WO2012012366A1 - Pesticidal 3-(aryloxy)azacycloalkanes - Google Patents

Pesticidal 3-(aryloxy)azacycloalkanes Download PDF

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Publication number
WO2012012366A1
WO2012012366A1 PCT/US2011/044436 US2011044436W WO2012012366A1 WO 2012012366 A1 WO2012012366 A1 WO 2012012366A1 US 2011044436 W US2011044436 W US 2011044436W WO 2012012366 A1 WO2012012366 A1 WO 2012012366A1
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Prior art keywords
compound
alkyl
formula
independently
chloro
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PCT/US2011/044436
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French (fr)
Inventor
David Alan Clark
George P. Lahm
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E. I. Du Pont De Nemours And Company
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Publication of WO2012012366A1 publication Critical patent/WO2012012366A1/en

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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
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/44—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom three- or four-membered rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—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
    • A01N43/58—1,2-Diazines; Hydrogenated 1,2-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
    • A01N43/60—1,4-Diazines; Hydrogenated 1,4-diazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention relates to certain 3-(aryloxy)azocycloalkanes, their N-oxides, salts and compositions suitable for agronomic and nonagronomic uses, and methods of their use for controlling invertebrate pests such as arthropods in both agronomic and nonagronomic environments.
  • invertebrate pests The control of invertebrate pests is extremely important in achieving high crop efficiency. Damage by invertebrate pests to growing and stored agronomic crops can cause significant reduction in productivity and thereby result in increased costs to the consumer.
  • the control of invertebrate pests in forestry, greenhouse crops, ornamentals, nursery crops, stored food and fiber products, livestock, household, turf, wood products, 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 sites of action.
  • PCT Patent Publication WO 2005/115146 Al discloses certain insecticidal, acaricidal molluscicidal and nematicidal compounds comprising a piperazine ring directly bonded to an aromatic or heteroaromatic ring.
  • the 3-(aryloxy)azacycloalkanes of the present invention are not disclosed in this publication.
  • This invention is directed to compounds of Formula 1 (including all stereoisomers), N-oxides, and salts thereof, and compositions containing them and their use for controlling invertebrate pests:
  • a 1 is N or CR 7 ;
  • a 2 is N or CR 8 ;
  • a 3 is N or CR 9 ;
  • a 4 is N or CR 10 ;
  • a 1 , A 2 , A 3 and A 4 are N;
  • T is O, S(0) k or NR 36 ;
  • Z is O, S(0) m , NR 37 or CR 8 R 39 ;
  • R 1 is a phenyl or 5- or 6-membered heteroaromatic ring optionally substituted with up to 5 substituents independently selected from R 14 ;
  • R 2 is H, hydroxy, C ⁇ -Cg alkyl, C ⁇ -Cg haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 3 -C 6 haloalkynyl, C3-C7 cycloalkyl, C 4 -C 8 cycloalkylalkyl,
  • each R 3 is independently halogen, cyano, C1-C4 alkyl or C1-C4 alkoxy;
  • R 4 is H or C!-C4 alkyl
  • RS is H or C ⁇ alkyl
  • R 6 is a phenyl or 5- or 6-membered heteroaromatic ring optionally substituted with up to 5 substituents independently selected from R 22 ;
  • R 7 , R 8 , R 9 and R 10 are independently H, halogen, cyano, nitro, OR 23 , NR 24 R 25 , C r C 6 alkyl, C ⁇ -Cg haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 3 -C 6 haloalkynyl, C 3 -C 7 cycloalkyl, C 4 -C 8 cycloalkylalkyl, C 5 -C 7 cycloalkenyl, -CHO, C(W )R 26 , C(0)OR 27 , C(0)NR 8 R 29 , S(0) q R 30 ,
  • S(0) 2 NR 28 R 29 or OC(0)R 31 or a phenyl or 5- or 6-membered heteroaromatic ring optionally substituted with up to 5 substituents independently selected from R 40 ; or a vicinal pair of R 7 and R 8 , or R 8 and R 9 , or R 9 and R 10 , are taken together with the carbon atoms to which the pair is attached to form a fused 5- or
  • R 1 1 and R 12 are independently H, halogen, C ⁇ -C 2 alkyl or C ⁇ -C 2 alkoxy;
  • each R 13 , R 14 , R 22 and R 40 is independently halogen, cyano, nitro, OR 23 , NR 24 R 25 ,
  • R 15 and R 16 are independently C ⁇ Cg alkyl, C ⁇ Cg haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 3 -C 6 haloalkynyl, C 3 -C 7 cycloalkyl, C 4 -C 8 cycloalkylalkyl or C 5 -C 7 cycloalkenyl; or phenyl optionally substituted with up to 3 substituents independently selected from halogen, cyano, nitro, OR 23 , NR 24 R 25 , C!-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, -C4 haloalkyl, C 2 -C 6 alkoxyalkyl, C 2 -C 4 haloalkenyl, -CHO, C(W 2 )R 26 , C(0)OR 27 , C(0)
  • each R 17 and R 20 is independently H, C j -Cg alkyl, C j -Cg haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 3 -C 6 haloalkynyl, C 3 -C7 cycloalkyl, C 4 - C 8 cycloalkylalkyl or C5-C7 cycloalkenyl; or phenyl optionally substituted with up to 3 substituents independently selected from halogen, cyano, nitro, OR 23 , NR 24 R 25 , C!-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, -Q haloalkyl, C 2 -C 6 alkoxyalkyl, C 2 -C 4 haloalkenyl, -CHO, C(W 2 )R 26 , C
  • each R 18 , R 21 , R 24 and R 29 is independently H, -Cg alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl;
  • each R 23 and R 31 is independently H, C ⁇ -Cg alkyl or C ⁇ -Cg haloalkyl;
  • each R 25 , R 36 and R 37 is independently H, -Cg alkyl, C(0)R 32 or C(0)OR 33 ; each R 28 and R 32 is independently H, C j -Cg alkyl, C j -Cg haloalkyl, C 2 -C 6 alkenyl,
  • each R 33 is independently -Cg alkyl, C j -Cg haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6
  • haloalkenyl C 2 -C 6 alkynyl, C 3 -C 6 haloalkynyl, C 3 -C7 cycloalkyl, C 4 -C 8 cycloalkylalkyl or C5-C7 cycloalkenyl;
  • R 34 is H, C!-C 4 alkyl, - ⁇ haloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, Ci ⁇ C 4 alkoxy or cyano;
  • R 35 is H or methyl
  • R 38 is H, OH, halogen, € ⁇ - € 2 alkyl or € ⁇ - € 2 alkoxy;
  • R 39 is selected from H, cyano and C ⁇ -C 2 alkyl, and when R 38 is halogen, then R 39 is additionally selected from halogen; or
  • R 38 and R 39 together with the carbon atom to which said R 38 and R 39 are attached represent a carbonyl moiety
  • W is O or S
  • W 1 is O or S
  • each W 2 is independently O or S;
  • k 0, 1 or 2;
  • n 0, 1 or 2;
  • n is an integer from 0 to 5;
  • p 0, 1 or 2;
  • each q is independently 0, 1 or 2;
  • s is 1, 2 or 3; and t is 1 or 2;
  • this invention relates to a compound selected from Formula 1, an N-oxide, or a salt thereof.
  • This invention also provides a composition comprising a compound of Formula 1, an
  • this invention also provides a composition for controlling an invertebrate pest comprising a compound of Formula 1, an N-oxide, or a salt thereof, and at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents, said composition optionally further comprising at least one additional biologically active compound or agent.
  • This invention further provides a spray composition for controlling an invertebrate pest comprising a compound of Formula 1, an N-oxide, or a salt thereof, or a composition described above, and a propellant.
  • This invention also provides a bait composition for controlling an invertebrate pest comprising a compound of Formula 1, an N-oxide, or a salt thereof, or a composition described in the embodiments above, one or more food materials, optionally an attractant, and optionally a humectant.
  • This invention further provides a trap device for controlling an invertebrate pest comprising said bait composition and a housing adapted to receive said bait composition, wherein the housing has at least one opening sized to permit the invertebrate pest to pass through the opening so the invertebrate pest can gain access to said bait composition from a location outside the housing, and wherein the housing is further adapted to be placed in or near a locus of potential or known activity for the invertebrate pest.
  • This invention provides a method for controlling an invertebrate pest comprising contacting the invertebrate pest or its environment with a biologically effective amount of a compound of Formula 1, an N-oxide, or a salt thereof (e.g., as a composition described herein).
  • This invention also relates to such method wherein the invertebrate pest or its environment is contacted with a composition comprising a compound of Formula 1, an N-oxide, or a salt thereof (i.e, in a biologically effective amount), and at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents, said composition optionally further comprising a biologically effective amount of at least one additional biologically active compound or agent.
  • This invention also provides a method for protecting a seed or a plant grown therefrom from an invertebrate pest comprising contacting the seed with a biologically effective amount of a compound of Formula 1, an N-oxide, or a salt thereof (e.g., as a composition described herein).
  • This invention also relates to the treated seed.
  • This invention further provides a method for protecting an animal from an invertebrate parasitic pest comprising administering to the animal a parasiticidally effective amount of a compound of Formula 1, an N-oxide, or a salt thereof (e.g., as a composition described herein).
  • This invention also provides for the use of a compound of Formula 1, an N-oxide, or a salt thereof, (e.g., as a composition described herein) in protecting an animal from an invertebrate pest.
  • compositions comprising, “comprising,” “includes,” “including,” “has,” “having,” “contains”, “containing,” “characterized by” or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated.
  • a composition, mixture, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, method, article, or apparatus.
  • invertebrate pest includes arthropods, gastropods and nematodes of economic importance as pests. More particularly, “invertebrate pest” relates to arthropods and gastropods, and most particularly, “invertebrate pest” relates to arthropods.
  • arthropod includes insects, mites, spiders, scorpions, centipedes, millipedes, pill bugs and symphylans.
  • gastropod includes snails, slugs and other Stylommatophora.
  • nematode includes members of the phylum Nematoda, such as phytophagous nematodes.
  • invertebrate pest control means inhibition of invertebrate pest development (including mortality, feeding reduction, and/or mating disruption), and related expressions are defined analogously.
  • agronomic refers to the production of field crops such as for food and fiber and includes the growth of corn, soybeans and other legumes, rice, cereal (e.g., wheat, oats, barley, rye, rice, maize), leafy vegetables (e.g., lettuce, cabbage, and other cole crops), fruiting vegetables (e.g., tomatoes, pepper, eggplant, crucifers and cucurbits), potatoes, sweet potatoes, grapes, cotton, tree fruits (e.g., pome, stone and citrus), small fruit (berries, cherries) and other specialty crops (e.g., canola, sunflower, olives).
  • wheat e.g., wheat, oats, barley, rye, rice, maize
  • leafy vegetables e.g., lettuce, cabbage, and other cole crops
  • fruiting vegetables e.g., tomatoes, pepper, eggplant, crucifers and cucurbits
  • potatoes e.g., sweet potatoes, grapes, cotton, tree fruits (e.g.
  • nonagronomic refers to other than field crops, such as horticultural crops (e.g., greenhouse, nursery or ornamental plants not grown in a field), residential, agricultural, commercial and industrial structures, turf (e.g., sod farm, pasture, golf course, lawn, sports field, etc.), wood products, stored product, agro-forestry and vegetation management, public health (i.e. human) and animal health (e.g., domesticated animals such as pets, livestock and poultry, undomesticated animals such as wildlife) applications.
  • horticultural crops e.g., greenhouse, nursery or ornamental plants not grown in a field
  • turf e.g., sod farm, pasture, golf course, lawn, sports field, etc.
  • wood products e.g., stored product, agro-forestry and vegetation management
  • public health i.e. human
  • animal health e.g., domesticated animals such as pets, livestock and poultry, undomesticated animals such as wildlife
  • alkylating agent refers to a chemical compound in which a carbon-containing radical is bound through a carbon atom to leaving group such as halide or sulfonate, which is displaceable by bonding of a nucleophile to said carbon atom. Unless otherwise indicated, the term “alkylating” does not limit the carbon-containing radical to alkyl; the carbon-containing radicals in alkylating agents include the variety of carbon-bound substituent radicals specified for R 4 , R 5 , R 6 and L.
  • alkyl used either alone or in compound words such as “alkylthio” or “haloalkyl” includes straight-chain or branched alkyl, such as, methyl, ethyl, n-propyl, /-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, n-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers.
  • Alkoxyalkyl denotes alkoxy substitution on alkyl. Examples of “alkoxyalkyl” include CH 3 OCH 2 -, CH 3 OCH 2 CH 2 -, CH 3 CH 2 OCH 2 -, CH 3 CH 2 CH 2 CH 2 OCH 2 - and CH 3 CH 2 OCH 2 CH 2 -.
  • Cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the term “cycloalkylalkyl” denotes cycloalkyl substitution on an alkyl moiety. Examples of “cycloalkylalkyl” include cyclopropylmethyl, cyclopentylethyl, and other cycloalkyl moieties bonded to straight-chain or branched alkyl groups.
  • Cycloalkenyl includes groups such as cyclopentenyl and cyclohexenyl as well as groups with more than one double bond such as 1,3- and 1,4-cyclohexadienyl.
  • halogen either alone or in compound words such as “haloalkyl”, or when used in descriptions such as “alkyl substituted with halogen” includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as “haloalkyl”, or when used in descriptions such as “alkyl substituted with halogen” said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of “haloalkyl” or “alkyl substituted with halogen” include F 3 C-, C1CH 2 -, CF 3 CH 2 - and CF 3 CC1 2 -.
  • haloalkoxy examples include CF 3 0-, CC1 3 CH 2 0-, HCF 2 CH 2 CH 2 0- and CF 3 CH 2 0-.
  • haloalkylthio examples include CC1 3 S-, CF 3 S-, CC1 3 CH 2 S- and C1CH 2 CH 2 CH 2 S-.
  • haloalkynyl examples include HC ⁇ CCHC1-, CF 3 C ⁇ C-, CC1 3 C ⁇ C- and FCH 2 C ⁇ CCH 2 -.
  • C 2 alkoxyalkyl designates CH 3 OCH 2 -
  • C 3 alkoxyalkyl designates, for example, CH 3 CH(OCH 3 )-, CH 3 OCH 2 CH 2 - or CH 3 CH 2 OCH 2 -
  • C 4 alkoxyalkyl designates the various isomers of an alkyl group substituted with an alkoxy group containing a total of four carbon atoms, examples including CH 3 CH 2 CH 2 OCH 2 - and CH 3 CH 2 OCH 2 CH 2 -.
  • substituents When a compound is substituted with a substituent bearing a subscript that indicates the number of said substituents can exceed 1, said substituents (when they exceed 1) are independently selected from the group of defined substituents, e.g., (R ) n , n is 1, 2, 3, 4 or 5.
  • substituents which can be hydrogen, for example R 2 , R 7 , R 8 , R 9 or R 10 , then when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted.
  • variable group When a variable group is shown to be optionally attached to a position, for example (R v ) r in U-30 of Exhibit 1 wherein r may be 0, then hydrogen may be at the position even if not recited in the variable group definition.
  • hydrogen atoms When one or more positions on a group are said to be "not substituted” or “unsubstituted”, then hydrogen atoms are attached to take up any free valency.
  • ring system denotes two or more fused rings.
  • fused ring refers to a ring that is fused to another ring to form a fused bicyclic ring system.
  • bicyclic ring system and fused bicyclic ring system denote a ring system consisting of two fused rings, in which either ring can be saturated, partially unsaturated or fully unsaturated unless otherwise indicated. Accordingly either ring can be aromatic or nonaromatic unless otherwise indicated.
  • carbocyclic ring denotes a ring or ring system wherein the atoms forming the ring backbone are selected only from carbon. Unless otherwise indicated, a carbocyclic ring can be a saturated, partially unsaturated, or fully unsaturated ring. When a fully unsaturated carbocyclic ring satisfies Huckel's rule, then said ring is also called an "aromatic ring".
  • heterocyclic ring denotes a ring or ring system in which at least one atom forming the ring backbone is not carbon, e.g., nitrogen, oxygen or sulfur.
  • a heterocyclic ring contains no more than 3 nitrogen atoms, no more than 2 oxygen atoms and no more than 2 sulfur atoms.
  • a heterocyclic ring can be a saturated, partially unsaturated, or fully unsaturated ring.
  • a heterocyclic ring can be aromatic or nonaromatic.
  • heterocyclic rings and ring systems can be attached through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.
  • Aromatic indicates that each of the ring atoms is essentially in the same plane and has a / ⁇ -orbital perpendicular to the ring plane, and in which (4n + 2) ⁇ electrons, where n is a positive integer, are associated with the ring to comply with Huckel's rule.
  • aromatic ring system denotes a carbocyclic or heterocyclic ring system in which at least one ring of the ring system is aromatic.
  • R 1 , R 6 , R 7 , R 8 , R 9 or R 10 is a 5- or 6-membered nitrogen-containing heteroaromatic ring, it can be attached to the remainder of Formula 1 though any available carbon or nitrogen ring atom, unless otherwise described.
  • R 1 , R 6 , R 7 , R 8 , R 9 or R 10 can be (among others) phenyl optionally substituted with one or more substituents selected from a group of substituents as defined in the Summary of Invention.
  • An example of phenyl optionally substituted with one to five substituents is the ring illustrated as U-l in Exhibit 1, wherein R v is R 14 , R 22 or R 40 as defined in the Summary of the Invention for R 1 , R 6 , R 7 , R 8 , R 9 or R 10 , respectively, and r is an integer from 0 to 5.
  • R 1 , R 6 , R 7 , R 8 , R 9 or R 10 can be (among others) 5- or 6-membered heteroaromatic ring, which is optionally substituted with substituents up to the number of available positions, and the substituents are independently selected from a group of radicals defined in the Summary of Invention (i.e. R 14 , R 22 or R 40 , respectively).
  • Examples of a 5- or 6-membered heteroaromatic ring optionally substituted with from one or more substituents include the rings U-2 through U-61 illustrated in Exhibit 1 wherein R v is any substituent as defined in the Summary of the Invention for R 1 , R 6 , R 7 , R 8 , R 9 or R 10 (i.e.
  • r is limited to the integers 0 or 1, and r being 0 means that the U group is unsubstituted and a hydrogen is present at the position indicated by (R v ) r .
  • R v groups are shown in the structures U-l through U-61, it is noted that they do not need to be present since they are optional substituents.
  • the nitrogen atoms that require substitution to fill their valence are substituted with H or R v .
  • (R v ) r can be attached to any available carbon atom or nitrogen atom of the U group.
  • the U group can be attached to the remainder of Formula 1 through any available carbon or nitrogen of the U group by replacement of a hydrogen atom.
  • some U groups can only be substituted with less than 4 R v groups (e.g., U-2 through U-5, U-7 through U-48, and U-52 through U-61).
  • a vicinal pair of R 7 and R 8 , or R 8 and R 9 , or R 9 and R 10 can be taken together with the carbon atoms to which they are attached to form a fused 5- or 6-membered aromatic or nonaromatic ring containing ring members selected from carbon atoms and up to 3 heteroatoms independently selected from N, O and S.
  • This ring comprising R 7 and R 8 , or R 8 and R 9 , or R 9 and R 10 is fused to the 6-membered aromatic ring comprising A 1 , A 2 , A 3 and A 4 , and thus is at least partially unsaturated, and may be fully unsaturated.
  • Compounds 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). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers.
  • the compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers or as an optically active form.
  • Compounds of this invention can exist as one or more conformational isomers due to restricted rotation about the amide bond in Formula 1.
  • This invention comprises mixtures of conformational isomers.
  • this invention includes compounds that are enriched in one conformer relative to others.
  • Non-crystalline forms include embodiments which are solids such as waxes and gums as well as embodiments which are liquids such as solutions and melts.
  • Crystalline forms include embodiments which represent essentially a single crystal type and embodiments which represent a mixture of polymorphs (i.e. different crystalline types).
  • polymorph refers to a particular crystalline form of a chemical compound that can crystallize in different crystalline forms, these forms having different arrangements and/or conformations of the molecules in the crystal lattice.
  • polymorphs can have the same chemical composition, they can also differ in composition due the presence or absence of co- crystallized water or other molecules, which can be weakly or strongly bound in the lattice. Polymorphs can differ in such chemical, physical and biological properties as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspensibility, dissolution rate and biological availability.
  • a polymorph of a compound represented by Formula 1 can exhibit beneficial effects (e.g., suitability for preparation of useful formulations, improved biological performance) relative to another polymorph or a mixture of polymorphs of the same compound represented by Formula 1.
  • Preparation and isolation of a particular polymorph of a compound represented by Formula 1 can be achieved by methods known to those skilled in the art including, for example, crystallization using selected solvents and temperatures.
  • 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 3-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane.
  • MCPBA peroxy acids
  • alkyl hydroperoxides such as t-butyl hydroperoxide
  • sodium perborate sodium perborate
  • dioxiranes such as dimethyldioxirane
  • salts of chemical compounds are in equilibrium with their corresponding nonsalt forms, salts share the biological utility of the nonsalt forms.
  • the salts of the compounds of Formula 1 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.
  • salts also include those formed with organic or inorganic bases such as pyridine, triethylamine or ammonia, or amides, hydrides, hydroxides or carbonates of sodium, potassium, lithium, calcium, magnesium or barium. Accordingly, the present invention comprises compounds selected from Formula 1, N-oxides, and biologically suitable salts thereof.
  • reference to Formula 1 includes N-oxides and salts thereof, and reference to "a compound of Formula 1" includes the definitions of substituents specified in the Summary of the Invention unless further defined in the Embodiments.
  • Embodiment 1 A compound of Formula 1 wherein A 1 is N.
  • Embodiment 2 A compound of Formula 1 wherein A 1 is CR 7 .
  • Embodiment 3 A compound of Formula 1 or Embodiment 1 or 2 wherein A 2 is CR 8 .
  • Embodiment 4. A compound of Formula 1 or any one of Embodiments 1 through 3 wherein A 3 is CR 9 .
  • Embodiment 5. A compound of Formula 1 or any one of Embodiments 1 through 4 wherein A 4 is CR 10 .
  • Embodiment 6 A compound of Formula 1 or any one of Embodiments 1 through 5 wherein R 7 , R 8 , R 9 and R 10 are independently H, halogen, cyano, nitro, OR 23 , NR24R 25 , C !-C 6 alkyl, C Y -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl,
  • Embodiment 7 A compound of Embodiment 6 wherein R 7 , R 8 , R 9 and R 10 are
  • Embodiment 8 A compound of Formula 1 or any one of Embodiments 1 through 7 wherein independently when R 7 , R 8 , R 9 or R 10 is separate (i.e. not taken together to form a ring), then said R 7 , R 8 , R 9 or R 10 is independently H, halogen, C j -C 4 alkyl, C j -C 4 haloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 haloalkenyl, C 2 -C 4 alkynyl, C 3 -C 4 haloalkynyl, C 3 -C 6 cycloalkyl, C j -C 4 alkoxy, C j -C 4 haloalkoxy, C j -C 4 alkylthio, C ⁇ -C 4 haloalkylthio or cyano.
  • Embodiment 9 A compound of Embodiment 8 wherein independently when R 7 , R 8 , R 9 or R 10 is separate, then said R 7 , R 8 , R 9 or R 10 is independently H, halogen or C ⁇ -C 4 haloalkyl.
  • Embodiment 10 A compound of Formula 1 or any one of Embodiments 1 through 9 wherein when R 7 is separate, then R 7 is H or halogen.
  • Embodiment 1 A compound of Embodiment 10 wherein when R 7 is separate, then R 7 is H or F.
  • Embodiment 12 A compound of Embodiment 1 1 wherein when R 7 is separate, then R 7 is H.
  • Embodiment 13 A compound of Formula 1 or any one of Embodiments 1 through 12 wherein when R 8 is separate, then R 8 is H, halogen or C ⁇ -C 2 haloalkyl.
  • Embodiment 14 A compound of Embodiment 13 wherein when R 8 is separate, then R 8 is H, halogen or C ⁇ fluoroalkyl (i.e. fluoromethyl, including CH 2 F, CHF 2 and CF 3 ).
  • Embodiment 15 A compound of Embodiment 14 wherein when R 8 is separate, then R 8 is H, halogen or CF 3 .
  • Embodiment 16 A compound of Embodiment 15 wherein when R 8 is separate, then R 8 is H, F, CI or CF 3 .
  • Embodiment 17 A compound of Embodiment 15 wherein when R 8 is separate, then R 8 is halogen or CF 3 .
  • Embodiment 18 A compound of Embodiment 17 wherein when R 8 is separate, then R 8 is F, CI or CF 3 .
  • Embodiment 19 A compound of Formula 1 or any one of Embodiments 1 through 18 wherein when R 9 is separate, then R 9 is H, halogen or C1-C2 haloalkyl.
  • Embodiment 20 A compound of Embodiment 19 wherein when R 9 is separate, then R 9 is H, halogen or C ⁇ fluoroalkyl (i.e. fluoromethyl).
  • Embodiment 21 A compound of Embodiment 20 wherein when R 9 is separate, then R 9 is H, halogen or CF 3 .
  • Embodiment 22 A compound of Embodiment 21 wherein when R 9 is separate, then R 9 is H, CI or CF 3 .
  • Embodiment 23 A compound of Formula 1 or any one of Embodiments 1 through 22 wherein when R 10 is separate, then R 10 is H or halogen.
  • Embodiment 24 A compound of Embodiment 23 wherein when R 10 is separate, then R 10 is H or F.
  • Embodiment 25 A compound of Embodiment 24 wherein when R 10 is separate, then R 10 is H.
  • Embodiment 27 A compound of Formula 1 or any one of Embodiments 1 through 26 wherein one vicinal pair of R 7 and R 8 , or R 8 and R 9 , or R 9 and R 10 , are taken together with the carbon atoms to which they are attached to form a fused ring as described.
  • Embodiment 28 A compound of Formula 1 or any one of Embodiments 1 through 27 wherein a vicinal pair of R 7 and R 8 are taken together with the carbon atoms to which they are attached to form a fused ring as described.
  • Embodiment 29 A compound of Formula 1 or any one of Embodiments 1 through 27 wherein a vicinal pair of R 8 and R 9 are taken together with the carbon atoms to which they are attached to form a fused ring as described.
  • Embodiment 30 A compound of Formula 1 or any one of Embodiments 1 through 27 wherein a vicinal pair of R 9 and R 10 are taken together with the carbon atoms to which they are attached to form a fused ring as described.
  • Embodiment 31 A compound of Formula 1 or any one of Embodiments 1 through 25 wherein each of R 7 , R 8 , R 9 and R 10 is separate (i.e. not taken together to form a fused ring).
  • Embodiment 34 A compound of Formula 1 or any one of Embodiments 1 through 33 wherein R 1 1 and R 12 are independently H, halogen or methyl.
  • Embodiment 35 A compound of Embodiment 34 wherein R 1 1 and R 12 are
  • Embodiment 36 A compound of Embodiment 35 wherein R 1 1 and R 12 are H.
  • Embodiment 37 A compound of Formula 1 or any one of Embodiments 1 through 32 wherein L is 1 ,4-diphenylene optionally substituted with up to 4 substituents independently selected from R 13 .
  • Embodiment 38 A compound of Formula 1 or any one of Embodiments 1 through 31 wherein L is -C(R 3 )(R 35 )-Z-, wherein the carbon atom bonded to R 34 and R 35 is also bonded to CR R 5 and Z is bonded to R 6 .
  • Embodiment 39 A compound of Formula 1 or any one of Embodiments 1 through 31 or Embodiment 38 wherein R 34 is H or C1-C4 alkyl.
  • Embodiment 40 A compound of Embodiment 39 wherein R 34 is H or C1-C2 alkyl.
  • Embodiment 41 A compound of Embodiment 40 wherein R 34 is H or methyl.
  • Embodiment 42 A compound of Embodiment 41 wherein R 34 is H.
  • Embodiment 43 A compound of Formula 1 or any one of Embodiments 1 through 31 or 38 through 42 wherein R 35 is H.
  • Embodiment 44 A compound of Formula 1 or any one of Embodiments 1 through 31 or 38 through 43 wherein Z is O, S, NR 37 or CR 38 R 39 (i.e. m is 0).
  • Embodiment 45 A compound of Embodiment 44 wherein Z is O, S or NR 37 .
  • Embodiment 46 A compound of Embodiment 45 wherein Z is O or NR 37 .
  • Embodiment 47 A compound of Embodiment 46 wherein Z is O.
  • Embodiment 48 A compound of Formula 1 or any one of Embodiments 1 through 47 wherein R 37 is H.
  • Embodiment 49 A compound of Formula 1 or any one of Embodiments 1 through 48 where R 38 and R 39 are H.
  • Embodiment 50 A compound of Formula 1 or any one of Embodiments 1 through 49 wherein when L comprises 1 ,4-diphenylene, then said 1 ,4-diphenylene is optionally substituted with up to 2 substituents independently selected from R 13 .
  • Embodiment 51 A compound of Embodiment 50 wherein when L comprises
  • Embodiment 52 A compound of Formula 1 or any one of Embodiments 1 through 51 wherein each R 13 is independently halogen or C1-C4 alkyl.
  • Embodiment 53 A compound of Embodiment 52 wherein each R 13 is independently halogen or methyl.
  • Embodiment 54 A compound of Formula 1 or any one of Embodiments 1 through 53 wherein R 1 is a phenyl or 5- or 6-membered heteroaromatic ring optionally substituted with up to 4 substituents independently selected from R 14 .
  • Embodiment 55 A compound of Embodiment 54 wherein R 1 is a phenyl or pyridinyl ring optionally substituted with up to 4 substituents independently selected from
  • Embodiment 56 A compound of Embodiment 55 wherein R 1 is a phenyl ring
  • Embodiment 57 A compound of Embodiment 55 wherein R 1 is a pyridinyl ring
  • Embodiment 58 A compound of Embodiment 57 wherein R 1 is a 4-pyridinyl ring optionally substituted with up to 4 substituents independently selected from R 14 .
  • Embodiment 59. A compound of Embodiment 58 wherein R 1 is a 4-pyridinyl ring substituted with 1 to 3 substituents independently selected from R 14 , wherein one of said substituents is located at the 2-position of the 4-pyridinyl ring (i.e. ortho to the pyridinyl ring nitrogen atom and meta to the bond connecting the pyridinyl ring to the remainder of Formula 1).
  • Embodiment 60 A compound of Embodiment 59 wherein R 1 is a 4-pyridinyl ring substituted with 1 substituent selected from R 14 , wherein said substituent is located at the 2-position of the 4-pyridinyl ring.
  • Embodiment 61 A compound of Formula 1 or any one of Embodiments 1 through 60 wherein each R 14 is independently halogen, C1-C4 alkyl, C1-C4 haloalkyl, cyano, C 2 -C 4 alkenyl, C 2 -C 4 haloalkenyl, C 2 -C 4 alkynyl, C3-C4 haloalkynyl, C 3 -C 6 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio or C1-C4 haloalkylthio.
  • Embodiment 62 A compound of Embodiment 61 wherein each R 14 is independently halogen or C1-C4 haloalkyl.
  • Embodiment 63 A compound of Embodiment 62 wherein each R 14 is independently F,
  • Embodiment 64 A compound of Embodiment 63 wherein each R 14 is CI.
  • Embodiment 65 A compound of Formula 1 or any one of Embodiments 1 through 64 wherein R 2 is H, C1-C4 alkyl, C1-C4 alkoxy, C 2 -C 5 alkoxyalkyl, C 2 -C 5 alkoxycarbonyl or C2-C5 alkylcarbonyl;
  • Embodiment 66 A compound of Embodiment 65 wherein R 2 is H, methyl, methoxy,
  • Embodiment 67 A compound of Embodiment 66 wherein R 2 is H, methyl,
  • Embodiment 68 A compound of Embodiment 67 wherein R 2 is H.
  • Embodiment 69 A compound of Formula 1 or any one of Embodiments 1 through 68 wherein each R 3 is independently C1-C4 alkyl.
  • Embodiment 70 A compound of Embodiment 69 wherein each R 3 is methyl.
  • Embodiment 71 A compound of Formula 1 or any one of Embodiments 1 through 70 wherein R 4 is H or C ⁇ -C 4 alkyl.
  • Embodiment 72 A compound of Embodiment 71 wherein R 4 is H or 1-C2 alkyl.
  • Embodiment 73. A compound of Embodiment 72 wherein R 4 is H or methyl.
  • Embodiment 74 A compound of Embodiment 73 wherein R 4 is H.
  • Embodiment 75 A compound of Formula 1 or any one of Embodiments 1 through 74 wherein R 5 is H.
  • Embodiment 76 A compound of Formula 1 or any one of Embodiments 1 through 75 wherein R 6 is a phenyl ring optionally substituted with up to 5 substituents independently selected from R 22 or a pyridinyl ring optionally substituted with up to 4 substituents independently seleted from R 22 .
  • Embodiment 77 A compound of Embodiment 76 wherein R 6 is a phenyl or pyridinyl ring substituted with 1 to 3 substituents independently selected from R 22 wherein one substituent is at the para position (relative to the bond connecting the ring to the remainder of Formula 1).
  • Embodiment 78 A compound of Embodiment 77 wherein R 6 is a phenyl or pyridinyl ring substituted with 1 or 2 substituents independently selected from R 22 wherein one substituent is at the para position.
  • Embodiment 79 A compound of Embodiment 78 wherein R 6 is a phenyl or pyridinyl ring substituted at the para position with a substituent independently selected from R 22 and optionally substituted at an ortho position with a substituent independently selected from R 22 .
  • Embodiment 80 A compound of Embodiment 79 wherein R 6 is a phenyl or pyridinyl ring substituted at the para position with a substituent selected from R 22 .
  • Embodiment 81 A compound of Formula 1 or any one of Embodiments 1 through 80 wherein when R 6 comprises a pyridinyl ring, said ring is bonded at the 2-position to the remainder of Formula 1.
  • Embodiment 82 A compound of Formula 1 or any one of Embodiments 1 through 80 wherein R 6 is a phenyl ring substituted as described.
  • Embodiment 83 A compound of Formula 1 or any one of Embodiments 1 through 81 wherein R 6 is a pyridinyl ring substituted as described.
  • Embodiment 84 A compound of Embodiment 76 wherein R 6 is a phenyl ring
  • Embodiment 85 A compound of Embodiment 84 wherein R 6 is a phenyl ring
  • Embodiment 86 A compound of Embodiment 85 wherein R 6 is a phenyl ring
  • Embodiment 87 A compound of Formula 1 or any one of Embodiments 1 through 86 wherein each R 22 is independently halogen, cyano, Ci ⁇ C 6 alkyl, Ci ⁇ C 6
  • haloalkyl C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl,
  • Embodiment 88 A compound of Embodiment 87 wherein each R 22 is independently F, CI, Br, cyano, CH 3 , CF 3 , cyclopropyl, HC ⁇ C, CH 3 0 or CF 3 0.
  • Embodiment 89 A compound of Embodiment 88 wherein each R 22 is independently F,
  • Embodiment 90 A compound of Embodiment 89 wherein each R 22 is independently F, CI, Br or CF 3 .
  • Embodiment 91 A compound of Embodiment 90 wherein each R 22 is independently F,
  • Embodiment 92 A compound of Embodiment 91 wherein each R 22 is F or CI.
  • Embodiment 93 A compound of Formula 1 or any one of Embodiments 1 through 92 wherein T is O, S or NR 36 (i.e. k is 0).
  • Embodiment 94 A compound of Embodiment 93 wherein T is O or NR 36 .
  • Embodiment 95 A compound of Embodiment 94 wherein T is O.
  • Embodiment 96 A compound of Formula 1 or any one of Embodiments 1 through 95 wherein R 36 is H.
  • Embodiment 97. A compound of Formula 1 or any one of Embodiments 1 through 96 wherein W is O.
  • Embodiment 98 A compound of Formula 1 or any one of Embodiments 1 through 97 wherein W 1 is O.
  • Embodiment 99 A compound of Formula 1 or any one of Embodiments 1 through 98 wherein each W 2 is O.
  • Embodiment 100 A compound of Formula 1 or any one of Embodiments 1 through 99 wherein n is an integer from 0 to 2.
  • Embodiment 101 A compound of Embodiment 100 wherein n is 0 or 1.
  • Embodiment 102 A compound of Embodiment 101 wherein n is 0.
  • Embodiment 103 A compound of Formula 1 or any one of Embodiments 1 through 102 wherein p is 0 or 2.
  • Embodiment 104 A compound of Embodiment 103 wherein p is 0.
  • Embodiment 105 A compound of Formula 1 or any one of Embodiments 1 through 104 wherein s is 1.
  • Embodiment 106 A compound of Formula 1 or any one of Embodiments 1 through 105 wherein t is 1.
  • Embodiment 107 A compound described in the Summary of the Invention or any one of Embodiments 1 through 106 that is not in the form of an N-oxide.
  • Embodiment 108. A compound of Embodiment 107 that is not in the form of an N- oxide or a salt.
  • Embodiment 109 A compound described in the Summary of the Invention or any one of Embodiments 1 through 108 wherein R 7 is other than NH 2 .
  • Embodiment 110 A compound of Embodiment 109 wherein R 7 is other than NR 24 R 25 .
  • Embodiments of this invention including Embodiments 1-110 above as well as any other embodiments described herein, can be combined in any manner, and the descriptions of variables in the embodiments pertain not only to the compounds of Formula 1 but also to the starting compounds and intermediate compounds useful for preparing the compounds of Formula 1.
  • embodiments of this invention including Embodiments 1-110 above as well as any other embodiments described herein, and any combination thereof, pertain to the compositions and methods of the present invention.
  • Embodiment Al A compound of Formula 1 wherein
  • T O
  • Z is O
  • R 1 is a 4-pyridinyl ring substituted with 1 to 3 substituents independently selected from R 14 , wherein one of said substituents is located at the 2-position of the 4-pyridinyl ring;
  • R 2 is H, methyl, C2-C5 alkoxyalkyl or C2-C4 alkoxycarbonyl;
  • R 4 is H or -C4 alkyl
  • R 5 is H
  • R 6 is a phenyl ring optionally substituted with up to 5 substituents independently selected from R 22 or a pyridinyl ring optionally substituted with up to 4 substituents independently seleted from R 22 ;
  • R 7 , R 8 , R 9 and R 10 are independently H, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 haloalkenyl, C 2 -C 4 alkynyl, C 3 -C 4 haloalkynyl, C 3 -C 6 cycloalkyl, Ci ⁇ C 4 alkoxy, Ci ⁇ C 4 haloalkoxy, Ci ⁇ C 4 alkylthio, Ci ⁇ C 4 haloalkylthio or cyano, or a vicinal pair of R 7 and R 8 , or R 8 and R 9 , or R 9 and
  • R 10 are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered aromatic or nonaromatic ring containing ring members selected from carbon atoms and up to 3 heteroatoms independently selected from N, O and S;
  • R 1 1 and R 12 are independently H, halogen or methyl
  • each R 13 is halogen or methyl
  • each R 14 is independently halogen, C j -C 4 alkyl, C j -C 4 haloalkyl, cyano, C 2 -C 4 alkenyl, C 2 -C 4 haloalkenyl, C 2 -C 4 alkynyl, C 3 -C 4 haloalkynyl, C 3 -C 6 cycloalkyl, C j -C 4 alkoxy, C j -C 4 haloalkoxy, C j -C 4 alkylthio or C j -C 4 haloalkylthio;
  • each R 22 is independently halogen, cyano, Ci ⁇ C 6 alkyl, Ci ⁇ C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, Ci ⁇ C 6 alkoxy or C ⁇ -C6 haloalkoxy;
  • R 34 is H or C ⁇ alkyl
  • R 5 is H
  • W is O
  • n 0;
  • s 1 ;
  • Embodiment A2 A compound of Embodiment A 1 wherein
  • a 1 is N or CR 7 ;
  • a 2 is N or CR 8 ;
  • a 3 is N or CR 9 ;
  • a 4 is CR 10 ;
  • R 1 is a 4-pyridinyl ring substituted with 1 substituent selected from R 14 , wherein said substituent is located at the 2-position of the 4-pyridinyl ring;
  • R 2 is H;
  • R 4 is H or methyl;
  • R 6 is a phenyl or pyridinyl ring substituted with 1 to 3 substituents independently selected from R 22 wherein one substituent is at the para position;
  • R 7 , R 8 , R 9 and R 10 are independently H, halogen or C1-C4 haloalkyl;
  • R 11 and R 12 are H
  • each R 14 is independently halogen or C1-C4 haloalkyl
  • each R 22 is independently F, CI, Br, cyano, CH 3 , CF 3 , cyclopropyl, HC ⁇ C, CH 3 0 or CF3O;
  • R 34 is H or methyl.
  • Embodiment A3 A compound of Embodiment A2 wherein
  • R 6 is a phenyl or pyridinyl ring substituted at the para position with a substituent independently selected from R 22 and optionally substituted at an ortho position with a substituent independently selected from R 22 ;
  • R 7 is H or F
  • R 8 and R 9 are independently H, halogen or C1-C4 haloalkyl
  • R 10 is H or F
  • each R 14 is independently F, CI, Br or CF 3 ;
  • each R 22 is independently F, CI, Br, CF 3 or CF 3 0.
  • Embodiment A4 A compound of Embodiment A3 wherein
  • R 6 is a phenyl ring substituted at the para position with a substituent selected from
  • R 7 is H
  • R 8 is H, halogen or CF 3 ;
  • R 9 is H, halogen or CF 3 ;
  • R 10 is H
  • R 14 is CI
  • R 22 is F, CI, Br or CF 3 .
  • Specific embodiments include compounds of Formula 1 selected from the group consisting of:
  • compounds of this invention are characterized by favorable metabolic and/or soil residual patterns and exhibit activity controlling a spectrum of agronomic and nonagronomic invertebrate pests.
  • compositions comprising a compound of any of the preceding Embodiments, as well as any other embodiments described herein, and any combinations thereof, and at least one additional component selected from the group consisting of a surfactant, a solid diluent and a liquid diluent, said compositions optionally further comprising at least one additional biologically active compound or agent.
  • compositions for controlling an invertebrate pest comprising a compound of any of the preceding Embodiments, as well as any other embodiments described herein, and any combinations thereof, and at least one additional component selected from the group consisting of a surfactant, a solid diluent and a liquid diluent, said compositions optionally further comprising at least one additional biologically active compound or agent.
  • Embodiments of the invention further include methods for controlling an invertebrate pest comprising contacting the invertebrate pest or its environment with a biologically effective amount of a compound of any of the preceding Embodiments alone or in combination (e.g., as a composition described herein).
  • Embodiments of the invention also include a composition comprising a compound of any of the preceding Embodiments, alone or in combination, in the form of a soil drench liquid formulation.
  • Embodiments of the invention further include methods for controlling an invertebrate pest comprising contacting the soil with a liquid composition as a soil drench comprising a biologically effective amount of a compound of any of the preceding Embodiments, alone or in combination.
  • Embodiments of the invention also include a spray composition for controlling an invertebrate pest comprising a biologically effective amount of a compound of any of the preceding Embodiments, alone or in combination, and a propellant.
  • Embodiments of the invention further include a bait composition for controlling an invertebrate pest comprising a biologically effective amount of a compound of any of the preceding Embodiments (alone or in combination), one or more food materials, optionally an attractant, and optionally a humectant.
  • Embodiments of the invention also include a device for controlling an invertebrate pest comprising said bait composition and a housing adapted to receive said bait composition, wherein the housing has at least one opening sized to permit the invertebrate pest to pass through the opening so the invertebrate pest can gain access to said bait composition from a location outside the housing, and wherein the housing is further adapted to be placed in or near a locus of potential or known activity for the invertebrate pest.
  • Embodiments of the invention also include methods for protecting a seed from an invertebrate pest comprising contacting the seed with a biologically effective amount of a compound of any of the preceding Embodiments, alone or in combination.
  • Embodiments of the invention also include methods for protecting an animal from an invertebrate parasitic pest comprising administering to the animal a parasiticidally effective amount of a compound of any of the preceding Embodiments, alone or in combination.
  • Embodiments of the invention also include methods for controlling an invertebrate pest comprising contacting the invertebrate pest or its environment with a biologically effective amount of a compound of Formula 1, an N-oxide, or a salt thereof, (e.g., as a composition described herein), provided that the methods are not methods of medical treatment of a human or animal body by therapy.
  • This invention also relates to such methods wherein the invertebrate pest or its environment is contacted with a composition comprising a biologically effective amount of a compound of Formula 1, an N-oxide, or a salt thereof, and at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents, said composition optionally further comprising a biologically effective amount of at least one additional biologically active compound or agent, provided that the methods are not methods of medical treatment of a human or animal body by therapy.
  • Embodiments of the invention also include any of the preceding embodiments (alone or in combination) wherein the invertebrate pest is an arthropod.
  • the arthropod is selected from the group consisting of insects, mites, spiders, scorpions, centipedes, millipedes, pill bugs and symphylans.
  • the arthropod is an insect.
  • Embodiments of the invention also include any of the preceding embodiments (alone or in combination) wherein the invertebrate pest is a gastropod.
  • Embodiments of the invention also include any of the preceding embodiments wherein the gastropod is selected from the group consisting of snails, slugs and other Stylommatophora.
  • One or more of the following methods and variations as described in Schemes 1-27 can be used to prepare the compounds of Formula 1.
  • a 1 , A 2 , A 3 , A 4 , L, T, R 1 , R 2 , R 3 , R4, R 5 , R 6 , R 36 , W, k, n, s and t in the compounds of Formulae 1-34 below are as defined above in the Summary of the Invention unless otherwise noted.
  • Formulae la- Id, 11a, 17a-17d, 20a, 22a, 24a, 26a-26c, 30a and 31a are various subsets of Formulae 1, 11, 17, 20, 22, 24, 26, 30 and 31, respectively. All substituents for Formulae la-Id are as defined above for Formula 1 unless otherwise noted.
  • a compound of Formula la i.e. Formula 1 wherein R 5 is H
  • a compound of Formula la is prepared by reacting an azetidine of Formula 2 with an aldehyde or ketone of Formula 3 and a suitable reducing agent, for example NaHB(OAc)3 or NaH 3 BCN, in a suitable solvent, for example tetrahydrofuran (THF) or 1,2-dichloroethane.
  • a suitable solvent for example tetrahydrofuran (THF) or 1,2-dichloroethane.
  • THF tetrahydrofuran
  • the method of Scheme 1 is illustrated by Step D of Synthesis Example 4, Step D of Synthesis Example 6, Step E of Synthesis Example 7 and Step D of Synthesis Example 8.
  • a compound of Formula 1 is prepared by reacting an azetidine of Formula 2 with an alkylating agent of Formula 4 wherein X 1 is a leaving group (i.e. nucleofuge) such as a halide (e.g., Br, I) or a sulfonate (e.g., mesylate, triflate) in the presence of an appropriate base such as triethylamine, N,N-diisopropyl- ethylamine or potassium carbonate in a suitable solvent, for example acetonitrile, N,N-dimethylformamide (DMF) or THF.
  • a suitable solvent for example acetonitrile, N,N-dimethylformamide (DMF) or THF.
  • DMF N,N-dimethylformamide
  • a compound of Formula la is prepared by reacting an azetidine of Formula 2 with an aldehyde of Formula 5 (or paraformaldehyde for R 4 being H) and a boronic acid (Formula 6, Y is OH) or derivative such as a boronate ester (e.g., Formula 6 wherein is -OCMe2CMe20-) or fluoroborate salt (Formula 7 wherein M ® is a counterion), optionally in the presence of a Lewis acid catalyst (such as BF3-OEt2 or T1F4), in a suitable solvent such as toluene, 1 ,2-dichloroethane, 1,4-dioxane or ethanol.
  • a Lewis acid catalyst such as BF3-OEt2 or T1F4
  • the reaction is typically conducted at between ambient temperature and the boiling point of the solvent, and the reaction mixture can be heated using microwave radiation. Examples of such conditions are found in numerous literature references such as Tetrahedron Lett. 2004, 3471-3474; Tetrahedron Lett. 2005, 8027-8031; and Chemtracts 2001, 14(14), 796-801 and the references cited therein.
  • the method of Scheme 3 is illustrated by Step F of Synthesis Example 1.
  • a compound of Formula 1 wherein R 2 is other than H is prepared by reacting a compound of Formula lb (i.e. Formula 1 wherein R 2 is H) with a suitable base, for example sodium hydride or lithium hexamethyldisilazide (LiHMDS), and a compound of Formula 9 wherein X 2 is a leaving group such as a halide (e.g., CI, Br) or a sulfonate (e.g., mesylate, triflate), in a suitable solvent such as THF or DMF.
  • a suitable solvent such as THF or DMF.
  • R is other than H.
  • an azetidine intermediate of Formula 2 is prepared from a suitably protected derivative of Formula 10 wherein Pg is a protecting group, for example, tert-butoxycarbonyl (BOC), benzyl, benzhydryl or, especially when T is NH, trifluoroacetyl by deprotection under conditions well known to those skilled in the art and reviewed in T. W. Greene and P. G. Wuts, Protecting Groups in Organic Synthesis, Wiley, 1991, pages 327-329 and 364-365.
  • the method of Scheme 5 wherein Pg is BOC is illustrated by Step E of Synthesis Example 1, Step D of Synthesis Example 4, Step C of Synthesis Example 5, Step C of Synthesis Example 6, Step D of Synthesis Example 7 and Step C of Synthesis Example 8.
  • a compound of Formula 10 is prepared by reacting an amino compound of Formula 11 (wherein Pg is as defined in Scheme 5) with an acid or derivative of Formula 12 (wherein, e.g., X 3 is OH or CI) under a variety of conditions known to those skilled in the art and described in numerous texts such as J. March, Advanced Organic Chemistry, Wiley, 1992, pages 417-421.
  • Exemplary conditions include treating an amino compound of Formula 11 with RiCOCl (as Formula 12) in the presence of a suitable base, such as triethylamine in a suitable solvent, for example THF or CH 2 Cl2, or by treating the amino compound of Formula 11 with a R!CC ⁇ H (as Formula 12) and an activating agent, for example (benzotriazol-l-yloxy)tris(dimethylamino)phosphonium hexafluoro- phosphate (CAS # 56602-33-6, BOP Reagent), in the presence of a suitable base, such as 4-methylmorpholine, in suitable solvent, for example DMF.
  • a suitable base such as triethylamine
  • a suitable solvent for example THF or CH 2 Cl2
  • an activating agent for example (benzotriazol-l-yloxy)tris(dimethylamino)phosphonium hexafluoro- phosphate (CAS # 56602-33-6, BOP Reagent)
  • Compounds of Formula 10 wherein Pg is an oxidative ly stable protecting group such as BOC, T is S(0)k and k is 1 or 2 can be prepared from corresponding compounds of Formula 10 wherein k is a lower integer by oxidation with a suitable oxidizing agent such as 2-chloroperbenzoic acid (MCPBA) or potassium peroxymonosulfate (OXONE®) in a suitable solvent such as dichloromethane or a water-methanol mixture, respectively.
  • MCPBA 2-chloroperbenzoic acid
  • OXONE® potassium peroxymonosulfate
  • a base such as sodium hydrogencarbonate can be included in the reaction mixture.
  • the oxidation is typically conducted at ambient temperature, although temperatures as low as -20 °C or as high as 80 °C may prove beneficial.
  • a compound of Formula 11 (wherein Pg is as defined for Scheme 5) in which R 2 is other than H is prepared by reacting a compound of Formula 11a (i.e. Formula 11 wherein R 2 is H) with a compound of Formula 13 wherein X 4 is a suitable leaving group, typically with use of a base in an appropriate solvent.
  • Typical leaving groups include halides (e.g., CI, Br, I) and sulfonates (e.g., mesylate, triflate). Iodo is particularly useful when R 2 is an alkyl group.
  • a variety of bases can be used, depending upon choice of Formula 13 and whether the base is used to deprotonate the amino group of Formula 11a or merely as a scavenger of acid byproduct from the reaction.
  • Strong bases such as sodium hydride are useful for deprotonation, while tertiary amine bases such as triethylamine are useful as acid scavengers in reactions wherein R 2 is an acyl group.
