WO2000071536A1 - Heteroaryloxypyrimidine insecticides and acaricides - Google Patents

Heteroaryloxypyrimidine insecticides and acaricides Download PDF

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WO2000071536A1
WO2000071536A1 PCT/US2000/013437 US0013437W WO0071536A1 WO 2000071536 A1 WO2000071536 A1 WO 2000071536A1 US 0013437 W US0013437 W US 0013437W WO 0071536 A1 WO0071536 A1 WO 0071536A1
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alkyl
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PCT/US2000/013437
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Thomas Paul Selby
Thomas Martin Stevenson
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E.I. Du Pont De Nemours And Company
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
    • A01N43/647—Triazoles; Hydrogenated triazoles
    • A01N43/653—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
    • A01N43/76—1,3-Oxazoles; Hydrogenated 1,3-oxazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
    • A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero atoms
    • 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
    • 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
    • C07D403/12—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 chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to certain heteroaryloxypyrimidines, their N-oxides, agriculturally suitable salts and compositions, and methods of their use as arthropodicides.
  • 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 that are more effective, less costly, less toxic, environmentally safer or have different modes of action.
  • 4,6-Diphenoxypyrimidmes (Q is O) are claimed in US Patent 5,707,995 as insecticides and acaricides.
  • 4-A_nlino-6-phenoxypyrimidines (Q is ⁇ H) are disclosed in WO 98/12184 and WO 98/54154 as insecticides and acaricides.
  • heteroaryloxypyrimidines of the present invention are not disclosed in these publications.
  • 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, ⁇ R 17 , CR 3 R 4 or OCR 18 R 19 ; wherein when Q 1 is OCR 18 R 19 , then Q 1 is attached to the pyrimidine through the O atom;
  • Q 2 is O, S, NR 17 , CR3R 4 , OCR 1 Rl 9 , SCRI8R 19 or NRl 7 CR 18 R 19 ; wherein when Q 2 is OCR18R1 , SCRISR 19 or NR 17 CRl 8 Rl9 then Q 2 is attached to the pyrimidine through the O, S or N atom;
  • W is O, S or NR 20 ;
  • X, Y, and Z are independently N or CR 22 ; provided that in J-3 and J-4, at least one of
  • R 1 and R 2 are each independently H, C1-C 4 alkyl, halogen, NR 7 R 8 , C1-C4 alkoxy, Ci- C 4 haloalkyl, C1-C4 alkylthio or nitro;
  • R 3 and R 4 are each independently H, halogen, hydroxy, C1-C4 alkyl, Ci -C 4 alkoxy,
  • R 3 and R 4 are taken together with the attached carbon to make a carbonyl;
  • R 5 and R 21 are each independently halogen, C1-C4 alkyl, C1-C4 haloalkoxy, C1-C 4 haloalkyl, C1-C4 alkoxy, C 2 -C 4 alkenyl, C2-C4 alkynyl, C3-C4 alkenyloxy,
  • each R 6 and each R 22 are independently H, halogen, cyano, C r C 4 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, C r C 4 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, COR i O, CO 2 R n , CHO, SO 2 Rl2 or OR 13 ;
  • each R 9 is independently C1-C4 alkyl or C1-C4 haloalkyl;
  • each R 10 is independently C r C 6 alkyl, phenyl optionally substituted by R 6 , Ci-C ⁇ haloalkyl, CO 2 R 14 , C r C
  • R13 and R 17 are each independently C r C 4 alkyl, H, COR 10 or CO 2 R n ; each R 14 is independently C ⁇ -C 4 alkyl; each R 15 is independently H, C r C 4 alkyl, C1-C4 alkoxy or phenyl optionally substituted by R 6 ;
  • R 16 and R 19 are each independently H or C ⁇ -C 4 alkyl; each R 18 is independently H, C r C 6 alkyl, C r C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or cyano; R 0 is H, C r C 4 alkyl or C r C 4 haloalkyl; n is 0-2; and p is 0-4.
  • alkyl used either alone or in compound words such as “alkylthio” or “haloalkyl” includes straight-chain or branched alkyl, such as, methyl, ethyl, rt-propyl, z ' -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.
  • alkynyloxy includes straight-chain or branched alkynyloxy moieties. Examples of “alkynyloxy” include HC ⁇ CCH 2 O, CH 3 C ⁇ CCH 2 O and CH 3 C ⁇ CCH 2 CH 2 O.
  • Alkylthio includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers.
  • Alkylsulfinyl includes both enantiomers of an alkylsulfinyl group. Examples of “alkylsulfinyl” include CH 3 S(O), CH 3 CH 2 S(O), CH 3 CH 2 CH 2 S(O), (CH 3 ) 2 CHS(O) and the different butylsulfinyl, pentylsulfinyl and hexylsulfinyl isomers.
  • alkylsulfonyl examples include CH 3 S(O) 2 , CH 3 CH 2 S(O) 2 , CH 3 CH 2 CH 2 S(O) 2 , (CH3) 2 CHS(O) 2 and the different butylsulfonyl, pentylsulfonyl and hexylsulfonyl 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 CH3CH 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 .
  • Alkylamino dialkylamino
  • alkenylthio alkenylsulfinyl
  • alkenylsulfonyl alkynylthio
  • alkynylsulfinyl alkynylsulfonyl
  • alkynylsulfonyl and the like, are defined analogously to the above examples.
  • halogen either alone or in compound words such as “haloalkyl”, includes fluorine, chlorine, bromine or iodine.
  • 1-2 halogen indicates that one or two of the available positions for that substituent may be halogen which are independently selected. 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 F 3 C, C1CH 2 , CF 3 CH 2 and CF 3 CC1 2 .
  • haloalkynyl examples include HC ⁇ CCHCl, CF 3 C ⁇ C, CC1 3 C ⁇ C and FCH 2 C ⁇ CCH 2 .
  • haloalkoxy examples include CF 3 O, CCl 3 CH 2 O, HCF 2 CH 2 CH 2 O and CF 3 CH 2 O.
  • haloalkylthio examples include CC1 3 S, CF 3 S, CC1 3 CH 2 S and C1CH 2 CH 2 CH 2 S.
  • haloalkylsulfinyl examples include CF 3 S(O), CCl 3 S(O), CF 3 CH 2 S(O) and CF 3 CF 2 S(O).
  • haloalkylsulfonyl examples include CF 3 S(O) 2 , CCl 3 S(O) 2 , CF 3 CH 2 S(O) 2 and CF 3 CF 2 S(O) 2 .
  • haloalkoxyalkoxy examples include CF 3 OCH 2 O, ClCH 2 CH 2 OCH 2 CH 2 O, Cl 3 CCH 2 OCH 2 O as well as branched alkyl derivatives.
  • the total number of carbon atoms in a substituent group is indicated by the “C j -C j " prefix where i and j are numbers from 1 to 6.
  • C ⁇ -C 3 alkylsulfonyl designates methylsulfonyl through propylsulfonyl.
  • alkylcarbonyl examples include C(O)CH 3 , C(O)CH 2 CH 2 CH 3 and C(O)CH(CH 3 ) 2 .
  • 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.
  • 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
  • Preferred compounds for reasons of better activity and/or ease of synthesis are: Preferred 1.
  • R 1 and R 2 are H; R 5 is C r C 2 haloalkyl; each R 6 is halogen; and
  • R 3 and R 4 are each H.
  • 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 r C 2 haloalkyl; each R 6 is halogen; and R 3 and R 4 are each H.
  • Preferred 3 Compounds of Formula I above, N-oxides and agriculturally suitable salts thereof, wherein: J is J-3;
  • R 1 and R 2 are H; R 5 is C r C 2 haloalkyl; each R 6 is halogen; and R 3 and R 4 are each H.
  • Preferred 4 Compounds of Formula I above, N-oxides and agriculturally suitable salts thereof, wherein: J is J-4;
  • R 1 and R 2 are H; R 5 is C r C 2 haloalkyl; each R 6 is halogen; and R 3 and R 4 are each H. Preferred 5.
  • This invention also relates to arthropodicidal compositions comprising arthropodicidally effective amounts of the compovmds of the invention and at least one additional component selected from the group consisting of surfactants, solid diluents or liquid diluents.
  • 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 preferred compounds above.
  • 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 , W, X, Y, Z, n and p in the compounds of Formulae 1-16 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.
  • the 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.
  • Compounds of Formula 2 where Q 1 is O are known in the art and their preparation is disclosed in EP 794177 and references cited therein.
  • L halogen, S0 2 (C ⁇ -C alkyl) or + N(Ci-C 4 alkyl) 3
  • 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)palladi ⁇ m.
  • 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 I, 1967 and Supplement II, 1985; Wiley, New York).
  • each L 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, dimethoxyethane or other aprotic solvent.
  • Reaction temperatures may range from 0 to 80 °C.
  • Compounds of Formula 2b 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 strong base such as an alkali hydride, preferrably sodium hydride
  • 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 preferred catalyst is 1 ,3-dimethylimidazolium iodide that may be present in a 10 to 100% catalyst load.
  • Compotmds of Formula 2c can be made by the reaction of compounds of Formula 9 with compovmds of Formula 5 in the presence of base as shown in Scheme 5.
  • Q 1 is OCR 18 R 19 it is advantageous to use strong bases such as alkali hydrides or alkoxides.
  • strong bases such as alkali hydrides or alkoxides may be used, but alkali carbonates and tertiary amine bases can also be employed.
  • Such displacements may occur at temperatures between 0 and 120 °C, but temperatures from 20 to 30 °C are preferred.
  • a variety of solvents may be employed, but dimethylformamide, tetrahydrofuran and dimethylsulfoxide are preferred.
  • L 1 is halogen or S0 2 (Ci-C 4 )alkyl
  • compounds of Formula I may also be made by the reaction of compounds of Formula 12 with compounds of Formula 9 in the presence of an acid acceptor.
  • 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.
  • L is halogen
  • compounds of Formula 12a can be readily prepared by the coupling of a zinc species of Formula 14 with a h ogenopyrimidine of Formula 5.
  • the coupling reaction can be catalyzed by either nickel or palladium complexes.
  • the preferred complexes for this transformation are tefraMs(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 I, 1967 and Supplement II, 1985; Wiley, New York).
  • OCR 18 R 19 , SCR 18 R 19 , or NR 17 R 18 R 19 can be made by the reaction of compounds of Formula 15 with compounds of Formula 5 in the presence of base as shown in Scheme 9.
  • Q 2 is OCR 18 R 19 it is advantageous to use strong bases such as alkali hydrides or alkoxides.
  • strong bases such as alkali hydrides or alkoxides may be used, but alkali carbonates and tertiary amine bases can also be employed. Such displacements may occur at temperatures between 0 and 120 °C, but temperatures from 20 to 30 °C are preferred.
  • a variety of solvents may be employed, but dimethylformamide, tetrahydrofuran and dimethylsulfoxide are preferred.
  • Compounds of Formula 12 can be prepared by the condensation of pyrimidines of Formula 5 and aldehydes of Formula 16 in the presence of an imidazolium catalyst of Formula 8 as shown in Scheme 10. This reaction is carried out in the presence of a strong base such as an alkali hydride, preferably 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 strong base such as an alkali hydride, preferably sodium hydride
  • 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 preferred catalyst is 1,3-dimethylimidazolium iodide that may be present in a 10 to 100% catalyst load.
  • L 1 is halogen or S0 (C ⁇ -C 4 ) alkyl
  • Heterocyclic compounds of structures 3, 11, 15, and 16 are commercially available, known in the art or can be prepared by modification of methods disclosed in the art. Both general and specific references to a wide variety of heterocycles including thiophenes, furans, pyridines, pyrimidines, triazoles, imidazoles, pyrazoles, thiazoles, oxazoles, isofhiazoles, thiadiazoles, oxadiazoles, triazines, pyrazines, pyridazines, and isoxazoles can be found in the following compendia: Rodd's Chemistry of Carbon Compounds, Vol. INa to INI., S.
  • Step A Preparation of 4-r4-fluoro-3-(trifluoromemyl phenoxyl-6-met_ ylthiopyrimidine
  • Step B Preparation of 4-[4-fluoro-3-(trifluorome v ⁇ phenoxyl-6-methylsulfonylpyrimidine
  • 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-r4-fluoro-3-(trifluoromethyl phenoxyl-6-fr5-(trifluoromethylV3- thienyll oxy]pyrimidine
  • Step B The compound of Step B (0.8 g, 2.4 mmol) was dissolved in dimethylformamide (5 mL) and treated sequentially with 2-trifluoromethyl-4-hydroxythiophene (US patent 5,851,952; 0.3 g, 2 mmol) and potassium carbonate (1.0 g, 7.2 mmol). The mixture was stirred overnight and was partitioned between water and ether. The aqueous layer was re-extracted with water. The combined organic layers were washed with water and saturated brine. The organic layer, after drying with magnesium sulfate, was evaporated under reduced pressure.
