in vacuo to an oily residue. Purification by flash chromatography on silica gel afforded 2.5 g of the titled compound, isolated as an oil. ^H NMR (CDCI3): δ 8.60 (s,lH), 7.70 (s, IH), 7.65-745 (m's, 3H), 6.86 (s, IH) 5.5 (s, 2H). Step B: Preparation of 4- 4-fluoro-3-(trifluoromethyl)phenyl1-6-[3-(trifluoromethyl)- phenyllmethoxypyrimidine
A stirred mixture of 4-chloro-6- [3 -(trifluoromethy l)phenyl]methoxypyrimidine (700 mg, 2.4 mmol), 4-fluoro-3-(trifluoromethyl)phenol (500 mg, 2.8 mmol) and powdered potassium carbonate (1.0 g, 7.2 mmol) was heated in 8 mL of N,N-dimethylformamide at 80 °C for 4 hours. The reaction mixture was partitioned between 75 mL of diethyl ether and 50 mL of water. The organic layer was separated, washed with water and brine and dried over magnesium sulfate. An oily residue was obtained after removing the solvent in vacuo. Purification by flash chromatography on silica gel afforded 715 mg of the titled compound, isolated as an oil. lH ΝMR (CDCI3): δ 8.44 (s,lH), 7.71 (s, IH), 7.65-7.20 (m's, 6H), 6.32 (s, lH) 5.51 (s, 2H). EXAMPLE 5
Preparation of 4- 4-fluoro-3-(trifluoromethyl phenoxy1-6-[ 4-fluoro-3- (trifluoromethyl1phenyl1methyl]-5-pyrimidinamine Step A: Preparation of 4-chloro-6-rr4-fluoro-3-(trifluoromethyl)phenyl]methyl -5- nitropyrimidine
Zinc powder (6.5 g, 100 mmol) in tetrahydrofuran (50 mL) was treated with dibromoethane (3 drops) and heated briefly to reflux. Upon cooling trimethylsilyl chloride (3 drops) was added and the mixture was heated at reflux briefly. After the mixture had cooled to 45 °C 4-fluoro-3-trifluoromethylbenzyl bromide (5.23 g, 20 mmol) dissolved in tetrahydrofuran (10 mL) was added dropwise. The addition caused an exotherm to reflux. After heating for 1 h at reflux the reaction was cooled to room temperature. The excess zinc was removed by centrifugation under an inert atmosphere. The supernate was added to a solution of 4,6-dichloro-5-nitropyrimidine (5.81 g, 30 mmol) dissolved in tetrahydrofuran (50 mL). Dichloro-bis-(triphenylphosphine) palladium (150 mg) was added as catalyst and the mixture was heated to reflux for 1 h. After stirring at 25 °C overnight the mixture was evaporated to dryness and subjected to column chromatography on silica gel using hexanes/ethyl acetate (1:1) as eluent. The titled compound (1.0 g) was isolated as an oil. ^H NMR (CDCI3): δ 4.13 (s, 2H), 7.17 (m, IH), 7.40-7.52 (m, IH), 7.57 (d, IH), 9.0 (S, IH). Step B: Preparation of 4-|"4-fluoro-3-(trifluoromethyl)phenoxy1-6-|"["4-fluoro-3- (trifluoromethyl phenyl1methyl]-5-pyrimidinamine
The compound of step A (0.65 g, 1.3 mmol) and 4-fluoro-3-trifluoromethylphenol (0.27 g, 1.5 mmol) were dissolved in tetrahydrofuran (15 mL) and treated with resin- supported l,5,7-triazabicyclo[4.4.0]-dec-5-ene (Fluka, 2.2 mmol/g, 1.5 g, 3.3 mmol). After stirring at 25 °C for 16 h the mixture was filtered and the solvent removed under reduced pressure. The residue was suspended in acetic acid (3 mL) and water (15 mL). The mixture was heated to 50 °C and iron powder 0.3 g was added. The mixture was heated at near reflux for 3 hours and then filtered through celite. The celite was washed with dichloromethane (200 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (50 mL) and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue subjected to column chromatography on silica gel using hexanes/ethyl acetate (7:3) as eluent. The titled compound (0.10 g) was isolated as an oil. IH NMR (CDCI3): δ 3.83 (s, 2H), 4.20 (s, 2H), 7.17 (m, IH), 7.2-7.58 (m, 5H), 8.19 ( s, IH). EXAMPLE 6 Preparation of 4-rr(4-chlorophenyl)methyl1thio]-6- 4-fluoro-3- (trifluoromethvDphenoxylpyrimidine Step A: Preparation of 4-F4-fluoro-3-ftrifluoromethyl)phenoxy~|-6- methylthiopyrimidine
A solution of 4-chloro-6-methylthiopyrimidine (1.08 g, 6.8 mmol) in dimethylformamide was treated with potassium carbonate (2.8 g, 20 mmol) and 4-fluoro-3- trifluorophenol (1.2 g, 6.6 mmol) and was heated at 90 °C for 5 h. The mixture was added to ice water (40 mL) and then filtered and washed with water to give the titled compound of step A (1.8 g). M.P. : 85-87 °C. !H NMR (CDC13): δ 8.54 (s, IH), 7.2-7.5 (m, 3H), 6.78 (s, IH), 2.59 (s, 3H).
Step B: Preparation of 4-[4-fluoro-3-(trifluoromethyl)phenoxy"|-6- methylsulfonylpyrimidine The compound of step A (2.5 g, 5 mmol) dissolved in dichloromethane (50 mL)was treated with m-chloroperbenzoic acid (64%>, 6.4 g, 24 mmol) and stirred at 25 °C for 3h. The organic layer was diluted with dichloromethane (100 mL) and washed with saturated aqueous NaHCO3 solution (200 mL). The organic layer was dried over magnesium sulfate and evaporated to give the titled compound of step B (2.3 g). lH NMR (CDCI3): δ 8.9 (s, IH), 7.7 (s, IH), 7.5-7.2 (m, 3H), 3.3 (s, 3H). Step C: Preparation of 4- (4-chlorophenyl)methyllthio]-6- 4-fluoro-3-(trifluoro- methyl)phenoxy]pyrimidine The compound of Step B (0.67 g, 2 mmol) was dissolved in dimethylformamide (5 mL) and treated with 4-chlorobenzylmercaptan (0.32 g, 1.8 mmol) and potassium carbonate (0.7 g, 5 mmol). The mixture was stirred at 25 °C for 24h and partitioned between water (50 mL) and ether (50 mL). The ether was dried over magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica gel with hexanes/ethyl acetate (9:1) as eluent. Pooling appropriate fractions provided the titled compound, a compound of the invention, (0.46 g) as a white solid. M.P.: 66-69 °C; lU NMR (CDCI3): δ 8.57 (s, IH), 7.2-7.5 (m, 7H), 6.75 (s, IH), 4.42 (s, 3H). By the procedures described herein together with methods known in the art, the following compounds of Tables 1 to 5 can be prepared. The following abbreviations are used in the Tables which follow: t is tertiary, s is secondary, n is normal, is iso, c is cyclo, Me is methyl, Et is ethyl, Pr is propyl, z'-Pr is isopropyl, Bu is butyl, Ph is phenyl, OMe is methoxy, OEt is ethoxy, SMe is methylthio, SEt is ethylthio, CN is cyano, NO2 is nitro, Hex is hexyl, S(O)Me is methylsulfinyl, S(O) Me is methylsulfonyl and Ac is acetyl.
Figure imgf000022_0001
Table 1
Figure imgf000022_0002
CR3R4 is CO. O1 is 0,
R22 R6 R22 R6 R22 R6 R22 R6 R22 R6
4-F 4-F 4-F 4-F 4-F 5-F 5-F 4-F 4-F 2-F
4-F 4-C1 4-C1 4-F 4-F 5-C1 5-C1 4-F 4-F 2-C1
4-F 4-CN 4-CN 4-F 4-F 5-CN 5-CN 4-F 4-F 2-CN 4-F 4-N02 4-N02 4-F 4-F 5-N02 5-N02 4-F 4-F 2-N02 4-F 4-CF3 4-CF3 4-F 4-F 5-CF3 5-CF3 4-F 4-F 2-CF3 4-F 4-OCF3 4-OCF3 4-F 4-F 5-OCF3 5-OCF3 4-F 4-F 2-0CF3 4-F 4-Me 4-Me 4-F 4-F 5-Me 5-Me 4-F 4-F 2-Me 4-F 4-OMe 4-OMe 4-F 4-F 5-OMe 5-OMe 4-F 4-F 2-OMe 4-F 4-SMe 4-SMe 4-F 4-F 5-SMe 5-SMe 4-F 4-F 2-SMe 4-F 4-SCF3 4-SCF3 4-F 4-F 5-SCF3 5-SCF3 4-F 4-F 2-SCF3 4-F 4-S02Me 4-S02Me 4-F 4-F 5-S02Me 5-S02Me 4-F 4-F 2-S02Me 4-F 4-Br 4-Br 4-F 4-F 5-Br 5-Br 4-F 4-F 2-Br 4-F 6-F 2-F 4-F 4-F 2,4-diF 6-F 4-F 2,4-diF 4-F 4-F 6-C1 2-C1 4-F 4-F 2,4-diCl 6-C1 4-F 2,4-diCl 4-F 4-F 6-CN 2-CN 4-F 4-F 2,6-diF 6-CN 4-F 2,6-diF 4-F 4-F 6-N02 2-N02 4-F 4-F 4,5-diF 6-N02 4-F 4,5-diF 4-F 4-F 6-CF3 2-CF3 4-F 4-F 2,6-diCl 6-CF3 4-F 2,6-diCl 4-F 4-F 6-OCF3 2-OCF3 4-F 4-F 4,5-diCl 6-OCF3 4-F 4,5-diCl 4-F 4-F 6-Me 2-Me 4-F 4-F 5,6-diF 6-Me 4-F 5,6-diF 4-F 4-F 6-OMe 2-OMe 4-F 4-F 5.6-diCl 6-OMe 4-F 5.6-diCl 4-F 4-F 6-SMe 2-SMe 4-F 4-F 2,5-diF 6-SMe 4-F 2,5-diF 4-F 4-F 6-SCF3 2-SCF3 4-F 4-F 2,5-diCl 6-SCF3 4-F 2,5-diCl 4-F 4-F 6-S02Me 2-S02Me 4-F 4-F 4,6-diF 6-S02Me 4-F 4,6-diF 4-F 4-F 6-Br 2-Br 4-F 4-F 4,6-diCl 6-Br 4-F 4,6-diCl 4-F
Figure imgf000023_0001
R22 R6 R22 R6 R22 R6 R22 R6 R22 R6
4-F 6-F 2-F 4-F 4-F 2,4-diF 6-F 4-F 2,4-diF 4-F
4-F 6-C1 2-C1 4-F 4-F 2,4-diCl 6-C1 4-F 2,4-diCl 4-F
4-F 6-CN 2-CN 4-F 4-F 2,6-diF 6-CN 4-F 2,6-diF 4-F
4-F 6-N02 2-N02 4-F 4-F 4,5-diF 6-N02 4-F 4,5-diF 4-F
4-F 6-CF3 2-CF3 4-F 4-F 2,6-diCl 6-CF3 4-F 2,6-diCl 4-F
4-F 6-OCF3 2-OCF3 4-F 4-F 4,5-diCl 6-OCF3 4-F 4,5-diCl 4-F
4-F 6-Me 2-Me 4-F 4-F 5,6-diF 6-Me 4-F 5,6-diF 4-F
4-F 6-OMe 2-OMe 4-F 4-F 5.6-diCl 6-OMe 4-F 5.6-diCl 4-F
4-F 6-SMe 2-SMe 4-F 4-F 2,5-diF 6-SMe 4-F 2,5-diF 4-F
4-F 6-SCF3 2-SCF3 4-F 4-F 2,5-diCl 6-SCF3 4-F 2,5-diCl 4-F
4-F 6-S02Me 2-S02Me 4-F 4-F 4,6-diF 6-S02Me 4-F 4,6-diF 4-F
4-F 6-Br 2-Br 4-F 4-F 4,6-diCl 6-Br 4-F 4,6-diCl 4-F
e
Figure imgf000024_0001
4-F 6-S02Me 2-S02Me 4-F 4-F 4,6-diF 6-S02Me 4-F 4,6-diF 4-F 4-F 6-Br 2-Br 4-F 4-F 4,6-diCl 6-Br 4-F 4,6-diCl 4-F
CR3R4 is CO. O1 is NH.