  • Useful solvents include polar aprotic solvents such as THF and DMF. Dichloromethane is particularly useful when R 2 is an acyl group and the base is a tertiary amine.
  • the reaction is typically conducted at ambient temperature, although cooling to -20 °C or heating to the lesser of 120 °C or the boiling point of the solvent may be beneficial.
  • Scheme 8 illustrates the preparation of amino compounds of Formula 11a (where Pg is as defined in Scheme 5) by reduction of the corresponding nitro compounds of Formula 14 by catalytic hydrogenation when the substituents R 7 , R 8 , R 9 and R 10 are compatible or by dissolving metal reduction.
  • a hydrogen source such as molecular hydrogen (preferably at a pressure ranging from atmospheric pressure to 350 kPa, although higher pressures can be used) or 1 ,4-cyclohexadiene or ammonium formate
  • a metal catalyst such as palladium (preferably supported on carbon or other substrate such as calcium carbonate) or platinum (optionally supported on carbon or alumina) in elemental form or in the form of its oxide.
  • the reaction is typically conducted in ethanol, methanol or ethyl acetate and at ambient temperature, although elevated temperatures up to the boiling point of the solution can be employed. Careful selection of conditions (i.e. low pressure, short reaction times) is required in the cases where Pg is benzyl or benzhydryl.
  • Examples of dissolving metal reduction include the use of finely powdered iron (for example with a particle size of 10 ⁇ ) in either acetic acid or in aqueous ethanol containing a catalyst such as ammonium chloride.
  • the reaction is conducted at elevated temperature, preferably ranging from 70 °C to the boiling point of the solvent. These conditions are preferred when other reducible functionality (e.g., alkenes, aromatic halides) is present in the compound.
  • the dissolving metal reduction method of Scheme 8 is illustrated by Step C of Synthesis Example 1 , Step B of Synthesis Example 4 and Step B of Synthesis Example 6.
  • Pg is as defined in Scheme 5, and T is other than NH) are prepared by Curtius Rearrangement of the acyl azides formed in situ by treatment of carboxylic acids of Formula 15 with, for example, diphenyl phosphoryl azide, or prepared from the acids of Formula 15 by conversion to the acid chloride (e.g., by treatment with oxalyl chloride) and then reaction with an azide source such as sodium azide in the presence of a base such as triethylamine.
  • the rearrangement is preferably conducted at an elevated temperature from 60 °C up to the boiling point of the solution, in for example toluene as solvent. Hydrolysis of the mixture then liberates the amino compound of Formula 11a.
  • the rearrangement can be conducted in an alcoholic solvent such tert-butanol as solvent, which provides the aniline in BOC-protected form.
  • the amino compound of Formula 11a is then liberated by treatment with a strong acid such as trifluoroacetic acid or hydrogen chloride in an ethereal solvent.
  • a strong acid such as trifluoroacetic acid or hydrogen chloride in an ethereal solvent.
  • Pg is generally chosen to be an acid- resistant group such as benzyl to prevent loss during the treatment with strong acid.
  • the Curtius Rearrangement is summarized in J. March, Advanced Organic Chemistry, Wiley, 1992, pages 1091-1092; see also Org. Synth., Coll. Vol. 6: 910-913.
  • a compound of Formula 14 is prepared by reacting a compound of Formula 16 wherein X 5 is a suitable leaving group such as a halide, with a protected azetidinol of Formula 17 (wherein Pg is as defined for Scheme 5) in the presence of a suitable base, for example sodium hydride, sodium hydroxide or potassium carbonate, and in a suitable solvent, for example DMF, acetonitrile, THF or toluene.
  • a suitable base for example sodium hydride, sodium hydroxide or potassium carbonate
  • a suitable solvent for example DMF, acetonitrile, THF or toluene.
  • T is S(C% and k is 1 or 2
  • Suitable oxidation conditions are the same as those already described under Scheme 6 for preparing compounds of Formula 10 wherein T is S(0 and k is 1 or 2 from corresponding compounds of Formula 10 wherein k is a lower integer.
  • an ester of Formula 19 wherein R a is lower alkyl e.g., methyl, ethyl, tert-butyl
  • R a is lower alkyl
  • X 5 is a suitable leaving group such as a halide
  • Pg is as defined for Scheme 5
  • X 5 is preferably F
  • a 1 is N
  • X 5 being CI also generally works well.
  • ester of Formula 19 is converted to the carboxylic acid of Formula 15 by saponification using aqueous base (e.g., NaOH), followed by acidification, in the case of methyl and ethyl esters or by treatment with a strong acid, for example trifluoroacetic acid or a solution of hydrogen chloride in ethanol or dioxane, in the case of tert-butyl esters.
  • aqueous base e.g., NaOH
  • a strong acid for example trifluoroacetic acid or a solution of hydrogen chloride in ethanol or dioxane, in the case of tert-butyl esters.
  • Co- solvents such as dichloromethane can be added to improve solubility.
  • Ethanol and dioxane are particularly useful as co-solvents for improving solubility of esters of Formula 19 in aqueous saponification mixtures.
  • the conversion of the ester of Formula 19 to the carboxylic acid of Formula 15 is typically conducted at ambient temperature, although cooling to -20 °C or heating to the lesser of 100 °C or the boiling point of the solvent may be beneficial. Many other conditions will also effect this transformation and a variety of carboxylic acid protecting groups besides R a being lower alkyl can be used in the method of Scheme 11.
  • Pertinent literature references can be found in T. W. Greene and P. G. Wuts, Protecting Groups in Organic Synthesis, Wiley, 1991, pages 229-263.
  • R a is lower alkyl (e.g., methyl, ethyl, feri-butyl)
  • compounds of Formula 22 are also prepared by reacting a hydroxy aromatic compound of Formula 20 with an azetidine of Formula 21 having an appropriate leaving group (X 6 ) such as mesylate or bromide in the presence of a suitable base (such as K2CO3, NaH or LiHMDS).
  • a suitable base such as K2CO3, NaH or LiHMDS.
  • R is a carboxylic acid protecting group such as lower alkyl.
  • G is a protecting group Pg as defined for Scheme 6 or CR 4 R 5 -L-R 6 .
  • Compounds of Formula 20 can be prepared by a wide variety of methods known in the art of organic chemical synthesis. Of note is preparation of compounds of Formula 20 wherein T is S from corresponding compounds of Formula 20 wherein T is O by the use of the Newman-Kwart Rearrangement (see Dirk Kusch, Specialty Chemicals Magazine 2003,
  • R is a carboxylic acid protecting group such as lower alkyl.
  • G is a protecting group Pg as defined for Scheme 6 or CR 4 R 5 -L-R 6 .
  • R B is preferably Et or z-Pr.
  • compounds of Formula 1 are alternatively prepared by acylation of anilines of Formula 24 with a suitable acid derivative of Formula 12 wherein X 3 is, e.g., OH or CI by analogy to the chemistry described above for Scheme 6.
  • X 3 is, e.g., OH or CI by analogy to the chemistry described above for Scheme 6.
  • the disclosure provided for the method of Scheme 6 extends to the method of Scheme 14.
  • the method of Scheme 14 is illustrated by Step D of Synthesis Example 2.
  • a compound of Formula 24 wherein R 2 is other than H is prepared by reacting a compound of Formula 24a (i.e. Formula 24 wherein R 2 is H) with a compound of Formula 13 wherein X 4 is a suitable leaving group, typically with use of a base in an appropriate solvent, analogous to the method described above for Scheme 7.
  • a compound of Formula 24a i.e. Formula 24 wherein R 2 is H
  • a compound of Formula 13 wherein X 4 is a suitable leaving group
  • an amino compound of Formula 24a is prepared by reduction of the corresponding nitro compound of Formula 25, analogous to the method described above in Scheme 8.
  • the disclosure provided for the method of Scheme 8 extends to the method of Scheme 16.
  • the method of Scheme 16 involving dissolving metal reduction is illustrated by Step C of Synthesis Example 2.
  • a nitro compound of Formula 25 is prepared by reaction of a compound of Formula 16 wherein X 5 is a suitable leaving group such as a halide, with an azetidinol of Formula 26 in the presence of a suitable base and solvent, analogous to the method described above for Scheme 10.
  • the disclosure provided for the method of Scheme 10 extends to the method of Scheme 17.
  • conducting the reaction at temperatures up to 120 °C or the boiling point of the solvent may be beneficial.
  • the method of Scheme 17 is illustrated by Step B of Synthesis Example 2.
  • Aromatic compounds of Formulae 16, 18 and 20 can be prepared by a wide variety of methods known in the art of organic chemical synthesis.
  • Compounds of Formula 26 can be also be prepared by a variety of methods. The following method of Scheme 18 is particularly useful for preparing compounds of Formula 26 wherein Y is O, and s and t are each 1.
  • an azetidinol of Formula 26a i.e.
  • Formula 26 wherein Y is O, and s and t are each 1) can be prepared by reacting an amine of Formula 28 with an epihalohydrin of Formula 27 wherein X 6 is CI, Br or I and most typically CI, or a derivative, optionally in the presence of additives such as triethylamine or magnesium bromide, according to published procedures (e.g., J. Het. Chem. 1971, 8, 1059-1062; J. Org. Chem. 1967, 32, 2972-2976; Tetrahedron Lett. 1997, 6059-6062).
  • the method of Scheme 18 is illustrated by Step A of Synthesis Example 2.
  • Amines of Formula 28 can be made by methods known in the art; for example, cinnamylamines can be prepared according to the general method described in J. Org. Chem. 1982, 47, 5395-5397.
  • Scheme 19 illustrates a method, analogous to the method of Scheme 18, for preparing hydroxy-substituted protected azetidines (i.e. protected azetidinols) of Formula 17a (i.e. Formula 17 wherein T is O) wherein Pg is, for example, benzhydryl or benzyl.
  • a protected azetidinol of Formula 17a is prepared by reacting a protected amine of Formula 29 with an epihalohydrin of Formula 27 using procedures analogous to those described for Scheme 18.
  • general methods well known in the art e.g., T. W. Greene and P. G.
  • the protecting group can be removed from the azetidinol of Formula 17a wherein Pg is, for example benzhydryl or benzyl, and then another protecting group can be attached to form a protected azetidinol of Formula 17a wherein Pg is, for example BOC.
  • an azetidinol of Formula 26b (i.e. Formula 26 wherein R 3 is not attached to the 3-position of the azetidine ring) wherein n' is an integer from 0 to 4 can also be prepared by reducing an azetidinone of Formula 30 with a reducing agent, such as sodium borohydride in methanol or ethanol, using procedures similar to those described in U.S. Patent 3668196.
  • a reducing agent such as sodium borohydride in methanol or ethanol
  • a protected azetidinol of Formula 17b (i.e. Formula 17 wherein T is O, and R 3 is not attached to the 3-position of the azetidine ring) wherein n' is an integer from 0 to 4, and Pg is a protecting group as defined for Scheme 5, can be prepared by reducing an azetidinone of Formula 31 with a reducing agent, analogous to the method of Scheme 20.
  • an azetidinol of Formula 26c (i.e. Formula 26 wherein an R 3 (as R 3a ) is attached to the 3-position of the azetidine ring) wherein n' is an integer from 0 to 4 and R 3a is alkyl is prepared by the addition of an organometallic reagent of Formula 32 (e.g., an organolithium or Grignard reagent) to an azetidinone of Formula 30 in an ethereal solvent, such as diethyl ether or THF, at ambient temperature, of if preferred, cooling to temperatures as low as -78 °C, using general procedures known in the art (e.g., Tetrahedron Lett. 1972, 5063-5064; U.S. Patent 3668196).
  • M 2 is, e.g., Li, MgCl, MgBr.
  • a protected azetidinol of Formula 17c (i.e. Formula 17 wherein T is O, and an R 3 (as R 3a ) is attached to the 3-position of the azetidine ring), wherein n' is an integer from 0 to 4, R 3a is alkyl and Pg is a protecting group as defined for Scheme 5, is prepared by the addition of an organometallic compound of Formula 32 to a protected azetidinone of Formula 31 in an ethereal solvent analogous to the method of Scheme 22.
  • M 2 is, e.g., Li, MgCl, MgBr.
  • Azetidinones of Formulae 30 and 31 can be prepared by general methods known in the art. For example, as shown in Scheme 24, geminally disubstituted azetidinones of Formula 30a (i.e. Formula 30 in which the 2-position of the azetidine ring is substituted with two R 3 ) can be prepared by treatment of corresponding l-bromo-2-butanones of Formula 33 with a base such as sodium hydrogencarbonate in a solvent such as DMF or aqueous methanol, using procedures similar to those described in U.S. Patent 3668196.
  • a base such as sodium hydrogencarbonate
  • a solvent such as DMF or aqueous methanol
  • R JU and R ⁇ are independently alkyl.
  • protected geminally disubstituted azetidinones of Formula 31a i.e. Formula 31 in which the 2-position of the azetidine ring is substituted with two R 3 ), wherein Pg is a suitable protecting group such as benzhydryl or benzyl, can be prepared by treatment of corresponding l-bromo-2-butanones of Formula 34, using reaction conditions similar to those described for the method of Scheme 24.
  • R 3b and R 3c are independently alkyl.
  • a thiol compound of Formula 17d (i.e. Formula 17 wherein T is S) can be prepared by treatment of a corresponding compound of Formula 21 (where X 6 is as defined in Scheme 12) with the thiol nucleophile Na 2 S.
  • a suitable thiol nucleophile in the form of PgSH (where Pg is suitable protecting group such as benzyl (Bn)) can be used in the presence of a suitable base such as NaH, followed by deprotection using, for example, sodium in liquid ammonia.
  • DMF is a particularly good solvent for this displacement reaction involving a thiol nucleophile, and mild heating (for example to 80 °C) is beneficial.
  • Compounds of Formula 21 can be prepared by a wide variety of methods known in the art of organic chemical synthesis, including preparation from corresponding compounds of Formula 17 wherein T is O.
  • Compounds of Formula 21 wherein Pg is BOC, n is 0, and X 6 is I or OMs are commercially available for each of the present values of s and t.
  • Certain other compounds of Formula 21 where Pg is another protecting group such as trifluoroacetyl, carboxybenzyl (CBz) or benzhydryl are also commercially available.
  • compounds of Formula lc can be prepared by thionation of corresponding compounds of Formula Id (i.e. Formula 1 wherein W is O).
  • Thionation involves treatment with a thionating reagent, for example phosphorus pentasulfide, or 2,4-bis(4-methoxyphenyl)-l,3,2,4-dithiadiphosphetane, 2,4-disulfide (Lawesson's Reagent), or 2,4-bis(4-phenoxyphenyl)-l,3,2,4-dithiadiphos- phetane, 2,4-disulfide (Belleau's Reagent).
  • the reaction is preferably conducted in solvents such as toluene, xylenes or dioxane and at elevated temperature from 80 °C to the boiling point of the solvent.
  • Mass spectra are reported as the molecular weight of the highest isotopic abundance positively charged parent ion (M+1) formed by addition of H + (molecular weight of 1) to the molecule or the highest isotopic abundance negatively charged ion (M-1) formed by loss of H + (molecular weight of 1), observed by mass spectrometry using electrospray ionization (ESI) where "amu” stands for atomic mass units.
  • Step B Preparation of 1 , 1 -dimethylethyl 3 - [ [3 -nitro-6-(trifluoromethyl)-2-pyridinyl] - oxy]- 1 -azetidinecarboxylate
  • Step C Preparation of 1,1-dimethylethyl 3-[[3-amino-6-(trifluoromethyl)-
  • Step D Preparation of 1,1-dimethylethyl 3-[[3-[[(2-chloro-4-pyridinyl)carbonyl]- amino]-6-(trifluoromethyl)-2-pyridinyl]oxy]-l -azetidinecarboxylate
  • Step E Preparation of N- [2-(3 -azetidinyloxy)-6-(trifluoromethyl)-3 -pyridinyl] -
  • reaction mixture was concentrated under reduced pressure, dissolved in dichloromethane, washed with 10% aqueous sodium hydrogencarbonate solution and dried (Na 2 S0 4 ). The residue after concentration was triturated with diethyl ether to give the title product as a yellow solid (275 mg).
  • Step F Preparation of 2-chloro-N-[2-[[l-[(2E)-3-(4-chlorophenyl)-2-propen-l-yl]-
  • Step A Preparation of l-[(2E)-3-(4-chlorophenyl)-2-propen-l-yl]-3-azetidinol
  • Step B Preparation of l-[(2E)-3-(4-chlorophenyl)-2-propen-l-yl]-3-(4,5-dichloro-
  • Step C Preparation of 4,5-dichloro-2-[[l-[(2E)-3-(4-chlorophenyl)-2-propen-l-yl]-
  • Step D Preparation of 2-chloro-N-[4,5-dichloro-2-[[l-[(2E)-3-(4-chlorophenyl)-
  • Example 2 the product of Example 2) (56 mg, 0.11 mmol) in dichloromethane (3 mL) with a solution of oxalic acid (4.8 mg, 53 ⁇ ) in ethanol (100 ⁇ ), followed by concentration and trituration with ethyl ether gave the title oxalate salt product, a compound of the present invention, as a light brown solid (29 mg).
  • Step A Preparation of 1,1-dimethylethyl 3-[(5-chloro-3-nitro-2-pyridinyl)oxy]-l- azetidinecarboxylate
  • Step B Preparation of 1 , 1 -dimethylethyl 3 - [(3 -amino-5 -chloro-2-pyridinyl)oxy] - 1 - azetidinecarboxylate
  • Step C Preparation of 1,1 -dimethylethyl 3-[[5-chloro-3-[[(2-chloro-4- pyridinyl)carbonyl]amino]-2-pyridinyl]oxy]- 1 -azetidinecarboxylate
  • Step D Preparation of 2-chloro-N-[5-chloro-2-[[l-[(2E)-3-(4-chlorophenyl)-
  • reaction mixture was concentrated in vacuo, treated with saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane (3 ⁇ ).
  • the combined organic phase was dried (MgSC ⁇ ) and concentrated in vacuo to give a product containing N-[2-(3-azetidinyloxy)-5-chloro-3-pyridinyl]-2-chloro-4-pyridinecarboxamide as a white solid (0.18 g, approximately 50% pure), which was used without further purification.
  • Step A Preparation of 1,1-dimethylethyl 3-[(3-amino-5,6-dichloro-2-pyridinyl)oxy]- 1-azetidinecarboxylate
  • Step B Preparation of 1,1-dimethylethyl 3-[[5,6-dichloro-3-[[(2-chloro-
  • Step D Preparation of N-[2-[[l-[2-(4-bromophenoxy)ethyl]-3-azetidinyl]oxy]-
  • the cooled solution was treated with saturated aqueous sodium bicarbonate solution (2 mL) and water (2 mL), and then diluted with dichloromethane before being filtered through a tube containing Celite® diatomaceous filter aid, eluting with dichloromethane.
  • the residue after concentration was purified by chromatography (silica gel, ethyl acetate to 5% methanol in ethyl acetate) to give the title product, a compound of the present invention, as a pale yellow oil (84 mg).
  • Step A Preparation of 1,1 -dimethylethyl 3-[(6-chloro-3-nitro-2-pyridinyl)oxy]-l- azetidinecarboxylate
  • Step B Preparation of 1 , 1 -dimethylethyl 3-[[6-chloro-3-[[(2-chloro-4-pyridinyl)- carbonyl]amino]-2-pyridinyl]oxy]- 1 -azetidinecarboxylate
  • Step C Preparation of N-[2-(3-azetidinyloxy)-6-chloro-3-pyridinyl]-2-chloro-
  • Step D Preparation of 2-chloro-N-[6-chloro-2-[[l-[(2E)-3-(4-chlorophenyl)-l- methyl-2-propen-l-yl]-3-azetidinyl]oxy]-3-pyridinyl]-4-pyridinecarboxamide
  • N-[2-(3-azetidinyloxy)-6-chloro-3-pyridinyl]-2-chloro-4-pyridine- carboxamide i.e.
  • Step C) the product of Step C) (79 mg, 0.23 mmol) was added (3E)-4-(4-chloro- phenyl)-3-buten-2-one (48 mg, 0.28 mmol), sodium triacetoxyborohydride (59 mg, 0.28 mmol), THF (3 mL) and acetic acid (16 ⁇ ), and the mixture was stirred at ambient temperature overnight. The mixture was treated with saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane (2x).
  • Step B Preparation of 1 , 1 -dimethylethyl 3 - [(5 -chloro-6-fluoro-3 -nitro-2- pyridinyl)oxy]- 1 -azetidienecarboxylate
  • 3-hydroxyazetidine (3.29 g, 1 equiv) and sodium carbonate (3.02 g, 1.5 equiv) were combined in toluene (50 mL), and the resultant mixture was stirred at ambient temperature overnight. The mixture was then diluted with ethyl ether, washed with water (3 X ) and dried (MgSOzj). The residue after concentration was purified by chromatography (silica gel, 5% to 15% ethyl acetate in hexanes) to give the title product (0.68 g, 80%> pure) which was used in the next step without further purification.
  • Step D Preparation of N- [6-amino-2-( 1 -azetidinyloxy)-5 -chloro-3 -pyridinyl] -
  • Step E Preparation of N-[6-amino-5-chloro-2-[[l-[(2E)-3-(4-chlorophenyl)-2-propen-
  • Step A Preparation of 1 , 1 -dimethylethyl 3-[(4-amino-6-chloro-3-pyridazinyl)oxy]-
  • Step B Preparation of 1 , 1 -dimethylethyl 3-[[6-chloro-4-[[(2-chloro-4-pyridinyl)- carbonyl]amino]-3-pyridazinyl]oxy]-l -azetidinecarboxylate
  • Step D Preparation of of 2-chloro-N-[6-chloro-3-[[l-[(2E)-3-(4-chlorophenyl)-
  • the present disclosure also includes Tables 2 through 30, each of which is constructed the same as Table 1 above, except that the row heading in Table 1 (i.e. "A 1 is CH; R 2 is H; R 10 is H; (R 1 ) a is 2-Cl; s is 1 ; and t is 1”) is replaced with the respective row heading shown below.
  • Table 2 the row heading is "A 1 is CH; R 2 is H; R 10 is H; (R 14 ) a is 2,5-di-Cl; s is 1 and t is 1", and R 8 , R 9 and R 22 are as defined in Table 1 above.
  • Table 2 specifically discloses 2,5-dichloro-N-[2-[[l-[(2E)- 3 -(4-chlorophenyl)-2-propen- 1 -yl] -3 -azetidinyljoxy] -4,5 -difluorophenyl]-4-pyridine- carboxamide.
  • Tables 3 through 30 are constructed similarly.
  • R 2 is CH
  • R 2 is H
  • R 10 is H
  • (R 14 ) a is 2,5-di-Cl
  • s is 1
  • t is 1.
  • R 3 is CH; R 2 is H; R 10 is H; (R 14 ) a is 2,6-di-Cl; s is 1; and t is 1.
  • R 12 is CH; R 2 is MeOC(O)-; R 10 is H; (R 14 ) a is 2-Cl; s is 1 ; and t is 1.
  • R 13 is CH; R 2 is EtOCH 2 -; R 10 is H; (R 14 ) a is 2-Cl; s is 1 ; and t is 1.
  • R 14 is CF; R 2 is H; R 10 is H; (R 14 ) a is 2-Cl; s is 1 ; and t is 1.
  • IS H R 10 is H; (R 14 ) a is 2-Cl, 5-F; s is 1; and t is 1.
  • A is N; R 2 is H; R 10 is CI; (R 14 ) a is 2-Cl; s is 1; and t is 1.
  • A is : R 2 is MeOC(O)-; R 10 is H; (R 14 ) a is 2-Cl; s is 1 ; and t is 1.
  • R 2 is EtOCH 2 -; R 10 is H; (R 14 ) a is 2-Cl; s is 1; and t is 1.
  • A is CH R 2 is H R 10 is H; (R 14 ) a is 2-Cl; s is 2; and t is 2.
  • A is CH R 2 is H R 10 is H; (R 14 ) a is 2-F; s is 2; and t is 2.
  • A is CH R 2 is H R 10 is H; (R 14 ) a is 2-CF 3 ; s is 2; and t is 2.
  • R 2 is H
  • R 10 is H
  • (R 14 ) a is 2-Cl
  • s is 2
  • t is 2.
  • R 2 is H
  • R 10 is H
  • (R 14 ) a is 2-F
  • s is 2
  • t is 2.
  • A is N: R 2 is H .
  • R 10 is H; (R 14 ) a is 2-CF 3 ; s is 2; and t is 2.
  • A is CH; R 2 is H; R 10 is H; (R 14 ) a is 2-Cl; s is 2; and t is 1.
  • a 1 is CH; R 2 is H; R 10 is H; (R 14 ) a is 2-Cl; s is 3; and t is 1.
  • a 1 is CH; R 2 is H; R 10 is H; and (R 14 ) a is 2-Cl.
  • the present disclosure also includes Tables 42 through 70, each of which is constructed the same as Table 41 above, except that the row heading in Table 41 (i.e. "A 1 is CH; R 2 is H; R 10 is H; and (R 1 ) a is 2-CL”) is replaced with the respective row heading shown below.
  • Table 40 the row heading is "A 1 is CH; R 2 is H; R 10 is H; and (R 14 ) a is 2,5-di-CL", and R 8 , R 9 and R 22 are as defined in Table 41 above.
  • Table 40 specifically discloses 2,5-dichloro-N-[2-[[l-[(4'-chloro[l,l'-biphenyl]- 4-yl)methyl]-3-azetidinyl]oxy]-4,5-difluorophenyl]-4-pyridinecarboxamide.
  • Tables 43 through 70 are constructed similarly.
  • Al is CH; (R 3 ) N is 2-Me; and R 4 , R11 and R!2 are H.
  • Tables 73 through 85 each of which is constructed the same as Table 72 above, except that the row heading in Table 72 (i.e. "Al is CH; (R ) n is 2-Me; and R 11 and R 12 are H.") is replaced with the respective row heading shown below.
  • Table 73 the row heading is "A 1 is CH; (R ) n is 3-Me; and R 1 1 and R 12 are H.”, and R 8 and R 9 are as defined in Table 72 above.
  • Table 73 specifically discloses 2-chloro-N-[2-[[l-[(2E)-3-(4-chlorophenyl)-2-propen-l-yl]- 3-methyl-3-azetidinyl]oxy]-4,5-difluorophenyl]-4-pyridinecarboxamide.
  • Tables 74 through 85 are constructed similarly.
  • a 1 is CH; (R 3 ) n is 2-Me; and R 4 is H.
  • Tables 87 through 91 each of which is constructed the same as Table 86 above, except that the row heading in Table 86 (i.e. "A 1 is CH; (R ) n is 2-Me; and R 4 is H.") is replaced with the respective row heading shown below.
  • Table 87 the row heading is "A 1 is CH; (R ) n is 3-Me; and R 4 is H.”
  • R 8 and R 9 are as defined in Table 86 above.
  • Table 87 specifically discloses 2-chloro-N-[4,5-difluoro-2-[[l-[(4'-fluoro[l, -biphenyl]-4-yl)methyl]-3-methyl-3- azetidinyl]oxy]phenyl]-4-pyridinecarboxamide.
  • Tables 88 through 91 are constructed similarly.
  • the present disclosure also includes Tables 93 through 110, each of which is constructed the same as Table 92 above, except that the row heading in Table 92 (i.e. "A 1 is CH; R 34 is H; Z is CH; s is 1; and t is 1.”) is replaced with the respective row heading shown below.
  • Table 93 the row heading is "A 1 is N; R 34 is H; Z is CH; s is 1; and t is 1."
  • R 8 , R 9 and R 22 are as defined in Table 92 above.
  • Table 93 specifically discloses 2-chloro-N-[2-[[l-[2-(4-chlorophenoxy)ethyl]-3-azetidinyl]oxy]- 5,6-difluoro-3-pyridinyl]-4-pyridinecarboxamide.
  • Tables 94 through 110 are constructed similarly.
  • a 1 is N; R 34 is H; Z is CH; s is 1; and t is 1.
  • a 1 is N; R 34 is Me; Z is CH; s is 1; and t is 1.
  • a 1 is CH; R 34 is H; Z is CH; s is 2; and t is 2.
  • 101 A 1 is N; R 34 is H; Z is CH; s is 2; and t is 2.
  • 102 A 1 is CH; R 34 is Me; Z is CH; s is 2; and t is 2.
  • a 1 is N; R 34 is Me; Z is CH; s is 2; and t is 2.
  • 104 A 1 is CH; R 34 is H; Z is CH; s is 2; and t is 1.
  • 105 A 1 is N; R 34 is H; Z is CH; s is 2; and t is 1.
  • a 1 is CH; R 34 is Me; Z is CH; s is 2; and t is 1.
  • 109 A 1 is CH; R 34 is H; Z is CH; s is 3; and t is 1.
  • the present disclosure also includes Tables 112 through 114, each of which is constructed the same as Table 111 above, except that the row heading in Table 111 (i.e. "R22b i s 2-F; and R 34 is H.") is replaced with the respective row heading shown below.
  • Table 112 the row heading is "R 22b is 3-F; and R 34 is H.” and R 8 , R 9 and R 22a are as defined in Table 111 above.
  • the first entry in Table 112 specifically discloses
  • Tables 113 through 114 are constructed similarly.
  • R 22b is 3_ F . and R 34 is H Table Row Heading
  • R 22b is 3_ F . and R 34 is Me _
  • the present disclosure also includes Tables 116 through 118, each of which is constructed the same as Table 115 above, except that the row heading in Table 115 (i.e. "s is 1; and t is 1.") is replaced with the respective row heading shown below.
  • Table 116 the row heading is "s is 2; and t is 2.”
  • R 9 , R 14 and R 22 are as defined in Table 115 above.
  • Table 116 specifically discloses 2-chloro-N-[6-chloro- 3-[[ 1 -[(2E)-3-(4-f uorophenyl)-2-propen- 1 -yl]-4-piperidinyl]oxy]-4-pyridazinyl]-4-pyridine- carboxamide.
  • Tables 117 through 118 are constructed similarly.
  • a compound of this invention will generally be used as an invertebrate pest control active ingredient in a composition, i.e. formulation, with at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents, which serves as a carrier.
  • a composition i.e. formulation
  • additional component selected from the group consisting of surfactants, solid diluents and liquid diluents, which serves as a carrier.
  • 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.
  • Liquid compositions include solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions and/or suspoemulsions) and the like, which optionally can be thickened into gels.
  • aqueous liquid compositions are soluble concentrate, suspension concentrate, capsule suspension, concentrated emulsion, microemulsion and suspo-emulsion.
  • nonaqueous liquid compositions are emulsifiable concentrate, microemulsifiable concentrate, dispersible concentrate and oil dispersion.
  • compositions are dusts, powders, granules, pellets, prills, pastilles, tablets, filled films (including seed coatings) and the like, which can be water-dispersible ("wettable") or water-soluble. Films and coatings formed from film- forming solutions or flowable suspensions are particularly useful for seed treatment.
  • 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.
  • An emulsifiable granule combines the advantages of both an emulsifiable concentrate formulation and a dry granular formulation. High-strength compositions are primarily used as intermediates for further formulation.
  • Sprayable formulations are typically extended in a suitable medium before spraying.
  • Such liquid and solid formulations are formulated to be readily diluted in the spray medium, usually water.
  • Spray volumes can range from about one to several thousand liters per hectare, but more typically are in the range from about ten to several hundred liters per hectare.
  • Sprayable formulations can be tank mixed with water or another suitable medium for foliar treatment by aerial or ground application, or for application to the growing medium of the plant.
  • Liquid and dry formulations can be metered directly into drip irrigation systems or metered into the furrow during planting.
  • Liquid and solid formulations can be applied onto seeds of crops and other desirable vegetation as seed treatments before planting to protect developing roots and other subterranean plant parts and/or foliage through systemic uptake.
  • 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.
  • Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, gypsum, cellulose, titanium dioxide, zinc oxide, starch, dextrin, sugars (e.g., lactose, sucrose), silica, talc, mica, diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate, and sodium sulfate.
  • Typical solid diluents are described in Watkins et al., Handbook of Insecticide Dust Diluents and Carriers, 2nd Ed., Dorland Books, Caldwell, New Jersey.
  • Liquid diluents include, for example, water, N,N-dimethylalkanamides (e.g., N,N-dimethylformamide), limonene, dimethyl sulfoxide, N-alkylpyrrolidones (e.g., N-methylpyrrolidinone), ethylene glycol, triethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, propylene carbonate, butylene carbonate, paraffins (e.g., white mineral oils, normal paraffins, isoparaffins), alkylbenzenes, alkylnaphthalenes, glycerine, glycerol triacetate, sorbitol, aromatic hydrocarbons, dearomatized aliphatics, alkylbenzenes, alkylnaphthalenes, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy- 4-methyl-2-pentan
  • Liquid diluents also include glycerol esters of saturated and unsaturated fatty acids (typically C 6 -C 2 2), such as plant seed and fruit oils (e.g., oils of olive, castor, linseed, sesame, corn (maize), peanut, sunflower, grapeseed, safflower, cottonseed, soybean, rapeseed, coconut and palm kernel), animal-sourced fats (e.g., beef tallow, pork tallow, lard, cod liver oil, fish oil), and mixtures thereof.
  • plant seed and fruit oils e.g., oils of olive, castor, linseed, sesame, corn (maize), peanut, sunflower, grapeseed, safflower, cottonseed, soybean, rapeseed, coconut and palm kernel
  • animal-sourced fats e.g., beef tallow, pork tallow, lard, cod liver oil, fish oil
  • Liquid diluents also include alkylated fatty acids (e.g., methylated, ethylated, butylated) wherein the fatty acids may be obtained by hydrolysis of glycerol esters from plant and animal sources, and can be purified by distillation.
  • alkylated fatty acids e.g., methylated, ethylated, butylated
  • Typical liquid diluents are described in Marsden, Solvents Guide, 2nd Ed., Interscience, New York, 1950.
  • the solid and liquid compositions of the present invention often include one or more surfactants.
  • surfactants also known as “surface-active agents”
  • surface-active agents generally modify, most often reduce, the surface tension of the liquid.
  • surfactants can be useful as wetting agents, dispersants, emulsifiers or defoaming agents.
  • Nonionic surfactants useful for the present compositions include, but are not limited to: alcohol alkoxylates such as alcohol alkoxylates based on natural and synthetic alcohols (which may be branched or linear) and prepared from the alcohols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof; amine ethoxylates, alkanolamides and ethoxylated alkanolamides; alkoxylated triglycerides such as ethoxylated soybean, castor and rapeseed oils; alkylphenol alkoxylates such as octylphenol ethoxylates, nonylphenol ethoxylates, dinonyl phenol ethoxylates and dodecyl phenol ethoxylates (prepared from the phenols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); block polymers prepared from ethylene oxide or propylene
  • Useful anionic surfactants include, but are not limited to: alkylaryl sulfonic acids and their salts; carboxylated alcohol or alkylphenol ethoxylates; diphenyl sulfonate derivatives; lignin and lignin derivatives such as lignosulfonates; maleic or succinic acids or their anhydrides; olefin sulfonates; phosphate esters such as phosphate esters of alcohol alkoxylates, phosphate esters of alkylphenol alkoxylates and phosphate esters of styryl phenol ethoxylates; protein-based surfactants; sarcosine derivatives; styryl phenol ether sulfate; sulfates and sulfonates of oils and fatty acids; sulfates and sulfonates of ethoxylated alkylphenols; sulfates of alcohols; sulfates of e
  • Useful cationic surfactants include, but are not limited to: amides and ethoxylated amides; amines such as N-alkyl propanediamines, tripropylenetriamines and dipropylenetetramines, and ethoxylated amines, ethoxylated diamines and propoxylated amines (prepared from the amines and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); amine salts such as amine acetates and diamine salts; quaternary ammonium salts such as quaternary salts, ethoxylated quaternary salts and diquaternary salts; and amine oxides such as alkyldimethylamine oxides and bis-(2-hydroxyethyl)-alkylamine oxides.
  • amines such as N-alkyl propanediamines, tripropylenetriamines and dipropylenetetramines, and ethoxylated amine
  • Nonionic, anionic and cationic surfactants and their recommended uses are disclosed in a variety of published references including McCutcheon 's Emulsifiers and Detergents, annual American and International Editions published by McCutcheon's Division, The Manufacturing Confectioner Publishing Co.; Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964; and A. S. Davidson and B. Milwidsky, Synthetic Detergents, Seventh Edition, John Wiley and Sons, New York, 1987.
  • compositions of this invention may also contain formulation auxiliaries and additives, known to those skilled in the art as formulation aids (some of which may be considered to also function as solid diluents, liquid diluents or surfactants).
  • formulation auxiliaries and additives may control: pH (buffers), foaming during processing (antifoams such polyorganosiloxanes), sedimentation of active ingredients (suspending agents), viscosity (thixotropic thickeners), in-container microbial growth (antimicrobials), product freezing (antifreezes), color (dyes/pigment dispersions), wash-off (film formers or stickers), evaporation (evaporation retardants), and other formulation attributes.
  • Film formers include, for example, polyvinyl acetates, polyvinyl acetate copolymers, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohols, polyvinyl alcohol copolymers and waxes.
  • formulation auxiliaries and additives include those listed in McCutcheon 's Volume 2: Functional Materials, annual International and North American editions published by McCutcheon's Division, The Manufacturing Confectioner Publishing Co.; and PCT Publication WO 03/024222.
  • the compound of Formula 1 and any other active ingredients are typically incorporated into the present compositions by dissolving the active ingredient in a solvent or by grinding in a liquid or dry diluent.
  • Solutions, including emulsifiable concentrates can be prepared by simply mixing the ingredients. If the solvent of a liquid composition intended for use as an emulsifiable concentrate is water-immiscible, an emulsifier is typically added to emulsify the active-containing solvent upon dilution with water.
  • Active ingredient slurries, with particle diameters of up to 2,000 ⁇ can be wet milled using media mills to obtain particles with average diameters below 3 ⁇ .
  • Aqueous slurries can be made into finished suspension concentrates (see, for example, U.S. 3,060,084) or further processed by spray drying to form water-dispersible granules. Dry formulations usually require dry milling processes, which produce average particle diameters in the 2 to 10 um range. Dusts and powders can be prepared by blending and usually grinding (such as with a hammer mill or fluid-energy mill). Granules and pellets can be prepared by spraying the active material upon preformed granular carriers or by agglomeration techniques.
  • 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.
  • Compound 2 65.0% dodecylphenol polyethylene glycol ether 2.0%> sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0% montmorillonite (calcined) 23.0%
  • Compound 1 10.0% attapulgite granules (low volatile matter, 0.71/0.30 mm; 90.0% U.S.S. No. 25-50 sieves)
  • Compound 2 25.0% anhydrous sodium sulfate 10.0% crude calcium ligninsulfonate 5.0%> sodium alkylnaphthalenesulfonate 1.0% calcium/magnesium bentonite 59.0%
  • Compound 1 20.00% polyvinylpyrrolidone -vinyl acetate copolymer 5.00% montan acid wax 5.00% calcium ligninsulfonate 1.00% polyoxyethylene/polyoxypropylene block copolymers 1.00% stearyl alcohol (POE 20) 2.00% polyorganosilane 0.20%> colorant red dye 0.05%> water 65.75%
  • Compound 31 65.0% dodecylphenol polyethylene glycol ether 2.0%> sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0%> montmorillonite (calcined) 23.0%
  • insects include, for example, invertebrates feeding on foliage (including leaves, stems, flowers and fruits), seeds, wood, textile fibers or animal blood or tissues, and thereby causing injury or damage to, for example, growing or stored agronomic crops, forests, greenhouse crops, ornamentals, nursery crops, stored foodstuffs or fiber products, or houses or other structures or their contents, or being harmful to animal health or public health.
  • foliage including leaves, stems, flowers and fruits
  • seeds wood, textile fibers or animal blood or tissues
  • the present compounds and compositions are thus useful agronomically for protecting field crops from phytophagous invertebrate pests, and also nonagronomically for protecting other horticultural crops and plants from phytophagous invertebrate pests.
  • This utility includes protecting crops and other plants (i.e. both agronomic and nonagronomic) that contain genetic material introduced by genetic engineering (i.e. transgenic) or modified by mutagenesis to provide advantageous traits.
  • traits include tolerance to herbicides, resistance to phytophagous pests (e.g., insects, mites, aphids, spiders, nematodes, snails, plant-pathogenic fungi, bacteria and viruses), improved plant growth, increased tolerance of adverse growing conditions such as high or low temperatures, low or high soil moisture, and high salinity, increased flowering or fruiting, greater harvest yields, more rapid maturation, higher quality and/or nutritional value of the harvested product, or improved storage or process properties of the harvested products.
  • Transgenic plants can be modified to express multiple traits.
  • plants containing traits provided by genetic engineering or mutagenesis include varieties of corn, cotton, soybean and potato expressing an insecticidal Bacillus thuringiensis toxin such as YIELD GARD ® , KNOCKOUT ® , STARLINK ® , BOLLGARD ® , NuCOTN ® and NEWLEAF ® , and herbicide-tolerant varieties of corn, cotton, soybean and rapeseed such as ROUNDUP READY ® , LIBERTY LINK ® ,
  • the present compounds and compositions may interact synergistically with traits introduced by genetic engineering or modified by mutagenesis, thus enhancing phenotypic expression or effectiveness of the traits or increasing the invertebrate pest control effectiveness of the present compounds and compositions.
  • the present compounds and compositions may interact synergistically with the phenotypic expression of proteins or other natural products toxic to invertebrate pests to provide greater-than-additive control of these pests.
  • compositions of this invention can also optionally comprise plant nutrients, e.g., a fertilizer composition comprising at least one plant nutrient selected from nitrogen, phosphorus, potassium, sulfur, calcium, magnesium, iron, copper, boron, manganese, zinc, and molybdenum.
  • a fertilizer composition comprising at least one plant nutrient selected from nitrogen, phosphorus, potassium, sulfur, calcium, magnesium, iron, copper, boron, manganese, zinc, and molybdenum.
  • compositions comprising at least one fertilizer composition comprising at least one plant nutrient selected from nitrogen, phosphorus, potassium, sulfur, calcium and magnesium.
  • Compositions of the present invention which further comprise at least one plant nutrient can be in the form of liquids or solids.
  • Solid formulations comprising a fertilizer composition can be prepared by mixing the compound or composition of the present invention with the fertilizer composition together with formulating ingredients and then preparing the formulation by methods such as granulation or extrusion.
  • solid formulations can be prepared by spraying a solution or suspension of a compound or composition of the present invention in a volatile solvent onto a previous prepared fertilizer composition in the form of dimensionally stable mixtures, e.g., granules, small sticks or tablets, and then evaporating the solvent.
  • Nonagronomic uses refer to invertebrate pest control in the areas other than fields of crop plants.
  • Nonagronomic uses of the present compounds and compositions include control of invertebrate pests in stored grains, beans and other foodstuffs, and in textiles such as clothing and carpets.
  • Nonagronomic uses of the present compounds and compositions also include invertebrate pest control in ornamental plants, forests, in yards, along roadsides and railroad rights of way, and on turf such as lawns, golf courses and pastures.
  • Nonagronomic uses of the present compounds and compositions also include invertebrate pest control in houses and other buildings which may be occupied by humans and/or companion, farm, ranch, zoo or other animals.
  • Nonagronomic uses of the present compounds and compositions also include the control of pests such as termites that can damage wood or other structural materials used in buildings.
  • Nonagronomic uses of the present compounds and compositions also include protecting human and animal health by controlling invertebrate pests that are parasitic or transmit infectious diseases.
  • the controlling of animal parasites particularly includes controlling external parasites that are parasitic to the surface of the body of the host animal (e.g., shoulders, armpits, abdomen, inner part of the thighs).
  • External parasitic or disease transmitting pests include, for example, chiggers, ticks, lice, mosquitoes, flies, mites and fleas.
  • Compounds and compositions of the present invention are suitable for systemic and/or non-systemic control of infestation or infection by parasites on animals.
  • Compounds and compositions of the present invention are suitable for combating external parasitic or disease-transmitting pests.
  • Compounds and compositions of the present invention are suitable for combating parasites that infest agricultural working animals, such as cattle, sheep, goats, horses, pigs, donkeys, camels, buffalos, rabbits, hens, turkeys, ducks, geese and bees; pet animals and domestic animals such as dogs, cats, pet birds and aquarium fish; as well as so-called experimental animals, such as hamsters, guinea pigs, rats and mice.
  • fatalities and performance reduction in terms of meat, milk, wool, skins, eggs, honey, etc.
  • agronomic or nonagronomic invertebrate pests include eggs, larvae and adults of the order Lepidoptera, such as armyworms, cutworms, loopers, and heliothines in the family Noctuidae (e.g., pink stem borer (Sesamia inferens Walker), corn stalk borer (Sesamia nonagrioides Lefebvre), southern armyworm (Spodoptera eridania Cramer), fall armyworm (Spodoptera fugiperda J. E.
  • Noctuidae e.g., pink stem borer (Sesamia inferens Walker), corn stalk borer (Sesamia nonagrioides Lefebvre), southern armyworm (Spodoptera eridania Cramer), fall armyworm (Spodoptera fugiperda J. E.
  • agronomic and nonagronomic pests include: eggs, adults and larvae of the order Dermaptera including earwigs from the family Forficulidae (e.g., European earwig (Forficula auricularia Linnaeus), black earwig (Chelisoches morio Fabricius)); eggs, immatures, adults and nymphs of the orders Hemiptera and Homoptera such as, plant bugs from the family Miridae, cicadas from the family Cicadidae, leafhoppers (e.g.
  • eggs, larvae, nymphs and adults of the order Acari such as spider mites and red mites in the family Tetranychidae (e.g., European red mite ⁇ Panonychus ulmi Koch), two spotted spider mite (Tetranychus urticae Koch), McDaniel mite (Tetranychus mcdanieli McGregor)); flat mites in the family Tenuipalpidae (e.g., citrus flat mite ⁇ Brevipalpus lewisi McGregor)); rust and bud mites in the family Eriophyidae and other foliar feeding mites and mites important in human and animal health, i.e.
  • Tetranychidae e.g., European red mite ⁇ Panonychus ulmi Koch
  • two spotted spider mite Tetranychus urticae Koch
  • McDaniel mite Tetranychus mcdanie
  • serpentine vegetable leafminer ⁇ Liriomyza sativae Blanchard
  • midges fruit flies
  • frit flies e.g., Oscinella frit Linnaeus
  • soil maggots e.g., house flies (e.g., Musca domestica Linnaeus), lesser house flies (e.g., Fannia canicularis Linnaeus, F.
  • femoralis Stein stable flies (e.g., Stomoxys calcitrans Linnaeus), face flies, horn flies, blow flies (e.g., Chrysomya spp., Phormia spp.), and other muscoid fly pests, horse flies (e.g., Tabanus spp.), bot flies (e.g., Gastrophilus spp., Oestrus spp.), cattle grubs (e.g., Hypoderma spp.), deer flies (e.g., Chrysops spp.), keds (e.g., Melophagus ovinus Linnaeus) and other Brachycera, mosquitoes (e.g., Aedes spp., Anopheles spp., Culex spp.), black flies (e.g., Prosimulium spp., Simulium s
  • Hymenoptera including bees (including carpenter bees), hornets, yellow jackets, wasps, and sawflies (Neodiprion spp.; Cephus spp.); insect pests of the order Isoptera including termites in the Termitidae (e.g., Macrotermes spp., Odontotermes obesus Rambur), Kalotermitidae (e.g., Cryptotermes spp.), and Rhinotermitidae (e.g., Reticulitermes spp., Coptotermes spp., Heterotermes tenuis Hagen) families, the eastern subterranean termite (Reticulitermes flavipes Kollar), western subterranean termite (Reticulitermes hesperus Banks), Formosan subterranean termite (Coptotermes formosanus Shiraki), West Indian drywood termite (Incisitermes immigrans
  • insect pests of the order Thysanura such as silverfish (Lepisma saccharina Linnaeus) and firebrat (Thermobia domestica Packard); insect pests of the order Mallophaga and including the head louse (Pediculus humanus capitis De Geer), body louse (Pediculus humanus Linnaeus), chicken body louse (Menacanthus stramineus Nitszch), dog biting louse (Trichodectes canis De Geer), fluff louse (Goniocotes gallinae De Geer), sheep body louse (Bovicola ovis Schrank), short-nosed cattle louse (Haematopinus eurysternus Nitzsch), long-nosed cattle louse (Linognathus vituli Linnaeus) and other sucking and chewing parasitic lice that attack man and animals; insect pests of the order Siphonoptera including the oriental rat fle
  • Additional arthropod pests covered include: spiders in the order Araneae such as the brown recluse spider (Loxosceles reclusa Gertsch & Mulaik) and the black widow spider (Latrodectus mactans Fabricius), and centipedes in the order Scutigeromorpha such as the house centipede (Scutigera coleoptrata Linnaeus).
  • spiders in the order Araneae such as the brown recluse spider (Loxosceles reclusa Gertsch & Mulaik) and the black widow spider (Latrodectus mactans Fabricius)
  • centipedes in the order Scutigeromorpha such as the house centipede (Scutigera coleoptrata Linnaeus).
  • Compounds of the invention show particularly high activity against pests in the order Lepidoptera (e.g., Alabama argillacea Hiibner (cotton leaf worm), Archips argyrospila Walker (fruit tree leaf roller), A. rosana Linnaeus (European leaf roller) and other Archips species, Chilo suppressalis Walker (rice stem borer), Cnaphalocrosis medinalis Guenee (rice leaf roller), Crambus caliginosellus Clemens (corn root webworm), Crambus teterrellus Zincken (bluegrass webworm), Cydia pomonella Linnaeus (codling moth), Earias insulana Boisduval (spiny bollworm), Earias vittella Fabricius (spotted bollworm), Helicoverpa armigera Hubner (American bollworm), Helicoverpa zea Boddie (corn earworm), Heliothis virescens Fabricius (tobacco budworm),
  • Compounds of the invention also have significant activity on members from the order Homoptera including: Acyrthosiphon pisum Harris (pea aphid), Aphis craccivora Koch (cowpea aphid), Aphis fabae Scopoli (black bean aphid), Aphis gossypii Glover (cotton aphid, melon aphid), Aphis pomi De Geer (apple aphid), Aphis spiraecola Patch (spirea aphid), Aulacorthum solani Kaltenbach (foxglove aphid), Chaetosiphon fragaefolii Cockerell (strawberry aphid), Diuraphis noxia Kurdjumov/Mordvilko (Russian wheat aphid), Dysaphis plantaginea Paaserini (rosy apple aphid), Eriosoma lanigerum Hausmann (woolly apple aphid), Hyalopter
  • Compounds of this invention also have activity on members from the order Hemiptera including: Acrosternum hilare Say (green stink bug), Anasa tristis De Geer (squash bug), Blissus leucopterus leucopterus Say (chinch bug), Cimex lectularius Linnaeus (bed bug) Corythuca gossypii Fabricius (cotton lace bug), Cyrtopeltis modesta Distant (tomato bug), Dysdercus suturellus Herrich-S chaffer (cotton stainer), Euchistus servus Say (brown stink bug), Euchistus variolarius Palisot de Beauvois (one-spotted stink bug), Graptosthetus spp.
  • Thysanoptera e.g., Frankliniella occidentalis Pergande (western flower thrips), Scirthothrips citri Moulton (citrus thrips), Sericothrips variabilis Beach (soybean thrips), and Thrips tabaci Lindeman (onion thrips); and the order Coleoptera (e.g., Leptinotarsa decemlineata Say (Colorado potato beetle), Epilachna varivestis Mulsant (Mexican bean beetle) and wireworms of the genera Agriotes, Athous or Limonius).
  • Thysanoptera e.g., Frankliniella occidentalis Pergande (western flower thrips), Scirthothrips citri Moulton (citrus thrips), Sericothrips variabilis Beach (soybean thrips), and Thrips tabaci Lindeman (onion thrips); and
  • compounds of this invention for controlling silverleaf whitefiy (Bemisia argentifolii).
  • compounds of this invention for controlling western flower thrip (Frankliniella occidentalis).