  • 2-trifluoromethyl-4-hydroxythiophene US patent 5,851,952; 0.3 g, 2 mmol
  • potassium carbonate 1.0 g, 7.2 mmol
  • Step B Preparation of 4-r4-fluoro-3-(trifluoromethyl)benzyll-6-rri-methyl-5- (trifluoromethyl -lH-pyrazol-3-ylloxylpyrimidine
  • O ⁇ H. O 2 OCH 2
  • O 1 0.
  • O 1 0.
  • O 1 O.
  • O 1 0.
  • O 2 OCH 2
  • O ⁇ NH. O 2 OCH 2

Abstract

Compounds of Formula (I), and their N-oxides and agriculturally suitable salts, are disclosed which are useful arthropodicides (I) wherein Q1 is O, S, NR?17, CR3R4 OR OCR18R19¿; wherein when Q?1 is OCR18R19¿, then Q1 is attached to the pyrimidine through the O atom; Q2 is O, S, NR?17, CR3R4, 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; J is (J-1); (J-2); (J-3) or (J-4); W is O, S or NR20; X, Y and Z are independently N or CR22; provided that in J-3 and J-4, at least one of X, Y or Z is N; and R?1, R2, R3, R4, R5, R6, R7, R17, R18, R19, R20, R21, R22¿ and p 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
HETEROARYLOXYPYREVIIDINE INSECTICIDES AND ACARICIDES
BACKGROUND OF THE INVENTION This invention relates to certain heteroaryloxypyrimidines, their N-oxides, agriculturally suitable salts and compositions, and methods of their use as arthropodicides.
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 that are more effective, less costly, less toxic, environmentally safer or have different modes of action.
4,6-Diphenoxypyrimidmes (Q is O) are claimed in US Patent 5,707,995 as insecticides and acaricides. 4-A_nlino-6-phenoxypyrimidines (Q is ΝH) are disclosed in WO 98/12184 and WO 98/54154 as insecticides and acaricides.
Figure imgf000002_0001
The heteroaryloxypyrimidines 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 imgf000002_0002
wherein:
Q1 is O, S, ΝR17, CR3R4 or OCR18R19; wherein when Q1 is OCR18R19, then Q1 is attached to the pyrimidine through the O atom; Q2 is O, S, NR17, CR3R4, OCR1 Rl9, SCRI8R19 or NRl7CR18R19; wherein when Q2 is OCR18R1 , SCRISR19 or NR17CRl8Rl9 then Q2 is attached to the pyrimidine through the O, S or N atom;
J is
Figure imgf000003_0001
W is O, S or NR20;
X, Y, and Z are independently N or CR22; provided that in J-3 and J-4, at least one of
X, Y or Z is N; 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, Ci -C4 alkoxy,
C!-C4 haloalkyl or cyano; or R3 and R4 are taken together with the attached carbon to make a carbonyl; R5 and R21 are each independently halogen, C1-C4 alkyl, C1-C4 haloalkoxy, C1-C4 haloalkyl, C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, C3-C4 alkenyloxy,
C3-C4 alkynyloxy, SF5, S(O)nR9, cyano or CO2Rπ; each R6 and each R22 are independently H, halogen, cyano, CrC4 alkyl, C1-C4 haloalkyl, CrC4 haloalkoxy, CrC4 alkoxy, NR17 or S(O)nR9; R7 and R8 are each independently H, CrC4 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, CORiO, CO2Rn, CHO, SO2Rl2 or OR13; each R9 is independently C1-C4 alkyl or C1-C4 haloalkyl; each R10 is independently CrC6 alkyl, phenyl optionally substituted by R6, Ci-Cβ haloalkyl, CO2R14, CrC6 alkoxyalkyl, C2-C4 alkenyl, C2-C6 alkynyl, C2-C6 cyanoalkyl orNR15R16; R1 ! and R12 are each independently CrC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl or
C2-C6 alkynyl; R13 and R17 are each independently CrC4 alkyl, H, COR10 or CO2Rn; each R14 is independently Cι-C4 alkyl; each R15 is independently H, CrC4 alkyl, C1-C4 alkoxy or phenyl optionally substituted by R6;
R16 and R19 are each independently H or Cι-C4 alkyl; each R18 is independently H, CrC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or cyano; R 0 is H, CrC4 alkyl or CrC4 haloalkyl; n is 0-2; and p is 0-4.
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, rt-propyl, z'-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. "Alkenyloxy" includes straight-chain or branched alkenyloxy moieties. Examples of "alkenyloxy" include H2C=CHCH2O, (CH3)2C=CHCH2O, (CH3)CH=CHCH2O, (CH3)CH=C(CH3)CH2O and CH =CHCH CH2O. "Alkynyloxy" includes straight-chain or branched alkynyloxy moieties. Examples of "alkynyloxy" include HC≡CCH2O, CH3C≡CCH2O and CH3C≡CCH2CH2O. "Alkylthio" includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers. "Alkylsulfinyl" includes both enantiomers of an alkylsulfinyl group. Examples of "alkylsulfinyl" include CH3S(O), CH3CH2S(O), CH3CH2CH2S(O), (CH3)2CHS(O) and the different butylsulfinyl, pentylsulfinyl and hexylsulfinyl isomers. Examples of "alkylsulfonyl" include CH3S(O)2, CH3CH2S(O)2, CH3CH2CH2S(O)2, (CH3)2CHS(O)2 and the different butylsulfonyl, pentylsulfonyl and hexylsulfonyl 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. "Alkylamino", "dialkylamino", "alkenylthio", "alkenylsulfinyl", "alkenylsulfonyl", "alkynylthio", "alkynylsulfinyl", "alkynylsulfonyl", and the like, are defined analogously to the above examples.
The term "halogen", either alone or in compound words such as "haloalkyl", includes fluorine, chlorine, bromine or iodine. The term "1-2 halogen" indicates that one or two of the available positions for that substituent may be halogen which are independently selected. 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 terms "haloalkenyl", "haloalkynyl", "haloalkoxy", "haloalkylthio", and the like, are defined analogously to the term "haloalkyl". Examples of "haloalkenyl" include (C1)2C=CHCH2 and CF3CH2CH=CHCH2. Examples of "haloalkynyl" include HC≡CCHCl, CF3C≡C, CC13C≡C and FCH2C≡CCH2. Examples of "haloalkoxy" include CF3O, CCl3CH2O, HCF2CH2CH2O and CF3CH2O. Examples of "haloalkylthio" include CC13S, CF3S, CC13CH2S and C1CH2CH2CH2S. Examples of "haloalkylsulfinyl" include CF3S(O), CCl3S(O), CF3CH2S(O) and CF3CF2S(O). Examples of "haloalkylsulfonyl" include CF3S(O)2, CCl3S(O)2, CF3CH2S(O)2 and CF3CF2S(O)2. Examples of "haloalkoxyalkoxy" include CF3OCH2O, ClCH2CH2OCH2CH2O, Cl3CCH2OCH2O as well as branched alkyl derivatives. The total number of carbon atoms in a substituent group is indicated by the "Cj-Cj" prefix where i and j are numbers from 1 to 6. For example, Cι-C3 alkylsulfonyl designates methylsulfonyl through propylsulfonyl. Examples of "alkylcarbonyl" include C(O)CH3, C(O)CH2CH2CH3 and C(O)CH(CH3)2. Examples of "alkoxycarbonyl" include CH3OC(=O), CH3CH2OC(=O), CH3CH2CH2OC(=O), (CH3)2CHOC(=O) and the different butoxy- or pentoxycarbonyl 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.
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. 7, pp 748-750, S. N. 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.
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 maybe 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.
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.
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;
R1 and R2 are H; R5 is CrC2 haloalkyl; each R6 is halogen; and
R3 and R4 are each H. Preferred 2. Compounds of Formula I above, N-oxides and agriculturally suitable salts thereof, wherein: J is J-2; R1 and R2 are H;
R5 is CrC2 haloalkyl; each R6 is halogen; and R3 and R4 are each H. Preferred 3. Compounds of Formula I above, N-oxides and agriculturally suitable salts thereof, wherein: J is J-3;
R1 and R2 are H; R5 is CrC2 haloalkyl; each R6 is halogen; and R3 and R4 are each H. Preferred 4. Compounds of Formula I above, N-oxides and agriculturally suitable salts thereof, wherein: J is J-4;
R1 and R2 are H; R5 is CrC2 haloalkyl; each R6 is halogen; and R3 and R4 are each H. Preferred 5. Compounds of Preferred 1 wherein Q1 and Q2 are both O.
Preferred 6. Compounds of Preferred 2 wherein Q1 and Q are both O. Preferred 7. Compounds of Preferred 3 wherein Q1 and Q2 are both O. Preferred 8. Compounds of Preferred 4 wherein Q1 and Q2 are both O. Specifically preferred for insecticidal and acaricidal activity and/or ease of synthesis is 4-[4-fluoro-3-(trifluoromethyl)phenoxy]-6-[[l-methyl-5-(trifluoromethyl)-lH- pyrazol-3-yl]oxy]pyrimidine. This invention also relates to arthropodicidal compositions comprising arthropodicidally effective amounts of the compovmds of the invention and at least one additional component selected from the group consisting of surfactants, solid diluents or liquid diluents. 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 preferred compounds above.
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, W, X, Y, Z, n and p in the compounds of Formulae 1-16 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 Q2 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 Q2 is NR17) is to carry out the reaction in aqueous acetone containing hydrochloric acid. Compounds of Formula 2 where Q1 is O are known in the art and their preparation is disclosed in EP 794177 and references cited therein.
Scheme 1
+ JQ2H Acceptor
Figure imgf000008_0001
L = halogen, S02(Cι-C alkyl) or+N(Ci-C4 alkyl)3
As shown in Scheme 2, compounds of Formula 2a (compounds of Formula 2 wherein Q1 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)palladiιιm. 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 I, 1967 and Supplement II, 1985; Wiley, New York).
Scheme 2
Q is
Figure imgf000009_0001
each L 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, dimethoxyethane or other aprotic solvent. Reaction temperatures may range from 0 to 80 °C.
Scheme 3
Figure imgf000009_0002
L is halogen
Compounds of Formula 2b (compounds of Formula 2 wherein Q1 is C(=O)) 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 that may be present in a 10 to 100% catalyst load.
Scheme 4
Figure imgf000010_0001
Compotmds of Formula 2c (compounds of Formula 2 in which Q1 is O, OCR18R19, SCR18R19, or NR17R18R19) can be made by the reaction of compounds of Formula 9 with compovmds of Formula 5 in the presence of base as shown in Scheme 5. In the case where Q1 is OCR18R19 it is advantageous to use strong bases such as alkali hydrides or alkoxides. In the cases of SCR18R19, or NR17R18R19 strong bases such as alkali hydrides or alkoxides may be used, but alkali carbonates and tertiary amine bases can also be employed. Such displacements may occur at temperatures between 0 and 120 °C, but temperatures from 20 to 30 °C are preferred. A variety of solvents may be employed, but dimethylformamide, tetrahydrofuran and dimethylsulfoxide are preferred.
Scheme 5
Figure imgf000010_0002
L1 is halogen or S02(Ci-C4)alkyl
An alternative coupling procedure for the synthesis of compounds of Formula I is shown in Scheme 6. Reaction of pyrimidines of Formula 10 with heterocycles of Formula 11 in the presence of an acid acceptor leads to 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.
Scheme 6
Figure imgf000011_0001
10
L is halogen
S02(Cι-C alkyl)
As shown in Scheme 7 compounds of Formula I may also be made by the reaction of compounds of Formula 12 with compounds of Formula 9 in the presence of an acid acceptor. 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.
Scheme 7
Figure imgf000011_0002
i2 y
L is halogen or
S02(Cι-C4 alkyl)
As shown in Scheme 8, compounds of Formula 12a (compounds of Formula 12 wherein Q2 is CR3R4) can be readily prepared by the coupling of a zinc species of Formula 14 with a h ogenopyrimidine of Formula 5. The coupling reaction can be catalyzed by either nickel or palladium complexes. The preferred complexes for this transformation are tefraMs(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 I, 1967 and Supplement II, 1985; Wiley, New York).
Scheme 8
Figure imgf000012_0001
14 Compounds of Formula 12b (compounds of Formula 12 in which Q2 is O,
OCR18R19, SCR18R19, or NR17R18R19) can be made by the reaction of compounds of Formula 15 with compounds of Formula 5 in the presence of base as shown in Scheme 9. In the case where Q2 is OCR18R19 it is advantageous to use strong bases such as alkali hydrides or alkoxides. In the cases of O, SCR18R19 or NR17R18R19, strong bases such as alkali hydrides or alkoxides may be used, but alkali carbonates and tertiary amine bases can also be employed. Such displacements may occur at temperatures between 0 and 120 °C, but temperatures from 20 to 30 °C are preferred. A variety of solvents may be employed, but dimethylformamide, tetrahydrofuran and dimethylsulfoxide are preferred.