R22 R6 R22 R6 R22 R6 R22 R6 R22 R6.
4-F F 4-F 4-F 4-F 5-F 5-F 4-F 4-F 2-F 4-F Cl 4-C1 4-F 4-F 5-C1 5-C1 4-F 4-F 2-C1 4-F CN 4-CN 4-F 4-F 5-CN 5-CN 4-F 4-F 2-CN 4-F N02 4-N02 4-F 4-F 5-N02 5-N02 4-F 4-F 2-N02 4-F CF3 4-CF3 4-F 4-F 5-CF3 5-CF3 4-F 4-F 2-CF3 4-F OCF3 4-OCF3 4-F 4-F 5-0CF3 5-OCF3 4-F 4-F 2-OCF3 4-F Me 4-Me 4-F 4-F 5-Me 5-Me 4-F 4-F 2-Me 4-F OMe 4-OMe 4-F 4-F 5-OMe 5-OMe 4-F 4-F 2-OMe 4-F SMe 4-SMe 4-F 4-F 5-SMe 5-SMe 4-F 4-F 2-SMe 4-F SCF3 4-SCF3 4-F 4-F 5-SCF3 5-SCF3 4-F 4-F 2-SCF3 4-F S02Me 4-S02Me 4-F 4-F 5-S02Me 5-S02Me 4-F 4-F 2-S02Me 4-F Br 4-Br 4-F 4-F 5-Br 5-Br 4-F 4-F 2-Br 4-F •F 2-F 4-F 4-F 2,4-diF 6-F 4-F 2,4-diF 4-F 4-F Cl 2-C1 4-F 4-F 2,4-diCl 6-C1 4-F 2,4-diCl 4-F 4-F ■CN 2-CN 4-F 4-F 2,6-diF 6-CN 4-F 2,6-diF 4-F 4-F ■N02 2-N02 4-F 4-F 4,5-diF 6-N02 4-F 4,5-diF 4-F 4-F ■CF3 2-CF3 4-F 4-F 2,6-diCl 6-CF3 4-F 2,6-diCl 4-F 4-F ■0CF3 2-OCF3 4-F 4-F 4,5-diCl 6-OCF3 4-F 4,5-diCl 4-F 4-F ■Me 2-Me 4-F 4-F 5,6-diF 6-Me 4-F 5,6-diF 4-F 4-F ■OMe 2-OMe 4-F 4-F 5.6-diCl 6-OMe 4-F 5.6-diCl 4-F 4-F ■SMe 2-SMe 4-F 4-F 2,5-diF 6-SMe 4-F 2,5-diF 4-F 4-F ■SCF3 2-SCF3 4-F 4-F 2,5-diCl 6-SCF3 4-F 2,5-diCl 4-F 4-F ■S02Me 2-S02Me 4-F 4-F 4,6-diF 6-SOMe2 4-F 4,6-diF 4-F 4-F ■Br 2-Br 4-F 4-F 4,6-diCl 6-Br 4-F 4,6-diCl 4-F
Figure imgf000025_0001
3 4-F 4-Me 4-Me 4-F 4-F 5-Me 5-Me 4-F 4-F Me 4-F 4-OMe 4-OMe 4-F 4-F 5-OMe 5-OMe 4-F 4-F OMe 4-F 4-SMe 4-SMe 4-F 4-F 5-SMe 5-SMe 4-F 4-F SMe 4-F 4-SCF3 4-SCF3 4-F 4-F 5-SCF3 5-SCF3 4-F 4-F SCF3 4-F 4-S02Me 4-S02Me 4-F 4-F 5-S02Me 5-S02Me 4-F 4-F S02Me 4-F 4-Br 4-Br 4-F 4-F 5-Br 5-Br 4-F 4-F Br 4-F 6-F 2-F 4-F 4-F 2,4-diF 6-F 4-F 2,4-diF 4-F 4-F 6-C1 2-C1 4-F 4-F 2,4-diCl 6-C1 4-F 2,4-diCl 4-F 4-F 6-CN 2-CN 4-F 4-F 2,6-diF 6-CN 4-F 2,6-diF 4-F 4-F 6-N02 2-N02 4-F 4-F 4,5-diF 6-N02 4-F 4,5-diF 4-F 4-F 6-CF3 2-CF3 4-F 4-F 2,6-diCl 6-CF3 4-F 2,6-diCl 4-F 4-F 6-0CF3 2-OCF3 4-F 4-F 4,5-diCl 6-OCF3 4-F 4,5-diCl 4-F 4-F 6-Me 2-Me 4-F 4-F 5,6-diF 6-Me 4-F 5,6-diF 4-F 4-F 6-OMe 2-OMe 4-F 4-F 5.6-diCl 6-OMe 4-F 5.6-diCl 4-F 4-F 6-SMe 2-SMe 4-F 4-F 2,5-diF 6-SMe 4-F 2,5-diF 4-F 4-F 6-SCF3 2-SCF3 4-F 4-F 2,5-diCl 6-SCF3 4-F 2,5-diCl 4-F 4-F 6-S02Me 2-S02Me 4-F 4-F 4,6-diF 6-S02Me 4-F 4,6-diF 4-F 4-F 6-Br 2-Br 4-F 4-F 4,6-diCl 6-Br 4-F 4,6-diCl 4-F
CR3R4 is CO. O1 is S.
R22 R6 R22 Rό R22 R6 R22 R6 R22 R6.
4-F 4-F 4-F 4-F 4-F 5-F 5-F 4-F 4-F 2-F 4-F 4-C1 4-C1 4-F 4-F 5-C1 5-C1 4-F 4-F 2-C1 4-F 4-CN 4-CN 4-F 4-F 5-CN 5-CN 4-F 4-F 2-CN 4-F 4-N02 4-N02 4-F 4-F 5-N02 5-N02 4-F 4-F 2-N02 4-F 4-CF3 4-CF3 4-F 4-F 5-CF3 5-CF3 4-F 4-F 2-CF3 4-F 4-OCF3 4-OCF3 4-F 4-F 5-0CF3 5-OCF3 4-F 4-F 2-OCF3 4-F 4-Me 4-Me 4-F 4-F 5-Me 5-Me 4-F 4-F 2-Me 4-F 4-OMe 4-OMe 4-F 4-F 5-OMe 5-OMe 4-F 4-F 2-OMe 4-F 4-SMe 4-SMe 4-F 4-F 5-SMe 5-SMe 4-F 4-F 2-SMe 4-F 4-SCF3 4-SCF3 4-F 4-F 5-SCF3 5-SCF3 4-F 4-F 2-SCF3 4-F 4-S0 Me 4-S02Me 4-F 4-F 5-S02Me 5-S02Me 4-F 4-F 2-S02Me 4-F 4-Br 4-Br 4-F 4-F 5-Br 5-Br 4-F 4-F 2-Br 4-F 6-F 2-F 4-F 4-F 2,4-diF 6-F 4-F 2,4-diF 4-F 4-F 6-C1 2-C1 4-F 4-F 2,4-diCl 6-C1 4-F 2,4-diCl 4-F 4-F 6-CN 2-CN 4-F 4-F 2,6-diF 6-CN 4-F 2,6-diF 4-F 4-F 6-N02 2-N02 4-F 4-F 4,5-diF 6-N02 4-F 4,5-diF 4-F 4-F 6-CF3 2-CF3 4-F 4-F 2,6-diCl 6-CF3 4-F 2,6-diCl 4-F 4-F 6-OCF3 2-OCF3 4-F 4-F 4,5-diCl 6-OCF3 4-F 4,5-diCl 4-F 4-F 6-Me 2-Me 4-F 4-F 5,6-diF 6-Me 4-F 5,6-diF 4-F 4-F 6-OMe 2-OMe 4-F 4-F 5.6-diCl 6-OMe 4-F 5.6-diCl 4-F 4-F 6-SMe 2-SMe 4-F 4-F 2,5-diF 6-SMe 4-F 2,5-diF 4-F 4-F 6-SCF3 2-SCF3 4-F 4-F 2,5-diCl 6-SCF3 4-F 2,5-diCl 4-F 4-F 6-S02Me 2-S02Me 4-F 4-F 4,6-diF 6-S02Me 4-F 4,6-diF 4-F 4-F 6-Br 2-Br 4-F 4-F 4,6-diCl 6-Br 4-F 4,6-diCl 4-F
Figure imgf000027_0001
Table 2
B is CH2. R22 is 4-F. R6 is 4-F, Z R8 Z R8 Z R8 EZ R8
H H H S02CF3 H COC02Me Me Me
H COMe H CO-w-Pr H COCH2OMe COMe COMe
H COEt H CO-/-Pr H COCH CH2 COEt COEt
H COOMe H CO-K-BU H COCH2CN COMe COEt
H S02Me H CO-i'-Bu H COOCH2CCH COMe OMe
H COPh H CO-w-Hex H COOCH2CF3 CONMe2 COMe
H CHO H COOEt H OH S02Me COMe
H CONHMe H CONMe2 H OMe COCF3 COCF3
H CONHPh H COCF3 H OCOMe Et OH
Me H Me S02CF3 Me COC02Me H Et
Me COMe Me CO-«-Pr Me COCH2OMe H Allyl
Me COEt Me CO-/-Pr Me COCH=CH2 H Propargyl
Me COOMe Me CO-H-BU Me COCH2CN CONHMe Et
Me S02Me Me CO-z'-Bu Me COOCH2CCH CONHPh Et
Me COPh Me CO-w-Hex Me C00CH2CF3 Et Et
Me CHO Me COOEt Me OH COPh COPh
Me CONHMe Me CONMe2 Me OMe COC02Me COMe
Me CONHPh Me COCF3 Me OCOMe H OC02Me B is CO, R22 is 4-F, R6 is 4-F,
EZ R8 EZ R8 Z R8 EZ R«
H H H S02CF3 H COC02Me Me Me
H COMe H CO-w-Pr H COCH2OMe COMe COMe
H COEt H CO- -Pr H COCH=CH2 COEt COEt
H COOMe H CO-M-BU H COCH2CN COMe COEt
H S02Me H CO-/-Bu H COOCH2CCH COMe OMe
H COPh H CO-«-Hex H COOCH2CF3 CONMe2 COMe
H CHO H COOEt H OH S02Me COMe
H CONHMe H CONMe2 H OMe COCF3 COCF3
H CONHPh H COCF3 H OCOMe Et OH
Me H Me S02CF3 Me COC02Me H Et
Me COMe Me CO-H-Pr Me COCH2OMe H Allyl
Me COEt Me CO-/-Pr Me COCH=CH2 H Propargyl
Me COOMe Me CO-H-BU Me COCH2CN CONHMe Et
Me S02Me Me CO- -Bu Me COOCH2CCH CONHPh Et
Me COPh Me CO-H-Hex Me COOCH2CF3 Et Et
Me CHO Me COOEt Me OH COPh COPh
Me CONHMe Me CONMe2 Me OMe COC02Me COMe
Me CONHPh Me COCF3 Me OCOMe H OC02Me
l
Figure imgf000028_0001
Me CHO Me COOEt Me OH COPh COPh Me CONHMe Me CONMe2 Me OMe COC02M COMe e
Me CONHPh Me COCF3 Me OCOMe H OC02Me
B is CH2. R22 is 4-F. R6 is 4-Cl.