  • compounds of this invention for controlling green peach aphid (Myzus persicae).
  • compounds of this invention for controlling diamondback moth (Plutella xylostella).
  • compounds of this invention for controlling fall armyworm (Spodoptera frugiperda).
  • Compounds of this invention can also be mixed with one or more other biologically active compounds or agents including insecticides, fungicides, nematocides, bactericides, acaricides, herbicides, herbicide safeners, growth regulators such as insect molting inhibitors and rooting stimulants, chemosterilants, semiochemicals, repellents, attractants, pheromones, feeding stimulants, other biologically active compounds or entomopathogenic bacteria, virus or fungi to form a multi-component pesticide giving an even broader spectrum of agronomic and nonagronomic utility.
  • insecticides fungicides, nematocides, bactericides, acaricides, herbicides, herbicide safeners
  • growth regulators such as insect molting inhibitors and rooting stimulants, chemosterilants, semiochemicals, repellents, attractants, pheromones, feeding stimulants, other biologically active compounds or entomopath
  • the present invention also pertains to a composition
  • a composition comprising a biologically effective amount of a compound of Formula 1, at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents, and at least one additional biologically active compound or agent.
  • the other biologically active compounds or agents can be formulated together with the present compounds, including the compounds of Formula 1, to form a premix, or the other biologically active compounds or agents can be formulated separately from the present compounds, including the compounds of Formula 1, and the two formulations combined together before application (e.g., in a spray tank) or, alternatively, applied in succession.
  • insecticides such as abamectin, acephate, acequinocyl, acetamiprid, acetoprole, acrinathrin, amidoflumet, amitraz, avermectin, azadirachtin, azinphos-methyl, bifenthrin, bifenazate, bistrifluron, borate, buprofezin, cadusafos, carbaryl, carbofuran, cartap, carzol, chlorantraniliprole, chlorfenapyr, chlorfluazuron, chlorpyrifos, chlorpyrifos-methyl, chromafenozide, clofentezin, clothianidin, cyantraniliprole (3-bromo-l- (3 -chloro-2-pyridinyl)-N- [4-cyano-2-methyl-6- [(methylamin
  • insecticides such as abamectin, acetamiprid, acrinathrin, amitraz, avermectin, azadirachtin, bifenthrin, buprofezin, cadusafos, carbaryl, cartap, chlorantraniliprole, chlorfenapyr, chlorpyrifos, clothianidin, cyantraniliprole, cyfluthrin, beta-cyfluthrin, cyhalothrin, gamma-cyhalothrin, lambda-cyhalothrin, cypermethrin, alpha-cypermethrin, zeta-cypermethrin, cyromazine, deltamethrin, dieldrin, dinotefuran, diofenolan, emamectin, endosulfan, esfenvalerate
  • One embodiment of biological agents for mixing with compounds of this invention includes entomopathogenic bacteria such as Bacillus thuringiensis, and the encapsulated delta-endotoxins of Bacillus thuringiensis (e.g., Cellcap, MPV, MPVII); entomopathogenic fungi such as green muscardine fungus; and entomopathogenic (both naturally occurring and genetically modified) viruses including baculovirus, nucleopolyhedro virus (NPV) such as Helicoverpa zea nucleopolyhedrovirus (HzNPV), Anagrapha falcifera nucleopolyhedrovirus (AfNPV); and granulosis virus (GV) such as Cydia pomonella granulosis virus (CpGV).
  • NPV nucleopolyhedro virus
  • HzNPV Helicoverpa zea nucleopolyhedrovirus
  • AfNPV Anagrapha
  • a composition of the present invention can further comprise a biologically effective amount of at least one additional invertebrate pest control active ingredient having a similar spectrum of control but belonging to a different chemical class or having a different site of action.
  • additional biologically active compounds or agents include, but are not limited to, sodium channel modulators such as bifenthrin, cypermethrin, cyhalothrin, lambda- cyhalothrin, cyfluthrin, beta-cyfluthrin, deltamethrin, dimefluthrin, esfenvalerate, fenvalerate, indoxacarb, mepyrflutrin, metofluthrin, profluthrin, pyrethrin, tetramethylfluthrin and tralomethrin; cholinesterase inhibitors such as chlorpyrifos, methomyl, oxamyl, thiodicarb and triazamate; neonicotinoids such as acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, nithiazine, thiacloprid and thiamethoxam;
  • fungicides such as acibenzolar (i.e. acibenzolar-iS*- methyl), aldimorph, ametoctradin, amisulbrom, anilazine, azaconazole, azoxystrobin, benalaxyl (including benalaxyl-M), benodanil, benomyl, benthiavalicarb, benthiavalicarb- isopropyl, bethoxazin, binapacryl, binomial, biphenyl, bitertanol, bixafen, blasticidin-S, Bordeaux mixture (tribasic copper sulfate), boscalid/nicobifen, bromuconazole, bupirimate, buthiobate, carboxin, carpropamid, captafol, captan, carbendazim, chinomethionat, chloroneb
  • acibenzolar i.e. acibenzolar-iS*-
  • phthalide picobenzamid, picoxystrobin, piperalin, polyoxin, probenazole, prochloraz, procymidone, propamocarb, propamocarb-hydrochloride, propiconazole, propineb, proquinazid, prothiocarb, prothioconazole, pyraclostrobin, pyrametostrobin, pyraoxystrobin, pyrazophos, pyribencarb, pyributicarb, pyrifenox, pyrimethanil, pyrifenox, pyriofenone, pyrrolnitrin, pyroquilon, quinconazole, quinoxyfen, quintozene, sedaxane, silthiofam, simeconazole, spiroxamine, streptomycin, sulfur, tebuconazole, tebufloquin, tecloftalam,
  • combinations of a compound of this invention with other biologically active (particularly invertebrate pest control) compounds or agents can result in a greater-than-additive (i.e. synergistic) effect. Reducing the quantity of active ingredients released in the environment while ensuring effective pest control is always desirable.
  • synergism of invertebrate pest control active ingredients occurs at application rates giving agronomically satisfactory levels of invertebrate pest control, such combinations can be advantageous for reducing crop production cost and decreasing environmental load.
  • Compounds of this invention and compositions thereof can be applied to plants genetically transformed to express proteins toxic to invertebrate pests (such as Bacillus thuringiensis delta-endotoxins). Such an application may provide a broader spectrum of plant protection and be advantageous for resistance management.
  • the effect of the exogenously applied invertebrate pest control compounds of this invention may be synergistic with the expressed toxin proteins.
  • the weight ratio of these various mixing partners (in total) to the compound of Formula 1 is typically between about 1 :3000 and about 3000: 1. Of note are weight ratios between about 1 :300 and about 300: 1 (for example ratios between about 1 :30 and about 30: 1).
  • weight ratios between about 1 :300 and about 300: 1 for example ratios between about 1 :30 and about 30: 1).
  • One skilled in the art can easily determine through simple experimentation the biologically effective amounts of active ingredients necessary for the desired spectrum of biological activity. It will be evident that including these additional components can expand the spectrum of invertebrate pests controlled beyond the spectrum controlled by the compound of Formula 1 alone.
  • Table A lists specific combinations of a compound of Formula 1 with other invertebrate pest control agents illustrative of the mixtures, compositions and methods of the present invention.
  • the first column of Table A lists the specific invertebrate pest control agents (e.g., "Abamectin" in the first line).
  • the second column of Table A lists the mode of action (if known) or chemical class of the invertebrate pest control agents.
  • the third column of Table A lists embodiment(s) of ranges of weight ratios for rates at which the invertebrate pest control agent can be applied relative to a compound of Formula 1 (e.g., "50: 1 to 1 :50" of abamectin relative to a compound of Formula 1 by weight).
  • the first line of Table A specifically discloses the combination of a compound of Formula 1 with abamectin can be applied in a weight ratio between 50: 1 to 1 :50.
  • the remaining lines of Table A are to be construed similarly.
  • Table A lists specific combinations of a compound of Formula 1 with other invertebrate pest control agents illustrative of the mixtures, compositions and methods of the present invention and includes additional embodiments of weight ratio ranges for application rates.
  • Azadirachtin ecdysone agonists 100 1 to 1 120
  • Fenoxycarb juvenile hormone mimics 500:1 to 1:100
  • Hydramethylnon mitochondrial electron transport inhibitors 150:1 to 1:250 are Hydramethylnon mitochondrial electron transport inhibitors 150:1 to 1:250
  • Methoprene juvenile hormone mimics 500:1 to 1:100
  • Pymetrozine 200 1 to 1 : 100
  • Pyriproxyfen juvenile hormone mimics 500 1 to 1 100
  • Tebufenozide ecdysone agonists 500 1 to 1 250
  • Tetramethylfluthrin sodium channel modulators 100 1 to 1 :40
  • Thiosultap-sodium 150 1 to 1 100
  • NPV e.g., Gemstar biological agents 50: 1 to 1 : 10
  • composition of the present invention comprising at least one additional biologically active compound or agent is selected from the Invertebrate Pest Control Agents listed in Table A above.
  • the weight ratios of a compound, including a compound of Formula 1, an N-oxide or a salt thereof, to the additional invertebrate pest control agent typically are between 1000:1 and 1 : 1000, with one embodiment being between 500: 1 and 1 :500, another embodiment being between 250:1 and 1 :200 and another embodiment being between 100:1 and 1 :50.
  • Tables B1-B45 are embodiments of specific compositions comprising a compound of Formula 1 (compound numbers (Cmpd. No.) refer to compounds in Index Tables A-F) and an additional invertebrate pest control agent.
  • Table Bl Listed below in Tables B1-B45 are embodiments of specific compositions comprising a compound of Formula 1 (compound numbers (Cmpd. No.) refer to compounds in Index Tables A-F) and an additional invertebrate pest control agent.
  • A-35 1 and Hydramethylnon A-71 1 and NPV e.g., Gemstar
  • Tables B2 through B45 are each constructed the same as Table B 1 above except that entries below the "Cmpd. No" column heading are replaced with the respective Cmpd. No. Column Entry shown below. Thus, for example, in Table B2 the entries below the "Cmpd. No.” column heading all recite “Compound 2", and the first line below the column headings in Table B2 specifically discloses a mixture of Compound 2 with abamectin. Tables B3 through B45 are constructed similarly.
  • Invertebrate pests are controlled in agronomic and nonagronomic applications by applying one or more compounds of this invention, typically in the form of a composition, in a biologically effective amount, to the environment of the pests, including the agronomic and/or nonagronomic locus of infestation, to the area to be protected, or directly on the pests to be controlled.
  • the present invention comprises a method for controlling an invertebrate pest in agronomic and/or nonagronomic applications, comprising contacting the invertebrate pest or its environment with a biologically effective amount of one or more of the compounds of the invention, or with a composition comprising at least one such compound or a composition comprising at least one such compound and a biologically effective amount of at least one additional biologically active compound or agent.
  • a plant in the environment of the invertebrate pest is contacted with a biologically effective amount of a compound of the invention (e.g., in the form of a composition of the invention).
  • the compound or composition is typically applied to the seed of the crop before planting, to the foliage (e.g., leaves, stems, flowers, fruits) of crop plants, or to the soil or other growth medium before or after the crop is planted.
  • foliage e.g., leaves, stems, flowers, fruits
  • a method of contact is by spraying.
  • a granular composition comprising a compound of the invention can be applied to the plant foliage or the soil.
  • Compounds of this invention can also be effectively delivered through plant uptake by contacting the plant with a composition comprising a compound of this invention applied as a soil drench of a liquid formulation, a granular formulation to the soil, a nursery box treatment or a dip of transplants.
  • a composition of the present invention in the form of a soil drench liquid formulation.
  • a method for controlling an invertebrate pest comprising contacting the invertebrate pest or its environment with a biologically effective amount of a compound of the present invention or with a composition comprising a biologically effective amount of a compound of the present invention.
  • this method wherein the environment is soil and the composition is applied to the soil as a soil drench formulation.
  • compounds of this invention are also effective by localized application to the locus of infestation.
  • Other methods of contact include application of a compound or a composition of the invention by direct and residual sprays, aerial sprays, gels, seed coatings, microencapsulations, systemic uptake, baits, ear tags, boluses, foggers, fumigants, aerosols, dusts and many others.
  • One embodiment of a method of contact is a dimensionally stable fertilizer granule, stick or tablet comprising a compound or composition of the invention.
  • the compounds of this invention can also be impregnated into materials for fabricating invertebrate control devices (e.g., insect netting). Compounds of this invention are also useful in seed treatments for protecting seeds from invertebrate pests.
  • treating a seed means contacting the seed with a biologically effective amount of a compound of this invention, which is typically formulated as a composition of the invention.
  • This seed treatment protects the seed from invertebrate soil pests and generally can also protect roots and other plant parts in contact with the soil of the seedling developing from the germinating seed.
  • the seed treatment may also provide protection of foliage by translocation of the compound of this invention or a second active ingredient within the developing plant.
  • an aspect of this invention is a method for protecting a seed, or a plant grown therefrom, from an invertebrate pest comprising contacting the seed with a biologically effective amount of a compound of Formula 1, an N-oxide, or a salt thereof (e.g., as a formulated composition).
  • Seed treatments can be applied to all types of seeds, including those from which plants genetically transformed to express specialized traits will germinate. Representative examples include those expressing proteins toxic to invertebrate pests, such as Bacillus thuringiensis toxin or those expressing herbicide resistance such as glyphosate acetyltransferase, which provides resistance to glyphosate.
  • compositions formulated for seed treatment generally comprise a film former or adhesive agent. Therefore typically a seed coating composition of the present invention comprises a biologically effective amount of a compound of Formula 1, an N-oxide, or a salt thereof, and a film former or adhesive agent. Treatment with this composition thus involves coating the seed with a compound of Formula 1, an N-oxide, or a salt thereof (i.e. in a biologically effective amount) formulated as a composition comprising a film former or adhesive agent. Seed can be coated by spraying a flowable suspension concentrate directly into a tumbling bed of seeds and then drying the seeds.
  • the treated seed typically comprises a compound of the present invention in an amount from about 0.1 g to 1 kg per 100 kg of seed (i.e. from about 0.0001 to 1% by weight of the seed before treatment) to provide a biologically effective amount.
  • a flowable suspension formulated for seed treatment typically comprises from about 0.5 to about 70% of the active ingredient, from about 0.5 to about 30% of a film-forming adhesive, from about 0.5 to about 20% of a dispersing agent, from 0 to about 5% of a thickener, from 0 to about 5% of a pigment and/or dye, from 0 to about 2% of an antifoaming agent, from 0 to about 1% of a preservative, and from 0 to about 75% of a volatile liquid diluent.
  • the compounds of this invention can be incorporated into a bait composition that is consumed by an invertebrate pest or used within a device such as a trap, bait station, and the like.
  • a bait composition can be in the form of granules which comprise (a) active ingredients, namely a biologically effective amount of a compound of Formula 1, an N-oxide, or a salt thereof; (b) one or more food materials; optionally (c) an attractant, and optionally (d) one or more humectants.
  • granules or bait compositions which comprise between about 0.001-5% active ingredients, about 40-99%) food material and/or attractant; and optionally about 0.05-10% humectants, which are effective in controlling soil invertebrate pests at very low application rates, particularly at doses of active ingredient that are lethal by ingestion rather than by direct contact.
  • Some food materials can function both as a food source and an attractant.
  • Food materials include carbohydrates, proteins and lipids. Examples of food materials are vegetable flour, sugar, starches, animal fat, vegetable oil, yeast extracts and milk solids.
  • attractants are odorants and flavorants, such as fruit or plant extracts, perfume, or other animal or plant component, pheromones or other agents known to attract a target invertebrate pest.
  • humectants i.e. moisture retaining agents, are glycols and other polyols, glycerine and sorbitol.
  • a bait composition (and a method utilizing such a bait composition) used to control at least one invertebrate pest selected from the group consisting of ants, termites and cockroaches.
  • a device for controlling an invertebrate pest can comprise the present bait composition and a housing adapted to receive the bait composition, wherein the housing has at least one opening sized to permit the invertebrate pest to pass through the opening so the invertebrate pest can gain access to the bait composition from a location outside the housing, and wherein the housing is further adapted to be placed in or near a locus of potential or known activity for the invertebrate pest.
  • the compounds of this invention can be applied without other adjuvants, but most often application will be of a formulation comprising one or more active ingredients with suitable carriers, diluents, and surfactants and possibly in combination with a food depending on the contemplated end use.
  • One method of application involves spraying a water dispersion or refined oil solution of a compound of the present invention. Combinations with spray oils, spray oil concentrations, spreader stickers, adjuvants, other solvents, and synergists such as piperonyl butoxide often enhance compound efficacy.
  • Such sprays can be applied from spray containers such as a can, a bottle or other container, either by means of a pump or by releasing it from a pressurized container, e.g., a pressurized aerosol spray can.
  • Such spray compositions can take various forms, for example, sprays, mists, foams, fumes or fog.
  • Such spray compositions thus can further comprise propellants, foaming agents, etc. as the case may be.
  • a spray composition comprising a biologically effective amount of a compound or a composition of the present invention and a carrier.
  • a spray composition comprises a biologically effective amount of a compound or a composition of the present invention and a propellant.
  • propellants include, but are not limited to, methane, ethane, propane, butane, isobutane, butene, pentane, isopentane, neopentane, pentene, hydrofluorocarbons, chlorofluorocarbons, dimethyl ether, and mixtures of the foregoing.
  • a spray composition (and a method utilizing such a spray composition dispensed from a spray container) used to control at least one invertebrate pest selected from the group consisting of mosquitoes, black flies, stable flies, deer flies, horse flies, wasps, yellow jackets, hornets, ticks, spiders, ants, gnats, and the like, including individually or in combinations.

Abstract

Disclosed are compounds of Formula 1, including all stereoisomers, N-oxides, and salts thereof, wherein A1 is N or CR7; A2 is N or CR8;A3 is N or CR9; A4 is N or CR10; provided that not more than two of A1, A2, A3 and A4 are N; T is O, S(O)k or NR36; L is -C(R11)=C(R12)-, wherein the carbon atom bonded to R11 is also bonded to CR4R5 and the carbon atom bonded to R12 is also bonded to R6; or 1,4-diphenylene optionally substituted with up to 4 substituents independently selected from R13; or C(R34)(R35)-Z-, wherein the carbon atom bonded to R34 and R35 is also bonded to CR4R5 and Z is bonded to R6; Z is O, S(O)m, NR37 or CR38R39; R1 is a phenyl or 5- or 6-membered heteroaromatic ring optionally substituted with up to 5 substituents independently selected from R14; R6 is a phenyl or 5- or 6-membered heteroaromatic ring optionally substituted with up to 5 substituents independently selected from R22; s is 1, 2 or 3; t is 1 or 2; provided that the sum of s and t is 2, 3 or 4; and R2, R3, R4, R5, R7, R8, R9, R10, R11, R12, R13, R14, R22, R34, R35, R36, R37, R38, R39, W, k, m and n are as defined in the disclosure. Also disclosed are compositions containing the compounds of Formula 1 and methods for controlling an invertebrate pest comprising contacting the invertebrate pest or its environment with a biologically effective amount of a compound or a composition of the invention.

Description

TITLE
PESTICIDAL 3-(ARYLOXY)AZACYCLOALKANES
FIELD OF THE INVENTION
This invention relates to certain 3-(aryloxy)azocycloalkanes, their N-oxides, salts and compositions suitable for agronomic and nonagronomic uses, and methods of their use for controlling invertebrate pests such as arthropods in both agronomic and nonagronomic environments.
BACKGROUND OF THE INVENTION
The control of invertebrate pests is extremely important in achieving high crop efficiency. Damage by invertebrate pests to growing and stored agronomic crops can cause significant reduction in productivity and thereby result in increased costs to the consumer. The control of invertebrate pests in forestry, greenhouse crops, ornamentals, nursery crops, stored food and fiber products, livestock, household, turf, wood products, 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 sites of action.
PCT Patent Publication WO 2005/115146 Al discloses certain insecticidal, acaricidal molluscicidal and nematicidal compounds comprising a piperazine ring directly bonded to an aromatic or heteroaromatic ring. The 3-(aryloxy)azacycloalkanes of the present invention are not disclosed in this publication.
SUMMARY OF THE INVENTION
This invention is directed to compounds of Formula 1 (including all stereoisomers), N-oxides, and salts thereof, and compositions containing them and their use for controlling invertebrate pests:
Figure imgf000002_0001
wherein
A1 is N or CR7;
A2 is N or CR8;
A3 is N or CR9;
A4 is N or CR10;
provided that not more than two of A1, A2, A3 and A4 are N;
T is O, S(0)k or NR36; L is -C(R1 1)=C(R12)-, wherein the carbon atom bonded to R1 1 is also bonded to CR R5 and the carbon atom bonded to R12 is also bonded to R6; or 1,4- diphenylene optionally substituted with up to 4 substituents independently selected from R13; or -C(R3 )(R35)-Z-, wherein the carbon atom bonded to R34 and R 5 is also bonded to CR4R5 and Z is bonded to R6;
Z is O, S(0)m, NR37 or CR 8R39;
R1 is a phenyl or 5- or 6-membered heteroaromatic ring optionally substituted with up to 5 substituents independently selected from R14;
R2 is H, hydroxy, C^-Cg alkyl, C^-Cg haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C3-C6 haloalkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl,
C5-C7 cycloalkenyl, C^Cg alkoxy, C2-C6 alkoxyalkyl, -CHO, C(W!)R15, C(0)OR16, C(0)NR17R18, S(0)pR19 or S(O)2NR 0R 1;
each R3 is independently halogen, cyano, C1-C4 alkyl or C1-C4 alkoxy;
R4 is H or C!-C4 alkyl;
RS is H or C^ alkyl;
R6 is a phenyl or 5- or 6-membered heteroaromatic ring optionally substituted with up to 5 substituents independently selected from R22;
R7, R8, R9 and R10 are independently H, halogen, cyano, nitro, OR23, NR24R25, Cr C6 alkyl, C^-Cg haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C3-C6 haloalkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl, C5-C7 cycloalkenyl, -CHO, C(W )R26, C(0)OR27, C(0)NR 8R29, S(0)qR30,
S(0)2NR28R29 or OC(0)R31; or a phenyl or 5- or 6-membered heteroaromatic ring optionally substituted with up to 5 substituents independently selected from R40; or a vicinal pair of R7 and R8, or R8 and R9, or R9 and R10, are taken together with the carbon atoms to which the pair is attached to form a fused 5- or
6-membered aromatic or nonaromatic ring containing ring members selected from carbon atoms and up to 3 heteroatoms independently selected from N, O and S;
R1 1 and R12 are independently H, halogen, C^-C2 alkyl or C^-C2 alkoxy;
each R13, R14, R22 and R40 is independently halogen, cyano, nitro, OR23, NR24R25,
Cj-Cg alkyl, C^-Cg haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C3-C6 haloalkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl, C5-C7 cycloalkenyl, -CHO, C(W )R26, C(0)OR27, C(0)NR 8R29, S(0)qR30,
S(0)2NR 8R29 or OC(0)R 1;
R15 and R16 are independently C^Cg alkyl, C^Cg haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C3-C6 haloalkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5-C7 cycloalkenyl; or phenyl optionally substituted with up to 3 substituents independently selected from halogen, cyano, nitro, OR23, NR24R25, C!-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, -C4 haloalkyl, C2-C6 alkoxyalkyl, C2-C4 haloalkenyl, -CHO, C(W2)R26, C(0)OR27, C(0)NR28R29, S(0)qR30, S(0)2NR 8R29 and OC(0)R31;
each R17 and R20 is independently H, Cj-Cg alkyl, Cj-Cg haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C3-C6 haloalkynyl, C3-C7 cycloalkyl, C4- C8 cycloalkylalkyl or C5-C7 cycloalkenyl; or phenyl optionally substituted with up to 3 substituents independently selected from halogen, cyano, nitro, OR23, NR24R25, C!-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, -Q haloalkyl, C2-C6 alkoxyalkyl, C2-C4 haloalkenyl, -CHO, C(W2)R26, C(0)OR27, C(0)NR28R29, S(0)qR30, S(0)2NR 8R29 and OC(0)R31;
each R18, R21, R24 and R29 is independently H, -Cg alkyl, C2-C6 alkenyl or C2-C6 alkynyl;
each R19, R26, R27 and R30 s independently -Cg alkyl or -Cg haloalkyl;
each R23 and R31 is independently H, C^-Cg alkyl or C^-Cg haloalkyl;
each R25, R36 and R37 is independently H, -Cg alkyl, C(0)R32 or C(0)OR33; each R28 and R32 is independently H, Cj-Cg alkyl, Cj-Cg haloalkyl, C2-C6 alkenyl,
C2-C6 haloalkenyl, C2-C6 alkynyl, C3-C6 haloalkynyl, C3-C7 cycloalkyl, C4-
Cg cycloalkylalkyl or C5-C7 cycloalkenyl;
each R33 is independently -Cg alkyl, Cj-Cg haloalkyl, C2-C6 alkenyl, C2-C6
haloalkenyl, C2-C6 alkynyl, C3-C6 haloalkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5-C7 cycloalkenyl;
R34 is H, C!-C4 alkyl, -^ haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, Ci~C4 alkoxy or cyano;
R35 is H or methyl;
R38 is H, OH, halogen,€γ-€2 alkyl or€γ-€2 alkoxy;
R39 is selected from H, cyano and C^-C2 alkyl, and when R38 is halogen, then R39 is additionally selected from halogen; or
R38 and R39 together with the carbon atom to which said R38 and R39 are attached represent a carbonyl moiety;
W is O or S;
W1 is O or S;
each W2 is independently O or S;
k is 0, 1 or 2;
m is 0, 1 or 2;
n is an integer from 0 to 5;
p is 0, 1 or 2;
each q is independently 0, 1 or 2;
s is 1, 2 or 3; and t is 1 or 2;
provided that the sum of s and t is 2, 3 or 4.
More particularly this invention relates to a compound selected from Formula 1, an N-oxide, or a salt thereof.
This invention also provides a composition comprising a compound of Formula 1, an
N-oxide, or a salt thereof (i.e. in a biologically effective amount), and at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents. In one embodiment, this invention also provides a composition for controlling an invertebrate pest comprising a compound of Formula 1, an N-oxide, or a salt thereof, and at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents, said composition optionally further comprising at least one additional biologically active compound or agent.
This invention further provides a spray composition for controlling an invertebrate pest comprising a compound of Formula 1, an N-oxide, or a salt thereof, or a composition described above, and a propellant. This invention also provides a bait composition for controlling an invertebrate pest comprising a compound of Formula 1, an N-oxide, or a salt thereof, or a composition described in the embodiments above, one or more food materials, optionally an attractant, and optionally a humectant.
This invention further provides a trap device for controlling an invertebrate pest comprising said bait composition and a housing adapted to receive said bait composition, wherein the housing has at least one opening sized to permit the invertebrate pest to pass through the opening so the invertebrate pest can gain access to said bait composition from a location outside the housing, and wherein the housing is further adapted to be placed in or near a locus of potential or known activity for the invertebrate pest.
This invention provides a method for controlling an invertebrate pest comprising contacting the invertebrate pest or its environment with a biologically effective amount of a compound of Formula 1, an N-oxide, or a salt thereof (e.g., as a composition described herein). This invention also relates to such method wherein the invertebrate pest or its environment is contacted with a composition comprising a compound of Formula 1, an N-oxide, or a salt thereof (i.e, in a biologically effective amount), and at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents, said composition optionally further comprising a biologically effective amount of at least one additional biologically active compound or agent.
This invention also provides a method for protecting a seed or a plant grown therefrom from an invertebrate pest comprising contacting the seed with a biologically effective amount of a compound of Formula 1, an N-oxide, or a salt thereof (e.g., as a composition described herein). This invention also relates to the treated seed. This invention further provides a method for protecting an animal from an invertebrate parasitic pest comprising administering to the animal a parasiticidally effective amount of a compound of Formula 1, an N-oxide, or a salt thereof (e.g., as a composition described herein). This invention also provides for the use of a compound of Formula 1, an N-oxide, or a salt thereof, (e.g., as a composition described herein) in protecting an animal from an invertebrate pest.
DETAILS OF THE INVENTION
As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," "contains", "containing," "characterized by" or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated. For example, a composition, mixture, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, method, article, or apparatus.
The transitional phrase "consisting of excludes any element, step, or ingredient not specified. If in the claim, such would close the claim to the inclusion of materials other than those recited except for impurities ordinarily associated therewith. When the phrase
"consisting of appears in a clause of the body of a claim, rather than immediately following the preamble, it limits only the element set forth in that clause; other elements are not excluded from the claim as a whole.
The transitional phrase "consisting essentially of is used to define a composition, method or apparatus that includes materials, steps, features, components, or elements, in addition to those literally disclosed, provided that these additional materials, steps, features, components, or elements do not materially affect the basic and novel characteristic(s) of the claimed invention. The term "consisting essentially of occupies a middle ground between
"comprising" and "consisting of.
Where applicants have defined an invention or a portion thereof with an open-ended term such as "comprising," it should be readily understood that (unless otherwise stated) the description should be interpreted to also describe such an invention using the terms
"consisting essentially of or "consisting of."
Further, unless expressly stated to the contrary, "or" refers to an inclusive or and not to an exclusive or. For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).
Also, the indefinite articles "a" and "an" preceding an element or component of the invention are intended to be nonrestrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore "a" or "an" should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular. As referred to in this disclosure, the term "invertebrate pest" includes arthropods, gastropods and nematodes of economic importance as pests. More particularly, "invertebrate pest" relates to arthropods and gastropods, and most particularly, "invertebrate pest" relates to arthropods. The term "arthropod" includes insects, mites, spiders, scorpions, centipedes, millipedes, pill bugs and symphylans. The term "gastropod" includes snails, slugs and other Stylommatophora. The term "nematode" includes members of the phylum Nematoda, such as phytophagous nematodes.
In the context of this disclosure "invertebrate pest control" means inhibition of invertebrate pest development (including mortality, feeding reduction, and/or mating disruption), and related expressions are defined analogously.
The term "agronomic" refers to the production of field crops such as for food and fiber and includes the growth of corn, soybeans and other legumes, rice, cereal (e.g., wheat, oats, barley, rye, rice, maize), leafy vegetables (e.g., lettuce, cabbage, and other cole crops), fruiting vegetables (e.g., tomatoes, pepper, eggplant, crucifers and cucurbits), potatoes, sweet potatoes, grapes, cotton, tree fruits (e.g., pome, stone and citrus), small fruit (berries, cherries) and other specialty crops (e.g., canola, sunflower, olives). The term "nonagronomic" refers to other than field crops, such as horticultural crops (e.g., greenhouse, nursery or ornamental plants not grown in a field), residential, agricultural, commercial and industrial structures, turf (e.g., sod farm, pasture, golf course, lawn, sports field, etc.), wood products, stored product, agro-forestry and vegetation management, public health (i.e. human) and animal health (e.g., domesticated animals such as pets, livestock and poultry, undomesticated animals such as wildlife) applications.
As used herein, the term "alkylating agent" refers to a chemical compound in which a carbon-containing radical is bound through a carbon atom to leaving group such as halide or sulfonate, which is displaceable by bonding of a nucleophile to said carbon atom. Unless otherwise indicated, the term "alkylating" does not limit the carbon-containing radical to alkyl; the carbon-containing radicals in alkylating agents include the variety of carbon-bound substituent radicals specified for R4, R5, R6 and L.
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, n-propyl, /-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, n-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers. "Alkoxyalkyl" denotes alkoxy substitution on alkyl. Examples of "alkoxyalkyl" include CH3OCH2-, CH3OCH2CH2-, CH3CH2OCH2-, CH3CH2CH2CH2OCH2- and CH3CH2OCH2CH2-.
"Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "cycloalkylalkyl" denotes cycloalkyl substitution on an alkyl moiety. Examples of "cycloalkylalkyl" include cyclopropylmethyl, cyclopentylethyl, and other cycloalkyl moieties bonded to straight-chain or branched alkyl groups. "Cycloalkenyl" includes groups such as cyclopentenyl and cyclohexenyl as well as groups with more than one double bond such as 1,3- and 1,4-cyclohexadienyl.
The term "halogen", either alone or in compound words such as "haloalkyl", or when used in descriptions such as "alkyl substituted with halogen" includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as "haloalkyl", or when used in descriptions such as "alkyl substituted with halogen" said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of "haloalkyl" or "alkyl substituted with halogen" include F3C-, C1CH2-, CF3CH2- and CF3CC12-. The terms "haloalkoxy", "haloalkylthio", "haloalkenyl", "haloalkynyl", and the like, are defined analogously to the term "haloalkyl". Examples of "haloalkoxy" include CF30-, CC13CH20-, HCF2CH2CH20- and CF3CH20-. Examples of "haloalkylthio" include CC13S-, CF3S-, CC13CH2S- and C1CH2CH2CH2S-. Examples of "haloalkynyl" include HC≡CCHC1-, CF3C≡C-, CC13C≡C- and FCH2C≡CCH2-.
"Alkylcarbonyl" denotes a straight-chain or branched alkyl moieties bonded to a C(=0) moiety. Examples of "alkylcarbonyl" include CH3C(=0)-, CH3CH2CH2C(=0)- and (CH3)2CHC(=0)-. Examples of "alkoxycarbonyl" include CH3OC(=0)-, CH3CH2OC(=0)-, CH3CH2CH2OC(=0)-, (CH3)2CHOC(=0)- and the different butoxy- or pentoxycarbonyl isomers.
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 8. For example, C2 alkoxyalkyl designates CH3OCH2-; C3 alkoxyalkyl designates, for example, CH3CH(OCH3)-, CH3OCH2CH2- or CH3CH2OCH2-; and C4 alkoxyalkyl designates the various isomers of an alkyl group substituted with an alkoxy group containing a total of four carbon atoms, examples including CH3CH2CH2OCH2- and CH3CH2OCH2CH2-.
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, e.g., (R )n, n is 1, 2, 3, 4 or 5. When a group contains a substituent which can be hydrogen, for example R2, R7, R8, R9 or R10, then when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted. When a variable group is shown to be optionally attached to a position, for example (Rv)r in U-30 of Exhibit 1 wherein r may be 0, then hydrogen may be at the position even if not recited in the variable group definition. When one or more positions on a group are said to be "not substituted" or "unsubstituted", then hydrogen atoms are attached to take up any free valency.
Unless otherwise indicated, a "ring" or "ring system" as a component of Formula 1
(e.g., substituent R1 or R6) is carbocyclic or heterocyclic. The term "ring system" denotes two or more fused rings. The term "fused ring" refers to a ring that is fused to another ring to form a fused bicyclic ring system. The terms "bicyclic ring system" and "fused bicyclic ring system" denote a ring system consisting of two fused rings, in which either ring can be saturated, partially unsaturated or fully unsaturated unless otherwise indicated. Accordingly either ring can be aromatic or nonaromatic unless otherwise indicated. The term "ring member" refers to an atom or other moiety (e.g., C(=0), C(=S), S(O) or S(0)2) forming the backbone of a ring or ring system.
The terms "carbocyclic ring", "carbocycle" or "carbocyclic ring system" denote a ring or ring system wherein the atoms forming the ring backbone are selected only from carbon. Unless otherwise indicated, a carbocyclic ring can be a saturated, partially unsaturated, or fully unsaturated ring. When a fully unsaturated carbocyclic ring satisfies Huckel's rule, then said ring is also called an "aromatic ring".
The terms "heterocyclic ring", "heterocycle" or "heterocyclic ring system" denote a ring or ring system in which at least one atom forming the ring backbone is not carbon, e.g., nitrogen, oxygen or sulfur. Typically a heterocyclic ring contains no more than 3 nitrogen atoms, no more than 2 oxygen atoms and no more than 2 sulfur atoms. Unless otherwise indicated, a heterocyclic ring can be a saturated, partially unsaturated, or fully unsaturated ring. Also unless otherwise indicated, a heterocyclic ring can be aromatic or nonaromatic. When a fully unsaturated heterocyclic ring satisfies Huckel's rule and thus is aromatic, then said ring is also called a "heteroaromatic ring" or "aromatic heterocyclic ring". Unless otherwise indicated, heterocyclic rings and ring systems can be attached through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.
"Aromatic" indicates that each of the ring atoms is essentially in the same plane and has a /^-orbital perpendicular to the ring plane, and in which (4n + 2) π electrons, where n is a positive integer, are associated with the ring to comply with Huckel's rule. The term "aromatic ring system" denotes a carbocyclic or heterocyclic ring system in which at least one ring of the ring system is aromatic.
As used herein, the following definitions shall apply unless otherwise indicated. The term "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted" or with the term "(un)substituted." Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other. When R1, R6, R7, R8, R9 or R10 is a 5- or 6-membered nitrogen-containing heteroaromatic ring, it can be attached to the remainder of Formula 1 though any available carbon or nitrogen ring atom, unless otherwise described. As noted above, R1, R6, R7, R8, R9 or R10 can be (among others) phenyl optionally substituted with one or more substituents selected from a group of substituents as defined in the Summary of Invention. An example of phenyl optionally substituted with one to five substituents is the ring illustrated as U-l in Exhibit 1, wherein Rv is R14, R22 or R40 as defined in the Summary of the Invention for R1, R6, R7, R8, R9 or R10, respectively, and r is an integer from 0 to 5.
As noted above, R1, R6, R7, R8, R9 or R10 can be (among others) 5- or 6-membered heteroaromatic ring, which is optionally substituted with substituents up to the number of available positions, and the substituents are independently selected from a group of radicals defined in the Summary of Invention (i.e. R14, R22 or R40, respectively). Examples of a 5- or 6-membered heteroaromatic ring optionally substituted with from one or more substituents include the rings U-2 through U-61 illustrated in Exhibit 1 wherein Rv is any substituent as defined in the Summary of the Invention for R1, R6, R7, R8, R9 or R10 (i.e. R14, R22 or R40, respectively) and r is an integer from 0 to 4, limited by the number of available positions on each U group. As U-29, U-30, U-36, U-37, U-38, U-39, U-40, U-41, U-42 and U-43 have only one available position, for these U groups r is limited to the integers 0 or 1, and r being 0 means that the U group is unsubstituted and a hydrogen is present at the position indicated by (Rv)r.
Exhibit 1
Figure imgf000010_0001
Figure imgf000011_0001
U-16 U-17 U-18 U-19 U-20
Figure imgf000011_0002
U-21 U-22 U-23 U-24 U-25
Figure imgf000011_0003
-26 U-27 U-28 U-29 U-30
Figure imgf000011_0004
U-36 U-37 U-38 U-39 U-40
Figure imgf000011_0005
-41 U-42 U-43 U-44 -45
Figure imgf000011_0006
U-51 U-52 U-53 U-54 U-55
Figure imgf000012_0001
U-56 U-57 U-58 U-59 U-60
Figure imgf000012_0002
U-61
Although Rv groups are shown in the structures U-l through U-61, it is noted that they do not need to be present since they are optional substituents. The nitrogen atoms that require substitution to fill their valence are substituted with H or Rv. Note that when the attachment point between (Rv)r and the U group is illustrated as floating, (Rv)r can be attached to any available carbon atom or nitrogen atom of the U group. Note that when the attachment point on the U group is illustrated as floating, the U group can be attached to the remainder of Formula 1 through any available carbon or nitrogen of the U group by replacement of a hydrogen atom. Note that some U groups can only be substituted with less than 4 Rv groups (e.g., U-2 through U-5, U-7 through U-48, and U-52 through U-61).
As noted above, a vicinal pair of R7 and R8, or R8 and R9, or R9 and R10, can be taken together with the carbon atoms to which they are attached to form a fused 5- or 6-membered aromatic or nonaromatic ring containing ring members selected from carbon atoms and up to 3 heteroatoms independently selected from N, O and S. This ring comprising R7 and R8, or R8 and R9, or R9 and R10, is fused to the 6-membered aromatic ring comprising A1, A2, A3 and A4, and thus is at least partially unsaturated, and may be fully unsaturated. Examples of vicinal pairs taken together include -CH=CH-CH=CH-, -N=CH-CH=CH-, -CH=N-CH=CH-, -CH=CH-N=CH-, -CH=CH-CH=N-, -N=N-CH=N-, -N=CH-N=N-, -S-CH=CH-, -CH=CH-S-, -0-CH=CH-, -CH=CH-0-, -0-CH=N-, -N=CH-0-, -0-N=CH-, -CH=N-0-, -S-CH=N-, -N=CH-S-, -S-N=CH-, -CH=N-S-, -(CH2)4-, -(CH2)3-, -CH=CH-CH , -CH2-CH=CH-, -OCH2CH2-, -CH2CH20- and -OCH2CH20-, wherein the left-hand connecting bond corresponds to the left member of R7 and R8, or R8 and R9, or R9 and R10, and the right-hand connecting bond corresponds to the right member of R7 and R8, or R8 and R9, or R9 and R10. Of particular note is a vicinal pair which is -CH=CH-CH=CH-.
A wide variety of synthetic methods are known in the art to enable preparation of aromatic heterocyclic rings and ring systems; for extensive reviews see the eight volume set of Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees editors-in-chief, Pergamon Press, Oxford, 1984 and the twelve volume set of Comprehensive Heterocyclic Chemistry II, A. R. Katritzky, C. W. Rees and E. F. V. Scriven editors-in-chief, Pergamon Press, Oxford, 1996.
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. The compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers or as an optically active form.
Compounds of this invention can exist as one or more conformational isomers due to restricted rotation about the amide bond in Formula 1. This invention comprises mixtures of conformational isomers. In addition, this invention includes compounds that are enriched in one conformer relative to others.
Compounds selected from Formula 1, stereoisomers, tautomers, N-oxides, and salts thereof, typically exist in more than one form, and Formula 1 thus includes all crystalline and non-crystalline forms of the compounds that Formula 1 represents. Non-crystalline forms include embodiments which are solids such as waxes and gums as well as embodiments which are liquids such as solutions and melts. Crystalline forms include embodiments which represent essentially a single crystal type and embodiments which represent a mixture of polymorphs (i.e. different crystalline types). The term "polymorph" refers to a particular crystalline form of a chemical compound that can crystallize in different crystalline forms, these forms having different arrangements and/or conformations of the molecules in the crystal lattice. Although polymorphs can have the same chemical composition, they can also differ in composition due the presence or absence of co- crystallized water or other molecules, which can be weakly or strongly bound in the lattice. Polymorphs can differ in such chemical, physical and biological properties as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspensibility, dissolution rate and biological availability. One skilled in the art will appreciate that a polymorph of a compound represented by Formula 1 can exhibit beneficial effects (e.g., suitability for preparation of useful formulations, improved biological performance) relative to another polymorph or a mixture of polymorphs of the same compound represented by Formula 1. Preparation and isolation of a particular polymorph of a compound represented by Formula 1 can be achieved by methods known to those skilled in the art including, for example, crystallization using selected solvents and temperatures.
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 3-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane. 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. V. Ley, Ed., Pergamon Press; M. Tisler and B. Stanovnik in Comprehensive Heterocyclic Chemistry, vol. 3, pp 18-20, A. J. Boulton and A. McKillop, Eds., Pergamon Press; M. R. Grimmett and B. R. T. Keene in Advances in Heterocyclic Chemistry, vol. 43, pp 149-161, A. R. Katritzky, Ed., Academic Press; M. Tisler and B. Stanovnik in Advances in Heterocyclic Chemistry, vol. 9, pp 285-291, A. R. Katritzky and A. J. Boulton, Eds., Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk in Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, A. R. Katritzky and A. J. Boulton, Eds., Academic Press. Azetidine N-oxides derived from compounds of Formula 1 appear to be most stable when R2 is other than H.
One skilled in the art recognizes that because in the environment and under physiological conditions salts of chemical compounds are in equilibrium with their corresponding nonsalt forms, salts share the biological utility of the nonsalt forms. Thus a wide variety of salts of the compounds of Formula 1 are useful for control of invertebrate pests. The salts of the compounds of Formula 1 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. When a compound of Formula 1 contains an acidic moiety such as a phenol, salts also include those formed with organic or inorganic bases such as pyridine, triethylamine or ammonia, or amides, hydrides, hydroxides or carbonates of sodium, potassium, lithium, calcium, magnesium or barium. Accordingly, the present invention comprises compounds selected from Formula 1, N-oxides, and biologically suitable salts thereof.
In the embodiments of the present invention, including those described below, reference to Formula 1 includes N-oxides and salts thereof, and reference to "a compound of Formula 1" includes the definitions of substituents specified in the Summary of the Invention unless further defined in the Embodiments.
Embodiment 1. A compound of Formula 1 wherein A1 is N.
Embodiment 2. A compound of Formula 1 wherein A1 is CR7.
Embodiment 3. A compound of Formula 1 or Embodiment 1 or 2 wherein A2 is CR8. Embodiment 4. A compound of Formula 1 or any one of Embodiments 1 through 3 wherein A3 is CR9. Embodiment 5. A compound of Formula 1 or any one of Embodiments 1 through 4 wherein A4 is CR10.
Embodiment 6. A compound of Formula 1 or any one of Embodiments 1 through 5 wherein R7, R8, R9 and R10 are independently H, halogen, cyano, nitro, OR23, NR24R25 , C !-C6 alkyl, C Y-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl,
C2-C6 alkynyl, C3-C6 haloalkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl, C5-C7 cycloalkenyl, -CHO, C(W2)R26, C(0)OR27, C(0)NR28R29, S(0)qR30, S(0)2NR28R29 or OC(0)R3 1; or a vicinal pair of R7 and R8, or R8 and R9, or R9 and R10, are taken together with the carbon atoms to which they are attached to form a fused 5- or 6-membered aromatic or nonaromatic ring containing ring members selected from carbon atoms and up to 3 heteroatoms independently selected from N, O and S.
Embodiment 7. A compound of Embodiment 6 wherein R7, R8, R9 and R10 are
independently H, halogen, y-C^ alkyl, y-C^ haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C3-C4 haloalkynyl, C3-C6 cycloalkyl, Cj-C4 alkoxy, C^-C4 haloalkoxy, C^-C4 alkylthio, C^-C4 haloalkylthio or cyano, or a vicinal pair of R7 and R8, or R8 and R9, or R9 and R10, are taken together with the carbon atoms to which they are attached to form a fused 5- or 6-membered aromatic or nonaromatic ring containing ring members selected from carbon atoms and up to 3 heteroatoms independently selected from N, O and S.
Embodiment 8. A compound of Formula 1 or any one of Embodiments 1 through 7 wherein independently when R7, R8, R9 or R10 is separate (i.e. not taken together to form a ring), then said R7, R8, R9 or R10 is independently H, halogen, Cj-C4 alkyl, Cj-C4 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C3-C4 haloalkynyl, C3-C6 cycloalkyl, Cj-C4 alkoxy, Cj-C4 haloalkoxy, Cj-C4 alkylthio, C^-C4 haloalkylthio or cyano.
Embodiment 9. A compound of Embodiment 8 wherein independently when R7, R8, R9 or R10 is separate, then said R7, R8, R9 or R10 is independently H, halogen or C}-C4 haloalkyl.
Embodiment 10. A compound of Formula 1 or any one of Embodiments 1 through 9 wherein when R7 is separate, then R7 is H or halogen.
Embodiment 1 1. A compound of Embodiment 10 wherein when R7 is separate, then R7 is H or F.
Embodiment 12. A compound of Embodiment 1 1 wherein when R7 is separate, then R7 is H.
Embodiment 13. A compound of Formula 1 or any one of Embodiments 1 through 12 wherein when R8 is separate, then R8 is H, halogen or C^-C2 haloalkyl. Embodiment 14. A compound of Embodiment 13 wherein when R8 is separate, then R8 is H, halogen or C^ fluoroalkyl (i.e. fluoromethyl, including CH2F, CHF2 and CF3).
Embodiment 15. A compound of Embodiment 14 wherein when R8 is separate, then R8 is H, halogen or CF3.
Embodiment 16. A compound of Embodiment 15 wherein when R8 is separate, then R8 is H, F, CI or CF3.
Embodiment 17. A compound of Embodiment 15 wherein when R8 is separate, then R8 is halogen or CF3.
Embodiment 18. A compound of Embodiment 17 wherein when R8 is separate, then R8 is F, CI or CF3.
Embodiment 19. A compound of Formula 1 or any one of Embodiments 1 through 18 wherein when R9 is separate, then R9 is H, halogen or C1-C2 haloalkyl.
Embodiment 20. A compound of Embodiment 19 wherein when R9 is separate, then R9 is H, halogen or C^ fluoroalkyl (i.e. fluoromethyl).
Embodiment 21. A compound of Embodiment 20 wherein when R9 is separate, then R9 is H, halogen or CF3.
Embodiment 22. A compound of Embodiment 21 wherein when R9 is separate, then R9 is H, CI or CF3.
Embodiment 23. A compound of Formula 1 or any one of Embodiments 1 through 22 wherein when R10 is separate, then R10 is H or halogen.
Embodiment 24. A compound of Embodiment 23 wherein when R10 is separate, then R10 is H or F.
Embodiment 25. A compound of Embodiment 24 wherein when R10 is separate, then R10 is H.
Embodiment 26. A compound of Formula 1 or any one of Embodiments 1 through 25 wherein when a vicinal pair of R7 and R8, or R8 and R9, or R9 and R10, are taken together with the carbon atoms to which they are attached to form a fused ring, said vicinal pair is -CH=CH-CH=CH- (i.e. the fused ring is benzo).
Embodiment 27. A compound of Formula 1 or any one of Embodiments 1 through 26 wherein one vicinal pair of R7 and R8, or R8 and R9, or R9 and R10, are taken together with the carbon atoms to which they are attached to form a fused ring as described.
Embodiment 28. A compound of Formula 1 or any one of Embodiments 1 through 27 wherein a vicinal pair of R7 and R8 are taken together with the carbon atoms to which they are attached to form a fused ring as described. Embodiment 29. A compound of Formula 1 or any one of Embodiments 1 through 27 wherein a vicinal pair of R8 and R9 are taken together with the carbon atoms to which they are attached to form a fused ring as described.
Embodiment 30. A compound of Formula 1 or any one of Embodiments 1 through 27 wherein a vicinal pair of R9 and R10 are taken together with the carbon atoms to which they are attached to form a fused ring as described.
Embodiment 31. A compound of Formula 1 or any one of Embodiments 1 through 25 wherein each of R7, R8, R9 and R10 is separate (i.e. not taken together to form a fused ring).
Embodiment 32. A compound of Formula 1 or any one of Embodiments 1 through 31 wherein L is -C(R11)=C(R12)-, wherein the carbon atom bonded to R1 1 is also bonded to CR R5 and the carbon atom bonded to R12 is also bonded to R6; or 1 ,4-diphenylene optionally substituted with up to 4 substituents independently selected from R13.
Embodiment 33. A compound of Formula 1 or any one of Embodiments 1 through 32 wherein L is -C(Rn)=C(R12)-.
Embodiment 34. A compound of Formula 1 or any one of Embodiments 1 through 33 wherein R1 1 and R12 are independently H, halogen or methyl.
Embodiment 35. A compound of Embodiment 34 wherein R1 1 and R12 are
independently H or methyl.
Embodiment 36. A compound of Embodiment 35 wherein R1 1 and R12 are H.
Embodiment 37. A compound of Formula 1 or any one of Embodiments 1 through 32 wherein L is 1 ,4-diphenylene optionally substituted with up to 4 substituents independently selected from R13.
Embodiment 38. A compound of Formula 1 or any one of Embodiments 1 through 31 wherein L is -C(R3 )(R35)-Z-, wherein the carbon atom bonded to R34 and R35 is also bonded to CR R5 and Z is bonded to R6.
Embodiment 39. A compound of Formula 1 or any one of Embodiments 1 through 31 or Embodiment 38 wherein R34 is H or C1-C4 alkyl.
Embodiment 40. A compound of Embodiment 39 wherein R34 is H or C1-C2 alkyl.
Embodiment 41. A compound of Embodiment 40 wherein R34 is H or methyl.
Embodiment 42. A compound of Embodiment 41 wherein R34 is H.
Embodiment 43. A compound of Formula 1 or any one of Embodiments 1 through 31 or 38 through 42 wherein R35 is H.