Scheme 9
Figure imgf000012_0002
Compounds of Formula 12 (Q2 is CO) can be prepared by the condensation of pyrimidines of Formula 5 and aldehydes of Formula 16 in the presence of an imidazolium catalyst of Formula 8 as shown in Scheme 10. This reaction is carried out in the presence of a strong base such as an alkali hydride, preferably 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 that may be present in a 10 to 100% catalyst load.
Scheme 10
Figure imgf000013_0001
L1 is halogen or S0 (Cι-C4) alkyl
Heterocyclic compounds of structures 3, 11, 15, and 16 are commercially available, known in the art or can be prepared by modification of methods disclosed in the art. Both general and specific references to a wide variety of heterocycles including thiophenes, furans, pyridines, pyrimidines, triazoles, imidazoles, pyrazoles, thiazoles, oxazoles, isofhiazoles, thiadiazoles, oxadiazoles, triazines, pyrazines, pyridazines, and isoxazoles can be found in the following compendia: Rodd's Chemistry of Carbon Compounds, Vol. INa to INI., S. Coffey editor, Elsevier Scientific Publishing, New York, 1973; Comprehensive Heterocyclic Chemistry, Vol. 1-7, A. R. Katritzky and C. W. Rees editors, Pergamon Press, New York, 1984; Comprehensive Heterocyclic Chemistry II, Vol. 1-9, A. R. Katritzky, C. W. Rees, and E. F. Scriven editors, Pergamon Press, New York, 1996; and the series, The Chemistry of Heterocyclic Compounds, E. C. Taylor, editor, Wiley, New York.
For a review of synthetic methods for haloalkyl substituted azoles see Elguero et. al., Organic Preparations and Procedures Int., 1995, 27, 33-74. For a variety of heterocycles, see WO 98/23156. For haloalkylthiophenes, see US Patents 5,851,952 and 5,869,426. 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 teframethylsilane; s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, br s = broad singlet.
EXAMPLE 1 Preparation of 4-r4-fluoro-3-(trifluoromethyl')phenoxyl-6-[T 1 -methyl-5-(trifluoromethyl - lH-pyrazol-3-ylloxylpyrimidine To a solution of 4-cUoro-6-(4-fluoro-3-trifluoromet_ ylphenoxy)pyrimidine
(EP 794177, 0.52 g) and 3-hydroxy-l-methyl-5-trifluoromethylpyrazole (Acros, 0.27 g) in acetonitrile (15 mL) was added potassium carbonate (0.7 g). The resulting mixture was heated at reflux for 7 h. After the mixture cooled to room temperature it was filtered. The acetonitrile was removed under reduced pressure and the residue was subjected to column chromatography on silica gel with hexanes/ethyl acetate (4:1) as eluent. Pooling of appropriate fractions gave the title compound (0.21 g) as an oil. NMR (CDC13) δ 3.96 (s,3Η), 6.51 (s,lH), 6.57 (s,lH), 7.2-7.45 (m,3H), 8.45 (s,lH).
EXAMPLE 2 Synthesis of 4-r4-fluoro-3-(trifluoromethyl phenoxyl-6-rr5-(trifluoromethyl)-3- thienyll oxylp yrimidine
Step A: Preparation of 4-r4-fluoro-3-(trifluoromemyl phenoxyl-6-met_ ylthiopyrimidine
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). The precipitated solid was filtered and washed with water to give the titled compound of Step A (1.8 g). M.P. : 85-87 °C. H NMR (CDCI3): δ 8.54 (s,lH), 7.2- 7.5 (m,3H), 6.78 (s,lH), 2.59 (s,3H). Step B: Preparation of 4-[4-fluoro-3-(trifluorome vπphenoxyl-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). !H NMR (CDCI3): δ 8.9 (s,lH), 7.7 (s,lH), 7.5-7.2 (m,3H), 3.3 (s,3H).
Step C: Preparation of 4-r4-fluoro-3-(trifluoromethyl phenoxyl-6-fr5-(trifluoromethylV3- thienyll oxy]pyrimidine
The compound of Step B (0.8 g, 2.4 mmol) was dissolved in dimethylformamide (5 mL) and treated sequentially with 2-trifluoromethyl-4-hydroxythiophene (US patent 5,851,952; 0.3 g, 2 mmol) and potassium carbonate (1.0 g, 7.2 mmol). The mixture was stirred overnight and was partitioned between water and ether. The aqueous layer was re-extracted with water. The combined organic layers were washed with water and saturated brine. The organic layer, after drying with magnesium sulfate, was evaporated under reduced pressure. The residue was subjected to silica gel chromatography with hexanes/ethyl acetate 3:1 as eluent to give the titled compound as an oil (0.40 g). lH NMR (CDCI3): δ 6.5 (s,lH), 7.20-7.43 (m,5H), 8.44 (s,lH).
EXAMPLE 3
Preparation of 4 4-fluoro-3-(trifluoromethvDphenoxyl- 6-|T 1 -methyl-3-(trifluoromethyl)- lH-pyrazol-5-ylloxy1-5-pyrimidinamine
5-Ammo-4-cWoro-6-[4-Fluoro-3-(trifluoromethyl)phenoxy]pyrimidine (World Patent Application WO 98/54154, 0.7 g, 2.3 mmol) was dissolved in dimethylformamide (10 mL) and treated with 5-hydroxy-l-methyl-3-trifluoromethylpyrazole (Acros, 0.28 g, 1.7 mmol) and potassium carbonate (1.0 g, 7 mmol). The reaction mixture was heated at 100 °C. for 4 h. The mixture was stirred at 23 °C. overnight and was partitioned between water and ether. The aqueous layer was re-extracted with water. The combined organic layers were washed with water and saturated brine. The organic layer, after drying with magnesium sulfate, was evaporated under reduced pressure. The residue was subjected to silica gel chromatography with hexanes/ethyl acetate (7:3) as eluent to give the titled compound as a solid (0.28 g). M. P.: 99-102 °C. *Η NMR (CDC13): δ 3.95 (s,3Η), 4.04 (s,2H), 6.57 (s,lH), 7.21-7.34 (m,lH), 7.38-7.50 (m,2H), 7.89 (s,lH). EXAMPLE 4
Preparation of 4-r4-fluoro-3-(trifluoromethyl)benzyll-6-IT 1 -methyl-5-(trifluoromethyl)- lH-pyrazol-3-ylloxylpyrimidine Step A: Preparation of 4-chloro-6-r[4-fluoro-3-(trifluoromethyl)phenyllmethyll-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 liquid 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. lH NMR (CDC13), δ 4.2 (s,2Η), 7.15-7.25 (m,2H),
7.42-7.55 (m,2H), 8.95 (s,lH). Step B: Preparation of 4-r4-fluoro-3-(trifluoromethyl)benzyll-6-rri-methyl-5- (trifluoromethyl -lH-pyrazol-3-ylloxylpyrimidine
The titled compound of Step B (0.50 g, 1,7 mmol) and 3-hydroxy-l-methyl-5- trifluoromethylpyrazole (0.28 g, 1.7 mmol) were dissolved in dimethylformamide (3 mL) and treated with potassium carbonate (0.7 g, 5 mmol). The mixture was heated at 80 °C for 18 h. The mixture was partitioned between water and ether. The aqueous layer was re-extracted with water. The combined organic layers were washed with water and saturated brine. The organic layer, after drying with magnesium sulfate, was evaporated under reduced pressure. The residue was subjected to silica gel chromatography with hexanes/ethyl acetate (4:1) as eluent to give the titled compound (0.40 g) as an oil. *Η NMR (CDC13), δ 3.94 (s, 3H), 4.11 (s,2H), 6.51 (s,lH), 6.80 (s,lH), 7.18 (t,lH), 7.42-7.55 (m,2H), 8.78 (s,lH).
By the procedures described herein together with methods known in the art, the following compounds of Tables 1 to 20 can be prepared. The following abbreviations are used in the Tables which follow: t = tertiary, s = secondary, n - normal, = iso, c = cyclo, Me = methyl, Et = ethyl, Pr = propyl, i-Pτ = isopropyl, Bu = butyl, Ph = phenyl, OMe = methoxy, OEt = ethoxy, SMe = methylthio, SEt = ethylthio, CN = cyano, NO2 = nitro, TMS - trimethylsilyl, S(O)Me = methylsulfinyl, and SO2Me = methylsulfonyl. Table 1
Figure imgf000017_0001
o1. o2 = o
Figure imgf000017_0002
H H CF3 4-F CF3 H
H H CF3 4-C1 CF3 4-C1
Me H CF3 4-Br CF3 H
H H CF3 4-F CF3 4-Br
H H CF3 4-OMe CF3 H
H H CF3 4-CN CF3 H
H H CF3 4-SMe CF3 4-Br
H H CF3 4-Me CF3 H
H H CF3 4-N02 CF3 H
H H CF3 5-F CF3 4-C1
H H CF3 2-F CF3 H
H H CF3 6-F CF3 H
H H CF2C1 4-F CF3 H
H H C2F5 4-F CF3 H
H Me C2F5 4-C1 CF3 4-C1
H H OCF3 4-F CF3 H
H Me OCHF2 4-F CF3 H
H H OCHF2 4-C1 CF3 4-Br
H H OCH2CF3 4-F CF3 H
H H OCF2CHF2 4-F CF3 H
H H SCF3 H CF3 H
H OMe SCF3 4-F CF3 4-C1
H H SCHF2 4-F CF3 H
H H S02CHF2 4-F CF3 H
H H Cl 4-F CF3 4-F
H H Br 4-F CF3 H
H H CN 4-C1 CF3 H
H H Me 4-C1 CF3 4-C1
H H SF5 H CF3 H H H CCH 4-F CF3 H
H H S0 Me 4-C1 CF3 H
H OMe CF3 H CF3 4-F
H H CF3 4-F CF3 4-F
Me H CF3 4-F CF3 4-C1
Cl H CF3 4-C1 CF3 4-C1
H H CF3 4-F CF3 4-Br
H H CF3 4-F CF3 4-Me
H H CF3 4-F CF3 4-OMe
H H CF3 4-C1 CF3 6-F
H H CF3 4-F OCHF2 4-C1
H OMe CF3 4-C1 OCHF2 4-C1
H H CF3 4-F SCHF2 H
H H CF3 4-F SCHF2 4-Cl
H H CF3 4-F SMe 4-C1
H H CF3 4-C1 SEt 4-Cl
H H CF3 4-C1 OMe 4-Cl
H H CF3 4-F OEt 4-Cl
H H CF3 4-F Me 4-Cl
H Cl CF3 4-F CF3 4-F
H Cl CF3 4-F CF3 4-Cl
H OMe CF3 4-F CF3 4-Cl
H Me CF3 4-C1 CF3 H
H Me CF3 4-F CF3 4-Cl
H SMe CF3 4-C1 CF3 4-Cl
H CF3 CF3 4-F CF3 H
H NHMe CF3 4-F CF3 4-Cl
H NMe CF3 4-F CF3 4-Cl
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-F CF3 4-Cl
NH2 H CF3 4-F CF3 4-Br
NH2 H OCF3 4-F CF3 4-F
NH2 H OCF3 4-C1 CF3 4-Cl
NH2 H SCF3 4-F CF3 4-Cl
NH2 H SCF3 4-C1 CF3 4-Br
NH2 H Cl 4-C1 CF3 4-Cl
NH2 H OCHF2 4-F CF3 4-Cl
NH2 H OCHF 4-C1 CF3 4-Cl NH2 H SCHF2 4-F CF3 4-Cl
NH2 H SCF2CHF2 H CF3 H
NH2 H OCH2CF3 H CF3 H H2 H SMe 4-Cl CF3 4-Cl
NH2 H SEt 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 H
NHMe H CF3 4-F CF3 4-Cl
NHMe H OCF3 4-F CF3 4-Cl
NHMe H SCF3 4-F CF3 4-Br
NMe H CF3 4-F CF3 4-Cl
NHCOMe H CF3 4-F CF3 4-Cl
NHS02Me H CF3 4-Cl CF3 H
NHC02Me H CF3 4-F CF3 4-Br
NHCONHMe H CF3 4-F CF3 H
NHCOEt H CF3 4-Cl CF3 H
NHCOCF3 H CF3 4-F CF3 H
NHCOC02Me H CF3 4-F CF3 4-Cl
NHCH2OMe H CF3 4-F CF3 H
NHCH2CHCH2 H CF3 4-F CF3 H
NHCH2CCH H CF3 4-F CF3 H
NHCONMe2 H CF3 4-F CF3 4-F
NHEt H CF3 4-F CF3 H
0! = 0. 02 = NH
Figure imgf000019_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 4-Cl
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 4-Br
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 4-F
H SMe CF3 4-Cl CF3 H NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl
O^ NH. O2 = o
Figure imgf000020_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 4-Cl
H H CF3 H CF3 H
H H C2F5 4-F CF3 4-Br
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 4-F
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl
O1 = O. C-2 = CH2
Figure imgf000020_0002
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 4-Cl
H H CF3 H CF3 H
H H C2F5 4-F CF3 4-Br
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl
H H CF3 H OCHF2 4-Cl H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 4-F
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl
01 = O. 02 = OCH2
Figure imgf000021_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 4-Cl
H H CF3 H CF3 H
H H C2F5 4-F CF3 4-Br
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 4-F
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl
O^ H. O2 = OCH2
Figure imgf000021_0002
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 4-Cl
H H C2F5 4-F CF3 4-Br
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl H H CF3 H OCHF2 4-Cl H Cl CF3 4-F CF3 4-F H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 4-Cl NH2 H OCF3 4-F CF3 4-F NH2 H SCF3 4-F CF3 4-Cl NHMe H CF3 4-F CF3 4-Cl
O^ O. Q2 = NMe
Figure imgf000022_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 4-Cl
H H C2F5 4-F CF3 4-Br
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl
Q^ O^ : = NCOMe
Figure imgf000022_0002
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 4-Cl
H H C2F5 4-F CF3 4-Br
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 4-F H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl
o1 = o. o2 = = NCONHMe
Figure imgf000023_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 4-Cl
H H C2F5 4-F CF3 4-Br
H H OCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl ol = o. d - = NC02Me
Figure imgf000023_0002
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 4-Cl
H H CF3 H CF3 H
H H C2F5 4-F CF3 4-Br