R7 R8 R7 R8 R7 R8 EZ R8
H H H S02CF3 H COC02Me Me Me
H COMe H C0-«-Pr H C0CH20Me COMe COMe
H COEt H CO-Z-Pr H COCH=CH2 COEt COEt
H COOMe H CO-H-Bu H COCH2CN COMe COEt
H S02Me H CO- -Bu H COOCH2CCH COMe OMe
H COPh H CO-H-Hex H C00CH2CF3 CONMe2 COMe
H CHO H COOEt H OH S02Me COMe
H CONHMe H CONMe2 H OMe COCF3 COCF3
H CONHPh H COCF3 H OCOMe Et OH
Me H Me S02CF3 Me COC02Me H Et
Me COMe Me CO-«-Pr Me COCH2OMe H Allyl
Me COEt Me CO- -Pr Me COCH=CH2 H Propargyl
Me COOMe Me CO-rt-Bu Me COCH2CN CONHMe Et
Me S02Me Me CO-Z-Bu Me COOCH2CCH CONHPh Et
Me COPh Me CO-w-Hex Me COOCH2CF3 Et Et
Me CHO Me COOEt Me OH COPh COPh
Me CONHMe Me CONMe2 Me OMe COC02M COMe e
Me CONHPh Me COCF3 Me OCOMe H OC02Me
Figure imgf000029_0001
O1 is O. Y is N. X is CH. Z is CR22, β5a R22 R6 R5a R22 R6 R5a R22 R6
CF3 H 4-F CF3CF2 H 4-F CF2C1 H 4-F CF3 H H CF3CF2 H H CF2C1 H H CF3 H 4-Cl CF3CF2 H 4-Cl CF2C1 H 4-Cl CF3 H 4-N02 CF3CF2 H 4-N02 CF2C1 H 4-N02 CF3 H 4-Br CF3CF2 H 4-Br CF2C1 H 4-Br CF3 Cl 4-F CF3CF2 Cl 4-F CF2C1 Cl 4-F CF3 Cl H CF3CF2 Cl H CF2C1 Cl H CF3 Cl 4-Cl CF3CF2 Cl 4-Cl CF2C1 Cl 4-Cl CF3 Cl 4-N02 CF3CF2 Cl 4-N02 CF2C1 Cl 4-N02
O1 is NH. Y is N. X is CH, Z is CR22,
R5a R22 R6 R5a R22 R6 R5a R22 R6
CF3 H 4-F CF3CF2 H 4-F CF2C1 H 4-F CF3 H H CF3CF2 H H CF2C1 H H CF3 H 4-Cl CF3CF2 H 4-Cl CF2C1 H 4-Cl CF3 H 4-N02 CF3CF2 H 4-N02 CF2C1 H 4-N02 CF3 H 4-Br CF3CF2 H 4-Br CF2C1 H 4-Br CF3 Cl 4-F CF3CF2 Cl 4-F CF2C1 Cl 4-F CF3 Cl H CF3CF2 Cl H CF2C1 Cl H CF3 Cl 4-Cl CF3CF2 Cl 4-Cl CF2C1 Cl 4-Cl CF3 Cl 4-N02 CF3CF2 Cl 4-N02 CF2C1 Cl 4-N02
O1 is O. Y is CR22. X is CH. Z is N,
R5a R22 R6 R5a R22 R6 R5a R22 R6
CF3 H 4-F CF3CF2 H 4-F CF2C1 H 4-F CF3 H H CF3CF2 H H CF2C1 H H CF3 H 4-Cl CF3CF2 H 4-Cl CF2C1 H 4-Cl CF3 H 4-N02 CF3CF2 H 4-N02 CF2C1 H 4-N02 CF3 H 4-Br CF3CF2 H 4-Br CF2C1 H 4-Br CF3 Cl 4-F CF3CF2 Cl 4-F CF2C1 Cl 4-F CF3 Cl H CF3CF2 Cl H CF2C1 Cl H CF3 Cl 4-Cl CF3CF2 Cl 4-Cl CF2C1 Cl 4-Cl CF3 Cl 4-N02 CF3CF2 Cl 4-N02 CF2C1 Cl 4-N02
o s H. Y is CR22. X is CH, Z is -N.
R5a R22 R6 R5a R22 R6 R5a R22 R6
CF3 H 4-F CF3CF2 H 4-F CF2C1 H 4-F
CF3 H H CF3CF2 H H CF2C1 H H
CF3 H 4-Cl CF3CF2 H 4-Cl CF2C1 H 4-C
CF3 H 4-N02 CF3CF2 H 4-N02 CF2C1 H 4-r- CF3 H 4-Br CF3CF2 H 4-Br CF2C1 H 4-Br CF3 Cl 4-F CF3CF2 Cl 4-F CF2C1 Cl 4-F CF3 Cl H CF3CF2 Cl H CF2C1 Cl H CF3 Cl 4-Cl CF3CF2 Cl 4-Cl CF2C1 Cl 4-Cl CF3 Cl 4-N02 CF3CF2 Cl 4-N02 CF2C1 Cl 4-N02
O1 is O. Y is N. X is CR22. Z is N
R5a R22 Rό R5a R22 R6 R5a R22 R6
CF3 H 4-F CF3CF2 H 4-F CF2C1 H 4-F
CF3 H H CF3CF2 H H CF2C1 H H
CF3 H 4-Cl CF3CF2 H 4-Cl CF2C1 H 4-Cl
CF3 H 4-N02 CF3CF2 H 4-N02 CF2C1 H 4-N02
CF3 H 4-Br CF3CF2 H 4-Br CF2C1 H 4-Br
CF3 Cl 4-F CF3CF2 Cl 4-F CF2C1 Cl 4-F
CF3 Cl H CF3CF2 Cl H CF2C1 Cl H
CF3 Cl 4-Cl CF3CF2 Cl 4-Cl CF2C1 Cl 4-Cl
CF3 Cl 4-N02 CF3CF2 Cl 4-N02 CF2C1 Cl 4-N02
O1 is NH. Y is N. X is CR22. Z is T
R5a R22 R6 R5a R22 R6 R5a R22 R6
CF3 H 4-F CF3CF2 H 4-F CF2C1 H 4-F
CF3 H H CF3CF2 H H CF2C1 H H
CF3 H 4-Cl CF3CF2 H 4-Cl CF2C1 H 4-Cl
CF3 H 4-N02 CF3CF2 H 4-N02 CF2C1 H 4-N02
CF3 H 4-Br CF3CF2 H 4-Br CF2C1 H 4-Br
CF3 Cl 4-F CF3CF2 Cl 4-F CF2C1 Cl 4-F
CF3 Cl H CF3CF2 Cl H CF2C1 Cl H
CF3 Cl 4-Cl CF3CF2 Cl 4-Cl CF2C1 Cl 4-Cl
CF3 Cl 4-N02 CF3CF2 Cl 4-N02 CF2C1 Cl 4-N02
O1 is O Y is CH. X is CH. Z is CR 22
R5a R22 R6 R5a R22 R6 R5a R22 R6 CF3 H 4-F CF3CF2 H 4-F CF2H H 4-F CF3 H H CF3CF2 H H CF2H H H CF3 H 4-Cl CF3CF2 H 4-Cl CF2H H 4-Cl CF3 H 4-N02 CF3CF2 H 4-N02 CF2H H 4-N02 CF3 H 4-Br CF3CF2 H 4-Br CF2H H 4-Br CF3 Cl 4-F CF3CF2 Cl 4-F CF2H Cl 4-F CF3 Cl H CF3CF2 Cl H CF2H Cl H
CF3 Cl 4-Cl CF3CF2 Cl 4-Cl CF2H Cl 4-Cl
CF3 Cl 4-N02 CF3CF2 Cl 4-N02 CF2H Cl 4-N02
Figure imgf000032_0001
Table 4
R1 R2 R3 R4 R5a R22 R5b R6 Ωl
Me H H H CF3 4-F CF3 4-F 0
Cl H H H CF3 4-F CF3 4-F o
OMe H H H CF3 4-F CF3 4-F o
CF3 H H H CF3 4-F CF3 4-F o
SMe H H H CF3 4-F CF3 4-F o
N02 H H H CF3 4-F CF3 4-F 0
H Me H H CF3 4-F CF3 4-F 0
H Cl H H CF3 4-F CF3 4-F 0
H OMe H H CF3 4-F CF3 4-F o
H CF3 H H CF3 4-F CF3 4-F o
H SMe H H CF3 4-F CF3 4-F o
H N02 H H CF3 4-F CF3 4-F 0
Me H H H CF3 4-F CF3 4-Cl 0
Cl H H H CF3 4-F CF3 4-Cl 0
OMe H H H CF3 4-F CF3 4-Cl 0
CF3 H H H CF3 4-F CF3 4-Cl 0
SMe H H H CF3 4-F CF3 4-Cl o
N02 H H H CF3 4-F CF3 4-Cl 0
H Me H H CF3 4-F CF3 4-Cl 0
H Cl H H CF3 4-F CF3 4-Cl o
H OMe H H CF3 4-F CF3 4-Cl 0
H CF3 H H CF3 4-F CF3 4-Cl 0
H SMe H H CF3 4-F CF3 4-Cl 0
H Cl H H CF3 4-F CF3 4-Cl o
H H H H CF3 4-Cl CF3 4-F 0
H H H H Cl 4-Cl CF3 4-F o
H Cl H H Cl 4-CF3 CF3 4-F 0 H H H H CF3 4-CF3 CF3 4-F 0
H H H H Me 4-F CF3 4-F 0
H H H H OCF3 4-F CF3 4-F 0
H H H H CF2CF3 4-F CF3 4-F o
H H H H CF2CF3 4-F CF3 4-Cl o
H H H H CF2CF3 4-F CF3 H o
H H H H CF2CF3 H CF3 4-F 0
H H H H CF3 H CF3 4-F 0
H H H H CF3 4-F CF3 H 0
H H H H CF2C1 4-F CF3 4-F 0
H H H H CF2C1 4-F CF3 4-Cl 0
H H H H CF2C1 4-Cl CF3 4-F 0
H H H H CF2C1 4-F CF3 H 0
H H H H CF2C1 4-F CF2C1 4-F o
H H H H OMe 4-F CF3 4-F o
H H H H SF5 H CF3 4-F 0
H H H H CF3 4-F Cl 4-Cl o
H H H H CF3 4-F Cl 4-CF3 0
H Cl H H CF3 4-F CF3 4-CF3 0
H H H H CF3 4-F Me 4-F 0
H H H H CF3 4-F OCF3 4-F 0
H H H H CF3 4-F CF2CF3 4-F 0
H H H H CF3 4-Cl CF2CF3 4-F o
H H H H CF3 H CF2CF3 4-F 0
H H H H CF3 4-F CF2CF3 H 0
H H H H CF3 4-F CF3 H o
H H H H CF3 H CF3 4-F 0
H H H H CF3 4-F CF2C1 4-F o
H H H H CF3 4-Cl CF2C1 4-F 0
H H H H CF3 4-F CF2C1 4-Cl 0
H H H H CF3 H CF2C1 4-F 0