Embodiment 44. A compound of Formula 1 or any one of Embodiments 1 through 31 or 38 through 43 wherein Z is O, S, NR37 or CR38R39 (i.e. m is 0).
Embodiment 45. A compound of Embodiment 44 wherein Z is O, S or NR37.
Embodiment 46. A compound of Embodiment 45 wherein Z is O or NR37. Embodiment 47. A compound of Embodiment 46 wherein Z is O.
Embodiment 48. A compound of Formula 1 or any one of Embodiments 1 through 47 wherein R37 is H.
Embodiment 49. A compound of Formula 1 or any one of Embodiments 1 through 48 where R38 and R39 are H.
Embodiment 50. A compound of Formula 1 or any one of Embodiments 1 through 49 wherein when L comprises 1 ,4-diphenylene, then said 1 ,4-diphenylene is optionally substituted with up to 2 substituents independently selected from R13. Embodiment 51. A compound of Embodiment 50 wherein when L comprises
1 ,4-diphenylene then said 1 ,4-diphenylene is unsubstituted (except for its bonds to C(R4)(R5) and R6).
Embodiment 52. A compound of Formula 1 or any one of Embodiments 1 through 51 wherein each R13 is independently halogen or C1-C4 alkyl.
Embodiment 53. A compound of Embodiment 52 wherein each R13 is independently halogen or methyl.
Embodiment 54. A compound of Formula 1 or any one of Embodiments 1 through 53 wherein R1 is a phenyl or 5- or 6-membered heteroaromatic ring optionally substituted with up to 4 substituents independently selected from R14.
Embodiment 55. A compound of Embodiment 54 wherein R1 is a phenyl or pyridinyl ring optionally substituted with up to 4 substituents independently selected from
Rl4.
Embodiment 56. A compound of Embodiment 55 wherein R1 is a phenyl ring
optionally substituted with up to 4 substituents independently selected from R14. Embodiment 57. A compound of Embodiment 55 wherein R1 is a pyridinyl ring
optionally substituted with up to 4 substituents independently selected from R14.
Embodiment 58. A compound of Embodiment 57 wherein R1 is a 4-pyridinyl ring optionally substituted with up to 4 substituents independently selected from R14. Embodiment 59. A compound of Embodiment 58 wherein R1 is a 4-pyridinyl ring substituted with 1 to 3 substituents independently selected from R14, wherein one of said substituents is located at the 2-position of the 4-pyridinyl ring (i.e. ortho to the pyridinyl ring nitrogen atom and meta to the bond connecting the pyridinyl ring to the remainder of Formula 1).
Embodiment 60. A compound of Embodiment 59 wherein R1 is a 4-pyridinyl ring substituted with 1 substituent selected from R14, wherein said substituent is located at the 2-position of the 4-pyridinyl ring.
Embodiment 61. A compound of Formula 1 or any one of Embodiments 1 through 60 wherein each R14 is independently halogen, C1-C4 alkyl, C1-C4 haloalkyl, cyano, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C3-C4 haloalkynyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio or C1-C4 haloalkylthio.
Embodiment 62. A compound of Embodiment 61 wherein each R14 is independently halogen or C1-C4 haloalkyl.
Embodiment 63. A compound of Embodiment 62 wherein each R14 is independently F,
CI, Br or CF3.
Embodiment 64. A compound of Embodiment 63 wherein each R14 is CI.
Embodiment 65. A compound of Formula 1 or any one of Embodiments 1 through 64 wherein R2 is H, C1-C4 alkyl, C1-C4 alkoxy, C2-C5 alkoxyalkyl, C2-C5 alkoxycarbonyl or C2-C5 alkylcarbonyl;
Embodiment 66. A compound of Embodiment 65 wherein R2 is H, methyl, methoxy,
C2-C5 alkoxyalkyl or C2-C5 alkoxycarbonyl.
Embodiment 67. A compound of Embodiment 66 wherein R2 is H, methyl,
C2-C5 alkoxyalkyl or C2-C5 alkoxycarbonyl
Embodiment 68. A compound of Embodiment 67 wherein R2 is H.
Embodiment 69. A compound of Formula 1 or any one of Embodiments 1 through 68 wherein each R3 is independently C1-C4 alkyl.
Embodiment 70. A compound of Embodiment 69 wherein each R3 is methyl.
Embodiment 71. A compound of Formula 1 or any one of Embodiments 1 through 70 wherein R4 is H or C {-C4 alkyl.
Embodiment 72. A compound of Embodiment 71 wherein R4 is H or 1-C2 alkyl. Embodiment 73. A compound of Embodiment 72 wherein R4 is H or methyl.
Embodiment 74. A compound of Embodiment 73 wherein R4 is H.
Embodiment 75. A compound of Formula 1 or any one of Embodiments 1 through 74 wherein R5 is H.
Embodiment 76. A compound of Formula 1 or any one of Embodiments 1 through 75 wherein R6 is a phenyl ring optionally substituted with up to 5 substituents independently selected from R22 or a pyridinyl ring optionally substituted with up to 4 substituents independently seleted from R22.
Embodiment 77. A compound of Embodiment 76 wherein R6 is a phenyl or pyridinyl ring substituted with 1 to 3 substituents independently selected from R22 wherein one substituent is at the para position (relative to the bond connecting the ring to the remainder of Formula 1).
Embodiment 78. A compound of Embodiment 77 wherein R6 is a phenyl or pyridinyl ring substituted with 1 or 2 substituents independently selected from R22 wherein one substituent is at the para position.
Embodiment 79. A compound of Embodiment 78 wherein R6 is a phenyl or pyridinyl ring substituted at the para position with a substituent independently selected from R22 and optionally substituted at an ortho position with a substituent independently selected from R22.
Embodiment 80. A compound of Embodiment 79 wherein R6 is a phenyl or pyridinyl ring substituted at the para position with a substituent selected from R22.
Embodiment 81. A compound of Formula 1 or any one of Embodiments 1 through 80 wherein when R6 comprises a pyridinyl ring, said ring is bonded at the 2-position to the remainder of Formula 1.
Embodiment 82. A compound of Formula 1 or any one of Embodiments 1 through 80 wherein R6 is a phenyl ring substituted as described.
Embodiment 83. A compound of Formula 1 or any one of Embodiments 1 through 81 wherein R6 is a pyridinyl ring substituted as described.
Embodiment 84. A compound of Embodiment 76 wherein R6 is a phenyl ring
optionally substituted with up to 5 substituents independently selected from R22. Embodiment 85. A compound of Embodiment 84 wherein R6 is a phenyl ring
substituted with 1 to 3 substituents independently selected from R22, wherein one of said substituents is located at the 4-position of the phenyl ring.
Embodiment 86. A compound of Embodiment 85 wherein R6 is a phenyl ring
substituted with 1 substituent selected from R22, wherein said substituent is located at the 4-position of the phenyl ring.
Embodiment 87. A compound of Formula 1 or any one of Embodiments 1 through 86 wherein each R22 is independently halogen, cyano, Ci~C6 alkyl, Ci~C6
haloalkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl,
C^-C6 alkoxy or C^-C6 haloalkoxy.
Embodiment 88. A compound of Embodiment 87 wherein each R22 is independently F, CI, Br, cyano, CH3, CF3, cyclopropyl, HC≡C, CH30 or CF30.
Embodiment 89. A compound of Embodiment 88 wherein each R22 is independently F,
CI, Br, CF3 or CF30.
Embodiment 90. A compound of Embodiment 89 wherein each R22 is independently F, CI, Br or CF3.
Embodiment 91. A compound of Embodiment 90 wherein each R22 is independently F,
CI or CF3.
Embodiment 92. A compound of Embodiment 91 wherein each R22 is F or CI.
Embodiment 93. A compound of Formula 1 or any one of Embodiments 1 through 92 wherein T is O, S or NR36 (i.e. k is 0).
Embodiment 94. A compound of Embodiment 93 wherein T is O or NR36.
Embodiment 95. A compound of Embodiment 94 wherein T is O.
Embodiment 96. A compound of Formula 1 or any one of Embodiments 1 through 95 wherein R36 is H. Embodiment 97. A compound of Formula 1 or any one of Embodiments 1 through 96 wherein W is O.
Embodiment 98. A compound of Formula 1 or any one of Embodiments 1 through 97 wherein W1 is O.
Embodiment 99. A compound of Formula 1 or any one of Embodiments 1 through 98 wherein each W2 is O.
Embodiment 100. A compound of Formula 1 or any one of Embodiments 1 through 99 wherein n is an integer from 0 to 2.
Embodiment 101. A compound of Embodiment 100 wherein n is 0 or 1.
Embodiment 102. A compound of Embodiment 101 wherein n is 0.
Embodiment 103. A compound of Formula 1 or any one of Embodiments 1 through 102 wherein p is 0 or 2.
Embodiment 104. A compound of Embodiment 103 wherein p is 0.
Embodiment 105. A compound of Formula 1 or any one of Embodiments 1 through 104 wherein s is 1.
Embodiment 106. A compound of Formula 1 or any one of Embodiments 1 through 105 wherein t is 1.
Embodiment 107. A compound described in the Summary of the Invention or any one of Embodiments 1 through 106 that is not in the form of an N-oxide. Embodiment 108. A compound of Embodiment 107 that is not in the form of an N- oxide or a salt.
Embodiment 109. A compound described in the Summary of the Invention or any one of Embodiments 1 through 108 wherein R7 is other than NH2.
Embodiment 110. A compound of Embodiment 109 wherein R7 is other than NR24R25. Embodiments of this invention, including Embodiments 1-110 above as well as any other embodiments described herein, can be combined in any manner, and the descriptions of variables in the embodiments pertain not only to the compounds of Formula 1 but also to the starting compounds and intermediate compounds useful for preparing the compounds of Formula 1. In addition, embodiments of this invention, including Embodiments 1-110 above as well as any other embodiments described herein, and any combination thereof, pertain to the compositions and methods of the present invention.
Combinations of Embodiments 1-110 are illustrated by:
Embodiment Al . A compound of Formula 1 wherein
T is O;
Z is O;
R1 is a 4-pyridinyl ring substituted with 1 to 3 substituents independently selected from R14, wherein one of said substituents is located at the 2-position of the 4-pyridinyl ring; R2 is H, methyl, C2-C5 alkoxyalkyl or C2-C4 alkoxycarbonyl;
R4 is H or -C4 alkyl;
R5 is H;
R6 is a phenyl ring optionally substituted with up to 5 substituents independently selected from R22 or a pyridinyl ring optionally substituted with up to 4 substituents independently seleted from R22;
R7, R8, R9 and R10 are independently H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C3-C4 haloalkynyl, C3-C6 cycloalkyl, Ci~C4 alkoxy, Ci~C4 haloalkoxy, Ci~C4 alkylthio, Ci~C4 haloalkylthio or cyano, or a vicinal pair of R7 and R8, or R8 and R9, or R9 and
R10, are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered aromatic or nonaromatic ring containing ring members selected from carbon atoms and up to 3 heteroatoms independently selected from N, O and S;
R1 1 and R12 are independently H, halogen or methyl;
each R13 is halogen or methyl;
each R14 is independently halogen, Cj-C4 alkyl, Cj-C4 haloalkyl, cyano, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C3-C4 haloalkynyl, C3-C6 cycloalkyl, Cj-C4 alkoxy, Cj-C4 haloalkoxy, Cj-C4 alkylthio or Cj-C4 haloalkylthio;
each R22 is independently halogen, cyano, Ci~C6 alkyl, Ci~C6 haloalkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, Ci~C6 alkoxy or C^-C6 haloalkoxy;
R34 is H or C^ alkyl;
R 5 is H;
W is O;
n is 0;
s is 1 ; and
t is 1.
Embodiment A2. A compound of Embodiment A 1 wherein
A1 is N or CR7;
A2 is N or CR8;
A3 is N or CR9;
A4 is CR10;
L is -C(R! !)=C(R12)-, -C(R34)(R35)0- or unsubstituted diphenylene;
R1 is a 4-pyridinyl ring substituted with 1 substituent selected from R14, wherein said substituent is located at the 2-position of the 4-pyridinyl ring; R2 is H; R4 is H or methyl;
R6 is a phenyl or pyridinyl ring substituted with 1 to 3 substituents independently selected from R22 wherein one substituent is at the para position; R7, R8, R9 and R10 are independently H, halogen or C1-C4 haloalkyl;
R11 and R12 are H;
each R14 is independently halogen or C1-C4 haloalkyl;
each R22 is independently F, CI, Br, cyano, CH3, CF3, cyclopropyl, HC≡C, CH30 or CF3O; and
R34 is H or methyl.
Embodiment A3. A compound of Embodiment A2 wherein
R6 is a phenyl or pyridinyl ring substituted at the para position with a substituent independently selected from R22 and optionally substituted at an ortho position with a substituent independently selected from R22;
R7 is H or F;
R8 and R9 are independently H, halogen or C1-C4 haloalkyl;
R10 is H or F;
each R14 is independently F, CI, Br or CF3; and
each R22 is independently F, CI, Br, CF3 or CF30.
Embodiment A4. A compound of Embodiment A3 wherein
R6 is a phenyl ring substituted at the para position with a substituent selected from
R22;
R7 is H;
R8 is H, halogen or CF3;
R9 is H, halogen or CF3;
R10 is H;
R14 is CI; and
R22 is F, CI, Br or CF3.
Specific embodiments include compounds of Formula 1 selected from the group consisting of:
2-chloro-N-[2-[[ 1 -[(2E)-3-(4-chlorophenyl)-2-propen- 1 -yl]-3-azetidinyl]oxy]- 6-(trifluoromethyl)-3 -pyridinyl] -4-pyridinecarboxamide, and
2- chloro-N-[4,5-dichloro-2-[[l-[(2E)-3-(4-chlorophenyl)-2-propen-l-yl]-
3- azetidinyl]oxy]phenyl]-4-pyridinecarboxamide,
2-chloro-N-[6-chloro-2-[[ 1 -[(2E)-3-(4-chlorophenyl)-2-propen- 1 -yl]-3-azetidinyl]- oxy] -5 -fluoro-3 -pyridinyl] -4-pyridinecarboxamide,
2-chloro-N-[5-chloro-2-[[ 1 -[(2E)-3-(4-chlorophenyl)-2-propen- 1 -yl]-3-azetidinyl]- oxy] -6-fluoro-3 -pyridinyl] -4-pyridinecarboxamide,
2-chloro-N-[2-[[l-[(2E)-3-(4-chlorophenyl)-2-propen-l-yl)-2-methyl-3-azetidinyl]- oxy] -6-(trifluoromethyl)-3 -pyridinyl] -4-pyridinecarboxamide, and
2-chloro-N-[6-chloro-2-[[l-[2-(4-chlorophenoxy)propyl]-3-azetidinyl]oxy]-5-fluoro- 3 -pyridinyl] -4-pyridinecarboxamide.
Of note is that compounds of this invention are characterized by favorable metabolic and/or soil residual patterns and exhibit activity controlling a spectrum of agronomic and nonagronomic invertebrate pests.
Of particular note, for reasons of invertebrate pest control spectrum and economic importance, protection of agronomic crops from damage or injury caused by invertebrate pests by controlling invertebrate pests are embodiments of the invention. Compounds of this invention because of their favorable translocation properties or systemicity in plants also protect foliar or other plant parts which are not directly contacted with a compound of Formula 1 or a composition comprising the compound.
Also noteworthy as embodiments of the present invention are compositions comprising a compound of any of the preceding Embodiments, as well as any other embodiments described herein, and any combinations thereof, and at least one additional component selected from the group consisting of a surfactant, a solid diluent and a liquid diluent, said compositions optionally further comprising at least one additional biologically active compound or agent.
Further noteworthy as embodiments of the present invention are compositions for controlling an invertebrate pest comprising a compound of any of the preceding Embodiments, as well as any other embodiments described herein, and any combinations thereof, and at least one additional component selected from the group consisting of a surfactant, a solid diluent and a liquid diluent, said compositions optionally further comprising at least one additional biologically active compound or agent. Embodiments of the invention further include methods for controlling an invertebrate pest comprising contacting the invertebrate pest or its environment with a biologically effective amount of a compound of any of the preceding Embodiments alone or in combination (e.g., as a composition described herein).
Embodiments of the invention also include a composition comprising a compound of any of the preceding Embodiments, alone or in combination, in the form of a soil drench liquid formulation. Embodiments of the invention further include methods for controlling an invertebrate pest comprising contacting the soil with a liquid composition as a soil drench comprising a biologically effective amount of a compound of any of the preceding Embodiments, alone or in combination.
Embodiments of the invention also include a spray composition for controlling an invertebrate pest comprising a biologically effective amount of a compound of any of the preceding Embodiments, alone or in combination, and a propellant. Embodiments of the invention further include a bait composition for controlling an invertebrate pest comprising a biologically effective amount of a compound of any of the preceding Embodiments (alone or in combination), one or more food materials, optionally an attractant, and optionally a humectant. Embodiments of the invention also include a device for controlling an invertebrate pest comprising said bait composition and a housing adapted to receive said bait composition, wherein the housing has at least one opening sized to permit the invertebrate pest to pass through the opening so the invertebrate pest can gain access to said bait composition from a location outside the housing, and wherein the housing is further adapted to be placed in or near a locus of potential or known activity for the invertebrate pest.
Embodiments of the invention also include methods for protecting a seed from an invertebrate pest comprising contacting the seed with a biologically effective amount of a compound of any of the preceding Embodiments, alone or in combination.
Embodiments of the invention also include methods for protecting an animal from an invertebrate parasitic pest comprising administering to the animal a parasiticidally effective amount of a compound of any of the preceding Embodiments, alone or in combination.
Embodiments of the invention also include methods for controlling an invertebrate pest comprising contacting the invertebrate pest or its environment with a biologically effective amount of a compound of Formula 1, an N-oxide, or a salt thereof, (e.g., as a composition described herein), provided that the methods are not methods of medical treatment of a human or animal body by therapy.
This invention also relates to such methods wherein the invertebrate pest or its environment is contacted with a composition comprising a biologically effective amount of a compound of Formula 1, an N-oxide, or a salt thereof, and at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents, said composition optionally further comprising a biologically effective amount of at least one additional biologically active compound or agent, provided that the methods are not methods of medical treatment of a human or animal body by therapy.
Embodiments of the invention also include any of the preceding embodiments (alone or in combination) wherein the invertebrate pest is an arthropod. Embodiments of the invention also include any of the preceding embodiments wherein the arthropod is selected from the group consisting of insects, mites, spiders, scorpions, centipedes, millipedes, pill bugs and symphylans. Embodiments of the invention also include any of the preceding embodiments wherein the arthropod is an insect.
Embodiments of the invention also include any of the preceding embodiments (alone or in combination) wherein the invertebrate pest is a gastropod. Embodiments of the invention also include any of the preceding embodiments wherein the gastropod is selected from the group consisting of snails, slugs and other Stylommatophora. One or more of the following methods and variations as described in Schemes 1-27 can be used to prepare the compounds of Formula 1. The definitions of A1, A2, A3, A4, L, T, R1 , R2, R3, R4, R5, R6, R36, W, k, n, s and t in the compounds of Formulae 1-34 below are as defined above in the Summary of the Invention unless otherwise noted. Formulae la- Id, 11a, 17a-17d, 20a, 22a, 24a, 26a-26c, 30a and 31a are various subsets of Formulae 1, 11, 17, 20, 22, 24, 26, 30 and 31, respectively. All substituents for Formulae la-Id are as defined above for Formula 1 unless otherwise noted.
As shown in Scheme 1, in one method a compound of Formula la (i.e. Formula 1 wherein R5 is H) is prepared by reacting an azetidine of Formula 2 with an aldehyde or ketone of Formula 3 and a suitable reducing agent, for example NaHB(OAc)3 or NaH3BCN, in a suitable solvent, for example tetrahydrofuran (THF) or 1,2-dichloroethane. The reaction is typically conducted near ambient temperature (e.g., -15-25 °C), but heating to the boiling point of the solvent may be beneficial. The method of Scheme 1 is illustrated by Step D of Synthesis Example 4, Step D of Synthesis Example 6, Step E of Synthesis Example 7 and Step D of Synthesis Example 8.
Scheme 1
Figure imgf000026_0001
As shown in Scheme 2, in another method a compound of Formula 1 is prepared by reacting an azetidine of Formula 2 with an alkylating agent of Formula 4 wherein X1 is a leaving group (i.e. nucleofuge) such as a halide (e.g., Br, I) or a sulfonate (e.g., mesylate, triflate) in the presence of an appropriate base such as triethylamine, N,N-diisopropyl- ethylamine or potassium carbonate in a suitable solvent, for example acetonitrile, N,N-dimethylformamide (DMF) or THF. The reaction is typically conducted near ambient temperature, but cooling to -20 °C or heating to the lesser of 120 °C or the boiling point of the solvent may be beneficial. The method of Scheme 2 is illustrated by Step D of Synthesis Example 5. Scheme 2
Figure imgf000027_0001
As shown in Scheme 3, in another method a compound of Formula la is prepared by reacting an azetidine of Formula 2 with an aldehyde of Formula 5 (or paraformaldehyde for R4 being H) and a boronic acid (Formula 6, Y is OH) or derivative such as a boronate ester (e.g., Formula 6 wherein is -OCMe2CMe20-) or fluoroborate salt (Formula 7 wherein M® is a counterion), optionally in the presence of a Lewis acid catalyst (such as BF3-OEt2 or T1F4), in a suitable solvent such as toluene, 1 ,2-dichloroethane, 1,4-dioxane or ethanol. The reaction is typically conducted at between ambient temperature and the boiling point of the solvent, and the reaction mixture can be heated using microwave radiation. Examples of such conditions are found in numerous literature references such as Tetrahedron Lett. 2004, 3471-3474; Tetrahedron Lett. 2005, 8027-8031; and Chemtracts 2001, 14(14), 796-801 and the references cited therein. The method of Scheme 3 is illustrated by Step F of Synthesis Example 1.
Scheme 3
R 6- \
BY 2
R4CHO + or *~ la
Solvent
5 W 6^ L\ © Θ
K BF3 M
7
In the method of Scheme 4, a compound of Formula 1 wherein R2 is other than H is prepared by reacting a compound of Formula lb (i.e. Formula 1 wherein R2 is H) with a suitable base, for example sodium hydride or lithium hexamethyldisilazide (LiHMDS), and a compound of Formula 9 wherein X2 is a leaving group such as a halide (e.g., CI, Br) or a sulfonate (e.g., mesylate, triflate), in a suitable solvent such as THF or DMF. The reaction is typically conducted near ambient temperature, but cooling to -20 °C or heating to the lesser of 120 °C or the boiling point of the solvent may be beneficial.
Scheme 4
Figure imgf000028_0001
R is other than H.
In the method of Scheme 5, an azetidine intermediate of Formula 2 is prepared from a suitably protected derivative of Formula 10 wherein Pg is a protecting group, for example, tert-butoxycarbonyl (BOC), benzyl, benzhydryl or, especially when T is NH, trifluoroacetyl by deprotection under conditions well known to those skilled in the art and reviewed in T. W. Greene and P. G. Wuts, Protecting Groups in Organic Synthesis, Wiley, 1991, pages 327-329 and 364-365. The method of Scheme 5 wherein Pg is BOC is illustrated by Step E of Synthesis Example 1, Step D of Synthesis Example 4, Step C of Synthesis Example 5, Step C of Synthesis Example 6, Step D of Synthesis Example 7 and Step C of Synthesis Example 8.
Scheme 5
Figure imgf000028_0002
As illustrated in Scheme 6, a compound of Formula 10 is prepared by reacting an amino compound of Formula 11 (wherein Pg is as defined in Scheme 5) with an acid or derivative of Formula 12 (wherein, e.g., X3 is OH or CI) under a variety of conditions known to those skilled in the art and described in numerous texts such as J. March, Advanced Organic Chemistry, Wiley, 1992, pages 417-421. Exemplary conditions include treating an amino compound of Formula 11 with RiCOCl (as Formula 12) in the presence of a suitable base, such as triethylamine in a suitable solvent, for example THF or CH2Cl2, or by treating the amino compound of Formula 11 with a R!CC^H (as Formula 12) and an activating agent, for example (benzotriazol-l-yloxy)tris(dimethylamino)phosphonium hexafluoro- phosphate (CAS # 56602-33-6, BOP Reagent), in the presence of a suitable base, such as 4-methylmorpholine, in suitable solvent, for example DMF. The reaction is typically conducted between 0 °C and ambient temperature, although cooling to -20 °C or heating to the lesser of 80 °C or the boiling point of the solvent may be beneficial. The method of Scheme 6 wherein X3 is CI is illustrated by Step D of Synthesis Example 1, Step C of Synthesis Example 4, Step B of Synthesis Example 5, Step B of Synthesis Example 6 and Step B of Synthesis Example 8.
Scheme 6
Figure imgf000029_0001
Compounds of Formula 10 wherein Pg is an oxidative ly stable protecting group such as BOC, T is S(0)k and k is 1 or 2 can be prepared from corresponding compounds of Formula 10 wherein k is a lower integer by oxidation with a suitable oxidizing agent such as 2-chloroperbenzoic acid (MCPBA) or potassium peroxymonosulfate (OXONE®) in a suitable solvent such as dichloromethane or a water-methanol mixture, respectively. The possible extent of oxidation is determined by the relative amount of oxidizing agent. A base such as sodium hydrogencarbonate can be included in the reaction mixture. The oxidation is typically conducted at ambient temperature, although temperatures as low as -20 °C or as high as 80 °C may prove beneficial.
In the method of Scheme 7, a compound of Formula 11 (wherein Pg is as defined for Scheme 5) in which R2 is other than H is prepared by reacting a compound of Formula 11a (i.e. Formula 11 wherein R2 is H) with a compound of Formula 13 wherein X4 is a suitable leaving group, typically with use of a base in an appropriate solvent. Compounds of Formula 13 with leaving groups X4 and reaction conditions suitable for attaching R2 are well known in the art of derivatizing amino groups. Typical leaving groups in include halides (e.g., CI, Br, I) and sulfonates (e.g., mesylate, triflate). Iodo is particularly useful when R2 is an alkyl group. A variety of bases can be used, depending upon choice of Formula 13 and whether the base is used to deprotonate the amino group of Formula 11a or merely as a scavenger of acid byproduct from the reaction. Strong bases such as sodium hydride are useful for deprotonation, while tertiary amine bases such as triethylamine are useful as acid scavengers in reactions wherein R2 is an acyl group. Useful solvents include polar aprotic solvents such as THF and DMF. Dichloromethane is particularly useful when R2 is an acyl group and the base is a tertiary amine. The reaction is typically conducted at ambient temperature, although cooling to -20 °C or heating to the lesser of 120 °C or the boiling point of the solvent may be beneficial.
Scheme 7
Figure imgf000030_0001
11a 11
Scheme 8 illustrates the preparation of amino compounds of Formula 11a (where Pg is as defined in Scheme 5) by reduction of the corresponding nitro compounds of Formula 14 by catalytic hydrogenation when the substituents R7, R8, R9 and R10 are compatible or by dissolving metal reduction. Examples of catalytic reduction involve the use of a hydrogen source, such as molecular hydrogen (preferably at a pressure ranging from atmospheric pressure to 350 kPa, although higher pressures can be used) or 1 ,4-cyclohexadiene or ammonium formate, and the use of a metal catalyst such as palladium (preferably supported on carbon or other substrate such as calcium carbonate) or platinum (optionally supported on carbon or alumina) in elemental form or in the form of its oxide. The reaction is typically conducted in ethanol, methanol or ethyl acetate and at ambient temperature, although elevated temperatures up to the boiling point of the solution can be employed. Careful selection of conditions (i.e. low pressure, short reaction times) is required in the cases where Pg is benzyl or benzhydryl. Examples of dissolving metal reduction include the use of finely powdered iron (for example with a particle size of 10 μιη) in either acetic acid or in aqueous ethanol containing a catalyst such as ammonium chloride. The reaction is conducted at elevated temperature, preferably ranging from 70 °C to the boiling point of the solvent. These conditions are preferred when other reducible functionality (e.g., alkenes, aromatic halides) is present in the compound. The dissolving metal reduction method of Scheme 8 is illustrated by Step C of Synthesis Example 1 , Step B of Synthesis Example 4 and Step B of Synthesis Example 6.
Scheme 8
Figure imgf000031_0001
Alternatively, in the method of Scheme 9, amino compounds of Formula 11a (where
Pg is as defined in Scheme 5, and T is other than NH) are prepared by Curtius Rearrangement of the acyl azides formed in situ by treatment of carboxylic acids of Formula 15 with, for example, diphenyl phosphoryl azide, or prepared from the acids of Formula 15 by conversion to the acid chloride (e.g., by treatment with oxalyl chloride) and then reaction with an azide source such as sodium azide in the presence of a base such as triethylamine. The rearrangement is preferably conducted at an elevated temperature from 60 °C up to the boiling point of the solution, in for example toluene as solvent. Hydrolysis of the mixture then liberates the amino compound of Formula 11a. Alternatively, the rearrangement can be conducted in an alcoholic solvent such tert-butanol as solvent, which provides the aniline in BOC-protected form. The amino compound of Formula 11a is then liberated by treatment with a strong acid such as trifluoroacetic acid or hydrogen chloride in an ethereal solvent. For this modification of the method of Scheme 9, Pg is generally chosen to be an acid- resistant group such as benzyl to prevent loss during the treatment with strong acid. The Curtius Rearrangement is summarized in J. March, Advanced Organic Chemistry, Wiley, 1992, pages 1091-1092; see also Org. Synth., Coll. Vol. 6: 910-913.
Scheme 9
Figure imgf000031_0002
In the method of Scheme 10, wherein T is O, S or NR36, a compound of Formula 14 is prepared by reacting a compound of Formula 16 wherein X5 is a suitable leaving group such as a halide, with a protected azetidinol of Formula 17 (wherein Pg is as defined for Scheme 5) in the presence of a suitable base, for example sodium hydride, sodium hydroxide or potassium carbonate, and in a suitable solvent, for example DMF, acetonitrile, THF or toluene. When A1 is CR7, X5 is preferably F, and when A1 is N, X5 being CI also generally works well. The reaction is typically conducted at ambient temperature, although cooling to -20 °C or heating to the lesser of 80 °C or the boiling point of the solvent may be beneficial. The method of Scheme 10 is illustrated by Step B of Synthesis Example 1, Step A of Synthesis Example 6 and Step B of Synthesis Example 7.
Scheme 10
Figure imgf000032_0001
16 17 14
Compounds of Formula 14 wherein Pg is an oxidatively stable protecting group such as BOC, T is S(C% and k is 1 or 2 can be prepared from corresponding compounds of Formula 14 wherein k is a lower integer by oxidation with a suitable oxidizing agent. Suitable oxidation conditions are the same as those already described under Scheme 6 for preparing compounds of Formula 10 wherein T is S(0 and k is 1 or 2 from corresponding compounds of Formula 10 wherein k is a lower integer..
In the method of Scheme 11, wherein T is O, S or NR36, an ester of Formula 19 wherein Ra is lower alkyl (e.g., methyl, ethyl, tert-butyl) is prepared by reacting a compound of Formula 18 wherein X5 is a suitable leaving group such as a halide, with a protected azetidinol of Formula 17 (wherein Pg is as defined for Scheme 5) in the presence of a base and solvent and under reaction conditions as described for the method of Scheme 10. When A1 is CR7, X5 is preferably F, and when A1 is N, X5 being CI also generally works well. Then the ester of Formula 19 is converted to the carboxylic acid of Formula 15 by saponification using aqueous base (e.g., NaOH), followed by acidification, in the case of methyl and ethyl esters or by treatment with a strong acid, for example trifluoroacetic acid or a solution of hydrogen chloride in ethanol or dioxane, in the case of tert-butyl esters. Co- solvents such as dichloromethane can be added to improve solubility. Ethanol and dioxane are particularly useful as co-solvents for improving solubility of esters of Formula 19 in aqueous saponification mixtures. The conversion of the ester of Formula 19 to the carboxylic acid of Formula 15 is typically conducted at ambient temperature, although cooling to -20 °C or heating to the lesser of 100 °C or the boiling point of the solvent may be beneficial. Many other conditions will also effect this transformation and a variety of carboxylic acid protecting groups besides Ra being lower alkyl can be used in the method of Scheme 11. Pertinent literature references can be found in T. W. Greene and P. G. Wuts, Protecting Groups in Organic Synthesis, Wiley, 1991, pages 229-263.
Scheme 11
Figure imgf000033_0001
18 17 19
Ra is lower alkyl (e.g., methyl, ethyl, feri-butyl)
Compounds of Formula 15 wherein Pg is an oxidatively stable protecting group such as BOC, T is 8(0)^ and k is 1 or 2 can be prepared from corresponding compounds of Formula 15 wherein k is a lower integer by oxidation with a suitable oxidizing agent. Suitable oxidation conditions are the same as those already described under Scheme 6 for preparing compounds of Formula 10 wherein T is 8(0)^ and k is 1 or 2 from corresponding compounds of Formula 10 wherein k is a lower integer.
In the methods of Schemes 10 and 11, a nitro or alkyl ester (C02Ra) substituent at an ortho position activates displacement of the leaving group X5. When A1 is N, the presence of an activating substituent may not be required, as is illustrated by Step A of Synthesis Example 8.
As illustrated in Scheme 12, wherein T is O, S or NR36, compounds of Formula 22 (in which the combinations of E and G relate to Formulae 1, 10, 14, 19 and 25) are also prepared by reacting a hydroxy aromatic compound of Formula 20 with an azetidine of Formula 21 having an appropriate leaving group (X6) such as mesylate or bromide in the presence of a suitable base (such as K2CO3, NaH or LiHMDS). The reaction is typically conducted at ambient temperature, although cooling to -20 °C or heating to the lesser of 120 °C or the boiling point of the solvent may be beneficial. Scheme 12
Figure imgf000034_0001
20 21 22
E is a 2 l a
N02, C02R or NR C(W)R ; R is a carboxylic acid protecting group such as lower alkyl.
G is a protecting group Pg as defined for Scheme 6 or CR4R5-L-R6.
Compounds of Formula 20 can be prepared by a wide variety of methods known in the art of organic chemical synthesis. Of note is preparation of compounds of Formula 20 wherein T is S from corresponding compounds of Formula 20 wherein T is O by the use of the Newman-Kwart Rearrangement (see Dirk Kusch, Specialty Chemicals Magazine 2003,
25(9), 41).
As shown in Scheme 13, compounds of Formula 22a (i.e. Formula 22 wherein T is O) are also prepared from intermediates of Formula 20a (i.e. Formula 20 wherein T is O) and Formula 23 (i.e. Formula 17 or 26 wherein T is O) under Mitsunobu conditions as described, for example, in Bioorg. Med. Chem. Lett. 2008, 18, 5581-5585. THF is a particularly useful solvent, and the reaction is typically conducted between -20 °C and ambient temperature, although warming to 60 °C may be beneficial. The method of Scheme 13 is illustrated by Step A of Synthesis Example 4.
Scheme 13
Figure imgf000034_0002
20a 23 22a
E is a 2 l a
N02, C02R or NR C(W)R ; R is a carboxylic acid protecting group such as lower alkyl.
G is a protecting group Pg as defined for Scheme 6 or CR4R5-L-R6.
RB is preferably Et or z-Pr. As illustrated in Scheme 14, compounds of Formula 1 are alternatively prepared by acylation of anilines of Formula 24 with a suitable acid derivative of Formula 12 wherein X3 is, e.g., OH or CI by analogy to the chemistry described above for Scheme 6. The disclosure provided for the method of Scheme 6 extends to the method of Scheme 14. The method of Scheme 14 is illustrated by Step D of Synthesis Example 2.
Scheme 14
Figure imgf000035_0001
In the method of Scheme 15, a compound of Formula 24 wherein R2 is other than H is prepared by reacting a compound of Formula 24a (i.e. Formula 24 wherein R2 is H) with a compound of Formula 13 wherein X4 is a suitable leaving group, typically with use of a base in an appropriate solvent, analogous to the method described above for Scheme 7. The disclosure provided for the method of Scheme 7 extends to the method of Scheme 15.
Scheme 15
Figure imgf000035_0002
In the method of Scheme 16, an amino compound of Formula 24a is prepared by reduction of the corresponding nitro compound of Formula 25, analogous to the method described above in Scheme 8. The disclosure provided for the method of Scheme 8 extends to the method of Scheme 16. However, for the method of Scheme 16, dissolving metal reduction is preferred over hydrogenation when L is -C(R11)=C(R12)-. The method of Scheme 16 involving dissolving metal reduction is illustrated by Step C of Synthesis Example 2.
Scheme 16
Figure imgf000036_0001
In the method of Scheme 17, wherein T is O, S or NR36, a nitro compound of Formula 25 is prepared by reaction of a compound of Formula 16 wherein X5 is a suitable leaving group such as a halide, with an azetidinol of Formula 26 in the presence of a suitable base and solvent, analogous to the method described above for Scheme 10. The disclosure provided for the method of Scheme 10 extends to the method of Scheme 17. However, for the method of Scheme 17, conducting the reaction at temperatures up to 120 °C or the boiling point of the solvent may be beneficial. The method of Scheme 17 is illustrated by Step B of Synthesis Example 2.
Scheme 17
Figure imgf000036_0002
Aromatic compounds of Formulae 16, 18 and 20 can be prepared by a wide variety of methods known in the art of organic chemical synthesis. Compounds of Formula 26 can be also be prepared by a variety of methods. The following method of Scheme 18 is particularly useful for preparing compounds of Formula 26 wherein Y is O, and s and t are each 1. As shown in Scheme 18, an azetidinol of Formula 26a (i.e. Formula 26 wherein Y is O, and s and t are each 1) can be prepared by reacting an amine of Formula 28 with an epihalohydrin of Formula 27 wherein X6 is CI, Br or I and most typically CI, or a derivative, optionally in the presence of additives such as triethylamine or magnesium bromide, according to published procedures (e.g., J. Het. Chem. 1971, 8, 1059-1062; J. Org. Chem. 1967, 32, 2972-2976; Tetrahedron Lett. 1997, 6059-6062). The method of Scheme 18 is illustrated by Step A of Synthesis Example 2. Amines of Formula 28 can be made by methods known in the art; for example, cinnamylamines can be prepared according to the general method described in J. Org. Chem. 1982, 47, 5395-5397.
Scheme 18
Figure imgf000037_0001
Methods for preparing hydroxy- and amino-substituted protected azetidines, pyrrolidines and piperidines of Formula 17 (wherein T is O or NR36) are well known in the art of organic chemical synthesis, and many of these compounds are commercially available.
Scheme 19 illustrates a method, analogous to the method of Scheme 18, for preparing hydroxy-substituted protected azetidines (i.e. protected azetidinols) of Formula 17a (i.e. Formula 17 wherein T is O) wherein Pg is, for example, benzhydryl or benzyl. In this method, a protected azetidinol of Formula 17a is prepared by reacting a protected amine of Formula 29 with an epihalohydrin of Formula 27 using procedures analogous to those described for Scheme 18. Furthermore, using general methods well known in the art (e.g., T. W. Greene and P. G. Wuts, Protecting Groups in Organic Synthesis, Wiley, 1991, pages 327-329 and 364-365), the protecting group can be removed from the azetidinol of Formula 17a wherein Pg is, for example benzhydryl or benzyl, and then another protecting group can be attached to form a protected azetidinol of Formula 17a wherein Pg is, for example BOC. The compound of Formula 17a wherein Pg is BOC and n is 0 is commercially available.
Scheme 19
Figure imgf000037_0002
As shown in Scheme 20, an azetidinol of Formula 26b (i.e. Formula 26 wherein R3 is not attached to the 3-position of the azetidine ring) wherein n' is an integer from 0 to 4 can also be prepared by reducing an azetidinone of Formula 30 with a reducing agent, such as sodium borohydride in methanol or ethanol, using procedures similar to those described in U.S. Patent 3668196.
Scheme 20
Figure imgf000038_0001
Also, as shown in Scheme 21, a protected azetidinol of Formula 17b (i.e. Formula 17 wherein T is O, and R3 is not attached to the 3-position of the azetidine ring) wherein n' is an integer from 0 to 4, and Pg is a protecting group as defined for Scheme 5, can be prepared by reducing an azetidinone of Formula 31 with a reducing agent, analogous to the method of Scheme 20.
Scheme 21
Figure imgf000038_0002
In the method of Scheme 22, an azetidinol of Formula 26c (i.e. Formula 26 wherein an R3 (as R3a) is attached to the 3-position of the azetidine ring) wherein n' is an integer from 0 to 4 and R3a is alkyl is prepared by the addition of an organometallic reagent of Formula 32 (e.g., an organolithium or Grignard reagent) to an azetidinone of Formula 30 in an ethereal solvent, such as diethyl ether or THF, at ambient temperature, of if preferred, cooling to temperatures as low as -78 °C, using general procedures known in the art (e.g., Tetrahedron Lett. 1972, 5063-5064; U.S. Patent 3668196). Scheme 22
Figure imgf000039_0001
M2 is, e.g., Li, MgCl, MgBr.
Similarly, as shown in Scheme 23, a protected azetidinol of Formula 17c (i.e. Formula 17 wherein T is O, and an R3 (as R3a) is attached to the 3-position of the azetidine ring), wherein n' is an integer from 0 to 4, R3a is alkyl and Pg is a protecting group as defined for Scheme 5, is prepared by the addition of an organometallic compound of Formula 32 to a protected azetidinone of Formula 31 in an ethereal solvent analogous to the method of Scheme 22.
Scheme 23
Figure imgf000039_0002
M2 is, e.g., Li, MgCl, MgBr.
Azetidinones of Formulae 30 and 31 can be prepared by general methods known in the art. For example, as shown in Scheme 24, geminally disubstituted azetidinones of Formula 30a (i.e. Formula 30 in which the 2-position of the azetidine ring is substituted with two R3) can be prepared by treatment of corresponding l-bromo-2-butanones of Formula 33 with a base such as sodium hydrogencarbonate in a solvent such as DMF or aqueous methanol, using procedures similar to those described in U.S. Patent 3668196.
Scheme 24
Figure imgf000039_0003
RJU and R^ are independently alkyl. Analogously, as shown in Scheme 25, protected geminally disubstituted azetidinones of Formula 31a (i.e. Formula 31 in which the 2-position of the azetidine ring is substituted with two R3), wherein Pg is a suitable protecting group such as benzhydryl or benzyl, can be prepared by treatment of corresponding l-bromo-2-butanones of Formula 34, using reaction conditions similar to those described for the method of Scheme 24.
Scheme 25
Figure imgf000040_0001
R3band R3c are independently alkyl.
As shown in Scheme 26, a thiol compound of Formula 17d (i.e. Formula 17 wherein T is S) can be prepared by treatment of a corresponding compound of Formula 21 (where X6 is as defined in Scheme 12) with the thiol nucleophile Na2S. Alternatively, a suitable thiol nucleophile in the form of PgSH (where Pg is suitable protecting group such as benzyl (Bn)) can be used in the presence of a suitable base such as NaH, followed by deprotection using, for example, sodium in liquid ammonia. DMF is a particularly good solvent for this displacement reaction involving a thiol nucleophile, and mild heating (for example to 80 °C) is beneficial.
Scheme 26
Figure imgf000040_0002
Compounds of Formula 21 can be prepared by a wide variety of methods known in the art of organic chemical synthesis, including preparation from corresponding compounds of Formula 17 wherein T is O. Compounds of Formula 21 wherein Pg is BOC, n is 0, and X6 is I or OMs are commercially available for each of the present values of s and t. Certain other compounds of Formula 21 where Pg is another protecting group such as trifluoroacetyl, carboxybenzyl (CBz) or benzhydryl are also commercially available.
As shown in Scheme 27, compounds of Formula lc (i.e. Formula 1 wherein W is S) can be prepared by thionation of corresponding compounds of Formula Id (i.e. Formula 1 wherein W is O). Thionation involves treatment with a thionating reagent, for example phosphorus pentasulfide, or 2,4-bis(4-methoxyphenyl)-l,3,2,4-dithiadiphosphetane, 2,4-disulfide (Lawesson's Reagent), or 2,4-bis(4-phenoxyphenyl)-l,3,2,4-dithiadiphos- phetane, 2,4-disulfide (Belleau's Reagent). The reaction is preferably conducted in solvents such as toluene, xylenes or dioxane and at elevated temperature from 80 °C to the boiling point of the solvent.
Scheme 27
Figure imgf000041_0001
It is recognized that some reagents and reaction conditions described above for preparing compounds of Formula 1 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, T. W. Greene, P. G. M. Wuts; Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). One skilled in the art will recognize that, in some cases, after introduction of the reagents depicted in the individual schemes, additional routine synthetic steps not described in detail may be needed to complete the synthesis of compounds of Formula 1. 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 1.
One skilled in the art will also recognize that compounds of Formula 1 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. For example, Step A of Synthesis Example 5 illustrates halogenation of intermediates.
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 Synthesis Examples are, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever. Steps in the following Synthesis Examples illustrate a procedure for each step in an overall synthetic transformation, and the starting material for each step may not have necessarily been prepared by a particular preparative run whose procedure is described in other Examples or Steps. 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. ¾ NMR spectra are reported in ppm downfield from tetramethylsilane in CDCI3 unless otherwise noted; "s" means singlet, "d" means doublet, "dd" means doublet of doublets, "dt" means doublet of triplets, "m" means multiplet, "br s" means broad singlet, "br d" means broad doublet, and "AB pair of d" means a pair of doublets wherein the chemical shift difference is not much larger than the coupling constant. Mass spectra (MS) are reported as the molecular weight of the highest isotopic abundance positively charged parent ion (M+1) formed by addition of H+ (molecular weight of 1) to the molecule or the highest isotopic abundance negatively charged ion (M-1) formed by loss of H+ (molecular weight of 1), observed by mass spectrometry using electrospray ionization (ESI) where "amu" stands for atomic mass units.
SYNTHESIS EXAMPLE 1
Preparation of 2-chloro-N-[2-[[ 1 -[(2E)-3-(4-chlorophenyl)-2-propen- 1 -yl]-3-azetidinyl]oxy]- 6-(trifluoromethyl)-3 -pyridinyl] -4-pyridinecarboxamide (Compound 1 ) Step A: Preparation of 2-chloro-3-nitro-6-(trifluoromethyl)pyridine
To a mixture of concentrated sulfuric acid (75 mL) and aqueous hydrogen peroxide (40%, 37 mL) at 0 °C was added dropwise a solution of 2-chloro-6-(trifluoromethyl)- 3-pyridinamine (7.00 g, 35.6 mmol) in sulfuric acid (93 mL). Then the reaction mixture was stirred for 20 h at ambient temperature. TLC analysis (20% EtOAc / petroleum ether) showed completion of the reaction. The mixture was poured into ice-water and neutralized to pH 8-9 by the addition of concentrated aqueous ammonia, and then extracted with ethyl acetate (3x). The combined organic layers were dried (Na2S04) and concentrated to give the title product as yellow solid (3.72 g).
!H NMR δ 8.4 (d, 1H), 7.8 (d, 1H).
Step B : Preparation of 1 , 1 -dimethylethyl 3 - [ [3 -nitro-6-(trifluoromethyl)-2-pyridinyl] - oxy]- 1 -azetidinecarboxylate
To a solution of 1,1 -dimethylethyl 3 -hydroxy- 1 -azetidinecarboxylate (2.61 g, 15.1 mmol) in N,N-dimethylformamide (35 mL) was added potassium carbonate (4 g, 28.9 mmol) and 2-chloro-3-nitro-6-(trifluoromethyl)pyridine (i.e. the product of Step A) (3.27 g, 14.4 mmol). The mixture was then stirred for 5 h at ambient temperature. The reaction mixture was filtered, and the filtrate was poured into ice-water and extracted with ethyl acetate. The organic phase was washed with brine and dried (Na2S04). The solvent was evaporated, and the residue was purified by column chromatography (60-120 mesh silica gel, 20% ethyl acetate in petroleum ether) to give the title product (1.72 g) as off-white solid melting at 96-98 °C.
!H NMR δ 8.43 (d, 1H), 7.5 (d, 1H), 5.5 (m, 1H), 4.4 (m, 2H), 4.1 (m, 2H), 1.5 (s, 9H). MS (ESI) 364 amu (M+l).
Step C: Preparation of 1,1-dimethylethyl 3-[[3-amino-6-(trifluoromethyl)-
2-pyridinyl]oxy] - 1 -azetidinecarboxylate
To a solution of 1,1-dimethylethyl 3-[[3-nitro-6-(trifluoromethyl)-2-pyridinyl]oxy]- 1 -azetidinecarboxylate (i.e. the product of Step B) (1.5 g, 4.1 mmol) in a mixture of ethanol (20 mL) and water (2 mL) was added iron powder (300 mesh (-50 μιη), 692 mg, 12.3 mmol) and ammonium chloride (110 mg, 2.1 mmol), and the mixture was heated at reflux for 4 h. The reaction mixture was cooled, filtered through Celite® diatomaceous filter aid and concentrated. The residue was diluted with dichloromethane and washed with water. The organic phase was dried (Na2S04) and concentrated to give the title product as a white solid (1.2 g) melting at 132-134 °C.
!H NMR δ 7.18 (d, 1 H), 6.9 (d, 1H), 5.4 (m, 1H), 4.38 (m, 2 H), 4.1 (br s, 2 H), 3.97 (m, 2H), 1.45 (s, 9H).
MS (ESI) 334 amu (M+l).
Step D: Preparation of 1,1-dimethylethyl 3-[[3-[[(2-chloro-4-pyridinyl)carbonyl]- amino]-6-(trifluoromethyl)-2-pyridinyl]oxy]-l -azetidinecarboxylate
To a solution of 2-chloro-4-pyridinecarbonyl chloride (640 mg, 3.63 mmol) in dichloromethane (15 mL) at 0 °C was added 1,1-dimethylethyl 3-[[3-amino-6-(trifluoro- methyl)-2-pyridinyl]oxy]-l -azetidinecarboxylate (i.e. the product of Step C) (1.1 g, 3.3 mmol) and triethylamine (1.1 mL, 8.25 mmol ), and the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was then diluted with dichloromethane, washed with water and dried (Na2S04). The solvent was evaporated, and the residue was purified by column chromatography to give the title product as an off- white solid (950 mg) melting at 85-87 °C.
!H NMR δ 8.85 (d, 1H), 8.65 (d, 1H), 8.38 (s, 1H), 7.79 (s, 1H), 7.62 (d, 1H), 7.41 (d, 1H), 5.5 (m, 1H), 4.43 (m, 2H), 1.43 (s, 9H).
MS (ESI) 471 amu (M-l).
Step E : Preparation of N- [2-(3 -azetidinyloxy)-6-(trifluoromethyl)-3 -pyridinyl] -
2-chloro-4-pyridinecarboxamide
To a solution of 1,1-dimethylethyl 3-[[3-[[(2-chloro-4-pyridinyl)carbonyl]amino]- 6-(trifluoromethyl)-2-pyridinyl]oxy]-l -azetidinecarboxylate (i.e. the product of Step D) (500 mg, 35.0 mmol) in methanol (145 mL) at 0 °C was added dropwise acetyl chloride (5 mL). The reaction mixture was stirred for 2 h more at 0 °C before being warmed to ambient temperature and then stirred for an additional 4 h. The reaction mixture was concentrated under reduced pressure, dissolved in dichloromethane, washed with 10% aqueous sodium hydrogencarbonate solution and dried (Na2S04). The residue after concentration was triturated with diethyl ether to give the title product as a yellow solid (275 mg).
!H NMR (DMSO-d6) δ 8.63 (d, 1H), 8.42 (d, 1H), 7.98 (s, 1H), 7.83 (d, 1H), 7.59 (d, 1H), 5.4 (m, 1H), 3.78 (m, 2H), 3.6 (m, 2H), (N-H resonances merged with broad water peak at 3.36).
MS (ESI) 373 amu (M+l).