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 4-Cl NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl
Figure imgf000024_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 4-Cl
H H CF3 H CF3 H
H H C2F5 4-F CF3 4-Br
H H OCF3 4-F CF3 H
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl
H H CF3 H OCHF2 4-Cl
H Cl CF3 •4-F CF3 4-F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl
01 = 0. 02 = S i Hi Hi R^ R2! R2
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 4-Cl
H H CF3 H CF3 H
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 4-Br
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 H NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl
01 = S. 02 = = 0
Figure imgf000025_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 4-Cl
H H CF3 H CF3 H
H H C2F5 4-F CF3 4-Br
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF, 4-F CF3 4-Cl
O1 = 0. O2 = = OCHflyleϊ
Figure imgf000025_0002
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 4-Cl
H H CF3 H CF3 H
H H C2F5 4-F CF3 4-Br
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 4-F H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 H NH2 H CF3 4-Cl CF3 4-Cl NH2 H OCF3 4-F CF3 4-F NH2 H SCF3 4-F CF3 4-Cl NHMe H CF3 4-F CF3 4-Cl
O. Q2 = CHMe
Figure imgf000026_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 4-Cl
H H CF3 H CF3 H
H H C2F5 4-F CF3 4-Br
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 H
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl
0l = p. p2 = j >CHo
Figure imgf000026_0002
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 4-Cl
H H CF3 H CF3 H
H H C2F5 4-F CF3 4-Br
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl H Cl CF3 4-F CF3 4-F
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl pi = p. p2 = = NHCHι
Ei ___. " R_. Hi R21 R22
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 4-Cl
H H CF3 H CF3 H
H H C2F5 4-F CF3 4-Br
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 4-F
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl Table 2
Figure imgf000027_0001
o^ o^o
Figure imgf000027_0002
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 4-Cl
H H CF3 4-Br CF3 H
H H CF3 H CF3 H H H CF3 4-Me CF3 H
H H CF3 4-N02 CF3 4-Cl
H H CF3 5-F CF3 H
H H CF3 2-F CF3 H
H H CF3 6-F CF3 4-F
H H CF2C1 4-F CF3 H
H H C2F5 4-F CF3 H
H H OCF3 H CF3 4-Br
H H OCF3 4-F CF3 H
H H OCHF2 4-F CF3 H
H H OCHF2 4-Cl CF3 H
H H OCH2CF3 4-F CF3 H
H H OCF2CHF2 4-F CF3 4-Cl
H H SCF3 H CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H SCHF2 4-Cl CF3 H
H H CF3 4-Cl CF3 6-F
H H CF3 4-F OCHF2 4-Cl
H H CF3 4-F SCHF2 4-Br
H H CF3 4-F SMe 4-Cl
H H CF3 4-Cl OMe 4-Cl
H H CF3 4-F Me 4-Br
H Cl CF3 4-Cl CF3 H
H Cl CF3 4-F CF3 4-Cl
H OMe CF3 4-F CF3 4-Cl
H Me CF3 4-F CF3 4-Br
H SMe CF3 4-Cl CF3 4-Cl
H NH2 CF3 4-F CF3 H
H NHMe CF3 4-F CF3 4-Cl
H NMe2 CF3 4-F CF3 4-Cl
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-F CF3 4-Cl
NH2 H CF3 4-F CF3 4-Br
NH2 H OCF3 4-F CF3 4-Cl
NH2 H SCF3 4-F CF3 4-Cl
NH2 H Cl 4-Cl CF3 4-Cl
NH2 H OCHF2 4-Cl CF3 4-Cl NH2 H SCHF2 4-F CF3 4-Cl
NH2 H SCF2CHF2 H CF3 H
NH2 H OCH2CF3 H CF3 H
NH2 H SMe 4-Cl CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl
NHMe H OCF3 4-F CF3 4-Cl
NMe2 H CF3 4-F CF3 4-Cl
NHCOMe H CF3 4-F CF3 4-Cl
NHS02Me H CF3 4-Cl CF3 H
NHC02Me H CF3 4-F CF3 H
NHCONHMe H CF3 4-F CF3 H
NHCOEt H CF3 4-Cl CF3 H
NHCOCF3 H CF3 4-F CF3 4-Cl
NHCH2OMe H CF3 4-F CF3 H
NHCH2CCH H CF3 4-F CF3 H
NHCONMe2 H CF3 4-F CF3 H
pl = p. p2 = NH
Figure imgf000029_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 H
H H C2F5 4-F CF3 4-Br
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 4-F
NH2 H C 3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl O^ NH. O2 = o
Figure imgf000030_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 H
H H C2F5 4-F CF3 4-Br
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 4-F
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl
Figure imgf000030_0002
H CF3 4-F CF3 H H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 H
H H C2 5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 . H CF3 4-Cl
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 4-F
NH2 H C 3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl pi _- p. p = pCH.
Figure imgf000031_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 4-Cl
H H CF3 H CF3 H
H H C2F5 4-F CF3 4-Br
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 4-F
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl
O^ NH. O2 ^ = OCH2
Figure imgf000031_0002
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 H
H H C F5 4-F CF3 4-Br
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF, 4-Cl 01 = 0, Q2 = S
Figure imgf000032_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 H
H H C2F5 4-F CF3 4-Br
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl
01 = S. 02 = = o
Figure imgf000032_0002
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 H
H H C2F5 4-F CF3 4-Br
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl
O1 = 0. O2 = = SCH2
Figure imgf000033_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 4-Br
H H C2F5 4-F CF3 H
H H OCF2 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 4-FH
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl Table 3
Figure imgf000033_0002
01. 02 = 0
Figure imgf000033_0003
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 H
H H CF3 4-OMe CF3 4-Cl
H H CF3 4-CN CF3 H
H H CF3 4-N02 CF3 H
H H CF3 5-1 F CF 3 H H H CF3 2-F CF3 4-Cl
H H CF2C1 4-F CF3 H
H H C2F5 4-F CF3 H
H H OCF3 H CF3 4-Cl
H H OCF3 4-Cl CF3 H
H H OCHF2 4-F CF3 H
H H OCH2CF3 4-F CF3 4-Br
H H OCF2CHF2 4-F CF3 H
H H SCF3 H CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-OMe
H H CF3 4-Cl CF3 5-Br
H H CF3 4-F Me 4-Cl
H Cl CF3 4-F CF3 4-Cl
H OMe CF3 4-F CF3 4-Cl
H Me CF3 4-Cl CF3 H
H NH2 CF3 4-F CF3 H
H NHMe CF3 4-F CF3 4-Cl
H NMe2 CF3 4-F CF3 4-Cl
NH2 H CF3 4-F CF3 4-Cl
NH2 H CF3 4-F CF3 4-Br
NH2 H OCF3 4-F CF3 4-Cl
NH2 H SCF3 4-F CF3 4-Cl
NH2 H OCHF2 4-F CF3 4-Cl
NH2 H SCHF2 4-F CF3 4-Cl
NH2 H SCF2CHF2 H CF3 H
NH2 H OCH2CF3 H CF3 H
NH2 H SMe 4-Cl CF3 4-Cl
NHMe H CF3 4-F CF3 HNMe2
NMe2 CF3 4-F CF3 4-Cl H
NHCOMe H CF3 4-F CF3 4-Cl
NHS02Me H CF3 4-Cl CF3 H
NHC02Me H CF3 4-F CF3 H
O1 = O. O2 = = NH
Figure imgf000034_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 4-Br
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl
O^ NH. O2 = 0
Figure imgf000035_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H C2F5 4-F CF3 4-Br
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 4-F
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl o1 = o. o = CH2
Figure imgf000035_0002
H H CF3 4-F CF3 H
H H C2F5 4-F CF3 H H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 4-F
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl
O1 = 0. O2 = OCH2
Figure imgf000036_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 H
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl
O^ NH. O2 = OCH2
Figure imgf000036_0002
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 4-F
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl
01 = 0. 0 = = S
Ei El B! E^ Eϋ R22
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 4-F
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl O1 = S. O2 = = o
Ei Hi Hi Hi Eli R22
H H CF3 4-F CF3 H
H H C F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl
Figure imgf000038_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Cl
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 4-F
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Cl
NHMe H CF3 4-F CF3 4-Cl Table 4
o1. o2 = o
Figure imgf000039_0002
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 5-C1
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 5-Br
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 5-F
H H CF3 H CF3 5-C1
H H CF3 H OCHF2 5-C1
H Cl CF3 4-F CF3 5-F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 5-C1
NH2 H OCF3 4-F CF3 5-F
NH2 H SCF3 4-F CF3 5-C1
NHMe H CF3 4-F CF3 5-C1
O1 = 0. 02 = = NH
Figure imgf000039_0003
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 5-C1
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 5-Br
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 5-F
H H CF3 H CF3 5-C1
H H CF3 H OCHF2 5-C1
H Cl CF3 4-F CF3 5-F
H OMe CF3 4-F CF3 H NH2 H CF3 4-Cl CF3 5-C1
NH2 H OCF3 4-F CF3 5-F
NH2 H SCF3 4-F CF3 5-C1
NHMe H CF3 4-F CF3 5-C1
O^ NH. O2 = o
Figure imgf000040_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 5-C1
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 5-Br
H H SCF3 4-F CF3 H
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 5-F
H H CF3 H CF3 5-C1
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 5-F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 5-C1
NH2 H OCF3 4-F CF3 5-F
NH2 H SCF3 4-F CF3 5-C1
NHMe H CF3 4-F CF3 5-C1
Figure imgf000040_0002
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 5-C1
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 5-Br
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 5-F
H H CF3 H CF3 5-C1
H H CF3 H OCHF2 5-C1
H Cl CF3 4-F CF3 5-F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 5-C1
NH2 H OCF3 4-F CF3 5-F NH2 H SCF3 4-F CF3 5-C1
NHMe H CF3 4-F CF3 5-C1
O1 = o, Q2 = OCH2
Figure imgf000041_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 5-C1
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 5-Br
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 5-F
H H CF3 H CF3 5-C1
H H CF3 H OCHF2 5-C1
H Cl CF3 4-F CF3 5-F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 5-C1
NH2 H OCF3 4-F CF3 5-F
NH2 H SCF3 4-F CF3 5-C1
NHMe H CF3 4-F CF3 5-C1
0J = NH. O2 = OCH2
Figure imgf000041_0002
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 5-C1
H H C F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 5-Br
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 5-F
H H CF3 H CF3 5-C1
H H CF3 H OCHF2 5-C1
H Cl CF3 4-F CF3 5-F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 5-C1
NH2 H OCF3 4-F CF3 5-F NH2 H SCF3 4-F CF3 5-C1
NHMe H CF3 4-F CF3 5-C1
o1 = o. o2 = = S
Figure imgf000042_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 5-C1
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 5-Br
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 5-F
H H CF3 H CF3 5-C1
H H CF3 H OCHF2 5-C1
H Cl CF3 4-F CF3 5-F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 5-C1
NH2 H OCF3 4-F CF3 5-F
NH2 H SCF3 4-F CF3 5-C1
NHMe H CF3 4-F CF3 5-C1 o1 = o. o2 = = SCH2
Figure imgf000042_0002
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H C2F5 4-F CF3 5-C1
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 5-Br
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 5-F
H H CF3 H CF3 5-C1
H H CF3 H OCHF2 5-C1
H Cl CF3 4-F CF3 5-F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 5-C1
NH2 H OCF3 4-F CF3 5-F NH2 H SCF3 4-F CF3 5-C1 NHMe H CF3 4-F CF3 5-C1
Table 5
Figure imgf000043_0001
o1. o2 = o
Ei H E! R^ El! R22a
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 H
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Br
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 H
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 4-F
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Br
NHMe H CF3 4-F CF3 4-Cl
pi __ o. p2 = = NH
Figure imgf000043_0002
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H H H CF3 H CF3 H
H H C F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Br
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 H
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 4-F