H H H H CF3 4-F OMe 4-F 0
H H H H CF3 4-F SF5 H 0
H H H H CN 4-F CF3 4-F 0
H H H H CF3 4-F CN 4-F o
H H H H SCF3 4-F CF3 4-F o
H H H H CF3 4-F SCF3 4-F 0
H H H H S02Me 4-F CF3 4-F 0 H H H H CF3 4-F S02Me 4-F O
H H H H CF2CF3 4-F CF3 4-F NH
H H H H CF2CF3 4-F CF3 4-Cl NH
H H H H CF2CF3 4-F CF3 H NH
H H H H CF2CF3 H CF3 4-F NH
H H H H CF3 H CF3 4-F NH
H H H H CF3 4-F CF3 H NH
H H H H CF2C1 4-F CF3 4-F NH
H H H H CF2C1 4-F CF3 4-Cl NH
H H H H CF2C1 4-Cl CF3 4-F NH
H H H H CF2C1 4-F CF3 H NH
H H H H CF2C1 4-F CF2C1 4-F NH
NH2 H H H CF3 H CF3 4-F 0
NHAc H H H CF3 H CF3 4-F 0
NAc2 H H H CF3 H CF3 4-F 0
NHMe H H H CF3 H CF3 4-F O
NMe2 H H H CF3 H CF3 4-F 0
NHCHO H H H CF3 H CF3 4-F 0
NH2 H H H CF3 4-F CF3 H 0
NHAc H H H CF3 4-F CF3 H O
NAc2 H H H CF3 4-F CF3 H 0
NHMe H H H CF3 4-F CF3 H 0
NMe2 H H H CF3 4-F CF3 H 0
NHCHO H H H CF3 4-F CF3 H 0
NH2 H H H CF2CF3 H CF3 4-F O
NH2 H H H CF3 4-F CF2CF3 4-F 0
NH2 H H H CF2C1 4-F CF3 4-F O
NH2 H H H CF3 4-F CF2C1 4-F 0
NH2 H H H CF3 H CF2CF3 4-F O
H H Me H CF3 4-F CF3 4-F 0
H H Me Me CF3 4-F CF3 4-F 0
H H Cl H CF3 4-F CF3 4-F O
H H OMe H CF3 4-F CF3 4-F O
H H CF3 H CF3 4-F CF3 4-F 0
H H CN H CF3 4-F CF3 4-F O
H H Cl Cl CF3 4-F CF3 4-F O El R2 CR3R4 R5a R22 R5b R6 ci
H H CO CF2CF3 4-F CF3 4-F 0
H H CO CF2CF3 4-F CF3 4-Cl 0
H H CO CF2CF3 4-F CF3 H o
H H CO CF2CF3 H CF3 4-F 0
H H CO CF3 H CF3 4-F 0
H H CO CF3 4-F CF3 H o
H H CO CF2C1 4-F CF3 4-F 0
H H CO CF2C1 4-F CF3 4-Cl 0
H H CO CF2C1 4-Cl CF3 4-F o
H H CO CF2C1 4-F CF3 H 0
H H CO CF2C1 4-F CF2C1 4-F 0
Figure imgf000035_0001
Table 5
El E2. Ql R5b R6 Ω2. R^a R22
H H 0 CF3 4-F CH20 F 4-F
H H 0 CF3 4-F CH20 F 2-F
H H 0 CF3 4-F CH20 F 5-F
H H o CF3 4-F CH20 F 6-F
H H 0 CF3 4-F CH20 F 4-Cl
H H o CF3 4-F CH20 F 2-C1
H H 0 CF3 4-F CH20 F 5-C1
H H 0 CF3 4-F CH20 F 6-C1
H H 0 CF3 4-F CH20 CF3 4-F
H H o CF3 4-F CH20 CF3 2-F
H H o CF3 4-F CH20 CF3 5-F
H H o CF3 4-F CH20 CF3 6-F
H H o CF3 4-F CH20 CF3 4-Cl
H H 0 CF3 4-F CH20 CF3 2-C1
H H 0 CF3 4-F CH20 CF3 5-C1
H H o CF3 4-F CH20 CF3 6-C1
H H o CF3 4-F CH20 F 4-CF3 H H O CF3 4-F CH20 F 2-CF3
H H O CF3 4-F CH20 F 5-CF3
H H O CF3 4-F CH20 F 6-CF3
H H O CF3 4-F CH20 F 4-OCF3
H H 0 CF3 4-F CH20 F 2-OCF3
H H 0 CF3 4-F CH20 F 5-OCF3
H H 0 CF3 4-F CH20 F 6-OCF3
H H o CF3 4-F CH20 CF3 4-CF3
H H o CF3 4-F CH20 CF3 2-CF3
H H o CF3 4-F CH20 CF3 5-CF3
H H o CF3 4-F CH20 CF3 6-CF3
H H 0 CF3 4-F CH20 CF3 4-OCF3
H H 0 CF3 4-F CH20 CF3 2-OCF3
H H o CF3 4-F CH20 CF3 5-OCF3
H H o CF3 4-F CH20 CF3 6-OCF3
H H o CF3 4-Cl CH20 F 4-F
H H 0 CF3 4-Cl CH20 F 2-F
H H 0 CF3 4-Cl CH20 F 5-F
H H o CF3 4-Cl CH20 F 6-F
H H 0 CF3 4-Cl CH20 F 4-Cl
H H o CF3 4-Cl CH20 F 2-C1
H H 0 CF3 4-Cl CH20 F 5-C1
H H 0 CF3 4-Cl CH20 F 6-C1
H H o CF3 4-Cl CH20 CF3 4-F
H H o CF3 4-Cl CH20 CF3 2-F
H H 0 CF3 4-Cl CH20 CF3 5-F
H H o CF3 4-Cl CH20 CF3 6-F
H H o CF3 4-Cl CH20 CF3 4-Cl
H H o CF3 4-Cl CH20 CF3 2-C1
H H 0 CF3 4-Cl CH20 CF3 5-C1
H H o CF3 4-Cl CH20 CF3 6-C1
H H 0 CF3 4-Cl CH20 F 4-CF3
H H 0 CF3 4-Cl CH20 F 2-CF3
H H o CF3 4-Cl CH20 F 5-CF3
H H o CF3 4-Cl CH20 F 6-CF3
H H o CF3 4-Cl CH20 F 4-OCF3
H H 0 CF3 4-Cl CH20 F 2-OCF3
H H o CF3 4-Cl CH20 F 5-OCF3 H H 0 CF3 4-Cl CH20 F 6-OCF3
H H O CF3 4-Cl CH20 CF3 4-CF3
H H 0 CF3 4-Cl CH20 CF3 2-CF3
H H 0 CF3 4-Cl CH20 CF3 5-CF3
H H 0 CF3 4-Cl CH20 CF3 6-CF3
H H 0 CF3 4-Cl CH20 CF3 4-OCF3
H H O CF3 4-Cl CH20 CF3 2-OCF3
H H 0 CF3 4-Cl CH20 CF3 5-OCF3
H H 0 CF3 4-Cl CH20 CF3 6-OCF3
H H O CF3 4-Cl S F 4-F
H H O CF3 4-Cl S F 2-F
H H 0 CF3 4-Cl S F 5-F
H H O CF3 4-Cl S F 6-F
H H 0 CF3 4-Cl s F 4-Cl
H H O CF3 4-Cl s F 2-C1
H H O CF3 4-Cl s F 5-C1
H H 0 CF3 4-Cl s F 6-C1
H H O CF3 4-Cl s CF3 4-F
H H 0 CF3 4-Cl s CF3 2-F
H H O CF3 4-Cl s CF3 5-F
H H O CF3 4-Cl s CF3 6-F
H H O CF3 4-Cl s CF3 4-Cl
H H O CF3 4-Cl s CF3 2-C1
H H 0 CF3 4-Cl s CF3 5-C1
H H 0 CF3 4-Cl s CF3 6-C1
NH2 H o CF3 4-F CH20 F 4-F
NH2 H o CF3 4-F CH20 F 2-F
NH2 H o CF3 4-F CH20 F 5-F
NH2 H 0 CF3 4-F CH20 F 6-F
NH2 H o CF3 4-F CH20 F 4-Cl
NH2 H 0 CF3 4-F CH20 F 2-C1
NH2 H 0 CF3 4-F CH20 F 5-C1
NH2 H 0 CF3 4-F CH20 F 6-C1
NH2 H 0 CF3 4-F CH20 CF3 4-F
NH2 H o CF3 4-F CH20 CF3 2-F
NH2 H o CF3 4-F CH20 CF3 5-F
NH2 H 0 CF3 4-F CH20 CF3 6-F
NH2 H o CF3 4-F CH20 CF3 4-Cl NH2 H O CF3 4-F CH20 CF3 2-C1
NH2 H 0 CF3 4-F CH20 CF3 5-C1
NH2 H 0 CF3 4-F CH20 CF3 6-C1
NH2 H O CF3 4-F CH20 F 4-CF3
NH2 H 0 CF3 4-F CH20 F 2-CF3
NH2 H O CF3 4-F CH20 F 5-CF3
NH2 H 0 CF3 4-F CH20 F 6-CF3
NH2 H 0 CF3 4-F CH20 F 4-0CF3
NH2 H O CF3 4-F CH20 F 2-OCF3
NH2 H 0 CF3 4-F CH20 F 5-OCF3
NH2 H O CF3 4-F CH20 F 6-OCF3
NH2 H O CF3 4-F CH20 CF3 4-CF3
NH2 H O CF3 4-F CH20 CF3 2-CF3
NH2 H 0 CF3 4-F CH20 CF3 5-CF3
NH2 H 0 CF3 4-F CH20 CF3 6-CF3
NH2 H 0 CF3 4-F CH20 CF3 4-OCF3
NH2 H 0 CF3 4-F CH20 CF3 2-OCF3
NH2 H O CF3 4-F CH20 CF3 5-OCF3
NH2 H O CF3 4-F CH20 CF3 6-OCF3
H H O CF3 4-F CH(CH3)0 F 4-F
H H O CF3 4-F CH(CH3)0 F 2-F
H H 0 CF3 4-F CH(CH3)0 F 5-F
H H 0 CF3 4-F CH(CH3)0 F 6-F
H H O CF3 4-F CH(CH3)0 F 4-Cl
H H O CF3 4-F CH(CH3)0 F 2-C1
H H 0 CF3 4-F CH(CH3)0 F 5-C1
H H O CF3 4-F CH(CH3)0 F 6-C1
H H o CF3 4-F CH(CH3)0 CF3 4-F
H H o CF3 4-F CH(CH3)0 CF3 2-F
H H o CF3 4-F CH(CH3)0 CF3 5-F
H H o CF3 4-F CH(CH3)0 CF3 6-F
H H 0 CF3 4-F CH(CH3)0 CF3 4-Cl
H H o CF3 4-F CH(CH3)0 CF3 2-C1
H H 0 CF3 4-F CH(CH3)0 CF3 5-C1
H H o CF3 4-F CH(CH3)0 CF3 6-C1