Step F: Preparation of 2-chloro-N-[2-[[l-[(2E)-3-(4-chlorophenyl)-2-propen-l-yl]-
3-azetidinyl]oxy]-6-(trifluoromethyl)-3-pyridinyl]-4-pyridinecarboxamide To a solution of N-[2-(3-azetidinyloxy)-6-(trifluoromethyl)-3-pyridinyl]-2-chloro- 4-pyridinecarboxamide (i.e. the product of Step E) (200 mg, 0.53 mmol) in dioxane (5 mL) was added paraformaldehyde (25 mg, 0.8 mmol), and the mixture was heated with stirring at 90 °C for 1 h. i?-[(lE)-2-(4-chlorophenyl)ethenyl]boronic acid (196 mg, 1.07 mmol) was then added, and the reaction mixture was stirred for 4 h at 90 °C. The mixture was cooled, diluted with ethyl acetate and washed with aqueous sodium hydroxide solution (I N). The organic phase was dried (Na2S04), and the residue after concentration was purified by column chromatography (100-200 mesh silica gel, 2% MeOH in CHCI3) to give the title product, a compound of the present invention, as an off-white solid (90 mg) melting at 100— 102 °C.
!H NMR δ 8.87 (d, 1H), 8.61 (d, 1H), 8.48 (s, 1H), 7.83 (s, 1H), 7.7(d, 1H), 7.4 (d, 1H), 7.3 (s, 4H), 6.5 (d, 1H), 6.2-6.12 (m, 1H), 5.42 (m, 1H), 3.84 (m, 2H), 3.4-3.32 (m, 4H).
MS (ESI) 523 amu (M+l).
SYNTHESIS EXAMPLE 2
Preparation of 2-chloro-N-[4,5-dichloro-2-[[ 1 -[(2E)-3-(4-chlorophenyl)-2-propen- 1 -yl]- 3-azetidinyl]oxy]phenyl]-4-pyridinecarboxamide (Compound 2)
Step A: Preparation of l-[(2E)-3-(4-chlorophenyl)-2-propen-l-yl]-3-azetidinol
A solution of epichlorohydrin (2.12 mL, 27.0 mmol) in 2-propanol (10 mL) was added to a solution of (2E)-3-(4-chlorophenyl)-2-propen-l -amine (J. Org. Chem. 1982, 5395; 4.52 g, 27 mmol) in 2-propanol (100 mL) at ambient temperature, and the mixture was stirred overnight. The reaction mixture was concentrated, and the residue was dissolved in acetonitrile (250 mL). Triethylamine (7.5 mL, 54 mmol) was added, and the mixture was heated at reflux for 2.5 h before being cooled and concentrated. The residue was treated with saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane (2x). The combined extracts were dried (MgSC^) and concentrated, and the residue was purified by chromatography (silica gel, gradient of EtOAc → 10% diethylamine / EtOAc) to give the title product as a white solid (2.44 g).
!H NMR δ 7.27 (AB pair of d, 4H), 6.46 (d, 1H), 6.12 (dt, 1H), 4.48 (quintet, 1H), 3.69 (m, 2H), 3.23 (dd, 2H), 2.95 (m, 2H).
Step B: Preparation of l-[(2E)-3-(4-chlorophenyl)-2-propen-l-yl]-3-(4,5-dichloro-
2-nitrophenoxy)azetidine
Sodium hydride (60%> in oil, 59 mg, 1.49 mmol) was added to a solution of 1-[(2E)- 3-(4-chlorophenyl)-2-propen-l-yl]-3-azetidinol (i.e. the product of Step A) (301 mg, 1.35 mmol) in N,N-dimethylformamide (5 mL) at ambient temperature. After stirring for 5 min, 1 ,2-dichloro-4-fluoro-5 -nitrobenzene (213 μΐ,, 1.62 mmol) was added, and the mixture was stirred overnight at ambient temperature. The mixture was diluted with ethyl acetate and washed with water (3x), and the organic phase was dried (MgS04) and concentrated. The residue was purified by chromatography (silica gel, gradient of 50%> EtOAc / hexanes→ 100% EtOAc) to give the title product as a yellow oil (0.23 g).
!H NMR δ 8.01 (s, 1H), 7.28 (AB pair of d, 4H), 6.90 (s, 1H), 6.50 (d, 1H), 6.13 (dt, 1H), 4.88 (quintet, 1H), 3.89 (m, 2H), 3.32 (dd, 2H), 3.24 (m, 2H).
Step C: Preparation of 4,5-dichloro-2-[[l-[(2E)-3-(4-chlorophenyl)-2-propen-l-yl]-
3 -azetidinyl]oxy]benzenamine
To a solution of l-[(2E)-3-(4-chlorophenyl)-2-propen-l-yl]-3-(4,5-dichloro- 2-nitrophenoxy)azetidine (i.e. the product of Step B) (0.13 g, 0.31 mmol) in ethanol- water (9: 1 by volume, 10 mL) was added ammonium chloride (10 mg, 0.19 mmol) and iron powder (10 μιη; 176 mg, 3.1 mmol), and the mixture was heated at reflux for 30 min before being cooled and filtered through a pad of Celite® diatomaceous filter aid. The Celite® was rinsed with dichloromethane, and the filtrate was washed with water. The aqueous phase was extracted with dichloromethane, and the combined organic extracts were dried (MgSOz^) and concentrated. The residue was purified by chromatography (silica gel, gradient of 40%> EtOAc containing 1% Et2NH / hexanes→ 70% EtOAc containing 1% Et2NH / hexanes) to give the title product as a yellow oil (0.09 g).
!H NMR δ 7.28 (m, 4H), 6.77 (d, 1H), 6.54 (d, 1H), 6.50 (m, 1H), 6.14 (m, 1H), 4.78 (m, 1H), 3.90-3.81 (m, 4H), 3.31 (m, 2H), 3.22 (m, 2H).
Step D: Preparation of 2-chloro-N-[4,5-dichloro-2-[[l-[(2E)-3-(4-chlorophenyl)-
2-propen- 1 -yl]-3-azetidinyl]oxy]phenyl]-4-pyridinecarboxamide A sample of 4,5-dichloro-2-[[l-[(2E)-3-(4-chlorophenyl)-2-propen-l-yl]-3-azetidinyl]- oxy]benzenamine (i.e. the product of Step C) (101 mg, 0.26 mmol) was dried by dissolution in toluene followed by concentration under reduced pressure. The residue was dissolved in N,N-dimethylformamide (2 mL) and treated sequentially with 2-chloro-4-pyridinecarboxylic acid (50 mg, 0.31 mmol), 4-methylmorpholine (116 μί, 1.04 mmol) and BOP reagent (233 mg, 0.52 mmol), and the mixture was then stirred overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate, washed with water (3x), dried (MgS04) and concentrated. The residue was purified by chromatography (silica gel, gradient of 40% EtOAc containing 1% Et2NH / hexanes→ 100% EtOAc containing 1% Et2NH) to give the title product, a compound of the present invention, as an orange solid (97 mg).
!H NMR δ 8.65 (s, 1H), 8.59 (d, 1H), 8.47 (br s, 1H), 7.78 (s, 1H), 7.63 (d, 1H), 7.27 (s,
4H), 6.75 (s, 1H), 6.49 (d, 1H), 6.12 (m, 1H), 4.87 (m, 1H), 3.80 (m, 2H), 3.35-3.29 (m,
4H).
SYNTHESIS EXAMPLE 3
Preparation of oxalate salt of 2-chloro-N-[4,5-dichloro-2-[[l-[(2E)-3-(4-chlorophenyl)-2- propen-l-yl]-3-azetidinyl]oxy]phenyl]-4-pyridinecarboxamide (Compound 3) Treatment of a solution of 2-chloro-N-[4,5-dichloro-2-[[l-[(2E)-3-(4-chlorophenyl)- 2-propen-l-yl]-3-azetidinyl]oxy]phenyl]-4-pyridinecarboxamide (i.e. the product of Example 2) (56 mg, 0.11 mmol) in dichloromethane (3 mL) with a solution of oxalic acid (4.8 mg, 53 μιηοΐ) in ethanol (100 μί), followed by concentration and trituration with ethyl ether gave the title oxalate salt product, a compound of the present invention, as a light brown solid (29 mg).
!H NMR (DMSO- ) δ 10.23 (br s, 1H), 8.63 (d, 1H), 8.06 (s, 1H), 7.97 (s, 1H), 7.87 (d, 1H), 7.47 (d, 2H), 7.40 (d, 2H), 7.24 (s, 1H), 6.71 (d, 1H), 6.28 (m, 1H), 5.12 (br s, 1H), 4.31 (br s, 2H), 3.82 (br s, 2H), 3.73 (br d, 2H).
SYNTHESIS EXAMPLE 4
Preparation of 2-chloro-N-[5-chloro-2-[[ 1 -[(2E)-3-(4-chlorophenyl)-2-propen- 1 -yl]-3- azetidinyl]oxy]-3-pyridinyl]-4-pyridinecarboxamide (Compound 16)
Step A: Preparation of 1,1-dimethylethyl 3-[(5-chloro-3-nitro-2-pyridinyl)oxy]-l- azetidinecarboxylate
To a solution of 5-chloro-3-nitro-2(lH)-pyridone (3.51 g, 20.1 mmol), 1,1-dimethylethyl 3 -hydroxy- 1-azetidinecarboxylate (3.48 g, 20.1 mmol) and triphenylphosphine (5.27 g, 24.1 mmol) in THF (100 mL) at 0 °C was added l,2-bis(l-methylethyl) 1,2-diazene- dicarboxylate (4.67 mL, 24.1 mmol), and the mixture was allowed to warm slowly to ambient temperature overnight. The mixture was then concentrated under reduced pressure and purified by chromatography (silica gel, 5% to 20% ethyl acetate in hexanes) to give the title product as a white solid (4.78 g).
!H NMR δ 8.32 (m, 2H), 5.42 (m, 1H), 4.35 (dd, 2H), 4.06 (dd, 2H), 1.45 (s, 9H). Step B : Preparation of 1 , 1 -dimethylethyl 3 - [(3 -amino-5 -chloro-2-pyridinyl)oxy] - 1 - azetidinecarboxylate
To a solution of 1,1 -dimethylethyl 3-[(5-chloro-3-nitro-2-pyridinyl)oxy]-l -azetidinecarboxylate (i.e. the product of Step A) (4.78 g, 14.5 mmol) in ethanol (45 mL) and water (5 mL) was added ammonium chloride (466 mg, 8.7 mmol) and iron powder (40 μιη, 8.12 g, 145 mmol), and then the mixture was heated at reflux for 1 h. The cooled mixture was diluted with dichloromethane and filtered through a pad of Celite® diatomaceous filter aid, eluting with dichloromethane. The filtrate was washed with water, dried (MgS04) and concentrated. The residue was filtered through a pad of silica gel, eluting with 30% ethyl acetate in hexanes, and the filtrate was concentrated to give the title product as a yellow foam (4.48 g).
!H NMR δ 7.43 (d, 1H), 6.89 (d, 1H), 5.31 (m, 1H), 4.33 (dd, 2H), 3.98 (dd, 2H), 3.89 (br s, 2H), 1.45 (s, 9H).
Step C: Preparation of 1,1 -dimethylethyl 3-[[5-chloro-3-[[(2-chloro-4- pyridinyl)carbonyl]amino]-2-pyridinyl]oxy]- 1 -azetidinecarboxylate
To a solution of 1,1 -dimethylethyl 3-[(3-amino-5-chloro-2-pyridinyl)oxy]-l -azetidinecarboxylate (i.e. the product of Step B) (1.80 g, 6.0 mmol) and triethylamine (1.25 mL, 9.0 mmol) in dichloromethane (20 mL) was added 2-chloro-4-pyridinecarbonyl chloride (0.79 mL, 6.6 mmol), and the reaction was stirred at ambient temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with dichloromethane (2x). The combined extracts were dried (MgSC^), and the residue after concentration was triturated with ethyl ether and then recrystallized from ethanol (60 mL) to give the title product as a pale yellow solid (1.80 g).
!H NMR δ 8.80 (d, 1H), 8.64 (d, 1H), 8.22 (br s, 1H), 7.85 (d, 1H), 7.77 (d, 1H), 7.60 (dd, 1H), 5.39 (m, 1H), 4.39 (dd, 2H), 4.01 (dd, 2H), 1.45 (s, 9H).
Step D: Preparation of 2-chloro-N-[5-chloro-2-[[l-[(2E)-3-(4-chlorophenyl)-
2-propen- 1 -yl] -3 -azetidinyljoxy] -3 -pyridinyl] -4-pyridinecarboxamide 1 , 1 -Dimethylethyl 3-[[5-chloro-3-[[(2-chloro-4-pyridinyl)carbonyl]amino]-2- pyridinyl]oxy]-l -azetidinecarboxylate (i.e. the product of Step C) (0.45 g) was treated with hydrogen chloride (5-6 N in isopropanol, 10 mL), and the mixture was vigorously stirred for 1 h. Dichloromethane (10 mL) was added, and the mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated in vacuo, treated with saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane (3χ). The combined organic phase was dried (MgSC^) and concentrated in vacuo to give a product containing N-[2-(3-azetidinyloxy)-5-chloro-3-pyridinyl]-2-chloro-4-pyridinecarboxamide as a white solid (0.18 g, approximately 50% pure), which was used without further purification. To a sample of this material (85 mg) was added (2E)-3-(4-chlorophenyl)-2-propenal (50 mg, 0.30 mmol), sodium triacetoxyborohydride (64 mg, 0.30 mmol), THF (3 mL) and acetic acid (17 μί), and the mixture was stirred at ambient temperature overnight. The mixture was treated with saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane (2x). The combined organic phase was dried (MgS04), and the residue after concentration was purified by chromatography (silica gel, 30% ethyl acetate (containing 1% Et2NH) in hexanes→ 1% Et2NH in ethyl acetate) to give the title product, a compound of the present invention (29 mg).
!H NMR δ 8.77 (d, 1H), 8.62 (d, 1H), 8.37 (br s, 1H), 7.84 (d, 1H), 7.78 (s, 1H), 7.63 (dd, 1H), 7.28 (s, 4H), 6.50 (d, 1H), 6.14 (dt, 1H), 5.34 (m, 1H), 3.83 (m, 2H), 3.35-3.30 (m, 4H).
SYNTHESIS EXAMPLE 5
Preparation of N-[2-[[l-[2-(4-bromophenoxy)ethyl]-3-azetidinyl]oxy]-5,6-dichloro-3- pyridinyl]-2-chloro-4-pyridinecarboxamide (Compound 80)
Step A: Preparation of 1,1-dimethylethyl 3-[(3-amino-5,6-dichloro-2-pyridinyl)oxy]- 1-azetidinecarboxylate
To 1,1 -dimethylethyl 3-[(3-amino-5-chloro-2-pyridinyl)oxy]- 1 -azetidinecarboxylate (i.e. the product of Example 4, Step B) (1.3 g, 4.34 mmol) in DMF (20 mL) was added N-chlorosuccinimide (608 mg, 4.56 mmol), and the reaction mixture was stirred at ambient temperature overnight. The mixture was diluted with ethyl ether and washed with water (3X) and dried (MgS04), and the residue after concentration was purified by chromatography (silica gel, 10% to 30% ethyl acetate in hexanes) to give the title product as an orange foam (0.85 g).
!H NMR δ 6.99 (s, 1H), 5.32 (m, 1H), 4.35 (dd, 2H), 3.98 (dd, 2H), 3.88 (br s, 2H), 1.45 (s, 9H).
Step B: Preparation of 1,1-dimethylethyl 3-[[5,6-dichloro-3-[[(2-chloro-
4-pyridinyl)carbonyl]amino]-2-pyridinyl]oxy]-l -azetidinecarboxylate
To a solution of 1,1-dimethylethyl 3-[(3-amino-5,6-dichloro-2-pyridinyl)oxy]- 1 -azetidinecarboxylate (i.e. the product of Step A) (0.85 g, 2.54 mmol) and triethylamine (531 μί, 3.81 mmol) in dichloromethane (20 mL) was added 2-chloro-4-pyridinecarbonyl chloride (0.36 mL, 2.54 mmol), and the reaction mixture was stirred at ambient temperature overnight. Water was added, and the mixture was extracted with dichloromethane (2x). The combined extracts were dried (MgSC^), and the residue after concentration was purified by chromatography (silica gel, 10% to 40% ethyl acetate in hexanes) to give a yellow foam. Trituration with ethyl ether gave the title product as a light brown solid (0.9 g).
¾ NMR δ 8.91 (s, 1H), 8.64 (d, 1H), 8.14 (s, 1H), 7.76 (d, 1H), 7.60 (dd, 1H), 5.41 (m, 1H), 4.42 (dd, 2H), 4.03 (dd, 2H), 1.46 (s, 9H). Step C: Preparation of N-[2-(3-azetidinyloxy)-5,6-dichloro-3-pyridinyl]-2-chloro-
4-pyridinecarboxamide
To 1,1 -dimethylethyl 3 -[ [5 ,6-dichloro-3 - [ [(2-chloro-4-pyridinyl)carbonyl] amino]- 2-pyridinyl]oxy]-l-azetidinecarboxylate (i.e. the product of Step B) (0.85 g) in dichloromethane (36 mL) was added hydrobromic acid (48% aqueous solution, 1.8 mL), and the mixture was vigorously stirred for 15 min. The supernatant was decanted, and the residue was carefully neutralized with saturated aqueous sodium hydrogencarbonate solution. The mixture was filtered, and the solid was dried in vacuo to give the title product as a yellow solid (0.4 g).
!H NMR (acetone-^) δ 8.76 (s, 1H), 8.61 (d, 1H), 7.91 (br s, 1H), 7.87 (br s, 1H), 5.18 (br s), 3.66 (br s, 2H), 3.34 (br s, 2H).
Step D: Preparation of N-[2-[[l-[2-(4-bromophenoxy)ethyl]-3-azetidinyl]oxy]-
5,6-dichloro-3-pyridinyl]-2-chloro-4-pyridinecarboxamide
l-Bromo-4-(2-bromoethoxy)benzene (95 mg, 0.34 mmol) was added to a mixture of N-[2-(3-azetidinyloxy)-5,6-dichloro-3-pyridinyl]-2-chloro-4-pyridinecarboxamide (i.e. the product of Step C) (100 mg, 0.28 mmol) and N,N-diisopropylethylamine (76 mL, 0.42 mmol) in acetonitrile (3 mL), and the reaction mixture was heated at 60 °C overnight. The cooled solution was treated with saturated aqueous sodium bicarbonate solution (2 mL) and water (2 mL), and then diluted with dichloromethane before being filtered through a tube containing Celite® diatomaceous filter aid, eluting with dichloromethane. The residue after concentration was purified by chromatography (silica gel, ethyl acetate to 5% methanol in ethyl acetate) to give the title product, a compound of the present invention, as a pale yellow oil (84 mg).
!H NMR δ 8.88 (s, 1H), 8.62 (d, 1H), 8.28 (br s, 1H), 7.77 (d, 1H), 7.62 (d, 1H), 7.37 (d, 2H), 6.78 (d, 2H), 5.35 (m, 1H), 3.99 (t, 2H), 3.92 (t, 2H), 3.42 (br s, 2H), 2.95 (t, 2H).
SYNTHESIS EXAMPLE 6
Preparation of 2-chloro-N-[6-chloro-2-[[l-[(2E)-3-(4-chlorophenyl)-l-methyl-2-propen-l- yl]-3-azetidinyl]oxy]-3-pyridinyl]-4-pyridinecarboxamide (Compound 17)
Step A: Preparation of 1,1 -dimethylethyl 3-[(6-chloro-3-nitro-2-pyridinyl)oxy]-l- azetidinecarboxylate
To a solution of 1,1 -dimethylethyl 3 -hydroxy- 1-azetidinecarboxylate (1.0 g, 5.78 mmol) and 2,6-dichloro-3-nitropyridine (1.12 g, 5.78 mmol) in toluene (20 mL) was added solid sodium hydroxide, and the mixture was stirred at ambient temperature overnight. The mixture was diluted with ethyl ether, washed with water and dried (MgSC^). The residue after concentration was purified by chromatography (silica gel, 5%> to 20%> ethyl acetate in hexanes) to give the title product as a pale yellow solid (1.21 g). in NMR δ 8.32 (d, 1H), 7.10 (d, 1H), 5.46 (m, 1H), 4.38 (dd, 2H), 4.08 (dd, 2H), 1.46 (s, 9H).
Step B : Preparation of 1 , 1 -dimethylethyl 3-[[6-chloro-3-[[(2-chloro-4-pyridinyl)- carbonyl]amino]-2-pyridinyl]oxy]- 1 -azetidinecarboxylate
To a solution of 1,1 -dimethylethyl 3-[(6-chloro-3-nitro-2-pyridinyl)oxy]-l -azetidinecarboxylate (i.e. the product of Step A) (1.21 g, 3.67 mmol) in a mixture of ethanol and water (9 : 1 by volume, 25 mL) was added ammonium chloride (118 mg, 2.20 mmol) and iron powder (40 um, 2.06 g, 36.7 mmol), and the mixture was heated at reflux for 1.5 h. The cooled mixture was diluted with dichloromethane and filtered through a pad of Celite® diatomaceous filter aid, eluting with dichloromethane. The filtrate was washed with water, dried (MgSC^) and concentrated. Toluene was added, and the resultant solution was again concentrated in vacuo. The residue containing 1,1 -dimethylethyl 3-[(3-amino-6-chloro- 2-pyridinyl)oxy]-l -azetidinecarboxylate was dissolved in dichloromethane (35 mL), and triethylamine (0.77 mL, 5.50 mmol) was added, followed by 2-chloro-4-pyridinecarbonyl chloride (0.48 mL, 4.04 mmol). The reaction was stirred at ambient temperature overnight. Water was added and the mixture was extracted with dichloromethane (2x). The combined extracts were dried (MgSC^), and the residue after concentration was purified by chromatography (silica gel, 10% to 40% ethyl acetate in hexanes) to give the title product (1.52 g).
!H NMR δ 8.70 (d, 1H), 8.63 (d, 1H), 8.17 (s, 1H), 7.77 (d, 1H), 7.60 (dd, 1H), 7.04 (d, 1H), 5.43 (m, 1H), 4.42 (dd, 2H), 4.03 (dd, 2H), 1.46 (s, 9H).
Step C: Preparation of N-[2-(3-azetidinyloxy)-6-chloro-3-pyridinyl]-2-chloro-
4-pyridinecarboxamide
To a solution of 1,1 -dimethylethyl 3-[[6-chloro-3-[[(2-chloro-4-pyridinyl)carbonyl]- amino]-2-pyridinyl]oxy]-l -azetidinecarboxylate (i.e. the product of Step B) (1.95 g) in dichloromethane (50 mL) was added hydrobromic acid (48%> aqueous solution, 4.45 mL), and the mixture was vigorously stirred for 15 min. The supernatant was decanted, and the residue was carefully neutralized with saturated aqueous sodium hydrogencarbonate solution. The aqueous phase was extracted with 10 vol. % methanol in dichloromethane and then with dichloromethane (4x). The combined extracts were dried (MgSOz}) and concentrated to give the title product (1.08 g, approximately 90%> pure), which was used in the next step without further purification.
!H NMR δ 8.68 (d, 1H), 8.61 (d, 1H), 8.30 (s, 1H), 7.78 (d, 1H), 7.63 (dd, 1H), 7.00 (d, 1H), 5.59 (m, 1H), 4.10 (dd, 2H), 3.78 (dd, 2H). Step D: Preparation of 2-chloro-N-[6-chloro-2-[[l-[(2E)-3-(4-chlorophenyl)-l- methyl-2-propen-l-yl]-3-azetidinyl]oxy]-3-pyridinyl]-4-pyridinecarboxamide To a solution of N-[2-(3-azetidinyloxy)-6-chloro-3-pyridinyl]-2-chloro-4-pyridine- carboxamide (i.e. the product of Step C) (79 mg, 0.23 mmol) was added (3E)-4-(4-chloro- phenyl)-3-buten-2-one (48 mg, 0.28 mmol), sodium triacetoxyborohydride (59 mg, 0.28 mmol), THF (3 mL) and acetic acid (16 μί), and the mixture was stirred at ambient temperature overnight. The mixture was treated with saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane (2x). The combined organic phase was dried (MgS04), and the residue after concentration was purified by chromatography (silica gel, 30% ethyl acetate (containing 1% Et2NH) in hexanes to 1% Et2NH in ethyl acetate) to give the title product, a compound of the present invention (21 mg).
!H NMR δ 8.66 (d, 1H), 8.61 (d, 1H), 8.31 (br s, 1H), 7.78 (d, 1H), 7.63 (dd, 1H), 7.28 (s, 4H), 7.00 (d, 1H), 6.48 (d, 1H), 6.01 (dd, 1H), 5.31 (m, 1H), 3.78 (m, 2H), 3.31 (m, 2H), 3.01 (m, 1H), 1.16 (d, 3H).
SYNTHESIS EXAMPLE 7
Preparation of N-[6-amino-5-chloro-2-[[ 1 -[(2E)-3-(4-chlorophenyl)-2-propen- 1 -yl]- 3-azetidinyl]oxy]-3-pyridinyl]-2-chloro-4-pyridinecarboxamide (Compound 92)
Step A: Preparation of 3-chloro-2,6-difluoro-5-nitropyridine
To a solution of 3-chloro-2,6-difluoropyridine (4.94 g, 33.0 mmol) in fuming nitric acid (density 1.5 g/mL, 40 mL) was added sulfuric acid (30 mL) dropwise. The temperature of the reaction mixture rose to 38 °C. The mixture was then heated at 60 °C for 1.5 h before being cooled, poured over ice and extracted with hexane (2x). Concentration of the hexane extracts gave the title product as yellow crystals (3.7 g). Extraction of the aqueous layer with dichloromethane, followed by drying (MgSC^) and concentration of the extract provided additional product (2.45 g).
lH NMR δ 8.71 (t, 1H).
Step B : Preparation of 1 , 1 -dimethylethyl 3 - [(5 -chloro-6-fluoro-3 -nitro-2- pyridinyl)oxy]- 1 -azetidienecarboxylate
3-Chloro-2,6-difluoro-5-nitropyridine (i.e. the product of Step A) (3.7 g, 19.0 mmol),
3-hydroxyazetidine (3.29 g, 1 equiv) and sodium carbonate (3.02 g, 1.5 equiv) were combined in toluene (50 mL), and the resultant mixture was stirred at ambient temperature overnight. The mixture was then diluted with ethyl ether, washed with water (3X) and dried (MgSOzj). The residue after concentration was purified by chromatography (silica gel, 5% to 15% ethyl acetate in hexanes) to give the title product (0.68 g, 80%> pure) which was used in the next step without further purification.
!H NMR δ 8.56 (d, 1H), 5.39 (m, 1H), 4.38 (m, 2H), 4.08 (m, 2H), 1.45 (s, 9H). Step C : Preparation of 1 , 1 -dimethylethyl 3-[[6-amino-5-chloro-3-[[(2-chloro-
4-pyridinyl)carbonyl]amino]-2-pyridinyl]oxy]-l-azetidinecarboxylate
A mixture of 1,1 -dimethylethyl 3-[(5-chloro-6-fluoro-3-nitro-2-pyridinyl)oxy]-
1- azetidienecarboxylate (i.e. the product of Step B) (0.68 g) in fert-butanol (18 mL) and water (2 mL) was treated with iron powder (40 μιη, 1.1 g, 19.6 mmol)) and ammonium chloride (63 mg, 1.18 mmol), and the resultant mixture was heated at reflux for 50 min. The cooled mixture was diluted with dichloromethane and filtered through a pad of Celite® diatomaceous filter aid, eluting with dichloromethane. The eluent was washed with water, dried (MgS04) and concentrated. The residue was dissolved in toluene and again concentrated. The residue was then re-dissolved in dichloromethane (20 mL), and 4-(dimethylamino)pyridine (24 mg, 0.20 mmol), triethylamine (0.68 mL, 4.9 mmol) and
2- chloro-4-pyridinecarbonyl chloride (500 mg) were added. The mixture was stirred 3 days at ambient temperature before being treated with 1 N aqueous sodium hydroxide solution. After a further 15 min, the mixture was separated, and the organic phase was dried (MgS04) and concentrated. The compounds in the residue were separated by chromatography (silica gel, gradient of 10%→ 40% ethyl acetate in hexanes) to provide 1,1 -dimethylethyl 3-[[5- chloro-3-[[(2-chloro-4-pyridinyl)carbonyl]amino]-6-fluoro-2-pyridinyl]oxy]-l-azetidine- carboxylate (0.37 g) and the title product (0.16 g).
!H NMR δ 8.59 (d, 1H), 8.56 (s, 1H), 7.92 (br s, 1H), 7.74 (s, 1H), 7.59 (dd, 1H), 5.29 (m, 1H), 4.67 (br s, 2H), 4.34 (dd, 2H), 4.00 (dd, 2H), 1.45 (s, 9H).
Step D : Preparation of N- [6-amino-2-( 1 -azetidinyloxy)-5 -chloro-3 -pyridinyl] -
2-chloro-4-pyridinecarboxamide
To a solution of 1,1 -dimethylethyl 3-[[6-amino-5-chloro-3-[[(2-chloro-4-pyridinyl)- carbonyl]amino]-2-pyridinyl]oxy]-l-azetidinecarboxylate (i.e. the product of Step C) (0.16 g) in dichloromethane (7 mL) was added hydrobromic acid (48%> aqueous solution, 0.35 mL), and the resultant mixture was stirred at ambient temperature for 15 min. The organic phase was decanted, and the residue was treated with saturated aqueous sodium hydrogencarbonate. The aqueous phase was extracted (2x) with 10% methanol in dichloromethane. The combined extracts were dried (MgSC^) and concentrated to provide the title product as a yellow solid (0.06 g).
!H NMR (DMSO- ) δ 9.97 (br s, 1H), 8.61 (d, 1H), 7.94 (s, 1H), 7.84 (dd, 1H), 7.69 (s, 1H), 6.26 (br s, 2H), 5.22 (m, 1H), 3.74 (t, 2H), 3.52 (t, 2H).
Step E: Preparation of N-[6-amino-5-chloro-2-[[l-[(2E)-3-(4-chlorophenyl)-2-propen-
1 -yl] -3 -azetidinyljoxy] -3 -pyridinyl]-2-chloro-4-pyridinecarboxamide
A solution of N-[6-amino-2-(l-azetidinyloxy)-5 -chloro-3 -pyridinyl] -2-chloro-
4-pyridinecarboxamide (i.e. the product of Step D) (57 mg, 0.16 mmol) in THF (3 mL) was treated with 3-(4-chlorophenyl)-2-propenal (32 mg, 1.2 equiv), sodium triacetoxy- borohydride (41 mg, 1.2 equiv) and acetic acid (11 μί, 1.2 equiv), and the resultant mixture was stirred overnight at ambient temperature. The mixture was treated with 1 N aqueous sodium hydroxide and then extracted (2x) with dichloromethane. The organic phase was dried (MgS04), and the residue after concentration was purified by chromatography (silica gel, EtOAc to 5% MeOH in EtOAc) to give the title product, a compound of the present invention (17 mg).
!H NMR δ 8.58 (d, 1H), 8.55 (s, 1H), 7.98 (br s, 1H), 7.74 (s, 1H), 7.60 (d, 1H), 7.28 (s, 4H), 6.49 (dt, 1H), 6.14 (dt, 1H), 5.23 (m, 1H), 4.63 (br s, 2H), 3.82 (m, 2H), 3.31 (d, 2H), 3.25 (m, 2H).
SYNTHESIS EXAMPLE 8
Preparation of 2-chloro-N-[6-chloro-3-[[l-[(2E)-3-(4-chlorophenyl)-2-propen-l-yl]- 3-azetidinyl]oxy]-4-pyridazinyl]-4-pyridinecarboxamide (Compound 96)
Step A: Preparation of 1 , 1 -dimethylethyl 3-[(4-amino-6-chloro-3-pyridazinyl)oxy]-
1 -azetidinecarboxylate
A solution of 1,1-dimethylethyl 3 -hydroxy- 1 -azetidinecarboxylate (3.8 g, 22.0 mmol) in DMF (100 mL) was treated with sodium hydride (60% in oil, 805 mg, 18.3 mmol), and the resultant mixture was stirred at ambient temperature for 10 min. 3,6-Dichloro- 4-pyridazinamine (3.0 g, 18.3 mmol) was added, and the mixture was stirred at 90 °C overnight. The cooled mixture was diluted with ethyl acetate and washed with water (3x), brine and dried (MgSC^). The residue after concentration was purified by chromatography (silica gel, gradient of 20%→ 50% EtOAc in hexanes) followed by trituration with ethyl ether to give the title product as a white solid (1.6 g).
!H NMR (acetone-^) δ 6.71 (s, 1H), 6.18 (br s, 2H), 5.46 (m, 1H), 4.32 (br m, 2H), 3.95 (m, 2H), 1.42 (s, 9H).
Step B : Preparation of 1 , 1 -dimethylethyl 3-[[6-chloro-4-[[(2-chloro-4-pyridinyl)- carbonyl]amino]-3-pyridazinyl]oxy]-l -azetidinecarboxylate
A solution of 1,1-dimethylethyl 3 -[(4-amino-6-chloro-3-pyridazinyl)oxy]-l -azetidinecarboxylate (i.e. the product of Step A) (1.55 g, 5.16 mmol) in dichloromethane (40 mL) was treated with 4-(dimethylamino)pyridine (63 mg, 0.1 equiv), triethylamine (2.15 mL, 3 equiv) and 2-chloro-4-pyridinecarbonyl chloride (1.32 g), and the resultant mixture was stirred at ambient temperature overnight. 1 N aqueous sodium hydroxide was added, and the mixture was stirred for a further 10 min before being extracted (2x) with dichloromethane. The combined organic phase was dried (MgSC^), and the residue after concentration was purified by chromatography (silica gel, gradient of 30%→ 60% ethyl acetate in hexanes) to give the title product as a yellow solid (1.42 g).
!H NMR δ 8.67 (d, 1H), 8.56 (s, 1H), 8.43 (br s, 1H), 7.77 (m, 1H), 7.61 (dd, 1H), 5.59 (m, 1H), 4.46 (dd, 2H), 4.07 (m, 2H), 1.45 (s, 9H). Step C: Preparation of N-[3-(3-azetidinyloxy)-6-chloro-4-pyridazinyl]-2-chloro-
4-pyridinecarboxamide
A solution of 1,1-dimethylethyl 3-[[6-chloro-4-[[(2-chloro-4-pyridinyl)carbonyl]- amino]-3-pyridazinyl]oxy]-l-azetidinecarboxylate (i.e. the product of Step B) (1.36 g, 3.09 mmol) in dichloromethane (60 mL) was treated with hydrobromic acid (48% aqueous solution, 3.1 mL), and the resultant mixture was stirred at ambient temperature for 15 min. The organic phase was decanted, and the residue was treated with a saturated aqueous sodium hydrogencarbonate. The resulting solid was filtered, washed with water and dried in vacuo to give the title product (0.80 g).
!H NMR (DMSO- ) δ 8.51 (s, 1H), 8.38 (s, 1H), 7.96 (s, 1H), 7.91 (s, 1H), 5.43 (m, 1H), 4.28 (t, 2H), 4.02 (m, 2H).
Step D: Preparation of of 2-chloro-N-[6-chloro-3-[[l-[(2E)-3-(4-chlorophenyl)-
2-propen-l-yl]-3-azetidinyl]oxy]-4-pyridazinyl]-4-pyridinecarboxamide N-[3-(3-Azetidinyloxy)-6-chloro-4-pyridazinyl]-2-chloro-4-pyridinecarboxamide (i.e. the product of Step C) (110 mg, 0.32 mmol) in THF (3 mL) was treated with 3-(4-chlorophenyl)-2-propenal (65 mg, 1.2 equiv), sodium triacetoxyborohydride (82 mg, 1.2 equiv) and acetic acid (22 μί, 1.2 equiv), and the resultant mixture was stirred overnight at ambient temperature. The mixture was treated with 1 N aqueous sodium hydroxide and then extracted (2x) with dichloromethane. The organic phase was dried (MgSC^) and the residue after concentration was purified by chromatography (silica gel, gradient of EtOAc→ 5% MeOH in EtOAc) to provide the title product, a compound of the present invention, as a white solid (44 mg).
!H NMR δ 8.65 (d, 1H), 8.53 (br s, 2H), 7.78 (s, 1H), 7.63 (dd, 1H), 7.28 (s, 4H), 6.50 (d, 1H), 6.13 (dt, 1H), 5.55 (m, 1H), 3.85 (m, 2H), 3.43 (dd, 2H), 3.34 (d, 2H).
By the procedures described herein together with methods known in the art, the following compounds of Tables 1 to 118 can be prepared. The following abbreviations are used in the Tables which follow: Me means methyl, and Et means ethyl. A dash ("-") specified for a substituent, e.g., (R3)n or (R13)c, denotes absence of the substituent.
Figure imgf000055_0001
2
Figure imgf000055_0002
Figure imgf000056_0001
The present disclosure also includes Tables 2 through 30, each of which is constructed the same as Table 1 above, except that the row heading in Table 1 (i.e. "A1 is CH; R2 is H; R10 is H; (R1 )a is 2-Cl; s is 1 ; and t is 1") is replaced with the respective row heading shown below. For Example, in Table 2 the row heading is "A1 is CH; R2 is H; R10 is H; (R14)a is 2,5-di-Cl; s is 1 and t is 1", and R8, R9 and R22 are as defined in Table 1 above. Thus, the first entry in Table 2 specifically discloses 2,5-dichloro-N-[2-[[l-[(2E)- 3 -(4-chlorophenyl)-2-propen- 1 -yl] -3 -azetidinyljoxy] -4,5 -difluorophenyl]-4-pyridine- carboxamide. Tables 3 through 30 are constructed similarly.
Table Row Heading
2 is CH R2 is H; R10 is H; (R14)a is 2,5-di-Cl; s is 1; and t is 1.
3 is CH; R2 is H; R10 is H; (R14)a is 2,6-di-Cl; s is 1; and t is 1.
4 is CH; R2 is H; R10 is H; (R14)a is 2-Cl, 5-F; s is 1 ; and t is 1.
5 is CH; R2 is H; R10 is H; (R14)a is 2-Cl, 6-F; s is 1 ; and t is 1.
6 is CH; R2 is H; R10 is H; (R14)a is 2-F; s is 1 ; and t is 1.
7 is CH; R2 is H; R10 is H; (R14)a is 2-F, 5-Cl; s is 1; and t is 1.
8 is CH; R2 is H; R10 is H; (R14)a is 2,5-di-F; s is 1 ; and t is 1.
9 is CH; R2 is H; R10 is H; (R14)a is 2,6-di-F; s is 1 ; and t is 1.
10 is CH; R2 is H; R10 is CI; (R14)a is 2-Cl; s is 1 ; and t is 1.
1 1 is CH; R2 is Me; R10 is H; (R14)a is 2-Cl; s is 1 ; and t is 1.
12 is CH; R2 is MeOC(O)-; R10 is H; (R14)a is 2-Cl; s is 1 ; and t is 1.
13 is CH; R2 is EtOCH2-; R10 is H; (R14)a is 2-Cl; s is 1 ; and t is 1.
14 is CF; R2 is H; R10 is H; (R14)a is 2-Cl; s is 1 ; and t is 1.
15 is CH; R2 is H; R10 is F; (R14)a is 2-Cl; s is 1 ; and t is 1.
16 is CH; R2 is H; R10 is H; (R14)a is 2-CF3; s is 1 ; and t is 1.
17 is N; R2 is H; R10 is H; (R14)a is 2-Cl; s is 1 ; and t is 1.
18 is N; R2 is H; R10 is H; (R14)a is 2,5-di-Cl; s is 1 ; and t is 1. Row Heading
A is N; Rz is H R10 is H; (R14)a is 2,6-di-Cl; s is 1; and t is 1.
IS H R10 is H; (R14)a is 2-Cl, 5-F; s is 1; and t is 1.
A1 is N; R2 is H R10 is H; (R14)a is 2-Cl, 6-F; s is 1 ; and t is 1..
A1 is N; R2 is H R10 is H; (R14)a is 2-F; s is 1; and t is 1.
A1 is N; R2 is H; R10 is H; (R14)a is 2-F, 5-Cl; s is 1; and t is 1.
A1 is N; R2 is H; R10 is H; (R14)a is 2,5-di-F; s is 1; and t is 1.
A is N; R2 is H; R10 is H; (R14)a is 2,6-di-F; s is 1; and t is 1.
A is N; R2 is H; R10 is CI; (R14)a is 2-Cl; s is 1; and t is 1.
A is N; R2 is Me; R10 is H; (R14)a is 2-Cl; s is 1 ; and t is 1.
A is : R2 is MeOC(O)-; R10 is H; (R14)a is 2-Cl; s is 1 ; and t is 1.
A is N R2 is EtOCH2-; R10 is H; (R14)a is 2-Cl; s is 1; and t is 1.
A is N R2 is H; R10 is H; (R14)a is 2-CF3; s is 1; and t is 1.
A is CH R2 is H R10 is H; (R14)a is 2-Cl; s is 2; and t is 2.
A is CH R2 is H R10 is H; (R14)a is 2-F; s is 2; and t is 2.
A is CH R2 is H R10 is H; (R14)a is 2-CF3; s is 2; and t is 2.
A is N R2 is H R10 is H; (R14)a is 2-Cl; s is 2; and t is 2.
A is R2 is H R10 is H; (R14)a is 2-F; s is 2; and t is 2.
A is N: R2 is H . R10 is H; (R14)a is 2-CF3; s is 2; and t is 2.
A is CH; R2 is H; R10 is H; (R14)a is 2-Cl; s is 2; and t is 1.
A1 is N; R2 is H; R10 is H; (R14)a is 2-Cl; s is 2; and t is 1.
A1 is CH; R2 is H; R10 is H; (R14)a is 2-Cl; s is 3; and t is 1.
A1 is N; R2 is H; R10 is H; (R14)a is 2-Cl; s is 3; and t is 1.
Figure imgf000057_0001
A1 is CH; R2 is H; R10 is H; and (R14)a is 2-Cl.
R8 R9 R22 R8 R9 R22 R8 R9 R22
F F CI F F Br F F H
F H CI F H Br F H H
Figure imgf000058_0001
The present disclosure also includes Tables 42 through 70, each of which is constructed the same as Table 41 above, except that the row heading in Table 41 (i.e. "A1 is CH; R2 is H; R10 is H; and (R1 )a is 2-CL") is replaced with the respective row heading shown below. For Example, in Table 40 the row heading is "A1 is CH; R2 is H; R10 is H; and (R14)a is 2,5-di-CL", and R8, R9 and R22 are as defined in Table 41 above. Thus, the first entry in Table 40 specifically discloses 2,5-dichloro-N-[2-[[l-[(4'-chloro[l,l'-biphenyl]- 4-yl)methyl]-3-azetidinyl]oxy]-4,5-difluorophenyl]-4-pyridinecarboxamide. Tables 43 through 70 are constructed similarly.
Row Heading
is CH; R2 is H; R10 is H; and (R14)a is 2,5-di-Cl.
is CH; R2 is H; R10 is H; and (R14)a is 2,6-di-Cl
is CH; R2 is H; R10 is H; and (R14)a is 2-Cl, 5-F.
is CH; R2 is H; R10 is H; and (R14)a is 2-Cl, 6-F.
is CH; R2 is H; R10 is H; and (R14)a is 2-F.
is CH; R2 is H; R10 is H; and (R14)a is 2-F, 5-Cl.
is CH; R2 is H; R10 is H; and (R14)a is 2,5-di-F.
is CH; R2 is H; R10 is H; and (R14)a is 2,6-di-F.
is CH; R2 is H; R10 is CI; and (R14)a is 2-Cl.
is CH; R2 is Me; R10 is H; and (R14)a is 2-Cl.
is CH; R2 is MeOC(O)-; R10 is H; and (R14)a is 2
is CH; R2 is EtOCH2-; R10 is H; and (R14) L. is 2-Cl.
is CF; R2 is H; n R 1100 i *s H; and ι
Figure imgf000059_0001
i *s 2 <->- /C~l.
is CH; R2 is H; R10 is F; and (R14)a is 2-Cl.
is CH; R2 is H; R10 is H; and (R14)a is 2-CF3.
is N; R2 is H; R10 is H; and (R14)a is 2-Cl.
is N; R2 is H; R10 is H; and (R14)a is 2,5-di-Cl.
is N; R2 is H; R10 is H; and (R14)a is 2,6-di-Cl.
is N; R2 is H; R10 is H; and (R14)a is 2-Cl, 5-F.
is N; R2 is H; R10 is H; and (R14)a is 2-Cl, 6-F.
is N; R2 is H; R10 is H; and (R14)a is 2-F.
is N; R2 is H; R10 is H; and (R14)a is 2-F, 5-Cl.
is N; R2 is H; R10 is H; and (R14)a is 2,5-di-F.
is N; R2 is H; R10 is H; and (R14)a is 2,6-di-F.
is N; R2 is H; R10 is CI; and (R14)a is 2-Cl.
is N; R2 is Me; R10 is H; and (R14)a is 2-CL
is N; R2 is MeOC(O)-; R10 is H; and (R14)a is 2-Cl.
is N; R2 is EtOCH2-; R10 is H; and (R14)a is 2-Cl.
is N; R2 is H; R10 is H; and (R14)a is 2-CF3.
Figure imgf000060_0001
Al (R22)b (R13)c Al (R22)b (R13)c Al (R22)b (R13)c
CH 4-Cl 2-F CH 2,6-di-F, 4-Cl 2-F N 2-F, 4-Cl 2-F
CH 4-Cl 3-F CH 2,6-di-F, 4-Cl 3-F N 2-F, 4-Cl 3-F
CH 2-F, 4-Cl CH 4-Cl 2-Me N 2,6-di-F, 4-Cl
CH 2-F, 4-Cl 2-F N 4-Cl 2-F N 2,6-di-F, 4-Cl 2-F
CH 2-F, 4-Cl 3-F N 4-Cl 3-F N 2,6-di-F, 4-Cl 3-F
CH 2,6-di-F, 4-Cl N 2-F, 4-Cl N 4-Cl 2-Me
Figure imgf000060_0002
Al is CH; (R3)N is 2-Me; and R4, R11 and R!2 are H.
R8 R9 R8 R9 R8 R9 R8 R9
F F F CF3 Br CI H F
F H Br CF3 CF3 CI H Br
H CI H CF3 CF3 F H CF3
CI H CI F CI Br I H
CI CI CF3 H H H CH3 H
CI CF3 Br F Br H CF2HO H The present disclosure also includes Tables 73 through 85, each of which is constructed the same as Table 72 above, except that the row heading in Table 72 (i.e. "Al is CH; (R )n is 2-Me; and R11 and R12 are H.") is replaced with the respective row heading shown below. For Example, in Table 73 the row heading is "A1 is CH; (R )n is 3-Me; and R1 1 and R12 are H.", and R8 and R9 are as defined in Table 72 above. Thus, the first entry in Table 73 specifically discloses 2-chloro-N-[2-[[l-[(2E)-3-(4-chlorophenyl)-2-propen-l-yl]- 3-methyl-3-azetidinyl]oxy]-4,5-difluorophenyl]-4-pyridinecarboxamide. Tables 74 through 85 are constructed similarly.
Table Row Heading
73 is CH; (R3)n is 3-Me; and R4, R1 1 and R12 are H.
74 is CH; (R3)n is "-" (n is 0); R4 is Me; and R1 1 and R12 are H.
75 is CH; (R3)n is "-" (n is 0); R4 and R12 are H; and R1 1 is F.
76 is CH; (R3)n is "-" (n is 0); R4 and R1 1 are H; and R12 is F.
77 is CH; (R3)n is "-" (n is 0); R4 and R12 are H; and R1 1 is Me.
78 is CH; (R3)n is "-" (n is 0); R4 and R1 1 are H; and R12 is Me.
79 is N: (R3)n is 2-Me; and R4, R1 1 and R12 are H.
80 is N: (R3)n is 3-Me; and R4, R1 1 and R12 are H.
81 is N: (R )n is "- -" " ((nn iiss 00)); R4 is Me; and R1 1 and R12 are H.
82 is N: (R )n is "- " " ((nn iiss 00)); R4 and R12 are H; and R1 1 is F.
83 is N: (R )n is "- " " ((nn iiss 00)); R4 and R1 1 are H; and R12 is F.
84 is N: (R )n is "- " " ((nn iiss 00)); R4 and R12 are H; and R1 1 is Me.
85 is N: (R3)n is "- -" " ((nn iiss 00)); R4 and R1 1 are H; and R12 is Me.
TABLE 86
Figure imgf000061_0001
A1 is CH; (R3)n is 2-Me; and R4 is H.
R8 R9 R8 R9 R8 R9 R8 R9
F F F CF3 Br CI H F
F H Br CF3 CF3 CI H Br
H CI H CF3 CF3 F H CF3
CI H CI F CI Br I H
CI CI CF3 H H H CH3 H
CI CF3 Br F Br H CF2HO H The present disclosure also includes Tables 87 through 91, each of which is constructed the same as Table 86 above, except that the row heading in Table 86 (i.e. "A1 is CH; (R )n is 2-Me; and R4 is H.") is replaced with the respective row heading shown below. For Example, in Table 87 the row heading is "A1 is CH; (R )n is 3-Me; and R4 is H.", and R8 and R9 are as defined in Table 86 above. Thus, the first entry in Table 87 specifically discloses 2-chloro-N-[4,5-difluoro-2-[[l-[(4'-fluoro[l, -biphenyl]-4-yl)methyl]-3-methyl-3- azetidinyl]oxy]phenyl]-4-pyridinecarboxamide. Tables 88 through 91 are constructed similarly.
Table Row Heading
87 A1 is CH; (R3)n is 3-Me; and R4 is H.
88 A1 is CH; (R3)n is "-" (n is 0); and R4 is Me.
89 A1 is N; (R3)n is 2-Me; and R4 is H.
90 A1 is N; (R3)n is 3-Me; and R4 is H.
91 A1 is N; (R3)n is "-" (n is 0); and R4 is Me.
TABLE 92
Figure imgf000062_0001
Figure imgf000062_0002
Figure imgf000063_0001
The present disclosure also includes Tables 93 through 110, each of which is constructed the same as Table 92 above, except that the row heading in Table 92 (i.e. "A1 is CH; R34 is H; Z is CH; s is 1; and t is 1.") is replaced with the respective row heading shown below. For Example, in Table 93 the row heading is "A1 is N; R34 is H; Z is CH; s is 1; and t is 1.", and R8, R9 and R22 are as defined in Table 92 above. Thus, the first entry in Table 93 specifically discloses 2-chloro-N-[2-[[l-[2-(4-chlorophenoxy)ethyl]-3-azetidinyl]oxy]- 5,6-difluoro-3-pyridinyl]-4-pyridinecarboxamide. Tables 94 through 110 are constructed similarly.
Table Row Heading
93 A1 is N; R34 is H; Z is CH; s is 1; and t is 1.
94 A1 is CH; R34 is Me; Z is CH; s is 1; and t is 1. Table Row Heading
95 A1 is N; R34 is Me; Z is CH; s is 1; and t is 1.
96 A1 is CH;R34is H;ZisN;sis l;andtis 1.
97 A1 is N; R34 is H; Z is N; s is 1 ; and t is 1.
98 A1 is CH;R34is Me;ZisN;sis l;andtis 1.
99 A1 is ; R34 is Me; Z isN; s is 1; and t is 1.
100 A1 is CH; R34 is H; Z is CH; s is 2; and t is 2.
101 A1 is N; R34 is H; Z is CH; s is 2; and t is 2.
102 A1 is CH; R34 is Me; Z is CH; s is 2; and t is 2.
103 A1 is N; R34 is Me; Z is CH; s is 2; and t is 2.
104 A1 is CH; R34 is H; Z is CH; s is 2; and t is 1.
105 A1 is N; R34 is H; Z is CH; s is 2; and t is 1.
107 A1 is CH; R34 is Me; Z is CH; s is 2; and t is 1.
108 A1 is N; R34 is Me; Z is CH; s is 2; and t is 1.
109 A1 is CH; R34 is H; Z is CH; s is 3; and t is 1.
110 A1 is N; R34 is Me; Z is CH; s is 3; and t is 1.
Figure imgf000064_0001
Figure imgf000064_0002
Figure imgf000065_0001
The present disclosure also includes Tables 112 through 114, each of which is constructed the same as Table 111 above, except that the row heading in Table 111 (i.e. "R22b is 2-F; and R34 is H.") is replaced with the respective row heading shown below. For Example, in Table 112 the row heading is "R22b is 3-F; and R34 is H." and R8, R9 and R22a are as defined in Table 111 above. Thus, the first entry in Table 112 specifically discloses
2- chloro-N-[2-[[l-[2-(4-chloro-3-fluorophenoxy)ethyl]-3-azetidinyl]oxy]-5,6-difluoro-
3- pyridinyl]-4-pyridinecarboxamide. Tables 113 through 114 are constructed similarly.