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Br
NHMe H CF3 4-F CF3 4-Cl
01 = NH. 02 = = o
Ei El R_. R^ R22 R22a
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 H
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Br
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 H
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 4-Br H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Br
NHMe H CF3 4-F CF3 4-Cl o1 =o, o2- = CH2
H∑ Hi Hi E^ R22 R22a
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 H
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Br
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 H
H Cl CF3 4-F CF3 4-Br
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 4-F
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 5-F
NH2 H SCF3 4-F CF3 4-Br
NHMe H CF3 4-F CF3 4-Cl
Figure imgf000045_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 H
H H C F5 4-F CF3 H H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Br
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 H
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 4-F
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Br
NHMe H CF3 4-F CF3 4-Cl
Figure imgf000046_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 H
H H C F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Br
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 H
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 4-F
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-F CF3 H NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Br
NHMe H CF3 4-F CF3 4-Cl
pl = p. p2 = = S
Figure imgf000047_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 H
H H C F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Br
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 H
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 4-F
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Br
NHMe H CF3 4-F CF3 4-Cl
Figure imgf000047_0002
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 H
H H C2 5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 4-F
H H CF3 H CF3 4-Br
H H CF3 H OCHF2 4-Cl
H Cl CF3 4-F CF3 H
H Cl CF3 4-F CF3 4-F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 4-F
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 4-Cl
NH2 H OCF3 4-F CF3 4-F
NH2 H SCF3 4-F CF3 4-Br
NHMe H CF3 4-F CF3 4-Cl
Table 6
Figure imgf000048_0001
o1. o2 = o
Figure imgf000048_0002
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 5-C1
H H CF3 H CF3 H
H H C F5 4-F CF3 H
H H OCF3 4-F CF3 5-Br
H H SCF3 4-F CF3 H
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 5-F
H H CF3 H CF3 5-Br
H H CF3 H OCHF2 5-C1
H Cl CF3 4-F CF3 5-F
H OMe CF3 4-F CF3 H NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 5-C1
NH2 H OCF3 4-F CF3 5-F
NH2 H SCF3 4-F CF3 5-Br
NHMe H CF3 4-F CF3 5-C1
O1 = 0. O2 = NH
Figure imgf000049_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 5-C1
H H CF3 H CF3 H
H H C F5 4-F CF3 5-Br
H H OCF3 4-F . CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 5-F
H H CF3 H CF3 5-Br
H H CF3 H OCHF2 5-C1
H Cl CF3 4-F CF3 5-F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 5-C1
NH2 H OCF3 4-F CF3 5-F
NH2 H SCF3 4-F CF3 5-Br
NHMe H CF3 4-F CF3 5-C1
O^ NH. O2 = 0
Ei Hi Hi E^ R22 R22a
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 5-C1
H H CF3 H CF3 H
H H C F5 4-F CF3 H
H H OCF3 4-F CF3 5-Br
H H SCF3 4-F CF3 H
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 5-F
H H CF3 H CF3 5-Br
H H CF3 H OCHF2 4-Cl H Cl CF3 4-F CF3 5-F
H OMe CF3 4-F CF3 HH
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 5-C1 H2 H OCF3 4-F CF3 5-F
NH2 H SCF3 4-F CF3 5-Br
NHMe H CF3 4-F CF3 5-C1
Figure imgf000050_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 5-C1
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 5-Br
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 5-F
H H CF3 H CF3 5-Br
H H CF3 H OCHF2 5-C1
H Cl CF3 4-F CF3 5-F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 5-F
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 5-C1
NH2 H OCF3 4-F CF3 5-F
NH2 H SCF3 4-F CF3 5-Br
NHMe H CF3 4-F CF3 5-C1
01 = 0. θ2 = = OCH2 i Hi Hi s£ £22 R22a
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 5-C1
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 5-Br
H H SCF3 4-F CF3 H
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 5-F H H CF3 H CF3 5-Br
H H CF3 H OCHF2 5-C1
H Cl CF3 4-F CF3 5-F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 5-C1
NH2 H OCF3 4-F CF3 5-F
NH2 H SCF3 4-F CF3 5-Br
NHMe H CF3 4-F CF3 5-C1
0J = NH. O2 = OCH2
Ei Hi El E^ R22 22a
H H CF3 4-F CF3 5-C1
H H CF3 4-Cl CF3 H
H H CF3 H CF3 5-C1
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 5-Br
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 5-F
H H CF3 H OCHF2 5-C1
H Cl CF3 4-F CF3 5-F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 5-C1
NH2 H OCF3 4-F CF3 5-F
NH2 H SCF3 4-F CF3 5-Br
NHMe H CF3 4-F CF3 5-C1 oi = o. o = S
Hi El E_. ≠ HH R22a
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 5-C1
H H C 5 4-F CF3 H
H H OCF3 4-F CF3 5-Br
H H SCF3 4-F CF3 H
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H H H CF3 4-F CF3 5-F
H H CF3 H CF3 5-Br
H Cl CF3 4-F CF3 H
H Cl CF3 4-F CF3 5-F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 5-C1
NH2 H OCF3 4-F CF3 5-F
NH2 H SCF3 4-F CF3 5-C1
NHMe H CF3 4-F CF3 5-C1
0! = O. 02 = = SCH2
Figure imgf000052_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 H
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 5-F
H H CF3 H CF3 5-C1
H H CF3 H OCHF2 5-C1
H Cl CF3 4-F CF3 5-F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 5-C1
NH2 H OCF3 4-F CF3 5-F
NH2 H SCF3 4-F CF3 5-C1
NHMe H CF3 4-F CF3 5-C1
Table 7
Figure imgf000053_0001
o1. o2- o
Ei El R_. E^ R22 R22a
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 Cl
H H CF3 H CF3 H
H H C F5 4-F CF3 H
H H OCF3 4-F CF3 Cl
H H SCF3 4-F CF3 H
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 F
H H CF3 H CF3 Cl
H H CF3 H OCHF2 Cl
H Cl C 3 4-F CF3 H
H Cl CF3 4-F CF3 F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 F
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-F CF3 Br
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 Cl
NH2 H OCF3 4-F CF3 Br
NH2 H SCF3 4-F CF3 Cl
NHMe H CF3 4-F CF3 Cl
O1 = 0. O2 = = NH
Figure imgf000053_0002
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 H
H H C F5 4-F CF3 Cl H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 Br
H H CF3 4-F CF3 F
H Cl CF3 4-F CF3 H
H Cl CF3 4-F CF3 F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 Br
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 Cl
NH2 H OCF3 4-F CF3 F
NHMe H CF3 4-F CF3 Cl
O^ NH. O2 = 0
Ei R_. El E^ R22 R22a
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 H
H H C2F5 4-F CF3 Br
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 Cl
H Cl CF3 4-F CF3 H
H Cl CF3 4-F CF3 F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 Br
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 Br
NH2 H OCF3 4-F CF3 F
NHMe H CF3 4-F CF3 Cl
0- = 0. 02 = CH2
Hi Hi Hi E^ E2! R22a
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H H H CF3 H CF3 Cl
H H C F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 Br
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 Br
H Cl CF3 4-F CF3 H
H Cl CF3 4-F CF3 F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 Br
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 Cl
NH2 H OCF3 4-F CF3 F
NHMe H CF3 4-F CF3 Cl o1 = o. o2 = = OCH2
Figure imgf000055_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 H
H H C2F5 4-F CF3 Br
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 Br
H H CF3 4-F CF3 F
H Cl CF3 4-F CF3 H
H Cl CF3 4-F CF3 F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 Br
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 Cl
NH2 H OCF3 4-F CF3 F
NHMe H CF3 4-F CF3 Cl Q1 = NH. 02 = OCH2
Figure imgf000056_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 Br
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 Br
H H CF3 4-F CF3 Cl
H Cl CF3 4-F CF3 H
H Cl CF3 4-F CF3 F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 F
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 Cl
NH2 H OCF3 4-F CF3 F
NHMe H CF3 4-F CF3 Cl pi = p. p2 = S
Hi Hi Hi El EH R22a
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 Cl
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 Br
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 F
H Cl CF3 4-F CF3 H
H Cl CF3 4-F CF3 F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 Br
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 Cl
NH2 H OCF3 4-F CF3 F
NHMe H CF3 4-F CF3 Cl Table 8
Figure imgf000057_0001
Q1. Q2 = 0
Ei Hi E! E! R22 R22a
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 Cl
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 Br
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 F
H H CF3 H CF3 Cl
H H CF3 H OCHF2 Cl
H Cl CF3 4-F CF3 H
H Cl CF3 4-F CF3 F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 Br
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 Cl
NH2 H OCF3 4-F CF3 Br
NH2 H SCF3 4-F CF3 Cl
NHMe H CF3 4-F CF3 Cl
pi = p. p2 - = NH
Figure imgf000057_0002
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 Cl
H H C2 5 4-F CF3 H H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 Br
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 F
H Cl CF3 4-F CF3 H
H Cl CF3 4-F CF3 Br
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 F
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-F CF3 Br
NH2 H CF3 4-Cl CF3 Cl
NH2 H OCF3 4-F CF3 Br
NHMe H CF3 4-F CF3 Cl
O^ NH. O2 = 0
El Hi El El R22 R22a
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 Cl
H H C F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 Br
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 F
H Cl CF3 4-F CF3 H
H Cl CF3 4-F CF3 Br
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 F
H SMe CF3 4-Cl CF3 Cl
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 Cl
NH2 H OCF3 4-F CF3 Br
NHMe H CF3 4-F CF3 Cl
Figure imgf000058_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 Cl H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 Br
H Cl CF3 4-F CF3 H
H Cl CF3 4-F CF3 F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 Br
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 Cl
NH2 H OCF3 4-F CF3 Br
NHMe H CF3 4-F CF3 Cl
Figure imgf000059_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 Cl
H H C F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 Br
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 Br
H Cl CF3 4-F CF3 H
H Cl CF3 4-F CF3 F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 Br
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 Cl
NH2 H OCF3 4-F CF3 Br
NHMe H CF3 4-F CF3 Cl
Figure imgf000059_0002
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H H H CF3 H CF3 Cl
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 Br
H Cl CF3 4-F CF3 H
H Cl CF3 4-F CF3 F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 F
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-F CF3 Br
NH2 H CF3 4-Cl CF3 Cl
NH2 H OCF3 4-F CF3 F
NHMe H CF3 4-F CF3 Cl
Q1 = 0, Q2 = = S
Figure imgf000060_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 Cl
H H C 5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 Br
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 Br
H Cl CF3 4-F CF3 H
H Cl CF3 4-F CF3 F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 F
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 Cl