H H o CF3 4-F CH(CH3)0 CF3 6-C1
H H 0 CF3 4-F S F 4-F
H H 0 CF3 4-F S F 2-F H H 0 CF3 4-F S F 5-F
H H 0 CF3 4-F S F 6-F
H H O CF3 4-F S F 4-Cl
H H 0 CF3 4-F S F 2-C1
H H 0 CF3 4-F S F 5-C1
H H 0 CF3 4-F S F 6-C1
H H O CF3 4-F S CF3 4-F
H H 0 CF3 4-F S CF3 2-F
H H 0 CF3 4-F S CF3 5-F
H H 0 CF3 4-F S CF3 6-F
H H O CF3 4-F S CF3 4-Cl
H H O CF3 4-F S CF3 2-C1
H H O CF3 4-F S CF3 5-C1
H H O CF3 4-F S CF3 6-C1
H H 0 CF3 4-F CH2S F 4-F
H H 0 CF3 4-F CH2S F 2-F
H H O CF3 4-F CH2S F 5-F
H H O CF3 4-F CH2S F 6-F
H H O CF3 4-F CH2S F 4-Cl
H H 0 CF3 4-F CH2S F 2-C1
H H 0 CF3 4-F CH2S F 5-C1
H H 0 CF3 4-F CH2S F 6-C1
H H 0 CF3 4-F CH2S CF3 4-F
H H 0 CF3 4-F CH2S CF3 2-F
H H O CF3 4-F CH2S CF3 5-F
H H O CF3 4-F CH2S CF3 6-F
H H 0 CF3 4-F CH2S CF3 4-Cl
H H o CF3 4-F CH2S CF3 2-C1
H H o CF3 4-F CH2S CF3 5-C1
H H 0 CF3 4-F CH2S CF3 6-C1
H H CH20 CF3 4-F CH2 F 4-F
H H CH20 CF3 4-F CH2 F 2-F
H H CH20 CF3 4-F CH2 F 5-F
H H CH20 CF3 4-F CH2 F 6-F
H H CH20 CF3 4-F CH2 F 4-Cl
H H CH20 CF3 4-F CH2 F 2-C1
H H CH20 CF3 4-F CH2 F 5-C1
H H CH20 CF3 4-F CH2 F 6-C1 H H CH20 CF3 4-F CH2 CF3 4-F
H H CH20 CF3 4-F CH2 CF3 2-F
H H CH20 CF3 4-F CH2 CF3 5-F
H H CH20 CF3 4-F CH2 CF3 6-F
H H CH20 CF3 4-F CH2 CF3 4-Cl
H H CH20 CF3 4-F CH2 CF3 2-C1
H H CH20 CF3 4-F CH2 CF3 5-C1
H H CH20 CF3 4-F CH2 CF3 6-C1
H H CH2NH CF3 4-F CH2 F 4-F
H H CH2NH CF3 4-F CH2 F 2-F
H H CH2NH CF3 4-F CH2 F 5-F
H H CH2NH CF3 4-F CH2 F 6-F
H H CH2NH CF3 4-F CH2 F 4-Cl
H H CH2NH CF3 4-F CH2 F 2-C1
H H CH2NH CF3 4-F CH2 F 5-C1
H H CH2NH CF3 4-F CH2 F 6-C1
H H CH2NH CF3 4-F CH2 CF3 4-F
H H CH2NH CF3 4-F CH2 CF3 2-F
H H CH2NH CF3 4-F CH2 CF3 5-F
H H CH2NH CF3 4-F CH2 CF3 6-F
H H CH2NH CF3 4-F CH2 CF3 4-Cl
H H CH2NH CF3 4-F CH2 CF3 2-C1
H H CH2NH CF3 4-F CH2 CF3 5-C1
H H CH2NH CF3 4-F CH2 CF3 6-C1
H H CH20 CF3 4-F CO F 4-F
H H CH20 CF3 4-F CO F 2-F
H H CH20 CF3 4-F CO F 5-F
H H CH20 CF3 4-F CO F 6-F
H H CH20 CF3 4-F CO F 4-Cl
H H CH20 CF3 4-F CO F 2-C1
H H CH20 CF3 4-F CO F 5-C1
H H CH20 CF3 4-F CO F 6-C1
H H CH20 CF3 4-F CO CF3 4-F
H H CH20 CF3 4-F CO CF3 2-F
H H CH20 CF3 4-F CO CF3 5-F
H H CH20 CF3 4-F CO CF3 6-F
H H CH20 CF3 4-F CO CF3 4-Cl
H H CH20 CF3 4-F CO CF3 2-C1 H H CH20 CF3 4-F CO CF3 5-C1
H H CH20 CF3 4-F CO CF3 6-C1
H H CH20 CF3 4-F CH20 F 4-F
H H CH20 CF3 4-F CH20 F 2-F
H H CH20 CF3 4-F CH20 F 5-F
H H CH20 CF3 4-F CH20 F 6-F
H H CH20 CF3 4-F CH20 F 4-Cl
H H CH20 CF3 4-F CH20 F 2-C1
H H CH20 CF3 4-F CH20 F 5-C1
H H CH20 CF3 4-F CH20 F 6-C1
H H CH20 CF3 4-F CH20 CF3 4-F
H H CH20 CF3 4-F CH20 CF3 2-F
H H CH20 CF3 4-F CH20 CF3 5-F
H H CH20 CF3 4-F CH20 CF3 6-F
H H CH20 CF3 4-F CH20 CF3 4-Cl
H H CH20 CF3 4-F CH20 CF3 2-C1
H H CH20 CF3 4-F CH20 CF3 5-C1
H H CH20 CF3 4-F CH20 CF3 6-C1
H H NH CF3 4-F CH20 F 4-F
H H NH CF3 4-F CH20 F 2-F
H H NH CF3 4-F CH20 F 5-F
H H NH CF3 4-F CH20 F 6-F
H H NH CF3 4-F CH20 F 4-Cl
H H NH CF3 4-F CH20 F 2-C1
H H NH CF3 4-F CH20 F 5-C1
H H NH CF3 4-F CH20 F 6-C1
H H NH CF3 4-F CH20 CF3 4-F
H H NH CF3 4-F CH20 CF3 2-F
H H NH CF3 4-F CH20 CF3 5-F
H H NH CF3 4-F CH20 CF3 6-F
H H NH CF3 4-F CH20 CF3 4-Cl
H H NH CF3 4-F CH20 CF3 2-C1
H H NH CF3 4-F CH20 CF3 5-C1
H H NH CF3 4-F CH20 CF3 6-C1
H H 0 CF3 4-F CH20 H 4-CF3
H H 0 CF3 4-F CH20 H 2-CF3
H H O CF3 4-F CH20 H 5-CF3
H H O CF3 4-F CH20 H 6-CF3 H H O CF3 4-F CH20 H 4-OCF3
H H O CF3 4-F CH20 H 2-OCF3
H H O CF3 4-F CH20 H 5-OCF3
H H O CF3 4-F CH20 H 6-OCF3
H H O CF3 4-Cl CH20 H 4-F
H H O CF3 4-Cl CH20 H 2-F
H H O CF3 4-Cl CH20 H 5-F
H H O CF3 4-Cl CH20 H 6-F
H H o CF3 4-Cl CH20 H 4-Cl
H H o CF3 4-Cl CH20 H 2-C1
H H 0 CF3 4-Cl CH20 H 5-C1
H H o CF3 4-Cl CH20 H 6-C1
H H 0 CF3 H S F 4-F
H H o CF3 H s F 2-F
H H o CF3 H s F 5-F
H H 0 CF3 H s F 6-F
H H 0 CF3 H s F 4-Cl
H H o CF3 H s F 2-C1
H H 0 CF3 H s F 5-C1
H H o CF3 H s F 6-C1
H H 0 CF3 H s CF3 4-F
H H o CF3 H s CF3 2-F
H H o CF3 H s CF3 5-F
H H 0 CF3 H s CF3 6-F
H H o CF3 H s CF3 4-Cl
H H 0 CF3 H s CF3 2-C1
H H o CF3 H s CF3 5-C1
H H o CF3 H s CF3 6-C1
Formulation/Utility
Compounds of this invention will generally be used as a Formulation or composition with an agriculturally suitable carrier comprising at least one of a liquid diluent, a solid diluent or a surfactant. The Formulation or composition ingredients are selected to be consistent with the physical properties of the active ingredient, mode of application and environmental factors such as soil type, moisture and temperature. Useful Formulations include liquids such as solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions and/or suspoemulsions) and the like which optionally can be thickened into gels. Useful Formulations further include solids such as dusts, powders, granules, pellets, tablets, films, and the like which can be water-dispersible ("wettable") or water-soluble. The active ingredient can be (micro)encapsulated and further formed into a suspension or solid Formulation; alternatively the entire Formulation of active ingredient can be encapsulated (or "overcoated"). Encapsulation can control or delay release of the active ingredient. Sprayable Formulations can be extended in suitable media and used at spray volumes from about one to several hundred liters per hectare. High-strength compositions are primarily used as intermediates for further Formulation.