Table Row Heading
112 R22b is 3_F. and R34 is H Table Row Heading
113 R22b is 2-F; and R34 is Me.
114 R22b is 3_F. and R34 is Me_
TABLE 115
Figure imgf000066_0001
The present disclosure also includes Tables 116 through 118, each of which is constructed the same as Table 115 above, except that the row heading in Table 115 (i.e. "s is 1; and t is 1.") is replaced with the respective row heading shown below. For example, in Table 116 the row heading is "s is 2; and t is 2.", and R9, R14 and R22 are as defined in Table 115 above. Thus, the first entry in Table 116 specifically discloses 2-chloro-N-[6-chloro- 3-[[ 1 -[(2E)-3-(4-f uorophenyl)-2-propen- 1 -yl]-4-piperidinyl]oxy]-4-pyridazinyl]-4-pyridine- carboxamide. Tables 117 through 118 are constructed similarly.
Table Row Heading
116 s is 2; and t is 2.
117 s is 2; and t is 1
118 s is 3; and t is 1. Formulation/Utility
A compound of this invention will generally be used as an invertebrate pest control active ingredient in a composition, i.e. formulation, with at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents, which serves as a carrier. 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 both liquid and solid compositions. Liquid compositions include solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions and/or suspoemulsions) and the like, which optionally can be thickened into gels. The general types of aqueous liquid compositions are soluble concentrate, suspension concentrate, capsule suspension, concentrated emulsion, microemulsion and suspo-emulsion. The general types of nonaqueous liquid compositions are emulsifiable concentrate, microemulsifiable concentrate, dispersible concentrate and oil dispersion.
The general types of solid compositions are dusts, powders, granules, pellets, prills, pastilles, tablets, filled films (including seed coatings) and the like, which can be water-dispersible ("wettable") or water-soluble. Films and coatings formed from film- forming solutions or flowable suspensions are particularly useful for seed treatment. 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. An emulsifiable granule combines the advantages of both an emulsifiable concentrate formulation and a dry granular formulation. High-strength compositions are primarily used as intermediates for further formulation.
Sprayable formulations are typically extended in a suitable medium before spraying.
Such liquid and solid formulations are formulated to be readily diluted in the spray medium, usually water. Spray volumes can range from about one to several thousand liters per hectare, but more typically are in the range from about ten to several hundred liters per hectare. Sprayable formulations can be tank mixed with water or another suitable medium for foliar treatment by aerial or ground application, or for application to the growing medium of the plant. Liquid and dry formulations can be metered directly into drip irrigation systems or metered into the furrow during planting. Liquid and solid formulations can be applied onto seeds of crops and other desirable vegetation as seed treatments before planting to protect developing roots and other subterranean plant parts and/or foliage through systemic uptake.
The formulations will typically contain effective amounts of active ingredient, diluent and surfactant within the following approximate ranges which add up to 100 percent by weight. Weight Percent
Active
Ingredient Diluent Surfactant
Water-Dispersible and Water- 0.001-90 0-99.999 0-15
soluble Granules, Tablets and
Powders
Oil Dispersions, Suspensions, 1-50 40-99 0-50
Emulsions, Solutions
(including Emulsifiable
Concentrates)
Dusts 1-25 70-99 0-5
Granules and Pellets 0.001-99 5-99.999 0-15
High Strength Compositions 90-99 0-10 0-2
Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, gypsum, cellulose, titanium dioxide, zinc oxide, starch, dextrin, sugars (e.g., lactose, sucrose), silica, talc, mica, diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate, and sodium sulfate. Typical solid diluents are described in Watkins et al., Handbook of Insecticide Dust Diluents and Carriers, 2nd Ed., Dorland Books, Caldwell, New Jersey.
Liquid diluents include, for example, water, N,N-dimethylalkanamides (e.g., N,N-dimethylformamide), limonene, dimethyl sulfoxide, N-alkylpyrrolidones (e.g., N-methylpyrrolidinone), ethylene glycol, triethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, propylene carbonate, butylene carbonate, paraffins (e.g., white mineral oils, normal paraffins, isoparaffins), alkylbenzenes, alkylnaphthalenes, glycerine, glycerol triacetate, sorbitol, aromatic hydrocarbons, dearomatized aliphatics, alkylbenzenes, alkylnaphthalenes, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy- 4-methyl-2-pentanone, acetates such as isoamyl acetate, hexyl acetate, heptyl acetate, octyl acetate, nonyl acetate, tridecyl acetate and isobornyl acetate, other esters such as alkylated lactate esters, dibasic esters and γ-butyrolactone, and alcohols, which can be linear, branched, saturated or unsaturated, such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutyl alcohol, n-hexanol, 2-ethylhexanol, n-octanol, decanol, isodecyl alcohol, isooctadecanol, cetyl alcohol, lauryl alcohol, tridecyl alcohol, oleyl alcohol, cyclohexanol, tetrahydrofurfuryl alcohol, diacetone alcohol and benzyl alcohol. Liquid diluents also include glycerol esters of saturated and unsaturated fatty acids (typically C6-C22), such as plant seed and fruit oils (e.g., oils of olive, castor, linseed, sesame, corn (maize), peanut, sunflower, grapeseed, safflower, cottonseed, soybean, rapeseed, coconut and palm kernel), animal-sourced fats (e.g., beef tallow, pork tallow, lard, cod liver oil, fish oil), and mixtures thereof. Liquid diluents also include alkylated fatty acids (e.g., methylated, ethylated, butylated) wherein the fatty acids may be obtained by hydrolysis of glycerol esters from plant and animal sources, and can be purified by distillation. Typical liquid diluents are described in Marsden, Solvents Guide, 2nd Ed., Interscience, New York, 1950.
The solid and liquid compositions of the present invention often include one or more surfactants. When added to a liquid, surfactants (also known as "surface-active agents") generally modify, most often reduce, the surface tension of the liquid. Depending on the nature of the hydrophilic and lipophilic groups in a surfactant molecule, surfactants can be useful as wetting agents, dispersants, emulsifiers or defoaming agents.
Surfactants can be classified as nonionic, anionic or cationic. Nonionic surfactants useful for the present compositions include, but are not limited to: alcohol alkoxylates such as alcohol alkoxylates based on natural and synthetic alcohols (which may be branched or linear) and prepared from the alcohols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof; amine ethoxylates, alkanolamides and ethoxylated alkanolamides; alkoxylated triglycerides such as ethoxylated soybean, castor and rapeseed oils; alkylphenol alkoxylates such as octylphenol ethoxylates, nonylphenol ethoxylates, dinonyl phenol ethoxylates and dodecyl phenol ethoxylates (prepared from the phenols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); block polymers prepared from ethylene oxide or propylene oxide and reverse block polymers where the terminal blocks are prepared from propylene oxide; ethoxylated fatty acids; ethoxylated fatty esters and oils; ethoxylated methyl esters; ethoxylated tristyrylphenol (including those prepared from ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); fatty acid esters, glycerol esters, lanolin-based derivatives, polyethoxylate esters such as polyethoxylated sorbitan fatty acid esters, polyethoxylated sorbitol fatty acid esters and polyethoxylated glycerol fatty acid esters; other sorbitan derivatives such as sorbitan esters; polymeric surfactants such as random copolymers, block copolymers, alkyd peg (polyethylene glycol) resins, graft or comb polymers and star polymers; polyethylene glycols (pegs); polyethylene glycol fatty acid esters; silicone-based surfactants; and sugar-derivatives such as sucrose esters, alkyl polyglycosides and alkyl polysaccharides.
Useful anionic surfactants include, but are not limited to: alkylaryl sulfonic acids and their salts; carboxylated alcohol or alkylphenol ethoxylates; diphenyl sulfonate derivatives; lignin and lignin derivatives such as lignosulfonates; maleic or succinic acids or their anhydrides; olefin sulfonates; phosphate esters such as phosphate esters of alcohol alkoxylates, phosphate esters of alkylphenol alkoxylates and phosphate esters of styryl phenol ethoxylates; protein-based surfactants; sarcosine derivatives; styryl phenol ether sulfate; sulfates and sulfonates of oils and fatty acids; sulfates and sulfonates of ethoxylated alkylphenols; sulfates of alcohols; sulfates of ethoxylated alcohols; sulfonates of amines and amides such as N,N-alkyltaurates; sulfonates of benzene, cumene, toluene, xylene, and dodecyl and tridecylbenzenes; sulfonates of condensed naphthalenes; sulfonates of naphthalene and alkyl naphthalene; sulfonates of fractionated petroleum; sulfosuccinamates; and sulfosuccinates and their derivatives such as dialkyl sulfosuccinate salts.
Useful cationic surfactants include, but are not limited to: amides and ethoxylated amides; amines such as N-alkyl propanediamines, tripropylenetriamines and dipropylenetetramines, and ethoxylated amines, ethoxylated diamines and propoxylated amines (prepared from the amines and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); amine salts such as amine acetates and diamine salts; quaternary ammonium salts such as quaternary salts, ethoxylated quaternary salts and diquaternary salts; and amine oxides such as alkyldimethylamine oxides and bis-(2-hydroxyethyl)-alkylamine oxides.
Also useful for the present compositions are mixtures of nonionic and anionic surfactants or mixtures of nonionic and cationic surfactants. Nonionic, anionic and cationic surfactants and their recommended uses are disclosed in a variety of published references including McCutcheon 's Emulsifiers and Detergents, annual American and International Editions published by McCutcheon's Division, The Manufacturing Confectioner Publishing Co.; Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964; and A. S. Davidson and B. Milwidsky, Synthetic Detergents, Seventh Edition, John Wiley and Sons, New York, 1987.
Compositions of this invention may also contain formulation auxiliaries and additives, known to those skilled in the art as formulation aids (some of which may be considered to also function as solid diluents, liquid diluents or surfactants). Such formulation auxiliaries and additives may control: pH (buffers), foaming during processing (antifoams such polyorganosiloxanes), sedimentation of active ingredients (suspending agents), viscosity (thixotropic thickeners), in-container microbial growth (antimicrobials), product freezing (antifreezes), color (dyes/pigment dispersions), wash-off (film formers or stickers), evaporation (evaporation retardants), and other formulation attributes. Film formers include, for example, polyvinyl acetates, polyvinyl acetate copolymers, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohols, polyvinyl alcohol copolymers and waxes. Examples of formulation auxiliaries and additives include those listed in McCutcheon 's Volume 2: Functional Materials, annual International and North American editions published by McCutcheon's Division, The Manufacturing Confectioner Publishing Co.; and PCT Publication WO 03/024222.
The compound of Formula 1 and any other active ingredients are typically incorporated into the present compositions by dissolving the active ingredient in a solvent or by grinding in a liquid or dry diluent. Solutions, including emulsifiable concentrates, can be prepared by simply mixing the ingredients. If the solvent of a liquid composition intended for use as an emulsifiable concentrate is water-immiscible, an emulsifier is typically added to emulsify the active-containing solvent upon dilution with water. Active ingredient slurries, with particle diameters of up to 2,000 μιη can be wet milled using media mills to obtain particles with average diameters below 3 μιη. Aqueous slurries can be made into finished suspension concentrates (see, for example, U.S. 3,060,084) or further processed by spray drying to form water-dispersible granules. Dry formulations usually require dry milling processes, which produce average particle diameters in the 2 to 10 um range. Dusts and powders can be prepared by blending and usually grinding (such as with a hammer mill or fluid-energy mill). 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 T. S. Woods, "The Formulator's Toolbox - Product Forms for Modern Agriculture" in Pesticide Chemistry and Bioscience, The Food-Environment Challenge, T. Brooks and T. R. Roberts, Eds., Proceedings of the 9th International Congress on Pesticide Chemistry, The Royal Society of Chemistry, Cambridge, 1999, pp. 120-133. See also 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; Hance et al, Weed Control Handbook, 8th Ed., Blackwell Scientific Publications, Oxford, 1989; and Developments in formulation technology, PJB Publications, Richmond, UK, 2000.
In the following Examples, all formulations are prepared in conventional ways. Compound numbers refer to compounds in Index Tables A-F. 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 where otherwise indicated. Example A
High Strength Concentrate
Compound 1 98.5% silica aerogel 0.5% synthetic amorphous fine silica 1.0%
Example B
Wettable Powder
Compound 2 65.0% dodecylphenol polyethylene glycol ether 2.0%> sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0% montmorillonite (calcined) 23.0%
Example C
Granule
Compound 1 10.0% attapulgite granules (low volatile matter, 0.71/0.30 mm; 90.0% U.S.S. No. 25-50 sieves)
Example D
Extruded Pellet
Compound 2 25.0% anhydrous sodium sulfate 10.0% crude calcium ligninsulfonate 5.0%> sodium alkylnaphthalenesulfonate 1.0% calcium/magnesium bentonite 59.0%
Example E
Emulsifiable Concentrate
Compound 1 10.0% polyoxyethylene sorbitol hexoleate 20.0%
C6-C10 fatty acid methyl ester 70.0%>
Example F
Microemulsion
Compound 2 5.0%> polyvinylpyrrolidone -vinyl acetate copolymer 30.0% alkylpolyglycoside 30.0%> glyceryl monooleate 15.0% water 20.0% Example G
Seed Treatment
Compound 1 20.00% polyvinylpyrrolidone -vinyl acetate copolymer 5.00% montan acid wax 5.00% calcium ligninsulfonate 1.00% polyoxyethylene/polyoxypropylene block copolymers 1.00% stearyl alcohol (POE 20) 2.00% polyorganosilane 0.20%> colorant red dye 0.05%> water 65.75%
Example H
Fertilizer Stick
Compound 2 2.5% pyrrolidone-styrene copolymer 4.8% tristyrylphenyl 16-ethoxylate 2.3% talc 0.8% corn starch 5.0%
Nitrophoska® Permanent 15-9-15 slow-release fertilizer 36.0% (BASF)
kaolin 38.0% water 10.6%
Example I
Wettable Powder
Compound 31 65.0% dodecylphenol polyethylene glycol ether 2.0%> sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0%> montmorillonite (calcined) 23.0%
Example J
Microemulsion
Compound 147 5.0% polyvinylpyrrolidone -vinyl acetate copolymer 30.0% alkylpolyglycoside 30.0%> glyceryl monooleate 15.0% water 20.0% Compounds of this invention exhibit activity against a wide spectrum of invertebrate pests. These pests include invertebrates inhabiting a variety of environments such as, for example, plant foliage, roots, soil, harvested crops or other foodstuffs, building structures or animal integuments. These pests include, for example, invertebrates feeding on foliage (including leaves, stems, flowers and fruits), seeds, wood, textile fibers or animal blood or tissues, and thereby causing injury or damage to, for example, growing or stored agronomic crops, forests, greenhouse crops, ornamentals, nursery crops, stored foodstuffs or fiber products, or houses or other structures or their contents, or being harmful to animal health or public health. Those skilled in the art will appreciate that not all compounds are equally effective against all growth stages of all pests.
The present compounds and compositions are thus useful agronomically for protecting field crops from phytophagous invertebrate pests, and also nonagronomically for protecting other horticultural crops and plants from phytophagous invertebrate pests. This utility includes protecting crops and other plants (i.e. both agronomic and nonagronomic) that contain genetic material introduced by genetic engineering (i.e. transgenic) or modified by mutagenesis to provide advantageous traits. Examples of such traits include tolerance to herbicides, resistance to phytophagous pests (e.g., insects, mites, aphids, spiders, nematodes, snails, plant-pathogenic fungi, bacteria and viruses), improved plant growth, increased tolerance of adverse growing conditions such as high or low temperatures, low or high soil moisture, and high salinity, increased flowering or fruiting, greater harvest yields, more rapid maturation, higher quality and/or nutritional value of the harvested product, or improved storage or process properties of the harvested products. Transgenic plants can be modified to express multiple traits. Examples of plants containing traits provided by genetic engineering or mutagenesis include varieties of corn, cotton, soybean and potato expressing an insecticidal Bacillus thuringiensis toxin such as YIELD GARD®, KNOCKOUT®, STARLINK®, BOLLGARD®, NuCOTN® and NEWLEAF®, and herbicide-tolerant varieties of corn, cotton, soybean and rapeseed such as ROUNDUP READY®, LIBERTY LINK®,
ΊΜΓ, STS and CLEARFIELD , as well as crops expressing N-acetyltransferase (GAT) to provide resistance to glyphosate herbicide, or crops containing the HRA gene providing resistance to herbicides inhibiting acetolactate synthase (ALS). The present compounds and compositions may interact synergistically with traits introduced by genetic engineering or modified by mutagenesis, thus enhancing phenotypic expression or effectiveness of the traits or increasing the invertebrate pest control effectiveness of the present compounds and compositions. In particular, the present compounds and compositions may interact synergistically with the phenotypic expression of proteins or other natural products toxic to invertebrate pests to provide greater-than-additive control of these pests.
Compositions of this invention can also optionally comprise plant nutrients, e.g., a fertilizer composition comprising at least one plant nutrient selected from nitrogen, phosphorus, potassium, sulfur, calcium, magnesium, iron, copper, boron, manganese, zinc, and molybdenum. Of note are compositions comprising at least one fertilizer composition comprising at least one plant nutrient selected from nitrogen, phosphorus, potassium, sulfur, calcium and magnesium. Compositions of the present invention which further comprise at least one plant nutrient can be in the form of liquids or solids. Of note are solid formulations in the form of granules, small sticks or tablets. Solid formulations comprising a fertilizer composition can be prepared by mixing the compound or composition of the present invention with the fertilizer composition together with formulating ingredients and then preparing the formulation by methods such as granulation or extrusion. Alternatively solid formulations can be prepared by spraying a solution or suspension of a compound or composition of the present invention in a volatile solvent onto a previous prepared fertilizer composition in the form of dimensionally stable mixtures, e.g., granules, small sticks or tablets, and then evaporating the solvent.
Nonagronomic uses refer to invertebrate pest control in the areas other than fields of crop plants. Nonagronomic uses of the present compounds and compositions include control of invertebrate pests in stored grains, beans and other foodstuffs, and in textiles such as clothing and carpets. Nonagronomic uses of the present compounds and compositions also include invertebrate pest control in ornamental plants, forests, in yards, along roadsides and railroad rights of way, and on turf such as lawns, golf courses and pastures. Nonagronomic uses of the present compounds and compositions also include invertebrate pest control in houses and other buildings which may be occupied by humans and/or companion, farm, ranch, zoo or other animals. Nonagronomic uses of the present compounds and compositions also include the control of pests such as termites that can damage wood or other structural materials used in buildings.
Nonagronomic uses of the present compounds and compositions also include protecting human and animal health by controlling invertebrate pests that are parasitic or transmit infectious diseases. The controlling of animal parasites particularly includes controlling external parasites that are parasitic to the surface of the body of the host animal (e.g., shoulders, armpits, abdomen, inner part of the thighs). External parasitic or disease transmitting pests include, for example, chiggers, ticks, lice, mosquitoes, flies, mites and fleas. Compounds and compositions of the present invention are suitable for systemic and/or non-systemic control of infestation or infection by parasites on animals. Compounds and compositions of the present invention are suitable for combating external parasitic or disease-transmitting pests. Compounds and compositions of the present invention are suitable for combating parasites that infest agricultural working animals, such as cattle, sheep, goats, horses, pigs, donkeys, camels, buffalos, rabbits, hens, turkeys, ducks, geese and bees; pet animals and domestic animals such as dogs, cats, pet birds and aquarium fish; as well as so-called experimental animals, such as hamsters, guinea pigs, rats and mice. By combating these parasites, fatalities and performance reduction (in terms of meat, milk, wool, skins, eggs, honey, etc.) are reduced, so that applying a composition comprising a compound of the present invention allows more economic and simple husbandry of animals.
Examples of agronomic or nonagronomic invertebrate pests include eggs, larvae and adults of the order Lepidoptera, such as armyworms, cutworms, loopers, and heliothines in the family Noctuidae (e.g., pink stem borer (Sesamia inferens Walker), corn stalk borer (Sesamia nonagrioides Lefebvre), southern armyworm (Spodoptera eridania Cramer), fall armyworm (Spodoptera fugiperda J. E. Smith), beet armyworm (Spodoptera exigua Hiibner), cotton leafworm (Spodoptera littoralis Boisduval), yellowstriped armyworm (Spodoptera ornithogaUi Guenee), black cutworm (Agrotis ipsilon Hufnagel), velvetbean caterpillar (Anticarsia gemmatalis Hiibner), green fruitworm (Lithophane antennata Walker), cabbage armyworm (Barathra brassicae Linnaeus), soybean looper (Pseudoplusia includens Walker), cabbage looper (Trichoplusia ni Hiibner), tobacco budworm (Heliothis virescens Fabricius)); borers, casebearers, webworms, coneworms, cabbageworms and skeletonizers from the family Pyralidae (e.g., European corn borer (Ostrinia nubilalis Hiibner), navel orangeworm (Amyelois transitella Walker), corn root webworm (Cr ambus caliginosellus Clemens), sod webworms (Pyralidae: Crambinae) such as sod worm (Herpetogramma licarsisalis Walker), sugarcane stem borer (Chilo infuscatellus Snellen), tomato small borer (Neoleucinodes elegantalis Guenee), green leafroller (Cnaphalocerus medinalis), grape leaffolder (Desmia funeralis Hiibner), melon worm (Diaphania nitidalis Stoll), cabbage center grub (Helluala hydralis Guenee), yellow stem borer (Scirpophaga incertulas Walker), early shoot borer (Scirpophaga infuscatellus Snellen), white stem borer (Scirpophaga innotata Walker), top shoot borer (Scirpophaga nivella Fabricius), dark- headed rice borer (Chilo polychrysus Meyrick), cabbage cluster caterpillar (Crocidolomia binotalis English)); leafrollers, budworms, seed worms, and fruit worms in the family Tortricidae (e.g., codling moth (Cydia pomonella Linnaeus), grape berry moth (Endopiza viteana Clemens), oriental fruit moth (Grapholita molesta Busck), citrus false codling moth (Cryptophlebia leucotreta Meyrick), citrus borer (Ecdytolopha aurantiana Lima), redbanded leafroller (Argyrotaenia velutinana Walker), obliquebanded leafroller (Choristoneura rosaceana Harris), light brown apple moth (Epiphyas postvittana Walker), European grape berry moth (Eupoecilia ambiguella Hiibner), apple bud moth (Pandemis pyrusana Kearfott), omnivorous leafroller (Platynota stultana Walsingham), barred fruit-tree tortrix (Pandemis cerasana Hiibner), apple brown tortrix (Pandemis heparana Denis & Schiffermuller)); and many other economically important lepidoptera (e.g., diamondback moth (Plutella xylostella Linnaeus), pink bollworm (Pectinophora gossypiella Saunders), gypsy moth (Lymantria dispar Linnaeus), peach fruit borer (Carposina niponensis Walsingham), peach twig borer (Anarsia lineatella Zeller), potato tuberworm (Phthorimaea operculella Zeller), spotted teniform leafminer (Lithocolletis blancardella Fabricius), Asiatic apple leafminer (Lithocolletis ringoniella Matsumura), rice leaffolder (Lerodea eufala Edwards), apple leafminer (Leucoptera scitella Zeller)); eggs, nymphs and adults of the order Blattodea including cockroaches from the families Blattellidae and Blattidae (e.g., oriental cockroach (Blatta orientalis Linnaeus), Asian cockroach (Blatella asahinai Mizukubo), German cockroach (Blattella germanica Linnaeus), brownbanded cockroach (Supella longipalpa Fabricius), American cockroach (Periplaneta americana Linnaeus), brown cockroach (Periplaneta brunnea Burmeister), Madeira cockroach (Leucophaea maderae Fabricius)), smoky brown cockroach (Periplaneta fuliginosa Service), Australian Cockroach (Periplaneta australasiae Fabr.), lobster cockroach (Nauphoeta cinerea Olivier) and smooth cockroach (Symploce pallens Stephens)); eggs, foliar feeding, fruit feeding, root feeding, seed feeding and vesicular tissue feeding larvae and adults of the order Coleoptera including weevils from the families Anthribidae, Bruchidae, and Curculionidae (e.g., boll weevil (Anthonomus grandis Boheman), rice water weevil (Lissorhoptrus oryzophilus Kuschel), granary weevil (Sitophilus granarius Linnaeus), rice weevil (Sitophilus oryzae Linnaeus)), annual bluegrass weevil (Listronotus maculicollis Dietz), bluegrass billbug (Sphenophorus parvulus Gyllenhal), hunting billbug (Sphenophorus venatus vestitus), Denver billbug (Sphenophorus cicatristriatus Fahraeus)); flea beetles, cucumber beetles, rootworms, leaf beetles, potato beetles, and leafminers in the family Chrysomelidae (e.g., Colorado potato beetle (Leptinotarsa decemlineata Say), western corn rootworm (Diabrotica virgifera virgifera LeConte)); chafers and other beetles from the family Scarabaeidae (e.g., Japanese beetle (Popillia japonica Newman), oriental beetle (Anomala orientalis Waterhouse, Exomala orientalis (Waterhouse) Baraud), northern masked chafer (Cyclocephala borealis Arrow), southern masked chafer (Cyclocephala immaculata Olivier or C lurida Bland), dung beetle and white grub (Aphodius spp.), black turfgrass ataenius (Ataenius spretulus Haldeman), green June beetle (Cotinis nitida Linnaeus), Asiatic garden beetle (Maladera castanea Arrow), May/June beetles (Phyllophaga spp.) and European chafer (Rhizotrogus majalis Razoumowsky)); carpet beetles from the family Dermestidae; wireworms from the family Elateridae; bark beetles from the family Scolytidae and flour beetles from the family Tenebrionidae. In addition, agronomic and nonagronomic pests include: eggs, adults and larvae of the order Dermaptera including earwigs from the family Forficulidae (e.g., European earwig (Forficula auricularia Linnaeus), black earwig (Chelisoches morio Fabricius)); eggs, immatures, adults and nymphs of the orders Hemiptera and Homoptera such as, plant bugs from the family Miridae, cicadas from the family Cicadidae, leafhoppers (e.g. Empoasca spp.) from the family Cicadellidae, bed bugs (e.g., Cimex lectularius Linnaeus) from the family Cimicidae, planthoppers from the families Fulgoroidae and Delphacidae, treehoppers from the family Membracidae, psyllids from the family Psyllidae, whiteflies from the family Aleyrodidae, aphids from the family Aphididae, phylloxera from the family Phylloxeridae, mealybugs from the family Pseudococcidae, scales from the families Coccidae, Diaspididae and Margarodidae, lace bugs from the family Tingidae, stink bugs from the family Pentatomidae, chinch bugs (e.g., hairy chinch bug (Blissus leucopterus hirtus Montandon) and southern chinch bug {Blissus insularis Barber)) and other seed bugs from the family Lygaeidae, spittlebugs from the family Cercopidae squash bugs from the family Coreidae, and red bugs and cotton stainers from the family Pyrrhocoridae. Also included are eggs, larvae, nymphs and adults of the order Acari (mites) such as spider mites and red mites in the family Tetranychidae (e.g., European red mite {Panonychus ulmi Koch), two spotted spider mite (Tetranychus urticae Koch), McDaniel mite (Tetranychus mcdanieli McGregor)); flat mites in the family Tenuipalpidae (e.g., citrus flat mite {Brevipalpus lewisi McGregor)); rust and bud mites in the family Eriophyidae and other foliar feeding mites and mites important in human and animal health, i.e. dust mites in the family Epidermoptidae, follicle mites in the family Demodicidae, grain mites in the family Glycyphagidae; ticks in the family Ixodidae, commonly known as hard ticks (e.g., deer tick {Ixodes scapularis Say), Australian paralysis tick {Ixodes holocyclus Neumann), American dog tick {Dermacentor variabilis Say), lone star tick {Amblyomma americanum Linnaeus)) and ticks in the family Argasidae, commonly known as soft ticks (e.g., relapsing fever tick {Ornithodoros turicata), common fowl tick {Argas radiatus)); scab and itch mites in the families Psoroptidae, Pyemotidae, and Sarcoptidae; eggs, adults and immatures of the order Orthoptera including grasshoppers, locusts and crickets (e.g., migratory grasshoppers (e.g., Melanoplus sanguinipes Fabricius, M. differ entialis Thomas), American grasshoppers (e.g., Schistocerca americana Drury), desert locust {Schistocerca gregaria Forskal), migratory locust {Locusta migratoria Linnaeus), bush locust {Zonocerus spp.), house cricket {Acheta domesticus Linnaeus), mole crickets (e.g., tawny mole cricket {Scapteriscus vicinus Scudder) and southern mole cricket {Scapteriscus borellii Giglio-Tos)); eggs, adults and immatures of the order Diptera including leafminers (e.g., Liriomyza spp. such as serpentine vegetable leafminer {Liriomyza sativae Blanchard)), midges, fruit flies (Tephritidae), frit flies (e.g., Oscinella frit Linnaeus), soil maggots, house flies (e.g., Musca domestica Linnaeus), lesser house flies (e.g., Fannia canicularis Linnaeus, F. femoralis Stein), stable flies (e.g., Stomoxys calcitrans Linnaeus), face flies, horn flies, blow flies (e.g., Chrysomya spp., Phormia spp.), and other muscoid fly pests, horse flies (e.g., Tabanus spp.), bot flies (e.g., Gastrophilus spp., Oestrus spp.), cattle grubs (e.g., Hypoderma spp.), deer flies (e.g., Chrysops spp.), keds (e.g., Melophagus ovinus Linnaeus) and other Brachycera, mosquitoes (e.g., Aedes spp., Anopheles spp., Culex spp.), black flies (e.g., Prosimulium spp., Simulium spp.), biting midges, sand flies, sciarids, and other Nematocera; eggs, adults and immatures of the order Thysanoptera including onion thrips {Thrips tabaci Lindeman), flower thrips {Frankliniella spp.), and other foliar feeding thrips; insect pests of the order Hymenoptera including ants of the Family Formicidae including the Florida carpenter ant {Camponotus floridanus Buckley), red carpenter ant {Camponotus ferrugineus Fabricius), black carpenter ant {Camponotus pennsylvanicus De Geer), white-footed ant {Technomyrmex albipes fr. Smith), big headed ants (Pheidole sp.), ghost ant (Tapinoma melanocephalum Fabricius); Pharaoh ant (Monomorium pharaonis Linnaeus), little fire ant {Wasmannia auropunctata Roger), fire ant (Solenopsis geminata Fabricius), red imported fire ant (Solenopsis invicta Buren), Argentine ant (Iridomyrmex humilis Mayr), crazy ant (Paratrechina longicornis Latreille), pavement ant (Tetramorium caespitum Linnaeus), cornfield ant (Lasius alienus Forster) and odorous house ant (Tapinoma sessile Say). Other Hymenoptera including bees (including carpenter bees), hornets, yellow jackets, wasps, and sawflies (Neodiprion spp.; Cephus spp.); insect pests of the order Isoptera including termites in the Termitidae (e.g., Macrotermes spp., Odontotermes obesus Rambur), Kalotermitidae (e.g., Cryptotermes spp.), and Rhinotermitidae (e.g., Reticulitermes spp., Coptotermes spp., Heterotermes tenuis Hagen) families, the eastern subterranean termite (Reticulitermes flavipes Kollar), western subterranean termite (Reticulitermes hesperus Banks), Formosan subterranean termite (Coptotermes formosanus Shiraki), West Indian drywood termite (Incisitermes immigrans Snyder), powder post termite (Cryptotermes brevis Walker), drywood termite (Incisitermes snyderi Light), southeastern subterranean termite (Reticulitermes virginicus Banks), western drywood termite (Incisitermes minor Hagen), arboreal termites such as Nasutitermes sp. and other termites of economic importance; insect pests of the order Thysanura such as silverfish (Lepisma saccharina Linnaeus) and firebrat (Thermobia domestica Packard); insect pests of the order Mallophaga and including the head louse (Pediculus humanus capitis De Geer), body louse (Pediculus humanus Linnaeus), chicken body louse (Menacanthus stramineus Nitszch), dog biting louse (Trichodectes canis De Geer), fluff louse (Goniocotes gallinae De Geer), sheep body louse (Bovicola ovis Schrank), short-nosed cattle louse (Haematopinus eurysternus Nitzsch), long-nosed cattle louse (Linognathus vituli Linnaeus) and other sucking and chewing parasitic lice that attack man and animals; insect pests of the order Siphonoptera including the oriental rat flea (Xenopsylla cheopis Rothschild), cat flea (Ctenocephalides felis Bouche), dog flea (Ctenocephalides canis Curtis), hen flea (Ceratophyllus gallinae Schrank), sticktight flea (Echidnophaga gallinacea Westwood), human flea (Pulex irritans Linnaeus) and other fleas afflicting mammals and birds. Additional arthropod pests covered include: spiders in the order Araneae such as the brown recluse spider (Loxosceles reclusa Gertsch & Mulaik) and the black widow spider (Latrodectus mactans Fabricius), and centipedes in the order Scutigeromorpha such as the house centipede (Scutigera coleoptrata Linnaeus).
Compounds of the invention show particularly high activity against pests in the order Lepidoptera (e.g., Alabama argillacea Hiibner (cotton leaf worm), Archips argyrospila Walker (fruit tree leaf roller), A. rosana Linnaeus (European leaf roller) and other Archips species, Chilo suppressalis Walker (rice stem borer), Cnaphalocrosis medinalis Guenee (rice leaf roller), Crambus caliginosellus Clemens (corn root webworm), Crambus teterrellus Zincken (bluegrass webworm), Cydia pomonella Linnaeus (codling moth), Earias insulana Boisduval (spiny bollworm), Earias vittella Fabricius (spotted bollworm), Helicoverpa armigera Hubner (American bollworm), Helicoverpa zea Boddie (corn earworm), Heliothis virescens Fabricius (tobacco budworm), Herpetogramma licarsisalis Walker (sod webworm), Lobesia botrana Denis & Schiffermuller (grape berry moth), Pectinophora gossypiella Saunders (pink bollworm), Phyllocnistis citrella Stainton (citrus leafminer), Pieris brassicae Linnaeus (large white butterfly), Pieris rapae Linnaeus (small white butterfly), Plutella xylostella Linnaeus (diamondback moth), Spodoptera exigua Hubner (beet armyworm), Spodoptera litura Fabricius (tobacco cutworm, cluster caterpillar), Spodoptera frugiperda J. E. Smith (fall armyworm), Trichoplusia ni Hubner (cabbage looper) and Tuta absoluta Meyrick (tomato leafminer)).
Compounds of the invention also have significant activity on members from the order Homoptera including: Acyrthosiphon pisum Harris (pea aphid), Aphis craccivora Koch (cowpea aphid), Aphis fabae Scopoli (black bean aphid), Aphis gossypii Glover (cotton aphid, melon aphid), Aphis pomi De Geer (apple aphid), Aphis spiraecola Patch (spirea aphid), Aulacorthum solani Kaltenbach (foxglove aphid), Chaetosiphon fragaefolii Cockerell (strawberry aphid), Diuraphis noxia Kurdjumov/Mordvilko (Russian wheat aphid), Dysaphis plantaginea Paaserini (rosy apple aphid), Eriosoma lanigerum Hausmann (woolly apple aphid), Hyalopterus pruni Geoffroy (mealy plum aphid), Lipaphis erysimi Kaltenbach (turnip aphid), Metopolophium dirrhodum Walker (cereal aphid), Macrosiphum euphorbiae Thomas (potato aphid), Myzus persicae Sulzer (peach-potato aphid, green peach aphid), Nasonovia ribisnigri Mosley (lettuce aphid), Pemphigus spp. (root aphids and gall aphids), Rhopalosiphum maidis Fitch (corn leaf aphid), Rhopalosiphum padi Linnaeus (bird cherry-oat aphid), Schizaphis graminum Rondani (greenbug), Sitobion avenae Fabricius (English grain aphid), Therioaphis maculata Buckton (spotted alfalfa aphid), Toxoptera aurantii Boyer de Fonscolombe (black citrus aphid) and Toxoptera citricida Kirkaldy (brown citrus aphid); Adelges spp. (adelgids); Phylloxera devastatrix Pergande (pecan phylloxera); Bemisia tabaci Gennadius (tobacco whitefly, sweetpotato whitefiy), Bemisia argentifolii Bellows & Perring (silverleaf whitefiy), Dialeurodes citri Ashmead (citrus whitefiy) and Trialeurodes vaporariorum Westwood (greenhouse whitefiy); Empoasca fabae Harris (potato leafhopper), Laodelphax striatellus Fallen (smaller brown planthopper), Macrolestes quadrilineatus Forbes (aster leafhopper), Nephotettix cinticeps Uhler (green leafhopper), Nephotettix nigropictus Stal (rice leafhopper), Nilaparvata lugens Stal (brown planthopper), Peregrinus maidis Ashmead (corn planthopper), Sogatella furcifera Horvath (white-backed planthopper), Sogatodes orizicola Muir (rice delphacid), Typhlocyba pomaria McAtee white apple leafhopper, Erythroneoura spp. (grape leafhoppers); Magicidada septendecim Linnaeus (periodical cicada); Icerya purchasi Maskell (cottony cushion scale), Quadraspidiotus perniciosus Comstock (San Jose scale); Planococcus citri Risso (citrus mealybug); Pseudococcus spp. (other mealybug complex); Cacopsylla pyricola Foerster (pear psylla) and Trioza diospyri Ashmead (persimmon psylla).
Compounds of this invention also have activity on members from the order Hemiptera including: Acrosternum hilare Say (green stink bug), Anasa tristis De Geer (squash bug), Blissus leucopterus leucopterus Say (chinch bug), Cimex lectularius Linnaeus (bed bug) Corythuca gossypii Fabricius (cotton lace bug), Cyrtopeltis modesta Distant (tomato bug), Dysdercus suturellus Herrich-S chaffer (cotton stainer), Euchistus servus Say (brown stink bug), Euchistus variolarius Palisot de Beauvois (one-spotted stink bug), Graptosthetus spp. (complex of seed bugs), Leptoglossus corculus Say (leaf-footed pine seed bug), Lygus lineolaris Palisot de Beauvois (tarnished plant bug), Nezara viridula Linnaeus (southern green stink bug), Oebalus pugnax Fabricius (rice stink bug), Oncopeltus fasciatus Dallas (large milkweed bug) and Pseudatomoscelis seriatus Reuter (cotton fleahopper). Other insect orders controlled by compounds of the invention include Thysanoptera (e.g., Frankliniella occidentalis Pergande (western flower thrips), Scirthothrips citri Moulton (citrus thrips), Sericothrips variabilis Beach (soybean thrips), and Thrips tabaci Lindeman (onion thrips); and the order Coleoptera (e.g., Leptinotarsa decemlineata Say (Colorado potato beetle), Epilachna varivestis Mulsant (Mexican bean beetle) and wireworms of the genera Agriotes, Athous or Limonius).
Note that some contemporary classification systems place Homoptera as a suborder within the order Hemiptera.
Of note is use of compounds of this invention for controlling silverleaf whitefiy (Bemisia argentifolii). Of note is use of compounds of this invention for controlling western flower thrip (Frankliniella occidentalis). Of note is use of compounds of this invention for controlling green peach aphid (Myzus persicae). Of note is use of compounds of this invention for controlling diamondback moth (Plutella xylostella). Of note is use of compounds of this invention for controlling fall armyworm (Spodoptera frugiperda).
Compounds of this invention can also be mixed with one or more other biologically active compounds or agents including insecticides, fungicides, nematocides, bactericides, acaricides, herbicides, herbicide safeners, growth regulators such as insect molting inhibitors and rooting stimulants, chemosterilants, semiochemicals, repellents, attractants, pheromones, feeding stimulants, other biologically active compounds or entomopathogenic bacteria, virus or fungi to form a multi-component pesticide giving an even broader spectrum of agronomic and nonagronomic utility. Thus the present invention also pertains to a composition comprising a biologically effective amount of a compound of Formula 1, at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents, and at least one additional biologically active compound or agent. For mixtures of the present invention, the other biologically active compounds or agents can be formulated together with the present compounds, including the compounds of Formula 1, to form a premix, or the other biologically active compounds or agents can be formulated separately from the present compounds, including the compounds of Formula 1, and the two formulations combined together before application (e.g., in a spray tank) or, alternatively, applied in succession.
Examples of such biologically active compounds or agents with which compounds of this invention can be formulated are insecticides such as abamectin, acephate, acequinocyl, acetamiprid, acetoprole, acrinathrin, amidoflumet, amitraz, avermectin, azadirachtin, azinphos-methyl, bifenthrin, bifenazate, bistrifluron, borate, buprofezin, cadusafos, carbaryl, carbofuran, cartap, carzol, chlorantraniliprole, chlorfenapyr, chlorfluazuron, chlorpyrifos, chlorpyrifos-methyl, chromafenozide, clofentezin, clothianidin, cyantraniliprole (3-bromo-l- (3 -chloro-2-pyridinyl)-N- [4-cyano-2-methyl-6- [(methylamino)carbonyl]phenyl] - 1H- pyrazole-5-carboxamide), cyflumetofen, cyfluthrin, beta-cyfluthrin, cyhalothrin, gamma- cyhalothrin, lambda-cyhalothrin, cypermethrin, alpha-cypermethrin, zeta-cypermethrin, cyromazine, deltamethrin, diafenthiuron, diazinon, dieldrin, diflubenzuron, dimefluthrin, dimehypo, dimethoate, dinotefuran, diofenolan, emamectin, endosulfan, esfenvalerate, ethiprole, etofenprox, etoxazole, fenbutatin oxide, fenothiocarb, fenoxycarb, fenpropathrin, fenvalerate, fipronil, flonicamid, flubendiamide, flucythrinate, flufenerim, flufenoxuron, fluvalinate, tau-fluvalinate, fonophos, formetanate, fosthiazate, halofenozide, hexaflumuron, hexythiazox, hydramethylnon, imidacloprid, indoxacarb, insecticidal soaps, isofenphos, lufenuron, malathion, mepyrfluthrin, metaflumizone, metaldehyde, methamidophos, methidathion, methiodicarb, methomyl, methoprene, methoxychlor, methoxyfenozide, metofluthrin, milbemycin oxime, monocrotophos, nicotine, nitenpyram, nithiazine, novaluron, noviflumuron, oxamyl, parathion, parathion-methyl, permethrin, phorate, phosalone, phosmet, phosphamidon, pirimicarb, profenofos, profluthrin, propargite, protrifenbute, pymetrozine, pyrafluprole, pyrethrin, pyridaben, pyridalyl, pyrifluquinazon, pyriprole, pyriproxyfen, rotenone, ryanodine, spinetoram, spinosad, spirodiclofen, spiromesifen, spirotetramat, sulfoxaflor, sulprofos, tebufenozide, tebufenpyrad, teflubenzuron, tefluthrin, terbufos, tetrachlorvinphos, tetramethrin, tetramethylfluthrin, thiacloprid, thiamethoxam, thiodicarb, thiosultap-sodium, tolfenpyrad, tralomethrin, triazamate, trichlorfon, triflumuron, Bacillus thuringiensis delta-endotoxins, entomopathogenic bacteria, entomopathogenic viruses and entomopathogenic fungi. Of note is the aforedescribed list excluding acetoprole, mepyrfluthrin, sulfoxaflor and tetramethylfluthrin .
Of note for combination with compounds of the present invention are insecticides such as abamectin, acetamiprid, acrinathrin, amitraz, avermectin, azadirachtin, bifenthrin, buprofezin, cadusafos, carbaryl, cartap, chlorantraniliprole, chlorfenapyr, chlorpyrifos, clothianidin, cyantraniliprole, cyfluthrin, beta-cyfluthrin, cyhalothrin, gamma-cyhalothrin, lambda-cyhalothrin, cypermethrin, alpha-cypermethrin, zeta-cypermethrin, cyromazine, deltamethrin, dieldrin, dinotefuran, diofenolan, emamectin, endosulfan, esfenvalerate, ethiprole, etofenprox, etoxazole, fenothiocarb, fenoxycarb, fenvalerate, fipronil, flonicamid, flubendiamide, flufenoxuron, fluvalinate, formetanate, fosthiazate, hexaflumuron, hydramethylnon, imidacloprid, indoxacarb, lufenuron, mepyrfluthrin, metaflumizone, methiodicarb, methomyl, methoprene, methoxyfenozide, nitenpyram, nithiazine, novaluron, oxamyl, pymetrozine, pyrethrin, pyridaben, pyridalyl, pyriproxyfen, ryanodine, spinetoram, spinosad, spirodiclofen, spiromesifen, spirotetramat, sulfoxaflor, tebufenozide, tetramethrin, tetramethylfluthrin, thiacloprid, thiamethoxam, thiodicarb, thiosultap-sodium, tralomethrin, triazamate, triflumuron, Bacillus thuringiensis delta-endotoxins, all strains of Bacillus thuringiensis and all strains of Nucleo polyhydrosis viruses. Of note is the aforedescribed list excluding mepyrfluthrin, sulfoxaflor and tetramethylfluthrin.
One embodiment of biological agents for mixing with compounds of this invention includes entomopathogenic bacteria such as Bacillus thuringiensis, and the encapsulated delta-endotoxins of Bacillus thuringiensis (e.g., Cellcap, MPV, MPVII); entomopathogenic fungi such as green muscardine fungus; and entomopathogenic (both naturally occurring and genetically modified) viruses including baculovirus, nucleopolyhedro virus (NPV) such as Helicoverpa zea nucleopolyhedrovirus (HzNPV), Anagrapha falcifera nucleopolyhedrovirus (AfNPV); and granulosis virus (GV) such as Cydia pomonella granulosis virus (CpGV).
Of particular note is such a combination where the other invertebrate pest control active ingredient belongs to a different chemical class or has a different site of action than the compound of Formula 1. In certain instances, a combination with at least one other invertebrate pest control active ingredient having a similar spectrum of control but a different site of action will be particularly advantageous for resistance management. Thus, a composition of the present invention can further comprise a biologically effective amount of at least one additional invertebrate pest control active ingredient having a similar spectrum of control but belonging to a different chemical class or having a different site of action. These additional biologically active compounds or agents include, but are not limited to, sodium channel modulators such as bifenthrin, cypermethrin, cyhalothrin, lambda- cyhalothrin, cyfluthrin, beta-cyfluthrin, deltamethrin, dimefluthrin, esfenvalerate, fenvalerate, indoxacarb, mepyrflutrin, metofluthrin, profluthrin, pyrethrin, tetramethylfluthrin and tralomethrin; cholinesterase inhibitors such as chlorpyrifos, methomyl, oxamyl, thiodicarb and triazamate; neonicotinoids such as acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, nithiazine, thiacloprid and thiamethoxam; insecticidal macrocyclic lactones such as spinetoram, spinosad, abamectin, avermectin and emamectin; GAB A (γ-aminobutyric acid)-gated chloride channel antagonists such as avermectin or blockers such as ethiprole and fipronil; chitin synthesis inhibitors such as buprofezin, cyromazine, flufenoxuron, hexaflumuron, lufenuron, novaluron, noviflumuron and triflumuron; juvenile hormone mimics such as diofenolan, fenoxycarb, methoprene and pyriproxyfen; octopamine receptor ligands such as amitraz; molting inhibitors and ecdysone agonists such as azadirachtin, methoxyfenozide and tebufenozide; ryanodine receptor ligands such as ryanodine, anthranilic diamides such as chlorantraniliprole and cyantraniliprole, and flubendiamide; nereistoxin analogs such as cartap; mitochondrial electron transport inhibitors such as chlorfenapyr, hydramethylnon and pyridaben; lipid biosynthesis inhibitors such as spirodiclofen and spiromesifen; cyclodiene insecticides such as dieldrin or endosulfan; pyrethroids; carbamates; insecticidal ureas; and biological agents including nucleopolyhedro viruses (NPV), members of Bacillus thuringiensis, encapsulated delta-endotoxins of Bacillus thuringiensis, and other naturally occurring or genetically modified insecticidal viruses.
Further examples of biologically active compounds or agents with which compounds of this invention can be formulated are: fungicides such as acibenzolar (i.e. acibenzolar-iS*- methyl), aldimorph, ametoctradin, amisulbrom, anilazine, azaconazole, azoxystrobin, benalaxyl (including benalaxyl-M), benodanil, benomyl, benthiavalicarb, benthiavalicarb- isopropyl, bethoxazin, binapacryl, binomial, biphenyl, bitertanol, bixafen, blasticidin-S, Bordeaux mixture (tribasic copper sulfate), boscalid/nicobifen, bromuconazole, bupirimate, buthiobate, carboxin, carpropamid, captafol, captan, carbendazim, chinomethionat, chloroneb, chlorothalonil, chlozolinate, clotrimazole, copper oxychloride, copper salts such as copper sulfate and copper hydroxide, cyazofamid, cyflufenamid, cymoxanil, cyproconazole, cyprodinil, dichlofluanid, diclocymet, diclomezine, dicloran, diethofencarb, difenoconazole, diflumetorim, dimethirimol, dimethomorph, dimoxystrobin, diniconazole, diniconazole-M, dinocap, discostrobin, dithianon, dodemorph, dodine, econazole, enestroburin, etaconazole, edifenphos, epoxiconazole, ethaboxam, ethirimol, etridiazole, famoxadone, fenamidone, fenarimol, fenbuconazole, fencaramid, fenfuram, fenhexamide, fenoxanil, fenpiclonil, fenpropidin, fenpropimorph, fentin acetate, fentin hydroxide, ferbam, ferfurazoate, ferimzone, fluazinam, fludioxonil, flumetover, flumorph, fluopicolide, fluopyram, fluoroimide, fluoxastrobin, fluquinconazole, flusilazole, flusulfamide, flutolanil, flutriafol, fluxapyroxad, folpet, fosetyl-aluminum, fuberidazole, furalaxyl, furametapyr, hexaconazole, hymexazol, guazatine, imazalil, imibenconazole, iminoctadine, iodicarb, ipconazole, iprobenfos, iprodione, iprovalicarb, isoconazole, isoprothiolane, isopyrazam, isotianil, kasugamycin, kresoxim-methyl, mancozeb, mandipropamid, maneb, mapanipyrin, mefenoxam, mepronil, meptyldinocap, metalaxyl (including metalaxyl-M), metconazole, methasulfocarb, metiram, metominostrobin/fenominostrobin, mepanipyrim, metrafenone, miconazole, myclobutanil, neo-asozin (ferric methanearsonate), nuarimol, octhilinone, ofurace, orysastrobin, oxadixyl, oxolinic acid, oxpoconazole, oxycarboxin, paclobutrazol, penconazole, pencycuron, penflufen, penthiopyrad, perfurazoate, phosphonic acid (i.e. phosphorous acid and salts thereof), phthalide, picobenzamid, picoxystrobin, piperalin, polyoxin, probenazole, prochloraz, procymidone, propamocarb, propamocarb-hydrochloride, propiconazole, propineb, proquinazid, prothiocarb, prothioconazole, pyraclostrobin, pyrametostrobin, pyraoxystrobin, pyrazophos, pyribencarb, pyributicarb, pyrifenox, pyrimethanil, pyrifenox, pyriofenone, pyrrolnitrin, pyroquilon, quinconazole, quinoxyfen, quintozene, sedaxane, silthiofam, simeconazole, spiroxamine, streptomycin, sulfur, tebuconazole, tebufloquin, tecloftalam, tecnazene, tetraconazole, thiabendazole, thifluzamide, thiophanate, thiophanate-methyl, thiram, tiadinil, tolclofos-methyl, tolylfluanid, triadimefon, triadimenol, triarimol, triazoxide, tridemorph, triflumizole, trimorphamide, tricyclazole, trifloxystrobin, triforine, triticonazole, uniconazole, validamycin, valifenalate, vinclozolin, zineb, ziram, and zoxamide; nematocides such as aldicarb, imicyafos, oxamyl 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. Of note is the aforedescribed list excluding anilazine, benodanil, bethoxazin, binapacryl, bixafen, chinomethionat, diflumetorim, dimethirimol, enestroburin, flumorph, fluopyram, fluoroimide, fluxapyroxad, isopyrazam, isotrianil, meptyldinocap, piperalin, prothiocarb, pyributicarb, pyriofenone, sedaxane and triflumizole.