NH2 H OCF3 4-F CF3 Br
NHMe H CF3 4-F CF3 Cl Table 9
Figure imgf000061_0001
01. 02 = 0
Hi El s£ E^ E2! R22a
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 Cl
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 Br
H H SCF3 4-Cl CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 F
H H CF3 H CF3 Cl
H H CF3 H OCHF2 Cl
H Cl CF3 4-F CF3 Br
H Cl CF3 4-F CF3 F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 Br
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 H
NH2 H CF3 4-Cl CF3 Cl
NH2 H OCF3 4-F CF3 Br
NH2 H SCF3 4-F CF3 Cl
NHMe H CF3 4-F CF3 Cl
oJ = o. o2 = = NH
El S2 El R! R22 22a
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 Cl H H C F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 Br
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 Br
H Cl CF3 4-F CF3 H
H Cl CF3 4-F CF3 F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 Br
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 Cl
NH2 H OCF3 4-F CF3 Br
NHMe H CF3 4-F CF3 Cl
01 = NH. O2 = o
Figure imgf000062_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 Cl
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 Br
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 F
H Cl CF3 4-F CF3 H
H Cl CF3 4-F CF3 Br
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 F
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 Cl
NH2 H OCF3 4-F CF3 Br
NHMe H CF3 4-F CF3 Cl o1 = o. o2 = CH2
Hi Hi s! E^ R22 R22a
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H rn o o Λ c. υ CN
PL, o a a w a p-, a oQ a to a a π w π u Pi a a υ a a w a cπ a a to a a f w ζj
co ro fo ro ro ro ro ro ro ro ro ro ro ro ro ro co co co ro ro ro ro r CO CO O CO to to ft to to to to to to to to to to to to cNl to to to to ft to ft ft ft ft to to to to ft to to
CN to to to to to to to U O to υ VO I to o to to to to to U U to U to to
CO * 4 4 4 4 τ_ ■«- 4 •* a to t 4 4 4 4 4 4 4 4 4 4 4
Figure imgf000063_0001
Figure imgf000063_0002
O^NH. O2 = OCH2
Ei Hi E_. El g22 R22a
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 Cl
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 Br
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 Br
H Cl CF3 4-F CF3 H
H Cl CF3 4-F CF3 F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 Br
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 Cl
NH2 H OCF3 4-F CF3 Br
NHMe H CF3 4-F CF3 Cl
01 = p. p2 = S
Figure imgf000064_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 Cl
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 Br
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 Br
H Cl CF3 4-F CF3 H
H Cl CF3 4-F CF3 F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 Br
H SMe CF3 4-Cl CF3 H
NH2 H CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 Cl
NH2 H OCF3 4-F CF3 Br
NHMe H CF3 4-F CF3 Cl Table 10
Figure imgf000065_0001
o1. o2 = o
Ei Hi El El R22 R22a
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 Cl
H H C F5 4-F CF3 H
H H OCF3 4-F CF3 Cl
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 F
H H CF3 H CF3 Cl
H H CF3 H OCHF2 Cl
H Cl CF3 4-F CF3 F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-F CF3 Br
NH2 H CF3 4-Cl CF3 Cl
NH2 H OCF3 4-F CF3 Br
NH2 H SCF3 4-F CF3 Cl
NHMe H CF3 4-F CF3 Cl
O^ O. O2 ; = NH
Figure imgf000065_0002
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H C2F5 4-F CF3 Cl
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 Br
H H CF3 4-F CF3 F
H Cl CF3 4-F CF3 F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 Cl NH2 H OCF3 4-F CF3 F
NHMe H CF3 4-F CF3 Cl
O^ NH. O2 ■ = 0
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H C2F5 4-F CF3 Br
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 Cl
H Cl CF3 4-F CF3 F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 Br
NH2 H CF3 4-Cl CF3 Br
NH2 H OCF3 4-F CF3 F
NHMe H CF3 4-F CF3 Cl
O1 = o, ζ)2 = = CH2
El El El H R22 R22a
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 Cl
H H C F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 Br
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 Br
H Cl CF3 4-F CF3 F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 Cl
NH2 H OCF3 4-F CF3 F
NHMe H CF3 4-F CF3 Cl
O1 = O. O2 = = OCH2
Ei El El El R22 R22a
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 H H H C F5 4-F CF3 Br
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 Br
H H CF3 4-F CF3 F
H Cl CF3 4-F CF3 F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 Cl
NH2 H OCF3 4-F CF3 F
NHMe H CF3 4-F CF3 Cl Table 11
Figure imgf000067_0001
o1. o2 = o
Ei Hi El El H R22a
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 Cl
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 Cl
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 F
H H CF3 H CF3 Cl
H H CF3 H OCHF Cl
H Cl CF3 4-F CF3 F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-F CF3 Br
NH2 H CF3 4-Cl CF3 Cl
NH2 H OCF3 4-F CF3 Br
NH2 H SCF3 4-F CF3 Cl
NHMe H CF3 4-F CF3 Cl a a a a a a
a a a a a a
Figure imgf000068_0001
O 8 o O O O O O O ζS O O too hi ohi ohi wI IΛ o o π o o o o ∞ ∞ o o o o j -J > > > |τi h-- ^ '"ri ci >τi π n n ^__ hn >n w O O
I <J< H- ^ _ t * ^i 'τi C_ θ _ tj >-n < i \ hi ) > w ιι hi j hϊ w •n M hi
. J σv hj hj h £j * £ n £ w ^ I σv f* t- f- t* . . . t hj* hj' i hj w n ^ I ov 'τJ τ| ,i1 >τl ,τj Tl η &
o o n o n O O O O O O O O O O O j Q hi w O O O O O O O O O O O O O hi hi hi hi I to hi hi ►_! h1 h1 h1 1 hl h1 hl h1 h1 h1 ιrθ O hj hj hj hj hj hj hrt h^ hj ^rt hj hi I t^-J ) > ω )
» a a Q a a to Q ^ S. » a ^ o a a a w a a to Q hi Q hi hi a a a o a t t to t
P 0) IS
a a a a a a w
a a a a a a w I to
Figure imgf000069_0001
Figure imgf000069_0002
a a Q a Q a t Q Q a >fl τ] w a a w a a a to Q hi Q hj hi tS a to to t-
H H CF3 4-F CF3 F
H H CF3 H CF3 Cl
H H CF3 H OCHF2 Cl
H Cl CF3 4-F CF3 F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-F CF3 Br
NH2 H CF3 4-Cl CF3 Cl
NH2 H OCF3 4-F CF3 Br
NH2 H SCF3 4-F CF3 Cl
NHMe H CF3 4-F CF3 Cl
pl = p. p2 = NH
Figure imgf000070_0001
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H C F5 4-F CF3 Cl
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 Br
H H CF3 4-F CF3 F
H Cl CF3 4-F CF3 F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 Cl
NH2 H OCF3 4-F CF3 F
NHMe H CF3 4-F CF3 Cl
O^ NH. O2 = 0
Figure imgf000070_0002
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H C2F5 4-F CF3 Br
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 Cl
H Cl CF3 4-F CF3 F
H OMe CF3 4-F CF3 H
H Me CF3 4-Cl CF3 Br
NH2 H CF3 4-Cl CF3 Br NH2 H OOCCFF33 44--FF CF3 F
NHMe H C CFF33 4 4--FF CF3 Cl
Q1 = 0. 02 = CH2
Ei B2 El El Eff ___a
H H CF3 4-F CF3 H
H H CF3 4-Cl CF3 H
H H CF3 H CF3 Cl
H H C2F5 4-F CF3 H
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 Br
H H SCHF2 4-F CF3 H
H H CF3 4-F CF3 Br
H Cl CF3 4-F CF3 F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 Cl
NH2 H OCF3 4-F CF3 F
NHMe H CF3 4-F CF3 Cl pl = p. p2 = ( _ CH i E_- EEll EEll HL_1 R22a
H H CCFF33 44--FF CF3 H
H H CCFF33 44--CCll CF3 H
H H CCFF33 HH CF3 H
H H CC2FF55 44--FF CF3 Br
H H OOCCFF33 44--FF CF3 H
H H SSCCFF33 44--FF CF3 H
H H SSCCHHFF22 44--FF CF3 Br
H H CCFF33 44--FF CF3 F
H Cl CCFF33 44--FF CF3 F
H OMe CCFF33 44--FF CF3 H
NH2 H CCFF33 44--CCll CF3 Cl
NH2 H OOCCFF33 44--FF CF3 F
NHMe H CCFF33 44--FF CF3 Cl a a a a a a a a a w p a a a a a a a a a a a to to to to
I
Figure imgf000072_0001
a o o a a a a a a a w to w to a a o o a a a a a a a
2 *
Figure imgf000072_0003
Figure imgf000072_0002
o a Ti tfl a a o a a to Ω Ω Ep Ω a a ^ Ω Ω to a a o a o t-
Figure imgf000073_0001
o o Q O O O O oo oo o O O O O O O O O O o o g O ^1 o ι-r] I W O O |!
H tΛ * o O h1 0 h1 h 11 hl Q hl hi fc^j u >1 u>1 uh1 Q O hi π ^ h_i. w ω>τ' hτ>1 lL', hl h hl hl O O O to hl hl l ω s o
,? .11 ,? liJ
>_ 4 4>- 4>_ ±» _ 4>> ±*. 4>_ ±± ^
B _ 5 κ I I I I T~ i i I i I PQ w w hj hi ^ hj hj hj hj hj hi hj o I Ov hi hi o o n hi hi hi hi O H I Ov hi hi
O O O O O O O O O O O O Q O O Q O Q O O O O O O O O * O O hl hl l hl hl hl hl hl hl hl hl hl hl to hi hi hi hi hi hj hj hj hj hj hj hi t U
Figure imgf000073_0002
> _J > U- > > 0- -- > -J > > > I to W > Oi > J ) > ) ) ) J > to > (_ n.
a a tu to n Ω a n ω a ω a a Ω a a w t Ω n ff ω a hi o a a a ω a a to t t t Ω n
H H C2F5 4-F CF3 Br
H H OCF3 4-F CF3 H
H H SCF3 4-F CF3 H
H H SCHF2 4-F CF3 Br
H H CF3 4-F CF3 F
H Cl CF3 4-F CF3 F
H OMe CF3 4-F CF3 H
NH2 H CF3 4-Cl CF3 Cl
NH2 H OCF3 4-F CF3 F
NHMe H CF3 4-F CF3 Cl Table 14
Figure imgf000074_0001
O1. ©2 = 0
Figure imgf000074_0002
H H CF3 4-F Me CF3 H
H H CF3 4-Cl Me CF3 Cl
H H C2F5 4-F Me CF3 H
H H OCF3 4-F Et CF3 Cl
H H SCF3 4-F CF3CH2 CF3 H
H H SCHF2 4-F Me CF3 H
H H CF3 4-F Me CF3 F
H H CF3 H CHF2 CF3 Cl
H H CF3 H Et OCHF2 Cl
H Cl CF3 4-F Me CF3 F
H OMe CF3 4-F Me CF3 H
NH2 H CF3 4-F Me CF3 Br
NH2 H CF3 4-Cl Me CF3 Cl
NH2 H OCF3 4-F CF3CH2 CF3 Br
NH2 H SCF3 4-F Me CF3 Cl
NHMe H CF3 4-F Me CF3 Cl 01 = C i. O2 = NH
Ei Hi El E_. R 0 R22 R22a
H H CF3 4-F Me CF3 H
H H CF3 4-Cl Me CF3 Cl
H H C F5 4-F Me CF3 H
H H OCF3 4-F Et CF3 Cl
H H SCF3 4-F CF3CH2 CF3 H
H H SCHF2 4-F Me CF3 H
H H CF3 4-F Me CF3 F
H H CF3 H CHF2 CF3 Cl
H H CF3 H Et OCHF2 Cl
H Cl CF3 4-F Me CF3 F
H OMe CF3 4-F Me CF3 H
NH2 H CF3 4-F Me CF3 Br
NH2 H CF3 4-Cl Me CF3 Cl
NH2 H OCF3 4-F CF3CH2 CF3 Br
NH2 H SCF3 4-F Me CF3 Cl
NHMe H CF3 4-F Me CF3 Cl
01 = NH. 02 = 0
Figure imgf000075_0001
H H CF3 4-F Me CF3 H
H H CF3 4-Cl Me CF3 Cl
H H C2F5 4-F Me CF3 H
H H OCF3 4-F Et CF3 Cl
H H SCF3 4-F CF3CH2 CF3 H
H H SCHF2 4-F Me CF3 H
H H CF3 4-F Me CF3 F
H H CF3 H CHF2 CF3 Cl
H H CF3 H Et OCHF2 Cl
H Cl CF3 4-F Me CF3 F
H OMe CF3 4-F Me CF3 H
NH2 H CF3 4-F Me CF3 Br
NH2 H CF3 4-Cl Me CF3 Cl
NH2 H OCF3 4-F CF3CH2 CF3 Br
NH2 H SCF3 4-F Me CF3 Cl
NHMe H CF3 4-F Me CF3 Cl
NHMe H CF3 4-F Me CF3 Cl 0] = 0. O2 = CH
El Hi El Hi R20 R22 R22a
H H CF3 4-F Me CF3 H
H H CF3 4-Cl Me CF3 Cl
H H C F5 4-F Me CF3 H
H H OCF3 4-F Et CF3 Cl
H H SCF3 4-F CF3CH2 CF3 H
H H SCHF2 4-F Me CF3 H
H H CF3 4-F Me CF3 F
H H CF3 H CHF2 CF3 Cl
H H CF3 H Et OCHF2 : C1
H Cl CF3 4-F Me CF3 F
H OMe CF3 4-F Me CF3 H
NH2 H CF3 4-F Me CF3 Br
NH2 H CF3 4-Cl Me CF3 Cl
NH2 H OCF3 4-F CF3CH2 CF3 Br
NH2 H SCF3 4-F Me CF3 Cl
NHMe H CF3 4-F Me CF3 Cl
O^ O . O2 = OCH
Ei Hi El El R20 R22 22a
H H CF3 4-F Me CF3 H
H H CF3 4-Cl Me CF3 Cl
H H C2F5 4-F Me CF3 H
H H OCF3 4-F Et CF3 Cl
H H SCF3 4-F CF3CH2 CF3 H
H H SCHF2 4-F Me CF3 H
H H CF3 4-F Me CF3 F
H H CF3 H CHF2 CF3 Cl
H H CF3 H Et OCHF2 : cl
H Cl CF3 4-F Me CF3 F
H OMe CF3 4-F Me CF3 H
NH2 H CF3 4-F Me CF3 Br
NH2 H CF3 4-Cl Me CF3 Cl
NH2 H OCF3 4-F CF3CH2 CF3 Br NH2 H SCF3 4-F Me CF3 Cl
NHMe H CF3 4-F Me CF3 Cl
0!,02 = 0
El Hi Hi sl R20 E_l R22a
H H CF3 4-F Me C F5 H
H H CF3 4-Cl Me C2F5 Cl
H H C2F5 4-F Me C2F5 H
H H OCF3 4-F Et C F5 Cl
H H SCF3 4-F CF3CH2 C2 5 H
H H SCHF2 4-F Me C F5 H
H H CF3 4-F Me C F5 F
H H CF3 H CHF2 C F5 Cl
H Cl CF3 4-F Me C F5 F
H OMe CF3 4-F Me C F5 H
NH2 H CF3 4-F Me C2F5 Br
NH2 H CF3 4-Cl Me C2F5 Cl
NH2 H OCF3 4-F CF3CH2 C2F5 Br
NH2 H SCF3 4-F Me C2F5 Cl
NHMe H CF3 4-F Me C F5 Cl
0^0 .θ2 = NH
Ei Hi Hi El R20 R22 R22a
H H CF3 4-F Me C F5 H
H H CF3 4-Cl Me C2F5 Cl
H H C F5 4-F Me C2F5 H
H H OCF3 4-F Et C F5 Cl
H H SCF3 4-F CF3CH2 C2F5 H
H H SCHF2 4-F Me C2F5 H
H H CF3 4-F Me C2F5 F
H H CF3 H CHF2 C2F5 Cl
H Cl CF3 4-F Me C F5 F
H OMe CF3 4-F Me C2F5 H
NH2 H CF3 4-F Me C2F5 Br
NH2 H CF3 4-Cl Me C2F5 Cl
NH2 H OCF3 4-F CF3CH2 C2 5 Br
NH2 H SCF3 4-F Me C2F5 Cl
NHMe H CF3 4-F Me C 5 Cl a w
* ft
Figure imgf000078_0001
9 w I <-*> Q ι
Figure imgf000078_0002
w h n 4- 4- 4». j-.