The Formulations will typically contain effective amounts of active ingredient, diluent and surfactant within the following approximate ranges which add up to 100 percent by weight.
Weight Percent
Active
Ingredient Diluent Surfactant
Water-Dispersible and Water-soluble 5-90 0-94 1-15
Granules, Tablets and Powders.
Suspensions, Emulsions, Solutions 5-50 40-95 0-15
(including Emulsifiable
Concentrates)
Dusts 1-25 70-99 0-5
Granules and Pellets 0.01-99 5-99.99 0-15
High Strength Compositions 90-99 0-10 0-2
Typical solid diluents are described in Watkins, et al, Handbook of Insecticide Dust Diluents and Carriers, 2nd Ed., Dorland Books, Caldwell, New Jersey. Typical liquid diluents are described in Marsden, Solvents Guide, 2nd Ed., Interscience, New York, 1950. McCutcheon 's Detergents and Emulsiβers Annual, Allured Publ. Corp., Ridgewood, New Jersey, as well as Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964, list surfactants and recommended uses. All Formulations can contain minor amounts of additives to reduce foam, caking, corrosion, microbiological growth and the like, or thickeners to increase viscosity.
Surfactants include, for example, polyethoxylated alcohols, polyethoxylated alkylphenols, polyethoxylated sorbitan fatty acid esters, dialkyl sulfosuccinates, alkyl sulfates, alkylbenzene sulfonates, organosilicones, N,N-dialkyltaurates, lignin sulfonates, naphthalene sulfonate formaldehyde condensates, polycarboxylates, and polyoxyethylene/polyoxypropylene block copolymers. Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, starch, sugar, silica, talc, diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate, and sodium sulfate. Liquid diluents include, for example, water, N,N-dimethylformamide, dimethyl sulfoxide, N-alkylpyrrolidone, ethylene glycol, polypropylene glycol, paraffins, alkylbenzenes, alkylnaphthalenes, oils of olive, castor, linseed, rung, sesame, corn, peanut, cotton-seed, soybean, rape-seed and coconut, fatty acid esters, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy-4-methyl-2-pentanone, and alcohols such as methanol, cyclohexanol, decanol and tetrahydrofurfuryl alcohol.
Solutions, including emulsifiable concentrates, can be prepared by simply mixing the ingredients. Dusts and powders can be prepared by blending and, usually, grinding as in a hammer mill or fluid-energy mill. Suspensions are usually prepared by wet-milling; see, for example, U.S. 3,060,084. Granules and pellets can be prepared by spraying the active material upon preformed granular carriers or by agglomeration techniques. See Browning, "Agglomeration", Chemical Engineering, December 4, 1967, pp 147-48, Perry's Chemical Engineer 's Handbook, 4th Ed., McGraw-Hill, New York, 1963, pages 8-57 and following, and WO 91/13546. Pellets can be prepared as described in U.S. 4,172,714. Water-dispersible and water-soluble granules can be prepared as taught in U.S. 4,144,050, U.S. 3,920,442 and DE 3,246,493. Tablets can be prepared as taught in U.S. 5,180,587, U.S. 5,232,701 and U.S. 5,208,030. Films can be prepared as taught in GB 2,095,558 and U.S. 3,299,566.
For further information regarding the art of Formulation, see U.S. 3,235,361, Col. 6, line 16 through Col. 7, line 19 and Examples 10-41; U.S. 3,309,192, Col. 5, line 43 through Col. 7, line 62 and Examples 8, 12, 15, 39, 41, 52, 53, 58, 132, 138-140, 162-164, 166, 167 and 169-182; U.S. 2,891,855, Col. 3, line 66 through Col. 5, line 17 and Examples 1-4; Klingman, Weed Control as a Science, John Wiley and Sons, Inc., New York, 1961, pp 81-96; and Hance et al., Weed Control Handbook, 8th Ed., Blackwell Scientific Publications, Oxford, 1989.
In the following Examples, all percentages are by weight and all formulations are prepared in conventional ways. Compound numbers refer to compounds in Index Table A. Example A Wettable Powder
Compound 7 65.0% dodecylphenol polyethylene glycol ether 2.0% sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0% montmorillonite (calcined) 23.0%.
Example B
Granule
Compound 7 10.0% attapulgite granules (low volatile matter,
0.71/0.30 mm; U.S.S. No. 25-50 sieves) 90.0%. Example C
Extruded Pellet
Compound 7 25.0% anhydrous sodium sulfate 10.0% crude calcium ligninsulfonate 5.0% sodium alkylnaphthalenesulfonate 1.0% calcium/magnesium bentonite 59.0%
Example D
Emulsifiable Concentrate Compound 7 20.0% blend of oil soluble sulfonates and polyoxyethylene ethers 10.0% isophorone 70.0%.
The compounds of this invention exhibit activity against a wide spectrum of foliar-feeding, fruit-feeding, stem or root feeding, seed-feeding, aquatic and soil-inhabiting arthropods (term "arthropods" includes insects, mites and nematodes) which are pests of growing and stored agronomic crops, forestry, greenhouse crops, ornamentals, nursery crops, stored food and fiber products, livestock, household, and public and animal health. Those skilled in the art will appreciate that not all compounds are equally effective against all growth stages of all pests. Nevertheless, all of the compounds of this invention display activity against pests that include: eggs, larvae and adults of the Order Lepidoptera; eggs, foliar-feeding, fruit-feeding, root-feeding, seed-feeding larvae and adults of the Order Coleoptera; eggs, immatures and adults of the Orders Hemiptera and Homoptera; eggs, larvae, nymphs and adults of the Order Acari; eggs, immatures and adults of the Orders Thysanoptera, Orthoptera and Dermaptera; eggs, immatures and adults of the Order Diptera; and eggs, juveniles and adults of the Phylum Nematoda. The compounds of this invention are also active against pests of the Orders Hymenoptera, Isoptera, Siphonaptera, Blattaria, Thysanura and Psocoptera; pests belonging to the Class Arachnida and Phylum Platyhelminthes. Specifically, the compounds are active against southern corn rootworm (Diabrotica undecimpunctata howardi), aster leafhopper (Mascrosteles fascifrons), boll weevil (Anthonomus grandis), two-spotted spider mite (Tetranychus urticae), fall armyworm (Spodoptera frugiperda), black bean aphid (Aphis fabae), green peach aphid (Myzus persica), cotton aphid (Aphis gossypii), Russian wheat aphid (Diuraphis noxia), English grain aphid (Sitobion avenae), tobacco budworm (Heliothis virescens), rice water weevil (Lissorhoptrus oryzophilus), rice leaf beetle (Oulema oryzae), whitebacked planthopper (Sogatella furcifera), green leafhopper (Nephotettix cincticeps), brown planthopper (Nilaparvata lugens), small brown planthopper (Laodelphax striatellus), rice stem borer (Chilo suppressalis), rice leafroller (Cnaphalocrocis medinalis), black rice stink bug (Scotinophara lurida), rice stink bug (Oebalus pugnax), rice bug (Leptocorisa chinensis), slender rice bug (Cletus puntiger), and southern green stink bug (Nezara viridula). The compounds are active on mites, demonstrating ovicidal, larvicidal and chemosterilant activity against such families as Tetranychidae including Tetranychus urticae, Tetranychus cinnabarinus, Tetranychus mcdanieli, Tetranychus pacificus, Tetranychus turkestani,
Byrobia rubrioculus, Panonychus ulmi, Panonychus citri, Eotetranychus carpini borealis, Eotetranychus, hicoriae, Eotetranychus sexmaculatus, Eotetranychus yumensis, Eotetranychus banksi and Oligonychus pratensis; Tenuipalpidae including Brevipalpus lewisi, Brevipalpus phoenicis, Brevipalpus calif ornicus and Brevipalpus obovatus; Eriophyidae including Phyllocoptruta oleivora, Eriophyes sheldoni, Aculus cornutus,
Epitrimerus pyri and Eriophyes mangiferae. See WO 90/10623 and WO 92/00673 for more detailed pest descriptions.
Compounds of this invention can also be mixed with one or more other insecticides, fungicides, nematocides, bactericides, acaricides, growth regulators, chemosterilants, semiochemicals, repellents, attractants, pheromones, feeding stimulants or other biologically active compounds to form a multi-component pesticide giving an even broader spectrum of agricultural protection. Examples of such agricultural protectants with which compounds of this invention can be formulated are: insecticides such as abamectin, acephate, azinphos-methyl, bifenthrin, buprofezin, carbofuran, chlorfenapyr, chlorpyrifos, chlorpyrifos-methyl, cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, deltamethrin, diafenthiuron, diazinon, diflubenzuron, dimethoate, esfenvalerate, fenoxycarb, fenpropathrin, fenvalerate, fipronil, flucythrinate, tau-fluvalinate, fonophos, imidacloprid, isofenphos, malathion, metaldehyde, methamidophos, methidathion, methomyl, methoprene, methoxychlor, methyl 7-chloro-2,5-dihydro-2-[[N-(methoxycarbonyl)-N-[4- (trifluoromethoxy)phenyl]amino]carbonyl]indeno[l,2-e][l,3,4]oxadiazine-4a(3H)- carboxylate (DPX-JW062), monocrotophos, oxamyl, parathion, parathion-methyl, permethrin, phorate, phosalone, phosmet, phosphamidon, pirimicarb, profenofos, rotenone, sulprofos, tebufenozide, tefluthrin, terbufos, tetrachlorvinphos, thiodicarb, tralomethrin, trichlorfon and triflumuron; fungicides such as acibenzolar, azoxystrobin, binomial, blasticidin-S, Bordeaux mixture (Triassic copper sulfate), bromuconazole, capropamid (KTU 3616), captafol, captan, carbendazim, chloroneb, chlorothalonil, copper oxy chloride, copper salts, cymoxanil, cyproconazole, cyprodinil (CGA 219417),(S)-3,5-dichloro-N-(3-chloro-l- ethyl-1 -methyl- 2-oxopropyl)-4-methylbenzamide (RΗ 7281), diclocymet (S-2900), diclomezine, dicloran, difenoconazole,(S)-3,5-dihydro-5-methyl-2-(methylthio)-5-phenyl- 3- (phenylamino)-4H-imidazol-4-one (RP 407213), dimethomorph, diniconazole, diniconazole-M, dodine, edifenphos, epoxiconazole (BAS 480F), famoxadone, fenarimol, fenbuconazole, fencaramid (SZX0722), fenpiclonil, fenpropidin, fenpropimorph, fentin acetate, fentin hydroxide, fluazinam, fludioxonil, flumetover (RPA 403397), fluquinconazole, flusilazole, flutolanil, flutriafol, folpet, fosetyl-aluminum, furalaxyl, furametapyr (S-82658), hexaconazole, ipconazole, iprobenfos, iprodione, isoprothiolane, kasugamycin, kresoxim-methyl, mancozeb, maneb, mefenoxam, mepronil, metalaxyl, metconazole, metominostrobin fenominostrobin (SSF-126), myclobutanil, neo-asozin (ferric methanearsonate), oxadixyl, penconazole, pencycuron, probenazole, prochloraz, propamocarb, propiconazole, pyrifenox, pyrimethanil, pyroquilon, quinoxyfen, spiroxamine, sulfur, tebuconazole, tetraconazole, thiabendazole, thifluzamide, thiophanate-methyl, thiram, triadimefon, triadimenol, tricyclazole, triticonazole, validamycin and vinclozolin; nematocides such as aldoxycarb and fenamiphos; bactericides such as streptomycin; acaricides such as amitraz, chinomethionat, chlorobenzilate, cyhexatin, dicofol, dienochlor, etoxazole, fenazaquin, fenbutatin oxide, fenpropathrin, fenpyroximate, hexythiazox, propargite, pyridaben and tebufenpyrad; and biological agents such as Bacillus thuringiensis, Bacillus thuringiensis delta endotoxin, baculovirus, and entomopathogenic bacteria, virus and fungi. In certain instances, combinations with other arthropodicides having a similar spectrum of control but a different mode of action will be particularly advantageous for resistance management.