In certain instances, combinations of a compound of this invention with other biologically active (particularly invertebrate pest control) compounds or agents (i.e. active ingredients) can result in a greater-than-additive (i.e. synergistic) effect. Reducing the quantity of active ingredients released in the environment while ensuring effective pest control is always desirable. When synergism of invertebrate pest control active ingredients occurs at application rates giving agronomically satisfactory levels of invertebrate pest control, such combinations can be advantageous for reducing crop production cost and decreasing environmental load.
Compounds of this invention and compositions thereof can be applied to plants genetically transformed to express proteins toxic to invertebrate pests (such as Bacillus thuringiensis delta-endotoxins). Such an application may provide a broader spectrum of plant protection and be advantageous for resistance management. The effect of the exogenously applied invertebrate pest control compounds of this invention may be synergistic with the expressed toxin proteins.
General references for these agricultural protectants (i.e. insecticides, fungicides, nematocides, acaricides, herbicides and biological agents) include The Pesticide Manual, 13th Edition, C. D. S. Tomlin, Ed., British Crop Protection Council, Farnham, Surrey, U.K., 2003 and The BioPesticide Manual, 2nd Edition, L. G. Copping, Ed., British Crop Protection Council, Farnham, Surrey, U.K., 2001.
For embodiments where one or more of these various mixing partners are used, the weight ratio of these various mixing partners (in total) to the compound of Formula 1 is typically between about 1 :3000 and about 3000: 1. Of note are weight ratios between about 1 :300 and about 300: 1 (for example ratios between about 1 :30 and about 30: 1). One skilled in the art can easily determine through simple experimentation the biologically effective amounts of active ingredients necessary for the desired spectrum of biological activity. It will be evident that including these additional components can expand the spectrum of invertebrate pests controlled beyond the spectrum controlled by the compound of Formula 1 alone.
Table A lists specific combinations of a compound of Formula 1 with other invertebrate pest control agents illustrative of the mixtures, compositions and methods of the present invention. The first column of Table A lists the specific invertebrate pest control agents (e.g., "Abamectin" in the first line). The second column of Table A lists the mode of action (if known) or chemical class of the invertebrate pest control agents. The third column of Table A lists embodiment(s) of ranges of weight ratios for rates at which the invertebrate pest control agent can be applied relative to a compound of Formula 1 (e.g., "50: 1 to 1 :50" of abamectin relative to a compound of Formula 1 by weight). Thus, for example, the first line of Table A specifically discloses the combination of a compound of Formula 1 with abamectin can be applied in a weight ratio between 50: 1 to 1 :50. The remaining lines of Table A are to be construed similarly. Of further note Table A lists specific combinations of a compound of Formula 1 with other invertebrate pest control agents illustrative of the mixtures, compositions and methods of the present invention and includes additional embodiments of weight ratio ranges for application rates.
Table A
Invertebrate Pest Mode of Action or Chemical Class Typical Control Agent Weight Ratio
Abamectin macrocyclic lactones 50 1 to 1 50
Acetamiprid neonicotinoids 150 1 to 1 200
Amitraz octopamine receptor ligands 200 1 to 1 100
Avermectin macrocyclic lactones 50 1 to 1 50
Azadirachtin ecdysone agonists 100 1 to 1 120
Beta-cyfluthrin sodium channel modulators 150 1 to 1 200
Bifenthrin sodium channel modulators 100: 1 to 1 : 10
Buprofezin chitin synthesis inhibitors 500: 1 to 1 :50
Cartap nereistoxin analogs 100 1 to 1 200
Chlorantraniliprole ryanodine receptor ligands 100 1 to 1 120
Chlorfenapyr mitochondrial electron transport inhibitors 300 1 to 1 200
Chlorpyrifos cholinesterase inhibitors 500 1 to 1 200
Clothianidin neonicotinoids 100 1 to 1 400
Cyantraniliprole ryanodine receptor ligands 100 1 to 1 120
Cyfluthrin sodium channel modulators 150 1 to 1 200 Invertebrate Pest Mode of Action or Chemical Class Typical Control Agent Weight Ratio
Cyhalothrin sodium channel modulators 150:1 to 1:200
Cypermethrin sodium channel modulators 150:1 to 1:200
Cyromazine chitin synthesis inhibitors 400:1 to 1:50
Deltamethrin sodium channel modulators 50:1 to 1:400
Dieldrin cyclodiene insecticides 200:1 to 1:100
Dinotefuran neonicotinoids 150:1 to 1:200
Diofenolan molting inhibitor 150:1 to 1:200
Emamectin macrocyclic lactones 50:1 to 1:10
Endosulfan cyclodiene insecticides 200:1 to 1:100
Esfenvalerate sodium channel modulators 100:1 to 1:400
Ethiprole GABA-regulated chloride channel 200:1 to 1:100 blockers
Fenothiocarb 150:1 to 1:200
Fenoxycarb juvenile hormone mimics 500:1 to 1:100
Fenvalerate sodium channel modulators 150:1 to 1:200
Fipronil GABA-regulated chloride channel 150:1 to 1:100 blockers
Flonicamid 200:1 to 1:100
Flubendiamide ryanodine receptor ligands 100:1 to 1:120
Flufenoxuron chitin synthesis inhibitors 200:1 to 1:100
Hexaflumuron chitin synthesis inhibitors 300:1 to 1:50
Hydramethylnon mitochondrial electron transport inhibitors 150:1 to 1:250
Imidacloprid neonicotinoids 1000:1 to 1:1000
Indoxacarb sodium channel modulators 200:1 to 1:50
Lambda-cyhalothrin sodium channel modulators 50:1 to 1:250
Lufenuron chitin synthesis inhibitors 500:1 to 1:250
Mepyrfluthrin sodium channel modulators 100:1 to 1:400
Metaflumizone 200:1 to 1:200
Methomyl cholinesterase inhibitors 500:1 to 1:100
Methoprene juvenile hormone mimics 500:1 to 1:100
Methoxyfenozide ecdysone agonists 50:1 to 1:50
Nitenpyram neonicotinoids 150:1 to 1:200
Nithiazine neonicotinoids 150:1 to 1:200
Novaluron chitin synthesis inhibitors 500:1 to 1:150
Oxamyl cholinesterase inhibitors 200:1 to 1:200 Invertebrate Pest Mode of Action or Chemical Class Typical Control Agent Weight Ratio
Pymetrozine 200: 1 to 1 : 100
Pyrethrin sodium channel modulators 100:1 to 1 : 10
Pyridaben mitochondrial electron transport inhibitors 200 1 to 1 100
Pyridalyl 200 1 to 1 100
Pyriproxyfen juvenile hormone mimics 500 1 to 1 100
Ryanodine ryanodine receptor ligands 100 1 to 1 120
Spinetoram macrocyclic lactones 150 1 to 1 100
Spinosad macrocyclic lactones 500: 1 to 1 : 10
Spirodiclofen lipid biosynthesis inhibitors 200 1 to 1 200
Spiromesifen lipid biosynthesis inhibitors 200 1 to 1 200
Sulfoxaflor 200 1 to 1 200
Tebufenozide ecdysone agonists 500 1 to 1 250
Tetramethylfluthrin sodium channel modulators 100: 1 to 1 :40
Thiacloprid neonicotinoids 100 1 to 1 200
Thiamethoxam neonicotinoids 1250 1 to 1 1000
Thiodicarb cholinesterase inhibitors 500 1 to 1 400
Thiosultap-sodium 150 1 to 1 100
Tralomethrin sodium channel modulators 150 1 to 1 200
Triazamate cholinesterase inhibitors 250 1 to 1 100
Triflumuron chitin synthesis inhibitors 200 1 to 1 100
Bacillus thuringiensis biological agents 50 1 to 1 10
Bacillus thuringiensis biological agents 50 1 to 1 10 delta-endotoxin
NPV (e.g., Gemstar) biological agents 50: 1 to 1 : 10
Of note is the composition of the present invention comprising at least one additional biologically active compound or agent is selected from the Invertebrate Pest Control Agents listed in Table A above.
The weight ratios of a compound, including a compound of Formula 1, an N-oxide or a salt thereof, to the additional invertebrate pest control agent typically are between 1000:1 and 1 : 1000, with one embodiment being between 500: 1 and 1 :500, another embodiment being between 250:1 and 1 :200 and another embodiment being between 100:1 and 1 :50.
Listed below in Tables B1-B45 are embodiments of specific compositions comprising a compound of Formula 1 (compound numbers (Cmpd. No.) refer to compounds in Index Tables A-F) and an additional invertebrate pest control agent. Table Bl
Mixture Cmpd. and Invertebrate Pest Mixture Cmpd. and Invertebrate Pest No. No. Control Agent No. No. Control Agent
A-l 1 and Abamectin A-37 1 and Indoxacarb
A-2 1 and Acetamiprid A-38 1 and Lambda-cyhalothrin
A-3 1 and Amitraz A-39 1 and Lufenuron
A-4 1 and Avermectin A-40 1 and Mepyriluthrin
A-5 1 and Azadirachtin A-41 1 and Metaflumizone
A-6 1 and Beta-cylluthrin A-42 1 and Methomyl
A-7 1 and Bifenthrin A-43 1 and Methoprene
A-8 1 and Buprofezin A-44 1 and Methoxyfenozide
A-9 1 and Cartap A-45 1 and Nitenpyram
A-10 1 and Chlorantraniliprole A-46 1 and Nithiazine
A-l l 1 and Chlorfenapyr A-47 1 and Novaluron
A-12 1 and Chlorpyrifos A-48 1 and Oxamyl
A-13 1 and Clothianidin A-49 1 and Pymetrozine
A-14 1 and Cyantraniliprole A-50 1 and Pyrethrin
A-15 1 and Cylluthrin A-51 1 and Pyridaben
A-16 1 and Cyhalothrin A-52 1 and Pyridalyl
A-17 1 and Cypermethrin A-53 1 and Pyriproxyfen
A-l 8 1 and Cyromazine A-54 1 and Ryanodine
A-19 1 and Deltamethrin A-55 1 and Spinetoram
A-20 1 and Dieldrin A-56 1 and Spinosad
A-21 1 and Dinotefuran A-57 1 and Spirodiclofen
A-22 1 and Diofenolan A-58 1 and Spiromesifen
A-23 1 and Emamectin A-59 1 and Sulfoxaflor
A-24 1 and Endosulfan A-60 1 and Tebufenozide
A-25 1 and Esfenvalerate A-61 1 and Tetramethylfluthrin
A-26 1 and Ethiprole A-62 1 and Thiacloprid
A-27 1 and Fenothiocarb A-63 1 and Thiamethoxam
A-28 1 and Fenoxycarb A-64 1 and Thiodicarb
A-29 1 and Fenvalerate A-65 1 and Thiosultap-sodium
A-30 1 and Fipronil A-66 1 and Tralomethrin
A-31 1 and Flonicamid A-67 1 and Triazamate
A-32 1 and Flubendiamide A-68 1 and Triflumuron
A-33 1 and Flufenoxuron A-69 1 and Bacillus thuringiensis and Hexaflumuron Bacillus thuringiensis
A-34 1 A-70 ' and
delta-endotoxin
A-35 1 and Hydramethylnon A-71 1 and NPV (e.g., Gemstar) Mixture Cmpd. and Invertebrate Pest Mixture Cmpd. and Invertebrate Pest No. No. Control Agent No. No. Control Agent
A-36 1 and Imidacloprid
Tables B2 through B45 are each constructed the same as Table B 1 above except that entries below the "Cmpd. No" column heading are replaced with the respective Cmpd. No. Column Entry shown below. Thus, for example, in Table B2 the entries below the "Cmpd. No." column heading all recite "Compound 2", and the first line below the column headings in Table B2 specifically discloses a mixture of Compound 2 with abamectin. Tables B3 through B45 are constructed similarly.
Table Number Cmpd. No. Column Entry Table Number Cmpd. No. Column Entry
B2 Compound 2 B24 Compound 112
B3 Compound 3 B25 Compound 114
B4 Compound 5 B26 Compound 119
B5 Compound 16 B27 Compound 120
B6 Compound 17 B28 Compound 121
B7 Compound 25 B29 Compound 122
B8 Compound 29 B30 Compound 123
B9 Compound 35 B31 Compound 127
BIO Compound 52 B32 Compound 130
Bl l Compound 58 B33 Compound 131
B12 Compound 59 B34 Compound 147
B13 Compound 60 B35 Compound 150
B14 Compound 66 B36 Compound 152
B15 Compound 68 B37 Compound 153
B16 Compound 69 B38 Compound 155
B17 Compound 71 B39 Compound 158
B18 Compound 72 B40 Compound 163
B19 Compound 80 B41 Compound 168
B20 Compound 85 B42 Compound 170
B21 Compound 91 B43 Compound 179
B22 Compound 94 B44 Compound 181
B23 Compound 103
Figure imgf000090_0001
B45 Compound 183
The specific mixtures listed in Tables B1-B45 typically combine a compound of Formula 1 with the other invertebrate pest agent in the ratios specified in Table A.
Invertebrate pests are controlled in agronomic and nonagronomic applications by applying one or more compounds of this invention, typically in the form of a composition, in a biologically 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 comprises a method for controlling an invertebrate pest in agronomic and/or nonagronomic applications, comprising contacting the invertebrate pest or its environment with a biologically effective amount of one or more of the compounds of the invention, or with a composition comprising at least one such compound or a composition comprising at least one such compound and a biologically effective amount of at least one additional biologically active compound or agent. Of note is said method wherein a plant in the environment of the invertebrate pest is contacted with a biologically effective amount of a compound of the invention (e.g., in the form of a composition of the invention). Examples of suitable compositions comprising a compound of the invention and a biologically effective amount of at least one additional biologically active compound or agent include granular compositions wherein the additional active compound is present on the same granule as the compound of the invention or on granules separate from those of the compound of the invention.
To achieve contact with a compound or composition of the invention to protect a field crop from invertebrate pests, the compound or composition is typically applied to the seed of the crop before planting, to the foliage (e.g., leaves, stems, flowers, fruits) of crop plants, or to the soil or other growth medium before or after the crop is planted.
One embodiment of a method of contact is by spraying. Alternatively, a granular composition comprising a compound of the invention can be applied to the plant foliage or the soil. Compounds of this invention can also be effectively delivered through plant uptake by contacting the plant with a composition comprising a compound of this invention applied as a soil drench of a liquid formulation, a granular formulation to the soil, a nursery box treatment or a dip of transplants. Of note is a composition of the present invention in the form of a soil drench liquid formulation. Also of note is a method for controlling an invertebrate pest comprising contacting the invertebrate pest or its environment with a biologically effective amount of a compound of the present invention or with a composition comprising a biologically effective amount of a compound of the present invention. Of further note is this method wherein the environment is soil and the composition is applied to the soil as a soil drench formulation. Of further note is that compounds of this invention are also effective by localized application to the locus of infestation. Other methods of contact include application of a compound or a composition of the invention by direct and residual sprays, aerial sprays, gels, seed coatings, microencapsulations, systemic uptake, baits, ear tags, boluses, foggers, fumigants, aerosols, dusts and many others. One embodiment of a method of contact is a dimensionally stable fertilizer granule, stick or tablet comprising a compound or composition of the invention. The compounds of this invention can also be impregnated into materials for fabricating invertebrate control devices (e.g., insect netting). Compounds of this invention are also useful in seed treatments for protecting seeds from invertebrate pests. In the context of the present disclosure and claims, treating a seed means contacting the seed with a biologically effective amount of a compound of this invention, which is typically formulated as a composition of the invention. This seed treatment protects the seed from invertebrate soil pests and generally can also protect roots and other plant parts in contact with the soil of the seedling developing from the germinating seed. The seed treatment may also provide protection of foliage by translocation of the compound of this invention or a second active ingredient within the developing plant. Therefore an aspect of this invention is a method for protecting a seed, or a plant grown therefrom, from an invertebrate pest comprising contacting the seed with a biologically effective amount of a compound of Formula 1, an N-oxide, or a salt thereof (e.g., as a formulated composition). Seed treatments can be applied to all types of seeds, including those from which plants genetically transformed to express specialized traits will germinate. Representative examples include those expressing proteins toxic to invertebrate pests, such as Bacillus thuringiensis toxin or those expressing herbicide resistance such as glyphosate acetyltransferase, which provides resistance to glyphosate.
One method of seed treatment is by spraying or dusting the seed with a compound of the invention (i.e. as a formulated composition) before sowing the seeds. Compositions formulated for seed treatment generally comprise a film former or adhesive agent. Therefore typically a seed coating composition of the present invention comprises a biologically effective amount of a compound of Formula 1, an N-oxide, or a salt thereof, and a film former or adhesive agent. Treatment with this composition thus involves coating the seed with a compound of Formula 1, an N-oxide, or a salt thereof (i.e. in a biologically effective amount) formulated as a composition comprising a film former or adhesive agent. Seed can be coated by spraying a flowable suspension concentrate directly into a tumbling bed of seeds and then drying the seeds. Alternatively, other formulation types such as wetted powders, solutions, suspoemulsions, emulsifiable concentrates and emulsions in water can be sprayed on the seed. This process is particularly useful for applying film coatings on seeds. Various coating machines and processes are available to one skilled in the art. Suitable processes include those listed in P. Kosters et al, Seed Treatment: Progress and Prospects, 1994 BCPC Mongraph No. 57, and references listed therein.
The treated seed typically comprises a compound of the present invention in an amount from about 0.1 g to 1 kg per 100 kg of seed (i.e. from about 0.0001 to 1% by weight of the seed before treatment) to provide a biologically effective amount. A flowable suspension formulated for seed treatment typically comprises from about 0.5 to about 70% of the active ingredient, from about 0.5 to about 30% of a film-forming adhesive, from about 0.5 to about 20% of a dispersing agent, from 0 to about 5% of a thickener, from 0 to about 5% of a pigment and/or dye, from 0 to about 2% of an antifoaming agent, from 0 to about 1% of a preservative, and from 0 to about 75% of a volatile liquid diluent.
The compounds of this invention can be incorporated into a bait composition that is consumed by an invertebrate pest or used within a device such as a trap, bait station, and the like. Such a bait composition can be in the form of granules which comprise (a) active ingredients, namely a biologically effective amount of a compound of Formula 1, an N-oxide, or a salt thereof; (b) one or more food materials; optionally (c) an attractant, and optionally (d) one or more humectants. Of note are granules or bait compositions which comprise between about 0.001-5% active ingredients, about 40-99%) food material and/or attractant; and optionally about 0.05-10% humectants, which are effective in controlling soil invertebrate pests at very low application rates, particularly at doses of active ingredient that are lethal by ingestion rather than by direct contact. Some food materials can function both as a food source and an attractant. Food materials include carbohydrates, proteins and lipids. Examples of food materials are vegetable flour, sugar, starches, animal fat, vegetable oil, yeast extracts and milk solids. Examples of attractants are odorants and flavorants, such as fruit or plant extracts, perfume, or other animal or plant component, pheromones or other agents known to attract a target invertebrate pest. Examples of humectants, i.e. moisture retaining agents, are glycols and other polyols, glycerine and sorbitol. Of note is a bait composition (and a method utilizing such a bait composition) used to control at least one invertebrate pest selected from the group consisting of ants, termites and cockroaches. A device for controlling an invertebrate pest can comprise the present bait composition and a housing adapted to receive the bait composition, wherein the housing has at least one opening sized to permit the invertebrate pest to pass through the opening so the invertebrate pest can gain access to the bait composition from a location outside the housing, and wherein the housing is further adapted to be placed in or near a locus of potential or known activity for the invertebrate pest.
The compounds of this invention can be applied without other adjuvants, but most often application will be of a formulation comprising one or more active ingredients with suitable carriers, diluents, and surfactants and possibly in combination with a food depending on the contemplated end use. One method of application involves spraying a water dispersion or refined oil solution of a compound of the present invention. Combinations with spray oils, spray oil concentrations, spreader stickers, adjuvants, other solvents, and synergists such as piperonyl butoxide often enhance compound efficacy. For nonagronomic uses such sprays can be applied from spray containers such as a can, a bottle or other container, either by means of a pump or by releasing it from a pressurized container, e.g., a pressurized aerosol spray can. Such spray compositions can take various forms, for example, sprays, mists, foams, fumes or fog. Such spray compositions thus can further comprise propellants, foaming agents, etc. as the case may be. Of note is a spray composition comprising a biologically effective amount of a compound or a composition of the present invention and a carrier. One embodiment of such a spray composition comprises a biologically effective amount of a compound or a composition of the present invention and a propellant. Representative propellants include, but are not limited to, methane, ethane, propane, butane, isobutane, butene, pentane, isopentane, neopentane, pentene, hydrofluorocarbons, chlorofluorocarbons, dimethyl ether, and mixtures of the foregoing. Of note is a spray composition (and a method utilizing such a spray composition dispensed from a spray container) used to control at least one invertebrate pest selected from the group consisting of mosquitoes, black flies, stable flies, deer flies, horse flies, wasps, yellow jackets, hornets, ticks, spiders, ants, gnats, and the like, including individually or in combinations.
Nonagronomic applications include protecting an animal, particularly a vertebrate, more particularly a homeothermic vertebrate (e.g., mammal or bird) and most particularly a mammal, from an invertebrate parasitic pest by administering a parasiticidally effective (i.e. biologically effective) amount of a compound of the invention, typically in the form of a composition formulated for veterinary use, to the animal to be protected. Therefore of note is a method for protecting an animal comprising administering to the animal a parasiticidally effective amount of a compound of the invention. As referred to in the present disclosure and claims, the terms "parasiticidal" and "parasiticidally" refers to observable effects on an invertebrate parasite pest to provide protection of an animal from the pest. Parasiticidal effects typically relate to diminishing the occurrence or activity of the target invertebrate parasitic pest. Such effects on the pest include necrosis, death, retarded growth, diminished mobility or lessened ability to remain on or in the host animal, reduced feeding and inhibition of reproduction. These effects on invertebrate parasite pests provide control (including prevention, reduction or elimination) of parasitic infestation or infection of the animal. Examples of invertebrate parasitic pests controlled by administering a parasiticidally effective amount of a compound of the invention to an animal to be protected particularly include ectoparasites (arthropods, acarines, etc.) In particular, the compounds of this invention are effective against ectoparasites including: flies such as Haematobia (Lyperosia) irritans (horn fly), Stomoxys calcitrans (stable fly), Simulium spp. (blackfly), Glossina spp. (tsetse flies), Hydrotaea irritans (head fly), Musca autumnalis (face fly), Musca domestica (house fly), Morellia simplex (sweat fly), Tabanus spp. (horse fly), Hypoderma bovis, Hypoderma lineatum, Lucilia sericata, Lucilia cuprina (green blowfly), Calliphora spp. (blowfly), Protophormia spp., Oestrus ovis (nasal botfly), Culicoides spp. (midges), Hippobosca equine, Gastrophilus intestinalis, Gastrophilus haemorrhoidalis and Gastrophilus naslis; lice such as Bovicola (Damalinia) bovis, Bovicola equi, Haematopinus asini, Felicola subrostratus, Heterodoxus spiniger, Lignonathus setosus and Trichodectes canis; keds such as Melophagus ovinus; mites such as Psoroptes spp., Sarcoptes scabei, Chorioptes bovis, Demodex equi, Cheyletiella spp., Notoedres cati, Trombicula spp. and Otodectes cyanotis (ear mites); ticks such as Ixodes spp., Boophilus spp., Rhipicephalus spp., Amblyomma spp., Dermacentor spp., Hyalomma spp. and Haemaphysalis spp.; and fleas such as Ctenocephalides felis (cat flea) and Ctenocephalides canis (dog flea).
Nonagronomic applications in the veterinary sector are by conventional means such as by enteral administration in the form of, for example, tablets, capsules, drinks, drenching preparations, granulates, pastes, boli, feed-through procedures, or suppositories; or by parenteral administration, such as by injection (including intramuscular, subcutaneous, intravenous, intraperitoneal) or implants; by nasal administration; by topical administration, for example, in the form of immersion or dipping, spraying, washing, coating with powder, or application to a small area of the animal, and through articles such as neck collars, ear tags, tail bands, limb bands or halters which comprise compounds or compositions of the present invention.
Typically a parasiticidal composition according to the present invention comprises a mixture of a compound of Formula 1, an N-oxide or a salt thereof, with one or more pharmaceutically or veterinarily acceptable carriers comprising excipients and auxiliaries selected with regard to the intended route of administration (e.g., oral, topical or parenteral administration such as injection) and in accordance with standard practice. Topical administration may provide the most favorable therapeutic index. In addition, a suitable carrier is selected on the basis of compatibility with the one or more active ingredients in the composition, including such considerations as stability relative to pH and moisture content. Therefore of note is a composition for protecting an animal from an invertebrate parasitic pest comprising a parasitically effective amount of a compound of the invention and at least one carrier.
For parenteral administration including intravenous, intramuscular and subcutaneous injection, a compound of the present invention can be formulated in suspension, solution or emulsion in oily or aqueous vehicles, and may contain adjuncts such as suspending, stabilizing and/or dispersing agents. Pharmaceutical compositions for injection include aqueous solutions of water-soluble forms of active ingredients (e.g., a salt of an active compound), preferably in physiologically compatible buffers containing other excipients or auxiliaries as are known in the art of pharmaceutical formulation.
For oral administration in the form of solutions (the most readily available form for absorption), emulsions, suspensions, pastes, gels, capsules, tablets, boluses powders, granules, rumen-retention and feed/water/lick blocks, a compound of the present invention can be formulated with binders/fillers known in the art to be suitable for oral administration compositions, such as sugars (e.g., lactose, sucrose, mannitol, sorbitol), starch (e.g., maize starch, wheat starch, rice starch, potato starch), cellulose and derivatives (e.g., methylcellulose, carboxymethylcellulose, ethylhydroxycellulose), protein derivatives (e.g., zein, gelatin), and synthetic polymers (e.g., polyvinyl alcohol, polyvinylpyrrolidone). If desired, lubricants (e.g., magnesium stearate), disintegrating agents (e.g., cross-linked polyvinylpyrrolidinone, agar, alginic acid) and dyes or pigments can be added. Pastes and gels often also contain adhesives (e.g., acacia, alginic acid, bentonite, cellulose, xanthan gum, colloidal magnesium aluminum silicate) to aid in keeping the composition in contact with the oral cavity and not being easily ejected.
If the parasiticidal compositions are in the form of feed concentrates, the carrier is typically selected from high-performance feed, feed cereals or protein concentrates. Such feed concentrate-containing compositions can, in addition to the parasiticidal active ingredients, comprise additives promoting animal health or growth, improving quality of meat from animals for slaughter or otherwise useful to animal husbandry. These additives can include, for example, vitamins, antibiotics, chemotherapeutics, bacteriostats, fungistats, coccidiostats and hormones.
Compounds of the present invention may have favorable pharmacokinetic and pharmacodynamic properties providing systemic availability from oral administration and ingestion. Therefore after ingestion by the animal to be protected, parasiticidally effective concentrations of compounds of the invention in the bloodstream protect the treated animal from blood-sucking pests such as fleas, ticks and lice. Therefore of note is a composition for protecting an animal from an invertebrate parasite pest in a form for oral administration (i.e. comprising, in addition to a parasiticidally effective amount of a compound of the invention, one or more carriers selected from binders and fillers suitable for oral administration and feed concentrate carriers).
Formulations for topical administration are typically in the form of a powder, cream, suspension, spray, emulsion, foam, paste, aerosol, ointment, salve or gel. More typically a topical formulation is a water-soluble solution, which can be in the form of a concentrate that is diluted before use. Parasiticidal compositions suitable for topical administration typically comprise a compound of the present invention and one or more topically suitable carriers. In applications of a parasiticidal composition topically to the exterior of an animal as a line or spot (i.e. "spot-on" treatment), the active ingredient migrates over the surface of the animal to cover most or all of its external surface area. As a result, the treated animal is particularly protected from invertebrate pests that feed off the epidermis of the animal such as ticks, fleas and lice. Therefore formulations for topical localized administration often comprise at least one organic solvent to facilitate transport of the active ingredient over the skin and/or penetration into the epidermis of the animal. Solvents commonly used as carriers in such formulations include propylene glycol, paraffins, aromatics, esters such as isopropyl myristate, glycol ethers, and alcohols such as ethanol and n-propanol.
The rate of application required for effective control (i.e. "biologically effective amount") will depend on such factors as the species of invertebrate 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 ingredients per hectare are sufficient to control pests in agronomic ecosystems, but as little as 0.0001 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. One skilled in the art can easily determine the biologically effective amount necessary for the desired level of invertebrate pest control.
In general for veterinary use, a compound of Formula 1, an N-oxide or a salt thereof, is administered in a parasiticidally effective amount to an animal to be protected from invertebrate parasite pests. A parasiticidally effective amount is the amount of active ingredient needed to achieve an observable effect diminishing the occurrence or activity of the target invertebrate parasite pest. One skilled in the art will appreciate that the parasitically effective dose can vary for the various compounds and compositions of the present invention, the desired parasitical effect and duration, the target invertebrate pest species, the animal to be protected, the mode of application and the like, and the amount needed to achieve a particular result can be determined through simple experimentation.
For oral administration to homeothermic animals, the daily dosage of a compound of the present invention typically ranges from about 0.01 mg/kg to about 100 mg/kg, more typically from about 0.5 mg/kg to about 100 mg/kg, of animal body weight. For topical (e.g., dermal) administration, dips and sprays typically contain from about 0.5 ppm to about 5000 ppm, more typically from about 1 ppm to about 3000 ppm, of a compound of the present invention.
The following Tests demonstrate the control efficacy of compounds of this invention on specific pests. "Control efficacy" represents inhibition of invertebrate pest development (including mortality) that causes significantly reduced feeding. The pest control protection afforded by the compounds is not limited, however, to these species. See Index Tables A-F for compound descriptions. The following abbreviations are used in the Index Tables which follow: Cmpd. No. means Compound Number, Ph is phenyl, and Py is pyridinyl. The abbreviation "Ex." stands for "Example" and is followed by a number indicating in which example the compound is prepared. A dash ("-") in the (R3)n column indicates that no R3 substituent is present. INDEX TABLE A
Figure imgf000098_0001
Cmpd. No. A A2 A3 Rl (R3)n R4 R6 m.p. (°C)
1 (Ex. 1) N CF3-C H-C 2-C ■4-Py H 4-Cl-Ph 100-102
2 (Ex. 2) H-C Cl-C Cl-C 2-C■4-Py H 4-Cl-Ph **
3 (Ex. 3) H-C Cl-C Cl-C 2-C■4-Py H 4-Cl-Ph ** (Note 1)
4 H-C H-C F3C-C 2-C■4-Py H 4-Cl-Ph
5 H-C Cl-C H-C 2-C■4-Py H 4-Cl-Ph
6 H-C F-C H-C 2-C■4-Py H 4-Cl-Ph
7 H-C Cl-C H-C 2-C■4-Py Me 4-Cl-Ph
8 H-C CF3-C H-C 2-C■4-Py H 4-Cl-Ph
9 H-C Cl-C Cl-C 2-C■4-Py Me 4-Cl-Ph
10 H-C CF3-C H-C 2-C■4-Py Me 4-Cl-Ph
11 H-C H-C F3C-C 2-C■4-Py Me 4-Cl-Ph
12 H-C F-C H-C 2-C■4-Py Me 4-Cl-Ph
13 N Cl-C H-C 2-C■4-Py H 4-Cl-Ph
14 N Cl-C H-C 2-C■4-Py H 4-Br-Ph
15 H-C Cl-C H-C 2-C■4-Py 3 -Me H 4-Cl-Ph
16 (Ex. 4) N H-C Cl-C 2-C■4-Py H 4-Cl-Ph
17 (Ex. 6) N Cl-C H-C 2-C■4-Py Me 4-Cl-Ph
18 N H-C Cl-C H 4-Cl-Ph 134-136 19 N H-C Cl-C 2,6-di-Cl-4-Py H 4-Cl-Ph 157-159 20 N Cl-C Cl-C 2- -CI- -4- -Py Me 4-Cl-Ph * 21 N H-C F3C-C 2- -Cl- -4- -Py H 4-Cl-Ph
22 N H-C F3C-C 2- -Cl- -4- -Py Me 4-Cl-Ph
23 N Cl-C H-C 2- -Cl- -4- -Py H 3- Cl-Ph
24 N Cl-C H-C 2- -Cl- -4- -Py H 2-Cl-Ph
25 N Cl-C H-C 2- -Cl- -4- -Py H 3-CF3-Ph
26 N Cl-C H-C 2- -Cl- -4- -Py H 4- F-Ph
81 N Cl-C Cl-C 2- -Cl- -4- -Py H 4-Cl-Ph
82 N Br-C Cl-C 2- -Cl- -4- -Py H 4-Cl-Ph
83 N H-C Br-C 2- -Cl- -4- -Py H 4-Cl-Ph Cmpd. No. Al A2 A3 Rl (R3)n R4 R6 m.p. (°C)
84 N H-C F-C 2-Cl-4-Py H 4-Cl-Ph *
85 N Cl-C F-C 2-Cl-4-Py H 4-Cl-Ph *
86 N Cl-C Br-C 2-Cl-4-Py H 4-Cl-Ph *
87 N Br-C F-C 2-Cl-4-Py H 4-Cl-Ph *
88 N Br-C Br-C 2-Cl-4-Py H 4-Cl-Ph *
89 N Br-C F3C-C 2-Cl-4-Py H 4-Cl-Ph *
90 N Cl-C F3C-C 2-Cl-4-Py H 4-Cl-Ph *
91 N F-C Cl-C 2-Cl-4-Py H 4-Cl-Ph *
92 (Ex. 7) N H2N-C Cl-C 2-Cl-4-Py H 4-Cl-Ph **
93 H-C Cl-C Cl-C 2-Cl-4-Py H 6-Cl-2-Py *
94 N F3C-C H-C 2-Cl-4-Py H 5-Cl-2-Py *
95 N F3C-C H-C 2-Cl-4-Py H 6-Cl-2-Py *
96 (Ex. 8) N N Cl-C 2-Cl-4-Py H 4-Cl-Ph **
97 N F3C-C H-C 2-Br-4-Py H 4-Cl-Ph *
98 N F3C-C H-C 2-F-4-Py H 4-Cl-Ph *
99 N F3C-C H-C 3-Cl-4-Py H 4-Cl-Ph *
100 N F3C-C H-C 2,3-di-Cl-4-Py H 4-Cl-Ph *
101 N F3C-C H-C 2-F3C-4-Py H 4-Cl-Ph *
102 N F3C-C H-C 2-Cl-3-F-4-Py H 4-Cl-Ph *
103 N F3C-C H-C 2-Cl-4-Py 2-Me H 4-Cl-Ph *
104 H-C F3C-C N 2-Cl-4-Py H 4-Cl-Ph *
105 N F3C-C H-C 4-pyrimidinyl H 4-Cl-Ph *
106 H-C Cl-C F-C 2-Cl-4-Py H 4-Cl-Ph *
107 H-C Br-C F-C 2-Cl-4-Py H 4-Cl-Ph *
108 N F3C-C H-C 2-Cl-5-thiazolyl H 4-Cl-Ph *
109 N Cl-C F-C 2-Cl-4-Py Me 4-Cl-Ph *
110 N Br-C F-C 2-Cl-4-Py Me 4-Cl-Ph *
111 N N Br-C 2-Cl-4-Py H 4-Cl-Ph *
Note 1: Oxalate salt of Compound 2.
* See Index Table G for 1 H NMR data.
** See Synthesis Example for ^H NMR data.
Figure imgf000100_0001
Cmpd. No. A1 A2 A3 Rl R6 m.p. (°C)
27 H-C H-C CF3-C 2-Cl-4-Py 4-F-Ph *
28 H-C H-C CF3-C 2-Cl-4-Py 4-F-Ph (Note 2)
29 H-C Cl-C Cl-C 2-Cl-4-Py 4-F-Ph *
30 H-C Cl-C Cl-C 2-Cl-4-Py 4-Cl-Ph *
31 H-C Cl-C H-C 2-Cl-4-Py 4-F-Ph *
32 H-C F-C H-C 2-Cl-4-Py 4-F-Ph *
33 H-C Cl-C H-C 2-Cl-4-Py 4-Cl-Ph *
34 H-C F-C H-C 2-Cl-4-Py 4-Cl-Ph *
35 N CF3-C H-C 2-Cl-4-Py 4-F-Ph *
36 N Cl-C Cl-C 2-Cl-4-Py 4-F-Ph *
37 N Br-C Cl-C 2-Cl-4-Py 4-F-Ph *
Note 2: HCl salt of Compound 27.
* See Index Table G for 1 H NMR data.
** See Synthesis Example for ^H NMR data.
Figure imgf000100_0002
Cmpd.
No. Al A2 A3 Rl R4 R34 R6 m.p. (°C)
38 H-C H-C F3C-C 2-Cl-4-Py H H 4-F-Ph *
39 H-C Cl-C H-C 2-Cl-4-Py H H 4-F-Ph *
40 H-C Cl-C Cl-C 2-Cl-4-Py H H 4-F-Ph *
41 H-C F3C-C H-C 2-Cl-4-Py H H 4-F-Ph *
42 H-C F-C H-C 2-Cl-4-Py H H 4-F-Ph *
43 H-C Cl-C H-C 2-Cl-4-Py H H 4-Br-Ph * Cmpd.
No. Al A2 A3 Rl R4 R34 R6 m.p. (°C)
44 H-C Cl-C H-C 2-Cl-4-Py H H 4-Cl-Ph *
45 H-C Cl-C Cl-C 2-Cl-4-Py H H 4-Cl-Ph *
46 H-C F3C-C H-C 2-Cl-4-Py H H 4-Cl-Ph *
47 H-C H-C F3C-C 2-Cl-4-Py H H 4-Cl-Ph *
48 H-C F-C H-C 2-Cl-4-Py H H 4-Cl-Ph *
49 H-C Cl-C H-C 2-Cl-4-Py Me H 4-F-Ph *
50 N H-C Cl-C 2-Cl-4-Py H H 4-F-Ph *
51 N Cl-C H-C 2-Cl-4-Py H H 4-F-Ph *
52 N Cl-C H-C 2-Cl-4-Py H H 4-Cl-Ph *
53 N Cl-C H-C 2-Cl-4-Py Me H 4-F-Ph *
54 H-C Cl-C H-C 2-Cl-4-Py H H 3-F-Ph *
55 H-C Cl-C H-C 2-Cl-4-Py H H 2,4-di-F-Ph *
56 H-C Cl-C H-C 2-Cl-4-Py H H 3,4-di-F-Ph *
57 N Cl-C Cl-C 2-Cl-4-Py H H 4-F-Ph *
58 N Cl-C Cl-C 2-Cl-4-Py H H 4-Cl-Ph *
59 N F3C-C H-C 2-Cl-4-Py H H 4-F-Ph *
60 N F3C-C H-C 2-Cl-4-Py H H 4-Cl-Ph *
61 H-C Cl-C Cl-C 2-Cl-4-Py H H 3-F-Ph *
62 H-C Cl-C Cl-C 2-Cl-4-Py H H 2,4-di-F-Ph *
63 H-C Cl-C Cl-C 2-Cl-4-Py H H 3,4-di-F-Ph *
64 H-C Cl-C H-C 2-Cl-4-Py H H 3-Cl-Ph *
65 H-C Cl-C H-C 2-Cl-4-Py H H 5-Cl-2-Py *
66 N F3C-C H-C 2-Cl-4-Py H H 3-F-Ph *
67 N F3C-C H-C 2-Cl-4-Py H H 2,4-di-F-Ph *
68 N F3C-C H-C 2-Cl-4-Py H H 3,4-di-F-Ph *
69 N F3C-C H-C 2-Cl-4-Py H H 5-Cl-2-Py *
70 H-C Cl-C Cl-C 2-Cl-4-Py H H 5-Cl-2-Py *
71 N F3C-C H-C 2-Cl-4-Py H Me 4-F-Ph *
72 N Cl-C Cl-C 2-Cl-4-Py H Me 4-F-Ph *
73 N Cl-C H-C 2-Cl-4-Py H Me 4-F-Ph *
74 H-C Cl-C H-C 2-Cl-4-Py H H 2-Cl-4-F-Ph *
75 H-C Cl-C H-C 2-Cl-4-Py H H 2-F-4-Cl-Ph *
76 H-C Cl-C H-C 2-Cl-4-Py H H 2,4-di-Cl-Ph *
77 H-C Cl-C Cl-C 2-Cl-4-Py H H 2-Cl-4-F-Ph *
78 H-C Cl-C Cl-C 2-Cl-4-Py H H 2-F-4-Cl-Ph *
79 H-C Cl-C Cl-C 2-Cl-4-Py H H 2,4-di-Cl-Ph * Cmpd.
No. Al A2 A3 Rl R4 R34 R6 m.p. (°i
80 (Ex. 5) N Cl-C Cl-C 2-Cl-4-Py H H 4-Br-Ph **
112 N H-C Br-C 2-Cl-4-Py H H 4-F-Ph *
113 N H-C Br-C 2-Cl-4-Py H H 4-Cl-Ph *
114 N H-C Br-C 2-Cl-4-Py H H 4-Br-Ph *
115 N H-C Br-C 2-Cl-4-Py H H 2,4-di-F-Ph *
116 N Cl-C H-C 2-Cl-4-Py H H 2,4-di-F-Ph *
117 N Cl-C H-C 2-Cl-4-Py H H 2-Cl-4-F-Ph *
118 N Cl-C H-C 2-Cl-4-Py H H 2-F-4-Cl-Ph *
119 N Cl-C H-C 2-Cl-4-Py H H 2,4-di-Cl-Ph *
120 N Cl-C H-C 2-Cl-4-Py H H 4-Br-Ph *
121 N F3C-C H-C 2-Cl-4-Py H H 2,4-di-Cl-Ph *
122 N F3C-C H-C 2-Cl-4-Py H H 2-F-4-Cl-Ph *
123 N F3C-C H-C 2-Cl-4-Py H H 2-Cl-4-F-Ph *
124 N H-C Cl-C 2-Cl-4-Py H H 2-F-4-F-Ph *
125 N H-C Cl-C 2-Cl-4-Py H H 4-Br-Ph *
126 N H-C Cl-C 2-Cl-4-Py H H 4-Cl-Ph *
127 N Cl-C Cl-C 2-Cl-4-Py H H 2,4-di-F-Ph *
128 N H-C F-C 2-Cl-4-Py H H 4-Cl-Ph *
129 N H-C F3C-C 2-Cl-4-Py H H 2,4-di-F-Ph *
130 N H-C F3C-C 2-Cl-4-Py H H 4-Br-Ph *
131 N H-C F3C-C 2-Cl-4-Py H H 4-Cl-Ph *
132 N H-C F3C-C 2-Cl-4-Py H H 4-F-Ph *
133 N H-C Br-C 2-Cl-4-Py H Me 4-F-Ph *
134 N H-C Cl-C 2-Cl-4-Py H Me 4-F-Ph *
135 N H-C F-C 2-Cl-4-Py H Me 4-F-Ph *
136 N H-C F3C-C 2-Cl-4-Py H Me 4-F-Ph *
137 N F3C-C H-C 2-Cl-4-Py H H 4-MeO-Ph *
138 N F3C-C H-C 2-Cl-4-Py H H 4-02N-Ph *
139 N F3C-C H-C 2-Cl-4-Py H H 4-F3CO-Ph *
140 N F3C-C H-C 2-Cl-4-Py H H 4-NC-Ph *
141 N F3C-C H-C 2-Cl-4-Py H H 4-i-Bu-Ph *
142 N F3C-C H-C 2-Cl-4-Py H H 4-F3C-Ph *
143 N H-C Cl-C 2-Cl-4-Py H Me 4-Cl-Ph *
144 N Cl-C F3C-C 2-Cl-4-Py H H 4-F-Ph *
145 N Cl-C F3C-C 2-Cl-4-Py H H 4-Cl-Ph *
146 N Cl-C F3C-C 2-Cl-4-Py H H 4-Br-Ph * Cmpd.
No. Al A2 A3 Rl R4 R34 R6 m.p. (°C)
147 N Cl-C F-C 2-Cl-4-Py H Me 4-Cl-Ph *
148 N Cl-C F3C-C 2-Cl-4-Py H Me 4-Cl-Ph *
149 N Cl-C Br-C 2-Cl-4-Py H Me 4-Cl-Ph *
150 N Cl-C Br-C 2-Cl-4-Py H H 4-F-Ph *
151 N Cl-C Br-C 2-Cl-4-Py H H 4-Cl-Ph *
152 N Cl-C Br-C 2-Cl-4-Py H H 4-Br-Ph *
153 N Cl-C F-C 2-Cl-4-Py H H 4-Cl-Ph *
154 N Cl-C F-C 2-Cl-4-Py H H 4-Br-Ph *
155 N Cl-C F-C 2-Cl-4-Py H H 4-F-Ph *
156 N Br-C F-C 2-Cl-4-Py H H 4-Br-Ph *
157 N Br-C F-C 2-Cl-4-Py H H 4-Cl-Ph *
158 N Br-C F-C 2-Cl-4-Py H H 4-F-Ph *
159 N Br-C F3C-C 2-Cl-4-Py H Me 4-Cl-Ph *
160 N Br-C Br-C 2-Cl-4-Py H Me 4-Cl-Ph *
161 N Br-C Cl-C 2-Cl-4-Py H Me 4-Cl-Ph *
162 N Br-C F-C 2-Cl-4-Py H Me 4-Cl-Ph *
163 N F3C-C H-C 2-Cl-4-Py H Et 4-Cl-Ph *
164 N Br-C Br-C 2-Cl-4-Py H H 4-Br-Ph *
165 N Br-C Br-C 2-Cl-4-Py H H 4-Cl-Ph *
166 N Br-C Br-C 2-Cl-4-Py H H 4-F-Ph *
167 N Br-C Cl-C 2-Cl-4-Py H H 4-Br-Ph *
168 N Br-C Cl-C 2-Cl-4-Py H H 4-Cl-Ph *
169 N Br-C Cl-C 2-Cl-4-Py H H 4-F-Ph *
170 N Br-C F3C-C 2-Cl-4-Py H H 4-Cl-Ph *
171 H-C Cl-C Cl-C 2-Cl-4-Py H Me 5-Cl-2-Py *
172 N F3C-C H-C 2-Cl-4-Py H Me 5-Cl-2-Py *
173 H-C Cl-C Cl-C 2-Cl-4-Py H H 6-Br-3-Py *
174 N F3C-C H-C 2-Cl-4-Py H H 6-C1-3- *
pyridazinyl
175 H-C Cl-C Cl-C 2-Cl-4-Py H H 6-Cl-3-Py *
176 H-C Cl-C Cl-C 2-Cl-4-Py H H 6-C1-3- *
pyridazinyl
177 N F3C-C H-C 2-Cl-4-Py H H 6-Cl-3-Py *
178 N F3C-C H-C 2-Cl-4-Py H H 6-Br-3-Py *
179 N F3C-C H-C 2-Cl-4-Py H Me 4-Cl-Ph *
180 N F-C Cl-C 2-Cl-4-Py H Me 4-Cl-Ph * Cmpd.
No. Al A2 A3 Rl R4 R34 R6 m.p. (°C)
181 N F-C Cl-C 2-Cl-4-Py H H 4-Cl-Ph *
182 H-C Cl-C Cl-C 2-Cl-4-Py H H 5-Br-2-Py *
183 N F3C-C H-C 2-Cl-4-Py H H 5-Br-2-Py *
184 H-C Cl-C Cl-C 2-Cl-4-Py H H 2-Cl-4-Py *
185 N F3C-C H-C 2-Cl-4-Py H H 2-Cl-4-Py *
186 H-C Cl-C Cl-C 2-Cl-4-Py H H 5-C1-2- *
pyrimidinyl
187 N F3C-C H-C 2-Cl-4-Py H H 5-C1-2- *
pyrimidinyl
188 N N Cl-C 2-Cl-4-Py H Me 4-Cl-Ph *
189 N F3C-C H-C 2-Br-4-Py H Me 4-Cl-Ph *
190 N F3C-C H-C 2-Br-4-Py H H 4-Cl-Ph *
191 N F3C-C H-C 2-Br-4-Py H H 4-F-Ph *
192 N F3C-C H-C 2-F-4-Py H Me 4-Cl-Ph *
193 N F3C-C H-C 2-F-4-Py H H 4-Cl-Ph *
194 N F3C-C H-C 2-F-4-Py H H 4-F-Ph *
195 N F3C-C H-C 3-Cl-4-Py H Me 4-Cl-Ph *
196 N F3C-C H-C 2,3-di-Cl-4-Py H Me 4-Cl-Ph *
197 N F3C-C H-C 2,3-di-Cl-4-Py H H 4-Cl-Ph *
198 N F3C-C H-C 2,3-di-Cl-4-Py H H 4-F-Ph *
199 N F3C-C H-C 3-Cl-4-Py H H 4-F-Ph *
200 N F3C-C H-C 3-Cl-4-Py H H 4-Cl-Ph *
201 N F3C-C H-C 2-F3C-4-Py H Me 4-Cl-Ph *
202 N F3C-C H-C 2-Cl-3-F-4-Py H Me 4-Cl-Ph *
203 N F3C-C H-C 2-C1-4- H Me 4-Cl-Ph *
pyrimidinyl
204 N F3C-C H-C 2-Cl-3-F-4-Py H H 4-Cl-Ph *
205 H-C F3C-C N 2-Cl-4-Py H Me 4-Cl-Ph *
206 N F3C-C H-C 4-pyrimidinyl H Me 4-Cl-Ph *
207 N F3C-C H-C 4-pyrimidinyl H H 4-Cl-Ph *
208 H-C Cl-C Cl-C 2-Cl-4-Py H H 5-F-2-Py *
209 N F3C-C H-C 2-Cl-4-Py H H 5-F-2-Py *
210 H-C Cl-C F-C 2-Cl-4-Py H Me 4-Cl-Ph *
211 H-C Br-C F-C 2-Cl-4-Py H Me 4-Cl-Ph *
212 N N Br-C 2-Cl-4-Py H Me 4-Cl-Ph *
* See Index Table G for 1 H NMR data. ** See Synthesis Example for NMR data.
INDEX TABLE D
Figure imgf000105_0001
Cmpd. No. Al A2 A3 A4 Rl R2 T R6 m.p. (°C)
213 H-C Cl-C H-C H-C 2-Cl-4-Py H S 4-Cl-Ph *
214 N F3C-C H-C H-C 2-Cl-4-Py H NH 4-Cl-Ph *
215 N F3C-C H-C H-C 2-Cl-4-Py Me O 4-Cl-Ph *
216 N Br-C H-C N 2-Cl-4-Py H O 4-Cl-Ph *
217 N Cl-C H-C N 2-Cl-4-Py H O 4-Cl-Ph *
218 N Cl-C Cl-C N 2-Cl-4-Py H O 4-Cl-Ph *
See Index Table G for ^H NMR data.
Figure imgf000105_0002
Cmpd. m.p. No. Al A2 A3 A4 Rl R2 R34 Z R6 (°Q
219 N F3C-C H-C H-C 2-Cl-4-Py H H NH 4-Cl-Ph *
220 N F3C-C H-C H-C 2-Cl-4-Py Me Me O 4-Cl-Ph *
221 N F3C-C H-C H-C 2-Cl-4-Py H H NMe 4-Cl-Ph *
222 N F3C-C H-C H-C 2-Cl-4-Py Me H O 4-Cl-Ph *
223 N Br-C H-C N 2-Cl-4-Py H Me O 4-Cl-Ph *
224 N Cl-C Cl-C N 2-Cl-4-Py H Me o 4-Cl-Ph *
* See Index Table G for 1 H NMR data.