11 n hl n hi H hi a h hj hi hi hj ^ hj I Ov hi hi hi hi p hi hi hi hj (-3 * hi" I I5! Ov
Figure imgf000078_0003
to n w to ro a toc. ton toc. too ton toc. too toc. ton toc. toc. ton tor. too hl lto hl hl hl hl hl hl hl hl hl hl hl hl hl hl hl
IΛ UΛ lΛ LΛ Cl lΛ lΛ Uh lΛ θl lΛ lΛ I_l lΛ tΛ <_l
Figure imgf000078_0004
a to ^ a a n a Ω * to to to Ω Ω Sp Ω ω B -n Ω t Ω Ω Ω E? Ω « a ^ Ω ι a a Ω * Ω * t
P (-
r-
CO
© o
CΛ
H υ CN u u a a to ςj to a m u m u u a u a u to j Q to cp m
Figure imgf000079_0001
Figure imgf000079_0002
a a a
Figure imgf000080_0001
Figure imgf000080_0002
n n n n ii n n n n n n n
Figure imgf000080_0003
9 £ 2 g f ct I co S Ω 2 2 Ω n w g g £ c? ft Ig? 2 2 n l n c 2» 2t 2 ct 2 Ω 2 2 n f n » 2 2 2 w I to c £t 2 ct n o n n n a t a to a to a
n hi nhi nhi nhi nhi Ωhj w to n hi o hi o hi n hi Ω hi Ω hi n hj nhj nhj ohj ohj ohj ohi O O wto O O > I to ) ) IjJ ) w w n n I to H H
Figure imgf000080_0004
Figure imgf000080_0005
S? Ω ts >τi Ω Ω ,τ a * Ω *
Figure imgf000080_0006
Figure imgf000081_0001
4
H Of 1 11 hi aw aw thi- hi hi hi P ISOv hj hj h (^ hj hj hj a a hi hi w - 4-
I Ov hi 11 hi
00
©
2 Cl 2 Cl 2Cl
Figure imgf000081_0002
Figure imgf000081_0003
∞ Ω ω a ^ Ω Ω n a a o a o a t O O » a o a r* to O n n to Ω ω a ^ Ω Ω n a a o to t-
K w a ffi MH W
Figure imgf000082_0001
Figure imgf000082_0002
n n
Figure imgf000082_0003
a a a a a a a a
a a a a a a a a
Figure imgf000083_0001
On OΩ Oo On nO On On On j hi μjj θ- ) -J i- -
Figure imgf000083_0002
4-
^ l hl l l hi o l l o hi hj hj hi (~) hi hi hj a a n hi hi hi n n fc H hi n hl hi hi a
oo
Figure imgf000083_0003
O O O O O O O O O l hl hl h o hi hi hi hi hi hi hi lt. hl hl h l hl hl fv Ohl Qhl Ohl Ohl Ohl Ohl Ol Ohl W to o h 11 hl oh1 oh1 oh1 oh1 oh1 o(-v m m m m m m m m m m m m m m m m ^ m m m m m m m m I to m ι*> m >
Figure imgf000084_0001
a a a a a w p a a a a a a a a a a w p a a a a a a a a to to to to to to to to a a a a a w I tO n. a a a a a o Q a a a a a a a w a a a a a o o a a a a a a 2 2
Figure imgf000085_0001
t ^ t f- t" pβ 11 11 11 n ι ' < hj hj r hj f t- t>
O ffl ffl ffl a w hi hi hi hi O 11 I ON 11 O hi hi a 11 11 11 hi ffl
oo
Figure imgf000085_0002
Figure imgf000086_0001
t* t- t f- 4- 4- 4i • 4- 4__ __ __ -f_- _. hj hj hj- t hi- t h- t- w j ^ hj I ov hj hj hj ~) hj hj hj 5 ffl ffl ffl 11 ό te ffl ffl O ffl ffl ffl a ^ 11 t 11*
00
O O O O O O O O O O O O O O W O O O O O O O O O O f— v Ωi Ω O O hi Ω hi 0 hi 0 hi Ω hi Ω hi I i^ to hi hi hi hi hi hi hi ffl ffl ffl ffl ffl ffl ffl to ^Λ m m m m m m m I to ) m m m m ι* m M m m m m > m m I to mffl mffl mffl mffl mffl mffl mffl U uffl uffl o
Figure imgf000086_0002
Figure imgf000086_0003
H Cl CF3 4-F CF3
H OMe CF3 4-F CF3
NH2 H CF3 4-F CF3
NH2 H CF3 4-Cl CF3
NH2 H OCF3 4-F CF3
NH2 H SCF3 4-F CF3
NHMe H CF3 4-F CF3
Table 18
Figure imgf000087_0001
Q1 1 Q2 = Q
Ei Hi Hi Hi R22
H H CF3 4-F CF3
H H CF3 4-Cl CF3
H H C2F5 4-F CF3
H H OCF3 4-F CF3
H H SCF3 4-F CF3
H H SCHF2 4-F CF3
H H CF3 4-F CF3
H H CF3 H OCHF2
H Cl CF3 4-F CF3
H OMe CF3 4-F CF3
NH2 H CF3 4-F CF3
NH2 H CF3 4-Cl CF3
NH2 H OCF3 4-F CF3
NH2 H SCF3 4-F CF3
NHMe H CF3 4-F CF3
01 = O. Q2 ^ NH
Ei R_. E R22
H H CF3 4-F CF3
H H CF3 4-Cl CF3
H H C2F5 4-F CF3
H H OCF3 4-F CF3 a a a a a a a
a a a a a
Figure imgf000088_0001
n 00 m n ffl o nfl wffl ffl ffl ffl ffl ii O O hi f ffl
Figure imgf000088_0002
4i hl hl l l i ci hl l0^ ffl ffl ffl o hj hj hj K r w 4- flf ffl f ffl ffl ffl o I ov ffl ffl o ffl hi a hi ffl ffl
OO
O ^ a O O O o o o hj O hj hj Ω hj ^hj hj ^ hj I!* ■ n n O o l fl o o o O O W O O O O to to m ffl ffl ffl> m n m ff m ffl mf o mlff ff ffl 11 ) 9 m m ffl ffl to o hi o hi o hi hi hi hi o hi ml I to m > > m _J _J > C_ ffl ffl ffl
8
H H CF3 H OCHF2
H Cl CF3 4-F CF3
H OMe CF3 4-F CF3
NH2 H CF3 4-F CF3
NH2 H CF3 4-Cl CF3
NH2 H OCF3 4-F CF3
NH2 H SCF3 4-F CF3
NHMe H CF3 4-F CF3
0^ 0 . O2 = OCHo
Figure imgf000089_0001
H H CF3 4-F CF3
H H CF3 4-Cl CF3
H H C2F5 4-F CF3
H H OCF3 4-F CF3
H H SCF3 4-F CF3
H H SCHF2 4-F CF3
H H CF3 4-F CF3
H H CF3 H OCHF2
H Cl CF3 4-F CF3
H OMe CF3 4-F CF3
NH2 H CF3 4-F CF3
NH2 H CF3 4-Cl CF3
NH2 H OCF3 4-F CF3
NH2 H SCF3 4-F CF3
NHMe H CF3 4-F CF3
Table 19
Figure imgf000089_0002
o1. o = o
Figure imgf000089_0003
H H CF3 4-F CF3
H H CF3 4-Cl CF3
H H C2 5 4-F CF3 a a a a a a w
a a a a a a w I tO
Figure imgf000090_0001
n
Figure imgf000090_0002
f- t pβ ■h 4-. f f ■T - 4*. hi ffl hi hi ffl ' ^ ff ffl ff n 11 11 ffl a f- 4=- *. 4-. i l n 11 11 11 11 t" t- w l n n I ov ffl ffl
o O ffl π ffl o ffl 0 ffl n hi o hi I wi ff ii Ω m m m m m ffl l mffl Ω mffl ^ ff fO Ω mffl ffl Oo ml mlf f Ω mffl ff Ω mffl Ωffl Ii^ mfl ml . m ffl m 9
H H CF3 4-F CF3
H H CF3 H OCHF2
H Cl CF3 4-F CF3
H OMe CF3 4-F CF3
NH2 H CF3 4-F CF3
NH2 H CF3 4-Cl CF3
NH2 H OCF3 4-F CF3
NH2 H SCF3 4-F CF3
NHMe H CF3 4-F CF3
0^ 0 , 02 = CH2
Ei s2 E_. R_. R22
H H CF3 4-F CF3
H H CF3 4-Cl CF3
H H C2F5 4-F CF3
H H OCF3 4-F CF3
H H SCF3 4-F CF3
H H SCHF2 4-F CF3
H H CF3 4-F CF3
H H CF3 H OCHF2
H Cl CF3 4-F CF3
H OMe CF3 4-F CF3
NH2 H CF3 4-F CF3
NH2 H CF3 4-Cl CF3
NH2 H OCF3 4-F CF3
NH2 H SCF3 4-F CF3
NHMe H CF3 4-F CF3
0^ 0 i. O2 = OCHo
Figure imgf000091_0001
H H CF3 4-F CF3
H H CF3 4-Cl CF3
H H C2F5 4-F CF3
H H OCF3 4-F CF3
H H SCF3 4-F CF3
H H SCHF2 4-F CF3
H H CF3 4-F CF3
H H CF3 H OCHF2
H Cl CF3 4-F CF3
Figure imgf000092_0001
Figure imgf000092_0002
92
H H SCHF2 4-F CF3
H H CF3 4-F CF3
H H CF3 H OCHF2
H Cl CF3 4-F CF3
H OMe CF3 4-F CF3
NH2 H CF3 4-F CF3
NH2 H CF3 4-Cl CF3
NH2 H OCF3 4-F CF3
NH2 H SCF3 4-F CF3
NHMe H CF3 4-F CF3
O^ NH. 02 = 0
Figure imgf000093_0001
H H CF3 4-F CF3
H H CF3 4-Cl CF3
H H C2F5 4-F CF3
H H OCF3 4-F CF3
H H SCF3 4-F CF3
H H SCHF2 4-F CF3
H H CF3 4-F CF3
H H CF3 H OCHF2
H Cl CF3 4-F CF3
H OMe CF3 4-F CF3
NH2 H CF3 4-F CF3
NH2 H CF3 4-Cl CF3
NH2 H OCF3 4-F CF3
NH2 H SCF3 4-F CF3
NHMe H CF3 4-F CF3
Figure imgf000093_0002
H H CF3 4-F CF3
H H CF3 4-Cl CF3
H H C F5 4-F CF3
H H OCF3 4-F CF3
H H SCF3 4-F CF3
H H SCHF2 4-F CF3
H H CF3 4-F CF3
H H CF3 H OCHF2 H Cl CF3 4-F CF3
H OMe CF3 4-F CF3
NH2 H CF3 4-F CF3
NH2 H CF3 4-Cl CF3
NH2 H OCF3 4-F CF3
NH2 H SCF3 4-F CF3
NHMe H CF3 4-F CF3
0^ 0 . O2 = OCHo
Figure imgf000094_0001
H H CF3 4-F CF3
H H CF3 4-Cl CF3
H H C 5 4-F CF3
H H OCF3 4-F CF3
H H SCF3 4-F CF3
H H SCHF2 4-F CF3
H H CF3 4-F CF3
H H CF3 H OCHF2
H Cl CF3 4-F CF3
H OMe CF3 4-F CF3
NH2 H CF3 4-F CF3
NH2 H CF3 4-Cl CF3
NH2 H OCF3 4-F CF3
NH2 H SCF3 4-F CF3
NHMe H CF3 4-F CF3
Figure imgf000094_0002
Q1, *.2 = 0
Figure imgf000094_0003
H H CF3 4-F Me CF3 H
H H CF3 4-Cl Me CF3 Cl
H H C 5 4-F Me CF3 H
H H OCF3 4-F Et CF3 Cl a a a a a w p
a a a a a w I to te
Figure imgf000095_0001
CΛ 0 ff <~> ^ ffl ffl m ffl O >τi o*ιi mffl mffl mffl mffl mffl mffl mffl O _H O hi oH H ffl I I? i? 0
Figure imgf000095_0002
ffl ffl ffl f O ffl f ' ffl ffl ό ffl ffl ffl * * ξ h. w
11 ffl o ffl I Ov ffl ffl ffl O ffl ffl ffl a a n n
Figure imgf000095_0003
fl ffl ffl hi 9 0 0 O 0 0 0 0 ff ffl> ffl O 0 0 0 O hi f to ffl 9 fl n o O hj hi hj o m ffl o m ffl l l 11 > 9 ff ff m 9 m f 9 t I to l > ffl ffl> ffl 0 ffl Ω > w n Ω 0
11 fl w m m m m to _ f-
a * Ω * 0 0 0 11 t a Ω n a a o a Ω a to o Ω oP a∞ oP ω a ^ Ω P ^ a a t to
a a a a a
a a a a a
Figure imgf000096_0001
0
Ω hi
Figure imgf000096_0002
4=- 4- ■ 4- 4-- w 4_ 4_ 4- 4- ffl ffl ffl O ffl 1 Ov hi hi hi O ffl ffl ffl 11 ffl ffl ffl n ffl I ov 11 11 ffl ffl O ffl ffl a a n f 1 ^1
VO
Figure imgf000096_0003
ini n11
Figure imgf000096_0004
a n a n a r* to a a hτl Ω Ω 'τi a a n a n a to Ω Ω Ω Ep Ω ω a ^ Ω Ω n a to Ω Ω !? Ω to
H H SCHF2 4-F Me CF3 H
H H CF3 4-F Me CF3 F
H H CF3 H CHF2 CF3 Cl
H H CF3 H Et OCHF2 Cl
H Cl CF3 4-F Me CF3 F
H OMe CF3 4-F Me CF3 H
NH2 H CF3 4-F Me CF3 Br
NH2 H CF3 4-Cl Me CF3 Cl
NH2 H OCF3 4-F CF3CH2 CF3 Br
NH2 H SCF3 4-F Me CF3 Cl
NHMe H CF3 4-F Me CF3 Cl
Formulation Utilitv
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. 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 Inεredient 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 Emulsifiers 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, NN-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 /V-dimethylformamide, dimethyl sulfoxide, N-alkylpyrrolidone, ethylene glycol, polypropylene glycol, paraffins, alkylbenzenes, alkylnaphthalenes, oils of olive, castor, linseed, tung, 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 3 65.0% dodecylphenol polyethylene glycol ether 2.0% sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0% rnontmorillonite (calcined) 23.0%.