Arthropod pests are controlled and protection of agronomic, horticultural and specialty crops, animal and human health is achieved by applying one or more of the compounds of this invention, in an effective amount, to the environment of the pests including the agronomic and/or nonagronomic locus of infestation, to the area to be protected, or directly on the pests to be controlled. Thus, the present invention further comprises a method for the control of foliar and soil inhabiting arthropods and nematode pests and protection of agronomic and/or nonagronomic crops, comprising applying one or more of the compounds of the invention, or compositions containing at least one such compound, in an effective amount, to the environment of the pests including the agronomic and/or nonagronomic locus of infestation, to the area to be protected, or directly on the pests to be controlled. A preferred method of application is by spraying. Alternatively, granular formulations of these compounds can be applied to the plant foliage or the soil. Other methods of application include direct and residual sprays, aerial sprays, seed coats, microencapsulations, systemic uptake, baits, eartags, boluses, foggers, fumigants, aerosols, dusts and many others. The compounds can be incorporated into baits that are consumed by the arthropods or in devices such as traps and the like.
The compounds of this invention can be applied in their pure state, but most often application will be of a formulation comprising one or more compounds with suitable carriers, diluents, and surfactants and possibly in combination with a food depending on the contemplated end use. A preferred method of application involves spraying a water dispersion or refined oil solution of the compounds. Combinations with spray oils, spray oil concentrates, spreader stickers, adjuvants, other solvents, and synergists such as piperonyl butoxide often enhance compound efficacy.
The rate of application required for effective control will depend on such factors as the species of arthropod 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. Under normal circumstances, application rates of about 0.01 to 2 kg of active ingredient per hectare are sufficient to control pests in agronomic ecosystems, but as little as 0.001 kg/hectare may be sufficient or as much as 8 kg hectare may be required. For nonagronomic applications, effective use rates will range from about 1.0 to 50 mg/square meter but as little as 0.1 mg/square meter may be sufficient or as much as 150 mg/square meter may be required.
The following Test A demonstrates the control efficacy of compounds of this invention on specific pests. "Control efficacy" represents inhibition of arthropod development (including mortality) that causes significantly reduced feeding. The pest control protection afforded by the compounds is not limited, however, to this species. See Index Tables A-B for compound descriptions. The abbreviation "Ex." stands for "Example" and is followed by a number indicating in which example the compound is prepared.
INDEX TABLE A
Figure imgf000048_0001
Compound Ωl Q± R^ RP_ Rj. Physical Property
(m.p. °α*
1 CH2 O H H H a
2 (Ex. 2) CO O H H H b
3 CO O F H H c
4 CO O F F H d
5 CH2 0 H F H e
6 CH2 o F F H f
7 (Ex. 1) CH2 o F H H g
8 CH2 o F Cl H h
9 CH2 o H Cl H
10 CH2 o F N02 H J
11 CO NH F F H 150-153
12 (Ex. 3) CH2 NH H F H 102-104 3 CF2 0 3-CF3, 4-Cl 4-F H k 4 CH2 0 3-CF3, 4-F 5-F H 1 5 CO 0 3-CF3, 4-Cl 4-F H m 6 CH2 0 3-CF3, 4-F 2-F H n 7 CH2 0 3-CF3, 4-F 6-F H 0 8 CF2 O 3-CF3, 4-F 4-F H P
19 CO O 3-CF3, 4-F 4-Cl H q 0 CO O 3-CF3, 4-F 5-F H r 1 (Ex. 5) CH2 O 3-CF3, 4-F 4-F NH2 s
Figure imgf000049_0001
3 CH20 O 3-CF3, 4-F 4-F H u
Figure imgf000049_0002
5 CH20 O 2,3-diF 4-F H V 6 CH20 O 3-CF3, 4-F H H 71-73 7 (Ex. 4) CH20 0 3-CF3 4-F H w
Figure imgf000049_0003
9 CH20 o 3-CF3, 4-F 4-Cl H y 0 CH20 o 3,4-diF 4-F H z 1 CH20 o 3-CF3, 2-F 4-F H aa 2 CH20 o 3-CF3, 4-F 4-F NH2 bb 3 CH20 o 3,4-diCl 4-F H cc 4 CH(CF3)0 0 H 4-F H dd 5 CH20 o 4-CF3, 2-F 4-F H ee 6 CH(CH3)0 0 3,4-diCl 4-F H ff 7 CH20 0 4-Cl 4-F H gg 8 CH20 o 3-N02, 4-Cl 4-F H hh 9 S o 3-F 4-F H ii 0 s 0 2-F 4-F H jj 1 s o 4-F 4-F H kk 2 s 0 3-CF3 4-F H 72-73 3 s o 2-C1, 4-F 4-F H 53-60 4 CH2S 0 4-OMe, 3-C1 4-F H 91-94
45 CH2S 0 4-OMe 4-F H 66-69
46 CH2S o 2-C1 4-F H 11
47 (Ex. 6) CH2S 0 4-Cl 4-F H 66-69
*See Index Table B for Η NMR data. INDEX TABLE B 1H MR in CDCl3 (δ) a) 4.16 (s,2H), 6.74 (s,lH), 7.35 m,lH), 7.41 (s,lH), 7.45-7.80 (m,6H), 8.71 (s,lH). b) 7.38-7.45 (m,lH), 7.49 (s,lH), 7.61 (d,3H), 7.62-7.72 (m,lH), 7.90 (d,lH), 8.38 (d,lH), 8.44 (s,lH), 8.92 (s,lH). c) 7.23-7.42 (m,3H), 7.45 (m,lH), 7.63 (s,lH), 8.42-8.60 (m,2H), 8.86 (s,lH). d) 7.27-7.54 (m,3H), 7.60-7.73 (m,2H), 7.85-7.95 (m,lH), 8.31-8.39 (m,lH), 8.46 (s,lH), 8.90 (s,lH). e) 4.16 (s,2H), 6.74 (s, 1 H), 7.2-7.42 (m,3H), 7.44-7.60 (m,4H), 8.69 (s, 1 H). f) 4.13 (s,2H), 6.76 (s,lH), 7.16-7.38 (m,3H), 7.38-7.41 (m,lH), 7.45-7.57 (m,2H), 8.68 (s,lH). g) 4.11 (s,2H), 6.75 (s,lH), 7.18 (t,lH), 7.28-7.38 (m,lH), 7.42 (s,lH), 7.43-7.60 (m,2H), 8.70 (s,lH). h) 4.16 (s, 1 H), 6.77 (s, 1 H), 7.20 (m, 1 H), 7.28 (m, 1 H), 7.45-7.60 (m,4H), 8.69 (s, 1 H). i) 4.16 (s,2H), 7.26-7.32 (m,lH), 7.43-7.60 (m,6H), 8.70 (s,lH). j) 4.15 (s,2H), 6.83 (s,lH), 7.20 (m,lH), 7.44-7.58 (m,3H0, 7.63 (s,lH), 8.02 (d,lH), 8.77 (s,lH). k) 7.28 (t, IH), 7.3-7.45 (m, 3H), 7.4 (d, IH), 7.8 (d, IH).
1) 4.13 (s, 2H), 6.78 (s, IH), 7.15 (m, 2H), 7.25 (m, 2H0, 8.7 (m, IH). m) 7.31 (t, IH), 7.35-7.5 (m, 3H), 7.58-7.76 (m, 2H), 8.35 (d, IH), 8.58 (s, IH), 8.9 (s, IH). n) 4.13 (s, 2H), 6.83 (s, IH), 7.19 (t, IH), 7.29 (t, IH), 7.38-7.6 (m, 4H), 8.68 (s, IH). o) 4.13 (s, IH), 6.83 (s, IH), 7.2 (t, IH), 7.43-7.6 (m, 4H), 8.68 (s, IH). p) 7.3-7.45 (m, 5H), 7.83-7.97 (m, 2H), 8.76 (s, IH). q) 7.3-7.41 (m, 2H), 7.49-7.65 (m, 3H), 8.43-8.52 (m, IH), 8.78 d, IH), 8.94 (s, IH). r) 7.2-7.4 (m, 4H), 7.6 (s, IH), 8.5 (m, IH), 8.6 (m, IH), 8.9 (s, IH). s) 3.83 (s, 2H), 4.2 (s, 2H), 7.17 (t, IH), 7.2-7.58 (m, 5H), 8.19 (s, IH). t) 3.81 (s, 2H0, 4.16 (s, 2H), 7.26 (t, IH), 7.32-7.58 (m, 6H), 8.2 (s, IH). u) 5.46 (s, 2H), 6.31 (s, IH), 7.43-7.18 (m, 4H), 7.75-7.60 (m, 2H), 8.43 (s, IH). v) 5.53 (s, 2H), 6.30 (s, IH), 7.43-7.05 (m, 6H), 8.44 (s, IH). w) 5.51 (s, 2H), 6.32 (s, IH), 7.65-7.20 (m, 6H), 7.71 (s, IH), 8.44 (s, IH). x) 8.61 (s, IH), 7.75-7.45 (m's, 7H), 6.86 (s, IH), 5.64 (s, 2H). y) 8.43 (s, IH), 7.75-7.15 (m's, 6H), 6.32 (s, IH), 5.46 (s, 2H). z) 8.42 (s, IH), 7.45-7.15 (m's, 6H), 6.29 (s, IH), 5.40 (s, 2H). aa) 8.45 (s, IH), 7.75-7.20 (m's, 6H), 6.31 (s, IH), 5.57 (s, 2H). bb) 7.90 (s, IH), 7.75-7.15 (m's, 6H), 5.50 (s, 2H), 3.82 (broad s, 2H) . cc) 8.43 (s, IH), 7.57-7.0 (m's, 6H), 6.29 (s, IH), 5.40 (s, 2H. dd) 8.40 (s, IH), 7.60-7.20 (m's, 8H), 6.65 (q, IH), 6.45 (s, IH). ee) 8.44 (s, IH), 7.65-7.20 (m's, 6H), 6.33 (s, IH), 5.57 (s, 2H). ff) 8.35 (s, IH), 7.55-7.20 (m's, 6H), 6.26 (s, IH), 6.20 (q, IH), 1.63 (d, 3H). gg) 8.45 (s, IH), 7.45-6.95 (m's, 7H), 6.26 (s, IH), 5.41 (s, 2H). hh) 8.59 (s, IH), 7.97 (s, IH), 7.58 (s, 2H), 7.27 (m, 3H), 6.87 (s, IH), 5.48 (s, 2H). ii) 8.51 (s, IH), 7.4-7.1 (m, 7H), 6.39 (s, IH). U) 8.50 (s, IH), 7.7-7.1 (m, 7H), 6.41 (s, IH) kk) 8.50 (s, IH), 7.6-7.0 (m, 7H), 6.33 (s, IH).
11) 8.58 (s, IH), 7.5-7.2 (m, 7H), 6.76 (s, IH), 4.6 (s, 2H)
ΪH NMR data are in ppm downfield from tetramethylsilane. Couplings are designated by (s)-singlet,
(d)-doublet, (t)-triplet, (q)-quartet, (m)-multiplet, (dd)-doublet of doublets, (dt)-doublet of triplets,
(br s)-broad singlet.
BIOLOGICAL EXAMPLES OF THE INVENTION
TEST A
Two-Spotted Spider Mite Pieces of kidney bean leaves, each approximately 6.5 cm2 (1 square inch) in area, that had been infested on the undersides with 25 to 30 adult mites (Tetranychus urticae), were sprayed with their undersides facing up on a hydraulic sprayer with a solution of the test compound in 75:25 acetone-distilled water solvent. Spraying was accomplished by passing the leaves, on a conveyor belt, directly beneath a flat fan hydraulic nozzle which discharged the spray at a rate of 0.138 kilograms of active ingredient per hectare (about 0.13 pounds per acre) at 207 kPa (30 p.s.i.). The leaf squares were then placed underside-up on a square of wet cotton in a petri dish and the perimeter of the leaf square was tamped down onto the cotton with forceps so that the mites could not escape onto the untreated leaf surface. The test units were held at 27°C and 50% relative humidity for 48 hours, after which time mortality readings were taken. Of the compounds tested, the following gave mortality levels of 80% or higher: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 35, 37, 39, 40, 41, 42 and 43.
TEST B Fall Armyworm Test units, each consisting of a H.I. S. (high impact styrene) tray with 16 cells were prepared. Wet filter paper and approximately 8 cm2 of lima bean leaf was placed into twelve of the cells. A 0.5-cm layer of wheat germ diet was placed into the four remaining cells. Fifteen to twenty third-instar larvae of fall armyworm (Spodoptera frugiperdd) were placed into a 230-nιL (8-ounce) plastic cup. Solutions of each of the test compounds in 75:25 acetone-distilled water solvent were sprayed into the tray and cup. Spraying was accomplished by passing the tray and cup on a conveyer belt directly beneath a flat fan hydraulic nozzle which discharged the spray at a rate of 0.138 kilograms of active ingredient per hectare (about 0.13 pounds per acre) at 207 kPa (30 p.s.i.). The insects were transferred from the 230-mL cup to the H.I.S. tray (one insect per cell). The trays were covered and held at 27°C and 50% relative humidity for 48 hours, after which time readings were taken on the twelve cells with lima bean leaves. The four remaining cells were read at 6-8 days for delayed toxicity. Of the compounds tested, the following gave control efficacy levels of 80% or greater: 41.
TEST C Corn Planthopper Test Test Unit: The test unit consisted of a plastic cup containing 126 +/- 4 grams of sterilized, non-fertilized sassafras (sandy loam) soil. One pre-germinated Pioneer variety 3394 corn seed is placed in a 1 inch depression in the soil and covered. The test unit was watered with 15mL of distilled water and placed in a closed plexiglas box inside a greenhouse operating at 24 degrees centigrade and 36% relative humidity for 4 days at which time it is ready for test. A snug-fitting test unit lid with a small opening at the top was placed on all test units prior to test.
Compound Application: Test compounds were formulated at 250 ppm in 20% acetone: 80% water containing 500 ppm Ortho X-77 surfactant. Compounds were applied through the opening in the test unit lid with an atomizer sprayer fitted with a Model 17690- 1/8JJAU nozzle and a spray set-up consisting of a J2850 Fluid Cap and J70 Air Cap (Spray Sytems, Inc.). The sprayer was operated at 12-13psi. For each compound, 2 test units were sprayed with a total of 2 mL each of test solution. After spraying, test units were placed in a ventilated enclosure for 10-15 minutes to dry.
Insect Infesting/Evaluation: After drying, a thin layer of white quartz sand was poured onto the soil of each test unit to aid in the evaluation of live and dead insects at the conclusion of the test. Each unit was infested with a minimum of 15 nymphs of the corn planthopper, Peregrinus maidis, which were approximately 21 days old. Infested test units were held in a growth chamber operating at 22 degrees centigrade and 50% relative humidity with a 16:8 ligh dark photoperiod. Insect mortality was evaluated at 6 days post-infestation. Moribund insects were counted as dead. Of the compounds tested, the following gave mortality of 80% or greater: 42.

Claims

CLAIMS What is claimed is:
1. A compound selected from Formula I, N-oxides and agriculturally suitable salts thereof,
Figure imgf000053_0001
wherein
Q1 is O, S, ΝR17, OCR.18R19, or ΝR^CR1^; wherein when Q1 is OCR.18R.19 or
ΝRl7CR18R19, then Q1 is attached to the pyrimidine through the O or N atom respectively; Q2 is S, CR3R4, OCR18R19, SCR18R19 or NR17CR18R19; wherein when Q2 is
OCR18R19, SCR18R19 or NR17CR18R19 then Q2 is attached to the pyrimidine through the O, S or N atom respectively; J is
Figure imgf000053_0002
X, Y and Z are each independently N or CR22;
R1 and R2 are each independently H, C J-C4 alkyl, halogen, NR7R8, C1-C4 alkoxy, Cj-
C4 haloalkyl, C1-C4 alkylthio or nitro; R3 and R4 are each independently H, halogen, hydroxy, C1-C4 alkyl, CJ-C4 alkoxy,
Cj-C4 haloalkyl or cyano; or R3 and R4 are taken together with the attached carbon to make a carbonyl; each R5 is independently H, halogen, C]-C4 alkyl, C]-C haloalkoxy, CrC4 haloalkyl,
CrC4 alkoxy, SF5, S(O)nR9, cyano or CO2R11; each R6 and each R22 is independently H, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, CrC4 haloalkoxy, CrC4 alkoxy, NR!7 or S(O)nR9; R7 and R8 are each independently H, C1-C4 alkyl, C3-C6 alkenyl, C3-C6 alkynyl,
CORl°, CO2RU, CHO, SO2Rl2 or ORI3; each R9 is independently C1-C4 alkyl or C1-C4 haloalkyl; each R10 is independently Ci-Cg alkyl, phenyl optionally substituted by R6, Cj-Cg haloalkyl, CO2R14, CrC6 alkoxyalkyl, C2-C4 alkenyl, C2-C6 alkynyl, C2-C6 cyanoalkyl or NR15R16; R1 ! and R12 are each independently Cj- alkyl, Cι-C6 haloalkyl, C2-C6 alkenyl or
C -Cg alkynyl; R13 and R17 are each independently CrC4 alkyl, H, COR10 or CO2RJ ; each R14 is independently C1-C4 alkyl; each R15 is independently H, C1-C4 alkyl, C1-C4 alkoxy or phenyl optionally substituted by R6;
R16 and R19 are each independently H or C1-C4 alkyl; each R18 is independently H, CrC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or cyano; n is 0-2; p is 0-4; and q is 0-4; provided that when Q2 is NR17CR18R19, then J is J2.
2. A compound of Claim 1 wherein J is Jl; Rl and R2 are H;
R5 is CrC2 haloalkyl; each R6 and each R22 is halogen; and
R3 and R4 are either each H or taken together with the attached carbon as a carbonyl.
3. A compound of Claim 1 wherein
J is J2;
R1 and R2 are H; R5 is Cj to C2 haloalkyl; each R6 and each R22 is halogen; R3 and R4 are each H; and
Y is N, X is CH and Z is CR22. 4. A compound of Claim 2 selected from the group: 4- [4-fluoro-3 -(trifluoromethy l)phenoxy] -6- [ [4-fluoro-3 - (trifluoromethyl)phenyl]methyl]pyrimidine; 4- [4-chloro-3 -(trifluoromethy l)phenoxy] -6- [ [4-fluoro-3 -
(trifluoromethyl)phenyl]methyl]pyrimidine;
[6-[4-fluoro-3-(frifluoromethyl)phenoxy]-4-pyrimidinyl][4-fluoro-3- (trifluoromethyl)phenyl]methanone; 4-[4-fluoro-3-(trifluoromethyl)phenyl]-6-[3-(trifluoromethyl)- phenyl]methoxypyrimidine;
4-[4-fluoro-3-(trifluoromethyl)phenoxy]-6-[[4-fluoro-3- (trifluoromethyl)phenyl]methyl]-5-pyrimidinamine; 4- [(3 ,4-difluorophenyl)methoxy] -6- [4-fluoro-3 -
(trifluoromethyl)phenoxy]pyrimidine and 4- [4-fluoro-3 -(trifluoromethy l)phenoxy] - 6- [(4-fluorophenyl)thio]pyrimidine.
5. An arthropodicidal composition comprising an arthropodicidally effective amount of a compound of Claim 1 and at least one of a surfactant, a solid diluent or a liquid diluent.
6. A method for controlling arthropods comprising contacting the arthropods or their environment with an arthropodicidally effective amount of a compound of Claim 1.
PCT/US2000/003180 1999-02-16 2000-02-08 Phenoxy-, phenylthio-, phenylamino-, benzyloxy-, benzylthio- or benzylaminopyrimidine insectidices and acaricides WO2000049001A2 (en)

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WO2012094451A1 (en) * 2011-01-06 2012-07-12 Beta Pharma Canada Inc. Novel ureas for the treatment and prevention of cancer
US10420764B2 (en) 2012-12-21 2019-09-24 Astrazeneca Ab Pharmaceutical formulation of N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-YL]-4-[(3R,5S)-3 ,5-dimethylpiperazin-1-YL] benzamide
CN113264924A (en) * 2020-02-14 2021-08-17 山东省联合农药工业有限公司 Dioxane pyrimidine derivative and preparation method and application thereof
CN113264924B (en) * 2020-02-14 2022-11-08 山东省联合农药工业有限公司 Dioxane pyrimidine derivative and preparation method and application thereof

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