Example B Granule Compound 3 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 3 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 3 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 (Spodopterafrugiperda), black bean aphid (Aphis fabae), green peach aphid (Myzus persicά), cotton aphid (Aphis gossypii), Russian wheat aphid (Diuraphis noxiά), English grain aphid (Sitobion avenae), tobacco budworm (Heliothis virescens), rice water weevil (Lissorhoptrus oryzophilus), rice leaf beetle (Oulema oryzae), whitebacked planthopper (Sogatella furciferd), 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 californicus 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[ 1 ,2-e] [ 1 ,3,4]oxadiazine-4a(3H)- carboxylate, 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, benomyl, blasticidin-S, Bordeaux mixture (Tribasic copper sulfate), bromuconazole, carpropamid (KTU 3616), captafol, captan, carbendazim, chloroneb, chlorothalonil, copper oxychloride, copper salts, cymoxanil, cyproconazole, cyprodinil (CGA 219417),(S)-3,5-dichloro-N-(3-chloro-l-ethyl-l-methyl- 2- oxopropyl)-4-methylbenzamide (RΗ 7281), diclocymet (S-2900), diclomezine, dicloran, difenoconazole,(ιS -3,5-dihydro-5-memyl-2-(memylt_ύo)-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, metommosttobin/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, thira , 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.
For the control arthropod pests, 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 concentrations, 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 TESTS demonstrate the control efficacy of compounds of this invention on specific pathogens and arthropod pests. For the tests on arthropod pests, "control efficacy" represents inhibition of arthropod development (including mortality) that causes significantly reduced feeding. The pathogen and arthropod pest control protection afforded by the compounds is not limited, however, to these species. See Index Table A for compound descriptions.
INDEX TABLE A
Figure imgf000103_0001
Figure imgf000103_0002
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000106_0002
*See Index Table B for lH NMR data.
INDEX TABLE B Cmpd No^ ^H NMR Data (CDCI3 solution unless indicated otherwise)a
6.74 (s,lH), 7.28-7.4 (m-2H), 7.5-7.65 (m,3H), 8.03 (m,lH), 8.45 (s,lH)
3.96 (s,3H), 6.51 (s,lH), 6.57 (s,lH), 7.2-7.45 (m,3H), 8.45 (s,lH)
3.96 (s,3H), 6.5 (s,lH), 6.7 (s,lH), 7.3 (m,lH), 7.5 (m,2H), 8.4 (s,lH)
3.96 (s,3H), 6.5 (s,lH), 6.6 (s,lH), 7.3 (m,lH), 7.5 (m,2H), 8.5 (s,lH)
Figure imgf000107_0001
a Η 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 compounds were first dissolved in acetone in an amount equal to 3% of the final volume and then suspended at a concentration of 200 ppm in purified water containing 250 ppm of the surfactant Trem® 014 (polyhydric alcohol esters). The resulting test suspensions were then used in Tests A-C. Spraying these 200 ppm test suspensions to the point of run-off on the test plants is the equivalent of a rate of 500 g/ha. TEST A
Southern Corn Rootworm
Test units, each consisting of a 230-mL (8-ounce) plastic cup containing a 6.5-cm2 (1 -square-inch) plug of a wheatgerm diet, were prepared. The test units were sprayed with individual solutions of the test compounds. After the spray on the cups had dried, five second-instar larvae of the southern corn rootworm (Diabrotica undecimpunctata howardi) were placed into each cup. The cups were held at 27°C and 50% relative humidity for 48 hours, after which time mortality readings were taken. The same units were read again at 6-8 days for delayed toxicity. Of the compounds tested, the following gave control efficacy levels of 80% or greater: 3, 6, 10, 11, 12, 15 and 17. TEST B
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, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22 and 23.
TEST C Corn Planthopper Test
The test unit consists 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 is 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 is placed on all test units prior to test.
Test compounds are formulated at 200ppm in 20% acetone: 80% water containing 500ppm Ortho X-77 surfactant. Compounds are applied through the opening in the test unit lid with an atomizer sprayer fitted with a Model 17690- 1/8 JJAU 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 are sprayed with a total of 2ml each of test solution. After spraying, test units are placed in a ventilated enclosure for 10-15 minutes to dry. After drying, a thin layer of white quartz sand is 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 is infested with a minimum of 15 nymphs of the corn planthopper, Peregrinus maidis, which are approximately 21 days old. Infested test units are held in a growth chamber operating at 22 degrees centigrade and 50% relative humidity with a 16:8 lightidark photoperiod. Insect mortality is evaluated at 6 days post-infestation. Moribund insects are counted as dead. Of the compounds tested, the following gave mortality of 80% or greater: 3, 7, 10, 11 and 17.

Claims

CLAIMS What is claimed is:
1. A compound selected from Formula I, N-oxides and agriculturally suitable salts thereof,
Figure imgf000109_0001
wherein
Q1 is O, S, ΝR17, CR3R4 or OCR18R19; wherein when Q1 is OCR18R19, then Q1 is attached to the pyrimidine through the O atom; Q2 is O, S, ΝR17, CR3R4, OCR18R19, SCR18R19 or ΝR17CR18R19; wherein when Q2 is OCR18R19, SCR18R19 or NR17CR18R19 then Q2 is attached to the pyrimidine through the O, S or N atom; is
Figure imgf000109_0002
W is O, S or NR20;
X, Y, and Z are independently N or CR22; provided that in J-3 and J-4, at least one of
X, Y or Z is N; R1 and R2 are each independently H, Ci -C4 alkyl, halogen, NR7R8, CrC4 alkoxy,
C1-C4 haloalkyl, C1-C4 alkylthio or nitro; R3 and R4 are each independently H, halogen, hydroxy, C -C4 alkyl, Ci -C4 alkoxy,
C1-C4 haloalkyl or cyano; or R3 and R4 are taken together with the attached carbon to make a carbonyl; R5 and R21 are each independently halogen, C1-C4 alkyl, C1-C4 haloalkoxy, C C4 haloalkyl, CrC4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, C3-C4 alkenyloxy,
C3-C4 alkynyloxy, SF5, S(O)nR9, cyano or CO2Rn; each R6 and each R22 are independently H, halogen, cyano, Cι-C 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,
COR10, CO2Rn, CHO, SO2R12 or OR13; each R9 is independently C1-C4 alkyl or C1-C4 haloalkyl; each R10 is independently C Cg alkyl, phenyl optionally substituted by R6, C C6 haloalkyl, CO2R14, CrC6 alkoxyalkyl, C2-C4 alkenyl, C2-C6 alkynyl, C2-C6 cyanoalkyl orNR15R16; R11 and R12 are each independently C C6 alkyl, Cj-C6 haloalkyl, C2-C£ alkenyl or
C2-C6 alkynyl; R13 and R17 are each independently CrC4 alkyl, H, COR10 or CO2Rπ; each R 14 is independently C j -C4 alkyl; each R15 is independently H, Cj-C4 alkyl, C 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;
R20 is H, CrC4 alkyl or CrC4 haloalkyl; n is 0-2; and p is 0-4.
2. A compound of Claim 1 wherein
J is J-1;
R1 and R2 are H;
R5 is CrC2 haloalkyl; each R6 is halogen; and R3 and R4 are each H.
3. A compound of Claim 2 wherein Q1 and Q2 are both O.
4. A compound of Claim 1 wherein J is J-2;
R1 and R2 are H; R5 is CrC2 haloalkyl; each R6 is halogen; and R3 and R4 are each H.
5. A compound of Claim 4 wherein Q1 and Q2 are both O.
6. The compound of Claim 5 which is 4-[4-fluoro-3-(trifluoromethyl)phenoxy]-6- [[ 1 -methyl-5-(trifluoromethyl)- lH-pyrazol-3-yl]oxy]pyrimidine.
7. A compound of Claim 1 wherein
J is J-3;
R1 and R2 are Η;
R5 is CrC2 haloalkyl; each R6 is halogen; and
R3 and R4 are each Η.
8. A compound of Claim 7 wherein Q1 and Q2 are both O.
9. A compound of Claim 8 wherein J is J-4; R! and R2 are Η;
R5 is CrC2 haloalkyl; each R6 is halogen; and R3 and R4 are each H.
10. A compound of Claim 1 wherein Q1 and Q2 are both O.
11. An arthropodicidal composition comprising an arthropodicidally effective amount of a compound of Claim 1 and at least one additional component selected from the group consisting of surfactants, solid diluents or liquid diluents.
12. A method for controlling arthropods comprising contacting the arthropods or their environment with an arthropodicidally effective amount of a compound of Claim 1.
PCT/US2000/013437 1999-05-20 2000-05-17 Heteroaryloxypyrimidine insecticides and acaricides WO2000071536A1 (en)

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