Figure imgf000106_0001
Cmpd. No. Al A2 A3 A4 Rl s t R6 m.p. (°C)
225 N F3C-C H-C H-C 2-Cl-4-Py 3 1 4-Cl-Ph *
226 N F3C-C H-C H-C 2-Cl-4-Py 2 2 4-Cl-Ph *
227 N F3C-C H-C H-C 2-Cl-4-Py 2 1 4-Cl-Ph *
* See Index Table G for 1 H NMR data.
INDEX TABLE G
Cmpd. No. ^H NMR Data (CDCI3 solution unless indicated otherwise)a
4 δ 8.81 (d, IH), 8.61 (d, IH), 8.57 (br s, IH), 7.80 (d, IH), 7.65 (dd, IH), 7.37 (dd, IH),
7.28 (s, 4H), 6.75 (d, IH), 6.50 (d, IH), 6.13 (dt, IH), 4.97 (m, IH), 3.85 (m, IH), 3.35-
3.29 (m, 4H).
5 δ 8.58 (d, IH), 8.46 (br s, IH), 8.41 (d, IH), 7.79 (s, IH), 7.64 (dd, IH), 7.28 (s, 4H), 7.04 (dd, IH), 6.66 (d, IH), 6.49 (d, IH), 6.12 (dt, IH), 4.88 (m, IH), 3.82 (m, 2H), 3.35-3.29 (m, 4H).
6 δ 8.58 (d, IH), 8.40 (dd, IH), 8.36 (br s, IH), 7.79 (s, IH), 7.64 (dd, IH), 7.28 (s, 4H), 6.77 (dt, IH), 6.50 (d, IH), 6.43 (dd, IH), 6.12 (dt, IH), 4.87 (m, IH), 3.83 (dd, 2H), 3.35- 3.29 (m, 4H).
7 δ 8.59 (d, IH), 8.44 (br s, IH), 8.40 (d, IH), 7.78 (d, IH), 7.63 (dd, IH), 7.28 (s, 4H), 7.03 (dd, IH), 6.66 (d, IH), 6.48 (d, IH), 5.98 (dd, IH), 4.83 (m, IH), 3.80 (m, IH), 3.74 (m, IH), 3.27 (m, 2H), 3.01 (pentet, IH), 1.16 (d, 3H).
8 δ 8.66 (s, IH), 8.62 (d, IH), 8.60 (s, IH), 7.82 (d, IH), 7.66 (dd, IH), 7.35 (d, IH), 7.28 (s, 4H), 6.89 (d, IH), 6.50 (d, IH), 6.13 (dt, IH), 4.96 (m, IH), 3.83 (m, 2H), 3.34 (m, 4H).
9 δ 8.64 (s, IH), 8.60 (d, IH), 8.47 (br s, IH), 7.78 (s, IH), 7.63 (dd, IH), 7.27 (s, 4H), 6.74 (s, IH), 6.48 (d, IH), 5.98 (dd, IH), 4.82 (m, IH), 3.78 (m, IH), 3.72 (m, IH), 3.28 (m, 2H), 3.02 (pentet, IH), 1.16 (d, 3H).
10 δ 8.64 (s, IH), 8.62-8.58 (m, 2H), 7.81 (s, IH), 7.64 (dd, IH), 7.34 (d, IH), 7.28 (s, 4H), 6.88 (d, IH), 6.48 (d, IH), 5.98 (dd, IH), 4.90 (m, IH), 3.81 (m, IH), 3.75 (m, IH), 3.29 (m, 2H), 3.02 (pentet, IH), 1.17 (d, 3H).
11 δ 8.79 (s, IH), 8.61 (d, IH), 8.54 (br s, IH), 7.79 (s, IH), 7.65 (d, IH), 7.36 (dd, IH), 7.28 (s, 4H), 6.75 (d, IH), 6.49 (d, IH), 5.99 (dd, IH), 4.92 (m, IH), 3.85 (m, IH), 3.78 (m, IH), 3.28 (m, 2H), 3.03 (br s, IH), 1.18 (d, 3H). δ 8.59 (d, IH), 8.42-8.31 (m, 2H), 7.79 (s, IH), 7.64 (m, IH), 7.28 (s, 4H), 6.76 (td, IH), 6.49 (d, IH), 6.43 (dd, IH), 5.99 (dd, IH), 4.83 (m, IH), 3.82 (m, IH), 3.76 (m, IH), 3.27 (m, 2H), 3.02 (br s, IH), 1.17 (d, 3H).
δ 8.67 (d, IH), 8.60 (d, IH), 8.32 (br s, IH), 7.78 (d, IH), 7.63 (dd, IH), 7.28 (s, 4H), 7.00 (d, IH), 6.50 (d, IH), 6.14 (dt, IH), 5.36 (m, IH), 3.83 (m, 2H), 3.36-3.30 (m, 4H).
δ (acetone-^) 9.21 (br s, IH), 8.57-8.53 (m, 2H), 7.97 (s, IH), 7.94 (d, IH), 7.48 (d, 2H), 7.27 (d, 2H), 7.06 (d, IH), 6.74 (d, IH), 6.18 (dt, IH), 5.57 (m, IH), 4.43-4.25 (m, 4H),
3.85 (d, 2H).
δ 9.16 (s, IH), 8.55 (d, IH), 8.45 (d, IH), 7.82 (s, IH), 7.66 (d, IH), 7.27 (d, 2H), 7.21 (d, 2H), 7.08 (dd, IH), 6.74 (d, IH), 6.40 (d, IH), 5.95 (dt, IH), 3.43 (d, 2H), 3.38 (d, 2H), 3.29 (d, 2H), 1.72 (s, 3H).
δ 8.87 (s, IH), 8.62 (d, IH), 8.30 (br s, IH), 7.77 (d, IH), 7.63 (d, IH), 7.28 (s, 4H), 6.48 (d, IH), 6.00 (dd, IH), 5.29 (m, IH), 3.80 (m, IH), 3.74 (m, IH), 3.31 (m, 2H), 3.01 (br s, IH), 1.17 (d, 3H).
δ 9.0 (s, IH), 8.62 (d, IH), 8.41 (bs, IH), 8.2 (s, IH), 7.8 (s, IH), 7.65 (d, IH), 7.25 (s, 4H), 6.5 (dd, IH), 6.18 (m, IH), 5.4 (m, IH), 3.9 (m, 2H), 3.36 (m, 4H).
δ 8.66 (d, IH), 8.61 (d, IH), 8.31 (br s, IH), 7.78 (d, IH), 7.63 (dd, IH), 7.28 (s, 4H), 7.00 (d, IH), 6.48 (d, IH), 6.01 (dd, IH), 5.31 (m, IH), 3.78 (m, 2H), 3.31 (m, 2H), 3.01 (m, IH), 1.16 (d, 3H).
δ 8.66 (d, IH), 8.60 (d, IH), 8.40 (br s, IH), 7.81 (s, IH), 7.66 (dd, IH), 7.35 (s, IH), 7.25-7.20 (m, 3H), 7.01 (d, IH), 6.50 (d, IH), 6.18 (dt, IH), 5.39 (m, IH), 3.86 (m, 2H), 3.43 (br s, 2H), 3.37 (d, 2H).
δ 8.68 (br s, IH), 8.63 (d, IH), 8.59 (d, IH), 7.88 (s, IH), 7.76 (d, IH), 7.52 (dd, IH), 7.36 (dd, IH), 7.25-7.18 (m, 2H), 7.06-6.98 (m, 2H), 6.50 (d, IH), 6.18 (dt, IH), 5.39 (m, IH),
3.86 (m, 2H), 3.43 (br s, 2H), 3.37 (d, 2H).
δ 8.67 (d, IH), 8.61 (d, IH), 8.32 (br s, IH), 7.79 (s, IH), 7.64 (dd, IH), 7.60 (s, IH), 7.53 (d, IH), 7.49 (d, IH), 7.43 (t, IH), 7.01 (d, IH), 6.58 (d, IH), 6.25 (dt, IH), 5.38 (m, IH), 3.86 (m, 2H), 3.40-3.34 (m, 4H).
δ 8.57 (d, IH), 8.53 (d, IH), 8.59-8.47 (br s, IH), 7.77 (s, IH), 7.63 (dd, IH), 7.26 (m, 2H), 6.96-6.88 (m, 3H), 6.47 (d, IH), 6.01 (dt, IH), 5.33 (m, IH), 3.78 (m, 2H), 3.45-3.37 (m, 2H), 3.31 (br d, 2H).
δ 8.80 (s, IH), 8.61 (d, IH), 8.54 (s, IH), 7.79 (s, IH), 7.64 (d, IH), 7.55-7.49 (m, 4H), 7.38-7.33 (m, 3H), 7.12 (t, 2H), 6.74 (d, IH), 4.97 (m, IH), 3.87 (t, 2H), 3.77 (s, 2H), 3.32 (m, 2H).
δ 8.65 (s, IH), 8.60 (d, IH), 8.45 (s, IH), 7.78 (s, IH), 7.62 (m, IH), 7.56-7.48 (m, 4H), 7.34 (d, 2H), 7.12 (t, 2H), 6.74 (s, IH), 4.88 (m, IH), 3.83 (m, 2H), 3.76 (s, 2H), 3.31 (m, 2H). δ 8.65 (s, IH), 8.60 (d, IH), 8.44 (br s, IH), 7.77 (s, IH), 7.62 (d, IH), 7.51 (dd, 4H), 7.40 (d, 2H), 7.35 (d, 2H), 6.74 (s, IH), 4.88 (m, IH), 3.82 (m, 2H), 3.76 (s, 2H), 3.30 (m, 2H). δ 8.59 (d, IH), 8.43 (s, IH), 8.40 (d, IH), 7.78 (s, IH), 7.63 (d, IH), 7.55-7.49 (m, 4H), 7.34 (d, 2H), 7.12 (t, 2H), 7.03 (dd, IH), 6.66 (d, IH), 4.89 (m, IH), 3.84 (m, 2H), 3.76 (s, 2H), 3.30 (m, 2H).
δ 8.59 (d, IH), 8.39 (dd, IH), 8.34 (s, IH), 7.78 (s, IH), 7.63 (d, IH), 7.55-7.49 (m, 4H), 7.34 (d, 2H), 7.12 (t, 2H), 6.76 (ddd, IH), 6.43 (dd, IH), 4.88 (m, IH), 3.85 (t, 2H), 3.76 (s, 2H), 3.30 (m, 2H).
δ 8.59 (d, IH), 8.46 (s, IH), 8.40 (d, IH), 7.79 (s, IH), 7.63 (d, IH), 7.51 (dd, 4H), 7.40 (d, 2H), 7.35 (d, 2H), 7.03 (dd, IH), 6.65 (d, IH), 4.89 (m, IH), 3.83 (m, 2H), 3.76 (s, 2H), 3.30 (m, 2H).
δ 8.58 (d, IH), 8.39 (dd, IH), 8.34 (s, IH), 7.78 (s, IH), 7.63 (d, IH), 7.51 (dd, 4H), 7.40 (d, 2H), 7.35 (d, 2H), 6.76 (ddd, IH), 6.43 (dd, IH), 4.88 (m, IH), 3.85 (t, 2H), 3.76 (s, 2H), 3.29 (m, 2H).
δ 8.84 (d, IH), 8.63 (d, IH), 8.50 (br s, IH), 7.80 (s, IH), 7.65 (m, IH), 7.55-7.49 (m, 4H), 7.39-7.34 (m, 3H), 7.12 (t, 2H), 5.44 (m, IH), 3.89 (t, 2H), 3.77 (s, 2H), 3.34 (br s, 2H). δ 8.87 (s, IH), 8.62 (d, IH), 8.33 (br s, IH), 7.78 (s, IH), 7.64 (d, IH), 7.55-7.49 (m, 4H), 7.36 (d, 2H), 7.12 (t, 2H), 5.35 (m, IH), 3.85 (m, 2H), 3.77 (s, 2H), 3.35 (br s, 2H).
δ 8.84 (s, IH), 8.62 (d, IH), 8.31 (br s, IH), 7.78 (s, IH), 7.63 (d, IH), 7.55-7.49 (m, 4H), 7.36 (d, 2H), 7.12 (t, 2H), 5.36 (m, IH), 3.85 (m, 2H), 3.76 (s, 2H), 3.34 (br s, 2H).
δ 8.80 (d, IH), 8.61 (d, IH), 8.58 (br s, IH), 7.79 (d, IH), 7.65 (dd, IH), 7.38 (dd, IH), 6.97 (t, 2H), 6.82 (m, 2H), 6.75 (d, IH), 4.97 (m, IH), 3.99 (t, 2H), 3.95 (m, 2H), 3.41 (m, 2H), 2.96 (t, 2H).
δ 8.58 (d, IH), 8.45 (br s, IH), 8.40 (d, IH), 7.78 (s, IH), 7.63 (dd, IH), 7.04 (dd, IH), 6.97 (t, 2H), 6.82 (m, 2H), 6.66 (d, IH), 4.89 (m, IH), 3.98 (t, 2H), 3.92 (m, 2H), 3.40 (m, 2H), 2.95 (t, 2H).
δ 8.65 (s, IH), 8.59 (d, IH), 8.46 (br s, IH), 7.77 (s, IH), 7.63 (dd, IH), 6.96 (t, 2H), 6.82 (m, 2H), 6.74 (s, IH), 4.88 (m, IH), 3.98 (t, 2H), 3.91 (m, 2H), 3.41 (m, 2H), 2.96 (t, 2H). δ 8.64 (br s, IH), 8.62-8.59 (m, 2H), 7.81 (d, IH), 7.65 (dd, IH), 7.35 (d, IH), 6.96 (t, 2H), 6.88 (d, IH), 6.82 (m, 2H), 4.96 (m, IH), 3.99 (t, 2H), 3.94 (m, 2H), 3.43 (m, 2H), 2.96 (t, 2H).
δ 8.58 (d, IH), 8.39 (dd, IH), 8.36 (br s, IH), 7.78 (s, IH), 7.63 (dd, IH), 6.96 (t, 2H), IH), 6.82 (m, 2H), 6.77 (dt, IH), 6.43 (dd, IH), 4.88 (m, IH), 3.98 (t, 2H), 3.93 (m, 2H), 3.39 (m, 2H), 2.96 (t, 2H).
δ 8.59 (d, IH), 8.44 (br s, IH), 8.40 (d, IH), 7.78 (d, IH), 7.63 (dd, IH), 7.37 (d, 2H), 7.04 (dd, IH), 6.77 (d, 2H), 6.66 (d, IH), 4.89 (m, IH), 3.99 (t, 2H), 3.92 (m, 2H), 3.39 (m, 2H), 2.96 (t, 2H). δ 8.58 (d, IH), 8.44 (br s, IH), 8.40 (d, IH), 7.78 (d, IH), 7.63 (dd, IH), 7.23 (d, 2H), 7.04 (dd, IH), 6.81 (d, 2H), 6.66 (d, IH), 4.88 (m, IH), 3.99 (t, 2H), 3.92 (m, 2H), 3.39 (m, 2H), 2.96 (t, 2H).
δ 8.64 (s, IH), 8.59 (d, IH), 8.47 (br s, IH), 7.77 (s, IH), 7.63 (dd, IH), 7.23 (d, 2H), 6.81 (d, 2H), 6.74 (s, IH), 4.87 (m, IH), 3.99 (t, 2H), 3.90 (m, 2H), 3.40 (m, 2H), 2.96 (t, 2H). δ 8.63 (br s, IH), 8.62-8.59 (m, 2H), 7.80 (d, IH), 7.65 (dd, IH), 7.35 (d, IH), 7.23 (d, 2H), 6.88 (d, IH), 6.81 (d, 2H), 4.96 (m, IH), 4.00 (t, 2H), 3.93 (m, 2H), 3.42 (m, 2H), 2.97 (t, 2H).
δ 8.80 (d, IH), 8.60 (d, IH), 8.56 (br s, IH), 7.79 (s, IH), 7.64 (dd, IH), 7.38 (dd, IH), 7.23 (d, 2H), 6.81 (d, 2H), 6.74 (d, IH), 4.97 (m, IH), 4.00 (t, 2H), 3.95 (m, 2H), 3.41 (m, 2H), 2.97 (t, 2H).
δ 8.58 (d, IH), 8.39 (dd, IH), 8.35 (br s, IH), 7.78 (s, IH), 7.63 (dd, IH), 7.23 (d, 2H), IH), 6.81 (d, 2H), 6.77 (dt, IH), 6.43 (dd, IH), 4.87 (m, IH), 3.99 (t, 2H), 3.93 (m, 2H), 3.39 (m, 2H), 2.96 (t, 2H).
δ 8.59 (d, IH), 8.48 (br s, IH), 8.40 (d, IH), 7.78 (s, IH), 7.63 (dd, IH), 7.04 (dd, IH), 6.97 (t, 2H), 6.82 (m, 2H), 6.68 (d, IH), 4.86 (m, IH), 3.89 (br m, 2H), 3.81 (d, 2H), 3.42 (dd, IH), 3.35 (dd, IH), 2.80 (m, IH), 1.09 (d, 3H).
δ 8.76 (d, IH), 8.61 (d, IH), 8.38 (br s, IH), 7.85 (d, IH), 7.78 (s, IH), 7.63 (dd, IH), 6.96 (t, 2H), 6.83 (m, 2H), 5.35 (m, IH), 3.98 (t, 2H), 3.91 (m, 2H), 3.40 (m, 2H), 2.95 (t, 2H). δ 8.66 (d, IH), 8.60 (d, IH), 8.34 (br s, IH), 7.79 (s, IH), 7.63 (dd, IH), 7.01 (d, IH), 6.96 (t, 2H), 6.83 (m, 2H), 5.38 (m, IH), 3.98 (t, 2H), 3.92 (m, 2H), 3.43 (br m, 2H), 2.95 (t, 2H).
δ 8.66 (d, IH), 8.60 (d, IH), 8.35 (br s, IH), 7.79 (s, IH), 7.63 (dd, IH), 7.23 (d, 2H), 7.01 (d, IH), 6.82 (d, 2H), 5.38 (m, IH), 3.99 (t, 2H), 3.92 (m, 2H), 3.43 (dd, 2H), 2.95 (t, 2H). δ 8.66 (d, IH), 8.61 (d, IH), 8.34 (br s, IH), 7.78 (s, IH), 7.63 (dd, IH), 7.01 (d, IH), 6.97 (t, 2H), 6.82 (m, 2H), 5.34 (m, IH), 3.89 (br m, 2H), 3.81 (m, 2H), 3.44 (dd, IH), 3.38 (dd, lH), 2.79 (m, IH), 1.09 (d, 3H).
δ 8.59 (d, IH), 8.47 (br s, IH), 8.40 (d, IH), 7.79 (d, IH), 7.63 (dd, IH), 7.22 (td, IH), 7.04 (dd, IH), 6.67 (m, 2H), 6.66 (d, IH), 6.60 (dt, IH), 4.89 (m, IH), 4.01 (t, 2H), 3.92 (m, 2H), 3.40 (m, 2H), 2.96 (t, 2H).
δ 8.58 (d, IH), 8.53 (br s, IH), 8.40 (d, IH), 7.80 (d, IH), 7.64 (dd, IH), 7.04 (dd, IH), 6.93-6.82 (m, 2H), 6.78 (m, IH), 6.66 (d, IH), 4.89 (m, IH), 4.05 (t, 2H), 3.91 (m, 2H), 3.44 (m, 2H), 2.97 (t, 2H).
δ 8.59 (d, IH), 8.45 (br s, IH), 8.40 (d, IH), 7.79 (s, IH), 7.64 (dd, IH), 7.09-7.02 (m, 2H), 6.71 (m, IH), 6.66 (d, IH), 6.58 (m, IH), 4.89 (m, IH), 3.96 (t, 2H), 3.92 (m, 2H), 3.39 (m, 2H), 2.95 (t, 2H).
δ 8.87 (s, IH), 8.62 (d, IH), 8.33 (br s, IH), 7.78 (s, IH), 7.63 (d, IH), 6.97 (t, 2H), 6.83 (m, 2H), 5.36 (m, IH), 3.98 (t, 2H), 3.91 (br t, 2H), 3.43 (br s, 2H), 2.95 (t, 2H). δ 8.88 (s, IH), 8.62 (d, IH), 8.29 (br s, IH), 7.77 (d, IH), 7.62 (dd, IH), 7.23 (d, 2H), 6.82 (d, 2H), 5.35 (m, IH), 3.99 (t, 2H), 3.91 (m, 2H), 3.42 (dd, 2H), 2.95 (t, 2H).
δ 8.85 (d, IH), 8.63 (d, IH), 8.48 (br s, IH), 7.80 (s, IH), 7.64 (dd, IH), 7.38 (d, IH), 6.96 (t, 2H), 6.83 (m, 2H), 5.43 (m, IH), 3.98 (t, 2H), 3.95 (m, 2H), 3.42 (m, 2H), 2.95 (t, 2H). δ 8.85 (d, IH), 8.63 (d, IH), 8.49 (br s, IH), 7.79 (s, IH), 7.64 (dd, IH), 7.38 (d, IH), 7.23 (d, 2H), 6.82 (d, 2H), 5.43 (m, IH), 3.99 (t, 2H), 3.95 (m, 2H), 3.42 (m, 2H), 2.95 (t, 2H). δ 8.65 (s, IH), 8.59 (d, IH), 8.46 (br s, IH), 7.78 (d, IH), 7.63 (dd, IH), 7.22 (m, IH), 6.74 (s, IH), 6.69-6.64 (m, 2H), 6.60 (dt, IH), 4.88 (m, IH), 4.01 (t, 2H), 3.90 (m, 2H), 3.40 (m, 2H), 2.96 (t, 2H).
δ 8.65 (s, IH), 8.59 (d, IH), 8.52 (br s, IH), 7.79 (s, IH), 7.64 (dd, IH), 6.92-6.82 (m, 2H), 6.78 (m, IH), 6.75 (s, IH), 4.88 (m, IH), 4.05 (t, 2H), 3.90 (m, 2H), 3.45 (m, 2H), 2.97 (t, 2H).
δ 8.65 (s, IH), 8.60 (d, IH), 8.45 (br s, IH), 7.77 (s, IH), 7.63 (dd, IH), 7.06 (m, IH), 6.74 (s, IH), 6.70 (m, IH), 6.58 (m, IH), 4.88 (m, IH), 3.96 (t, 2H), 3.90 (m, 2H), 3.39 (m, 2H), 2.95 (t, 2H).
δ 8.59 (d, IH), 8.45 (br s, IH), 8.40 (d, IH), 7.79 (d, IH), 7.63 (dd, IH), 7.19 (t, IH), 7.04 (d, IH), 6.94 (m, IH), 6.89 (t, IH), 6.78 (dd, IH), 6.66 (d, IH), 4.89 (m, IH), 4.01 (t, 2H), 3.92 (m, 2H), 3.40 (m, 2H), 2.96 (t, 2H).
δ 8.59 (d, IH), 8.46 (br s, IH), 8.40 (d, IH), 8.07 (d, IH), 7.78 (d, IH), 7.63 (dd, IH), 7.52 (dd, IH), 7.04 (dd, IH), 6.71 (d, IH), 6.66 (d, IH), 4.88 (m, IH), 4.33 (t, 2H), 3.90 (m, 2H), 3.36 (m, 2H), 2.95 (t, 2H).
δ 8.85 (d, IH), 8.63 (d, IH), 8.52 (br s, IH), 7.80 (s, IH), 7.65 (dd, IH), 7.38 (d, IH), 7.21 (m, IH), 6.70-6.63 (m, 2H), 6.61 (dt, IH), 5.43 (m, IH), 4.01 (t, 2H), 3.94 (m, 2H), 3.42 (m, 2H), 2.96 (t, 2H).
δ 8.84 (d, IH), 8.63 (d, IH), 8.58 (br s, IH), 7.81 (s, IH), 7.66 (dd, IH), 7.38 (d, IH), 6.94-6.82 (m, 2H), 6.78 (m, IH), 5.44 (m, IH), 4.05 (t, 2H), 3.94 (m, 2H), 3.45 (m, 2H), 2.97 (t, 2H).
δ 8.85 (d, IH), 8.63 (d, IH), 8.49 (br s, IH), 7.80 (s, IH), 7.65 (dd, IH), 7.38 (d, IH), 7.05 (m, IH), 6.71 (m, IH), 6.55 (m, IH), 5.43 (m, IH), 3.98-3.92 (m, 4H), 3.41 (m, 2H), 2.95 (t, 2H).
δ 8.84 (d, IH), 8.63 (d, IH), 8.47 (br s, IH), 8.08 (d, IH), 7.79 (s, IH), 7.64 (dd, IH), 7.52 (dd, IH), 7.38 (d, IH), 6.72 (d, IH), 5.42 (m, IH), 4.33 (t, 2H), 3.94 (m, 2H), 3.38 (m, 2H), 2.94 (t, 2H).
δ 8.65 (s, IH), 8.60 (d, IH), 8.46 (br s, IH), 8.07 (d, IH), 7.77 (s, IH), 7.63 (d, IH), 7.52 (dd, IH), 6.74 (s, IH), 6.70 (d, IH), 4.87 (m, IH), 4.33 (t, 2H), 3.88 (br t, 2H), 3.37 (m, 2H), 2.95 (t, 2H). 71 δ 8.84 (d, IH), 8.63 (d, IH), 8.43 (br s, IH), 7.78 (s, IH), 7.62 (d, IH), 7.37 (d, IH), 6.95 (t, 2H), 6.84 (m, 2H), 5.40 (m, IH), 4.36 (m, IH), 3.94 (m, 2H), 3.36 (m, 2H), 2.78 (m, 2H), 1.27 (d, 3H).
72 δ 8.87 (s, IH), 8.61 (d, IH), 8.25 (br s, IH), 7.76 (s, IH), 7.61 (d, IH), 6.96 (t, 2H), 6.84 (m, 2H), 5.33 (m, IH), 4.35 (m, IH), 3.89 (m, 2H), 3.36 (br m, 2H), 2.77 (m, 2H), 1.26 (d, 3H).
73 δ 8.65 (d, IH), 8.60 (d, IH), 8.36 (br s, IH), 7.78 (s, IH), 7.62 (dd, IH), 7.00 (d, IH), 6.96 (t, 2H), 6.84 (m, 2H), 5.36 (m, IH), 4.35 (m, IH), 3.88 (m, 2H), 3.38 (m, 2H), 2.77 (ddd, 2H), 1.26 (d, 3H).
74 δ 8.58 (d, IH), 8.51 (br s, IH), 8.41 (d, IH), 7.79 (d, IH), 7.64 (dd, IH), 7.13 (dd, IH), 7.04 (dd, IH), 6.92 (td, IH), 6.83 (dd, IH), 6.67 (d, IH), 4.88 (m, IH), 4.05 (t, 2H), 3.96 (m, 2H), 3.49 (m, 2H), 3.00 (t, 2H).
75 δ 8.58 (d, IH), 8.50 (br s, IH), 8.40 (d, IH), 7.79 (s, IH), 7.64 (dd, IH), 7.10 (dd, IH), 7.04 (m, 2H), 6.83 (t, IH), 6.66 (d, IH), 4.88 (m, IH), 4.06 (t, 2H), 3.92 (m, 2H), 3.44 (m, 2H), 2.98 (t, 2H).
76 δ 8.58 (d, IH), 8.50 (br s, IH), 8.41 (d, IH), 7.78 (s, IH), 7.63 (dd, IH), 7.37 (d, IH), 7.18 (dd, IH), 7.04 (dd, IH), 6.81 (d, IH), 6.67 (d, IH), 4.88 (m, IH), 4.06 (t, 2H), 3.96 (m, 2H), 3.49 (m, 2H), 3.01 (t, 2H).
77 δ 8.64 (s, IH), 8.59 (d, IH), 8.53 (br s, IH), 7.78 (s, IH), 7.63 (dd, IH), 7.13 (dd, IH), 6.92 (td, IH), 6.83 (dd, IH), 6.75 (s, IH), 4.87 (m, IH), 4.04 (t, 2H), 3.94 (m, 2H), 3.50 (m, 2H), 3.00 (t, 2H).
78 δ 8.65 (s, IH), 8.59 (d, IH), 8.51 (br s, IH), 7.78 (s, IH), 7.63 (dd, IH), 7.10 (dd, IH), 7.04 (m, IH), 6.86 (t, IH), 6.75 (s, IH), 4.87 (m, IH), 4.06 (t, 2H), 3.90 (m, 2H), 3.45 (m, 2H), 2.98 (t, 2H).
79 δ 8.65 (s, IH), 8.59 (d, IH), 8.52 (br s, IH), 7.78 (d, IH), 7.63 (dd, IH), 7.37 (d, IH), 7.18 (dd, IH), 6.80 (d, IH), 6.75 (d, IH), 4.87 (m, IH), 4.06 (t, 2H), 3.94 (m, 2H), 3.49 (m, 2H), 3.01 (t, 2H).
80 8.88 (s, IH), 8.62 (d, IH), 8.28 (br s, IH), 7.77 (s, IH), 7.62 (d, IH), 7.37 (d, 2H), 6.78 (d, 2H), 5.35 (m, IH), 3.99 (t, 2H), 3.92 (m, 2H), 3.42 (br s, 2H), 2.95 (t, 2H).
81 8.88 (s, IH), 8.62 (d, IH), 8.27 (br s, IH), 7.76 (s, IH), 7.62 (dd, IH), 7.28 (s, 4H), 6.50 (dt, IH), 6.14 (dt, IH), 5.34 (m, IH), 3.83 (m, 2H), 3.36-3.31 (m, 4H).
82 8.85 (s, IH), 8.62 (dd, IH), 8.25 (br s, IH), 7.76 (m, IH), 7.62 (dd, IH), 7.28 (s, 4H), 6.50 (d, IH), 6.14 (dt, IH), 5.34 (m, IH), 3.83 (m, 2H), 3.36-3.31 (m, 4H).
83 8.88 (d, IH), 8.61 (d, IH), 8.35 (br s, IH), 7.94 (d, IH), 7.78 (s, IH), 7.63 (dd, IH), 7.28 (s, 4H), 6.50 (d, IH), 6.14 (dt, IH), 5.34 (m, IH), 3.83 (m, 2H), 3.36-3.31 (m, 4H).
84 8.63-8.58 (m, 2H), 8.40 (br s, IH), 7.79 (m, IH), 7.74 (d, IH), 7.64 (dd, IH), 7.28 (s, 4H), 6.50 (dt, IH), 6.15 (dt, IH), 5.33 (m, IH), 3.84 (m, 2H), 3.35-3.29 (m, 4H). 85 8.71 (d, IH), 8.62 (d, IH), 8.31 (br s, IH), 7.77 (s, IH), 7.62 (dd, IH), 7.28 (s, 4H), 6.50 (d, IH), 6.14 (dt, IH), 5.33 (m, IH), 3.83 (m, 2H), 3.33-3.30 (m, 4H).
86 9.00 (s, IH), 8.62 (d, IH), 8.23 (br s, IH), 7.76 (s, IH), 7.61 (dd, IH), 7.28 (s, 4H), 6.50 (d, IH), 6.14 (dt, IH), 5.33 (m, IH), 3.83 (m, 2H), 3.36-3.30 (m, 4H).
87 8.67 (d, IH), 8.62 (d, IH), 8.30 (br s, IH), 7.77 (s, IH), 7.62 (dd, IH), 7.28 (s, 4H), 6.50 (d, IH), 6.14 (dt, IH), 5.34 (m, IH), 3.84 (m, 2H), 3.36-3.31 (m, 4H).
88 8.96 (s, IH), 8.62 (d, IH), 8.23 (br s, IH), 7.76 (s, IH), 7.62 (dd, IH), 7.28 (s, 4H), 6.50 (d, IH), 6.14 (dt, IH), 5.33 (m, IH), 3.83 (m, 2H), 3.36-3.31 (m, 4H).
89 9.05 (s, IH), 8.60 (d, IH), 8.30 (br s, IH), 7.77 (s, IH), 7.63 (dd, IH), 7.28 (s, 4H), 6.50 (d, IH), 6.14 (dt, IH), 5.42 (m, IH), 3.85 (m, 2H), 3.37 (dd, 2H), 3.34 (d, 2H).
90 8.62 (d, IH), 8.39 (s, IH), 7.83 (s, IH), 7.70 (m, 2H), 7.26 (s, 4H), 6.47 (dt, IH), 6.11 (dt, IH), 5.36 (m, IH), 3.78 (m, 2H), 3.29 (d, 2H), 3.24 (m, 2H).
91 8.90 (d, IH), 8.62 (d, IH), 8.20 (br s, IH), 7.77 (s, IH), 7.62 (d, IH), 7.28 (s, 4H), 6.50 (d, IH), 6.14 (dt, IH), 5.29 (m, IH), 3.83 (m, 2H), 3.38-3.31 (m, 4H).
93 8.65 (s, IH), 8.61 (d, IH), 8.49 (br s, IH), 7.79 (s, IH), 7.64 (dd, IH), 7.58 (dd, IH), 7.16 (dd, 2H), 6.75 (s, IH), 6.70 (m, IH), 6.58 (d, IH), 4.87 (m, IH), 3.82 (t, 2H), 3.39 (m, 2H),
3.36 (m, 2H).
94 8.85 (d, IH), 8.64 (d, IH), 8.50 (br s, IH), 8.48 (d, IH), 7.80 (s, IH), 7.65 (dd, IH), 7.59 (dd, IH), 7.39 (d, IH), 7.24 (d, IH), 6.64 (m, 2H), 5.43 (m, IH), 3.89 (t, 2H), 3.39 (m, 2H), 3.37 (m, 2H).
95 8.85 (d, IH), 8.64 (d, IH), 8.46 (br s, IH), 7.80 (s, IH), 7.64 (dd, IH), 7.58 (dd, IH), 7.38 (d, IH), 7.17 (m, 2H), 6.73 (m, IH), 6.60 (d, 2H), 5.42 (m, IH), 3.91 (t, 2H), 3.39 (m, 2H),
3.37 (m, 2H).
97 8.84 (d, IH), 8.59 (d, IH), 8.56 (s, IH), 7.97 (s, IH), 7.69 (d, IH), 7.38 (d, IH), 7.29 (m, 4H), 6.52 (d, IH), 6.15 (dt, IH), 5.45 (m, IH), 3.88 (m, 2H), 3.45 (m, 2H), 3.37 (m, 2H).
98 8.87 (d, IH), 8.47 (d, IH), 8.45 (s, IH), 7.61 (m, IH), 7.40 (m, IH), 7.38 (d, IH), 7.28 (m, 4H), 6.50 (d, IH), 6.15 (dt, IH), 5.42 (m, IH), 3.87 (m, 2H), 3.35-3.31 (m, 4H).
99 8.93 (s, IH), 8.89 (d, IH), 8.78 (s, IH), 8.71 (d, IH), 7.79 (d, IH), 7.37 (d, IH), 7.28 (m, 4H), 6.49 (d, IH), 6.14 (dt, IH), 5.43 (m, IH), 3.86 (m, 2H), 3.31 (m, 2H), 3.27 (m, 2H).
100 8.86 (d, IH), 8.61 (s, IH), 8.48 (d, IH), 7.61 (d, IH), 7.38 (d, IH), 7.27 (s, 4H), 6.48 (d, IH), 6.13 (dt, IH), 5.43 (m, IH), 3.84 (m, 2H), 3.30 (m, 2H), 3.28 (m, 2H).
101 8.99 (d, IH), 8.86 (d, IH), 8.58 (s, IH), 8.15 (s, IH), 7.93 (d, IH), 7.39 (d, IH), 7.28 (s, 4H), 6.50 (d, IH), 6.14 (dt, IH), 5.44 (m, IH), 3.85 (m, 2H), 3.45 (m, 2H), 3.36-3.31 (m, 4H).
102 9.14 (d, IH), 8.88 (d, IH), 8.44 (d, IH), 7.96 (t, IH), 7.37 (d, IH), 7.29 (AB d, 4H), 6.52 (d, IH), 6.17 (dt, IH), 5.43 (m, IH), 3.92 (m, 2H), 3.34 (d, 2H), 3.30 (m, 2H). 103 (major diastereomer only) 8.85 (d, IH), 8.64 (s, IH), 8.61 (d, IH), 7.82 (s, IH), 7.67 (d, IH), 7.37 (d, IH), 7.28 (s, 4H), 6.51 (d, IH), 6.17 (dt, IH), 5.54 (t, IH), 3.70 (t, IH), 3.62 (d, IH), 3.46-3.38 (m, 2H), 3.23 (dd, IH), 1.24 (d, 3H).
104 9.70 (s, IH), 8.62 (d, IH), 8.42 (br s, IH), 7.81 (s, IH), 7.67 (d, IH), 7.28 (s, 4H), 6.96 (s, IH), 6.51 (d, IH), 6.12 (dt, IH), 5.04 (m, IH), 3.87 (m, 2H), 3.41 (m, 2H), 3.36(d, 2H).
105 10.45 (s, IH), 9.38 (d, IH), 9.08 (d, IH), 8.93 (d, IH), 8.21 (dd, IH), 7.37 (d, IH), 7.29 (m, 4H), 6.52 (d, IH), 6.18 (dt, IH), 5.42 (m, IH), 3.95 (m, 2H), 3.37-3.32 (m, 4H).
106 8.61 (br s, IH), 8.59 (d, IH), 8.42 (d, IH), 7.81 (s, IH), 7.66 (d, IH), 7.27 (s, 4H), 6.69 (d, IH), 6.50 (d, IH), 6.11 (dt, IH), 4.86 (m, IH), 3.78 (t, 2H), 3.34 (br d, 4H).
107 8.62-8.56 (m, 2H), 8.42 (d, IH), 7.80 (s, IH), 7.65 (d, IH), 7.27 (s, 4H), 6.83 (d, IH), 6.49 (d, IH), 6.11 (dt, IH), 4.86 (m, IH), 3.77 (t, 2H), 3.36-3.29 (br d, 4H).
108 8.73 (d, IH), 8.29 (br s, IH), 8.08 (s, IH), 7.35 (d, IH), 7.29 (m, 4H), 6.52 (d, IH), 6.16 (dt, IH), 5.42 (m, IH), 3.87 (m, 2H), 3.37-3.27 (m, 4H).
109 8.66 (d, IH), 8.62 (d, IH), 8.34 (br s, IH), 7.77 (s, IH), 7.62 (dd, IH), 7.28 (s, 4H), 6.48 (d, IH), 6.00 (dd, IH), 5.28 (m, IH), 3.80 (t, IH), 3.74 (t, IH), 3.29 (m, 2H), 3.00 (m, IH), 1.16 (d, 3H).
110 8.70 (d, IH), 8.62 (d, IH), 8.34 (br s, IH), 7.77 (s, IH), 7.62 (dd, IH), 7.28 (s, 4H), 6.48 (d, IH), 6.00 (dd, IH), 5.27 (m, IH), 3.80 (t, IH), 3.74 (t, IH), 3.30 (m, 2H), 3.00 (m, IH), 1.16 (d, 3H).
111 8.65 (d, IH), 8.65 (s, IH), 8.52 (br s, IH), 7.78 (s, IH), 7.63 (dd, IH), 7.28 (s, 4H), 6.50 (d, IH), 6.13 (dt, IH), 5.54 (m, IH), 3.86 (dd, 2H), 3.44 (m, 2H), 3.34 (d, 2H).
112 8.88 (d, IH), 8.61 (d, IH), 8.35 (br s, IH), 7.94 (d, IH), 7.78 (s, IH), 7.63 (dd, IH), 6.96 (t, 2H), 6.83 (m, 2H), 5.34 (m, IH), 3.98 (t, 2H), 3.92 (m, 2H), 3.40 (dd, 2H), 2.95 (t, 2H).
113 8.88 (d, IH), 8.61 (d, IH), 8.32 (br s, IH), 7.94 (d, IH), 7.77 (s, IH), 7.62 (dd, IH), 7.22 (d, 2H), 6.82 (d, 2H), 5.34 (m, IH), 3.99 (t, 2H), 3.91 (m, 2H), 3.39 (m, 2H), 2.95 (t, 2H).
114 8.88 (d, IH), 8.61 (d, IH), 8.32 (br s, IH), 7.94 (d, IH), 7.77 (s, IH), 7.62 (dd, IH), 7.36 (d, 2H), 6.77 (d, 2H), 5.34 (m, IH), 3.99 (t, 2H), 3.91 (m, 2H), 3.39 (m, 2H), 2.95 (t, 2H).
115 8.88 (d, IH), 8.61 (d, IH), 8.37 (br s, IH), 7.95 (d, IH), 7.78 (s, IH), 7.63 (dd, IH), 6.90 (td, IH), 6.85 (m, IH), 6.77 (m, IH), 5.34 (m, IH), 4.05 (t, 2H), 3.92 (m, 2H), 3.43 (dd, 2H), 2.97 (t, 2H).
116 8.66 (d, IH), 8.61 (d, IH), 8.39 (br s, IH), 7.79 (s, IH), 7.64 (dd, IH), 7.01 (d, IH), 6.90 (td, IH), 6.85 (m, IH), 6.78 (m, IH), 5.38 (m, IH), 4.05 (t, 2H), 3.92 (m, 2H), 3.45 (dd, 2H), 2.97 (t, 2H).
117 8.67 (d, IH), 8.60 (d, IH), 8.38 (br s, IH), 7.79 (s, IH), 7.64 (dd, IH), 7.13 (dd, IH), 7.01 (d, IH), 6.92 (m, IH), 6.84 (dd, IH), 5.38 (m, IH), 4.05 (t, 2H), 3.97 (m, 2H), 3.50 (dd, 2H), 3.00 (t, 2H). 118 8.67 (d, IH), 8.61 (d, IH), 8.37 (br s, IH), 7.79 (s, IH), 7.64 (dd, IH), 7.10 (dd, IH), 7.04 (m, IH), 7.01 (d, IH), 6.87 (t, IH), 5.38 (m, IH), 4.05 (t, 2H), 3.92 (m, 2H), 3.45 (dd, 2H), 2.97 (t, 2H).
119 8.67 (d, IH), 8.61 (d, IH), 8.35 (br s, IH), 7.78 (d, IH), 7.63 (dd, IH), 7.37 (d, IH), 7.18 (dd, IH), 7.01 (d, IH), 6.82 (d, IH), 5.38 (m, IH), 4.07 (t, 2H), 3.97 (m, 2H), 3.49 (dd, 2H), 3.00 (t, 2H).
120 8.67 (d, IH), 8.61 (d, IH), 8.25 (br s, IH), 7.77 (s, IH), 7.62 (dd, IH), 7.37 (d, 2H), 7.01 (d, IH), 6.78 (d, 2H), 5.37 (m, IH), 3.99 (t, 2H), 3.93 (m, 2H), 3.40 (m, 2H), 2.95 (t, 2H).
121 8.85 (d, IH), 8.63 (d, IH), 8.48 (br s, IH), 7.79 (d, IH), 7.64 (dd, IH), 7.38 (d, IH), 7.36 (d, IH), 7.17 (dd, IH), 6.82 (d, IH), 5.42 (m, IH), 4.07 (t, 2H), 4.01 (m, 2H), 3.49 (dd, 2H), 3.01 (t, 2H).
122 8.85 (d, IH), 8.63 (d, IH), 8.48 (br s, IH), 7.80 (s, IH), 7.64 (dd, IH), 7.38 (d, IH), 7.10 (dd, IH), 7.04 (m, IH), 6.88 (t, IH), 5.42 (m, IH), 4.07 (t, 2H), 3.97 (m, 2H), 3.44 (dd, 2H), 2.98 (t, 2H).
123 8.85 (d, IH), 8.63 (d, IH), 8.48 (br s, IH), 7.79 (s, IH), 7.64 (dd, IH), 7.38 (d, IH), 7.13 (dd, IH), 6.92 (m, IH), 6.84 (dd, IH), 5.42 (m, IH), 4.06 (t, 2H), 4.01 (m, 2H), 3.49 (dd, 2H), 3.00 (t, 2H).
124 8.76 (d, IH), 8.62 (d, IH), 8.38 (br s, IH), 7.85 (d, IH), 7.78 (s, IH), 7.63 (dd, IH), 6.90 (td, IH), 6.85 (m, IH), 6.78 (m, IH), 5.35 (m, IH), 4.05 (t, 2H), 3.93 (m, 2H), 3.43 (dd, 2H), 2.97 (t, 2H).
125 8.77 (d, IH), 8.62 (d, IH), 8.33 (br s, IH), 7.85 (d, IH), 7.77 (s, IH), 7.62 (dd, IH), 7.37 (d, 2H), 6.78 (d, 2H), 5.34 (m, IH), 3.99 (t, 2H), 3.92 (m, 2H), 3.39 (br m, 2H), 2.95 (t, 2H).
126 8.77 (d, IH), 8.62 (d, IH), 8.33 (br s, IH), 7.85 (d, IH), 7.77 (s, IH), 7.63 (dd, IH), 7.23 (d, 2H), 6.82 (d, 2H), 5.34 (m, IH), 3.99 (t, 2H), 3.92 (m, 2H), 3.39 (br m, 2H), 2.95 (t, 2H).
127 8.88 (s, IH), 8.62 (d, IH), 8.35 (br s, IH), 7.78 (s, IH), 7.63 (d, IH), 6.90 (td, IH), 6.85 (m, IH), 6.78 (m, IH), 5.36 (m, IH), 4.05 (t, 2H), 3.92 (m, 2H), 3.46 (m, 2H), 2.97 (t, 2H).
128 8.63-8.58 (m, 2H), 8.41 (br s, IH), 7.79 (m, IH), 7.75 (d, IH), 7.63 (dd, IH), 7.23 (d, 2H), 6.82 (d, 2H), 5.34 (m, IH), 3.92 (t, 2H), 3.92 (m, 2H), 3.39 (m, 2H), 2.96 (t, 2H).
129 8.98 (d, IH), 8.63 (m, IH), 8.53 (br s, IH), 8.19 (m, IH), 7.80 (m, IH), 7.66 (m, IH), 6.92 (td, IH), 6.86 (m, IH), 6.78 (m, IH), 5.45 (m, IH), 4.06 (t, 2H), 3.94 (m, 2H), 3.47 (dd, 2H), 2.98 (t, 2H).
130 8.98 (d, IH), 8.63 (dd, IH), 8.45 (br s, IH), 8.19 (m, IH), 7.79 (dd, IH), 7.64 (dd, IH), 7.37 (d, 2H), 6.78 (d, 2H), 5.43 (m, IH), 4.00 (t, 2H), 3.94 (m, 2H), 3.43 (m, 2H), 2.96 (t, 2H). 131 8.98 (d, IH), 8.63 (dd, IH), 8.45 (br s, IH), 8.19 (m, IH), 7.79 (dd, IH), 7.64 (dd, IH), 7.23 (d, 2H), 6.82 (d, 2H), 5.43 (m, IH), 4.00 (t, 2H), 3.94 (m, 2H), 3.43 (m, 2H), 2.96 (t, 2H).
132 8.98 (d, IH), 8.63 (dd, IH), 8.47 (br s, IH), 8.19 (m, IH), 7.79 (dd, IH), 7.65 (dd, IH), 6.97 (t, 2H), 6.83 (m, 2H), 5.44 (m, IH), 3.99 (t, 2H), 3.94 (m, 2H), 3.44 (dd, 2H), 2.96 (t, 2H).
133 8.87 (d, IH), 8.61 (d, IH), 8.34 (br s, IH), 7.93 (d, IH), 7.77 (br s, IH), 7.62 (dd, IH), 6.96 (t, 2H), 6.84 (m, 2H), 5.31 (m, IH), 4.36 (m, IH), 3.88 (m, 2H), 3.35 (m, 2H), 2.77 (ddd, 2H), 1.26 (d, 3H).
134 8.76 (d, IH), 8.61 (dd, IH), 8.35 (br s, IH), 7.84 (d, IH), 7.77 (dd, IH), 7.62 (dd, IH), 6.96 (t, 2H), 6.84 (m, 2H), 5.31 (m, IH), 4.36 (m, IH), 3.88 (m, 2H), 3.35 (m, 2H), 2.77 (ddd, 2H), 1.26 (d, 3H).
135 8.63-8.57 (m, 2H), 8.40 (br s, IH), 7.78 (m, IH), 7.74 (d, IH), 7.62 (dd, IH), 6.96 (t, 2H), 6.84 (m, 2H), 5.31 (m, IH), 4.36 (m, IH), 3.89 (m, 2H), 3.34 (m, 2H), 2.78 (ddd, 2H), 1.26 (d, 3H).
136 8.97 (d, IH), 8.62 (d, IH), 8.45 (br s, IH), 8.18 (m, IH), 7.78 (dd, IH), 7.63 (dd, IH), 6.96 (t, 2H), 6.84 (m, 2H), 5.41 (m, IH), 4.37 (m, IH), 3.91 (m, 2H), 3.38 (m, 2H), 2.78 (ddd, 2H), 1.26 (d, 3H).
137 8.84 (d, IH), 8.63 (d, IH), 8.51 (br s, IH), 7.80 (s, IH), 7.64 (m, IH), 7.38 (d, IH), 6.83 (s, 4H), 5.43 (m, IH), 3.98 (t, 2H), 3.94 (m, 2H), 3.76 (s, 3H), 3.42 (m, 2H), 2.94 (t, 2H).
138 8.85 (d, IH), 8.63 (d, IH), 8.44 (br s, IH), 8.20 (d, 2H), 7.78 (s, IH), 7.64 (dd, IH), 7.39 (d, IH), 6.96 (d, 2H), 5.43 (m, IH), 4.12 (t, 2H), 3.99 (m, 2H), 3.43 (m, 2H), 3.01 (t, 2H).
139 8.85 (d, IH), 8.63 (d, IH), 8.47 (br s, IH), 7.79 (s, IH), 7.64 (m, IH), 7.38 (d, IH), 7.14 (d, 2H), 6.88 (d, 2H), 5.43 (m, IH), 4.01 (t, 2H), 3.96 (m, 2H), 3.42 (m, 2H), 2.96 (t, 2H).
140 8.85 (d, IH), 8.63 (d, IH), 8.45 (br s, IH), 7.79 (s, IH), 7.65 (m, IH), 7.59 (d, 2H), 7.39 (d, IH), 6.95 (d, 2H), 5.42 (m, IH), 4.07 (t, 2H), 3.97 (m, 2H), 3.42 (m, 2H), 2.99 (t, 2H).
141 8.84 (d, IH), 8.63 (d, IH), 8.52 (br s, IH), 7.81 (s, IH), 7.65 (m, IH), 7.38 (d, IH), 7.29 (d, 2H), 6.84 (d, 2H), 5.43 (m, IH), 4.01 (t, 2H), 3.93 (m, 2H), 3.43 (m, 2H), 2.95 (t, 2H), 1.29 (s, 9H).
142 8.85 (d, IH), 8.63 (d, IH), 8.46 (br s, IH), 7.79 (s, IH), 7.64 (m, IH), 7.54 (d, 2H), 7.39 (d, IH), 6.96 (d, 2H), 5.43 (m, IH), 4.07 (t, 2H), 3.97 (m, 2H), 3.43 (br s, 2H), 2.99 (t, 2H).
143 8.76 (d, IH), 8.61 (d, IH), 8.30 (br s, IH), 7.84 (d, IH), 7.76 (s, IH), 7.61 (dd, IH), 7.22 (d, 2H), 6.82 (d, 2H), 5.30 (m, IH), 4.40 (m, IH), 3.89 (m, 2H), 3.33 (ddd, 2H), 2.77 (ddd, 2H), 1.27 (d, 3H).
144 8.62 (d, IH), 8.39 (s, IH), 7.83 (s, IH), 7.74 (br s, IH), 7.71 (dd, IH), 6.95 (t, 2H), 6.81 (m, 2H), 5.37 (m, IH), 3.95 (t, 2H), 3.86 (m, 2H), 3.32 (m, 2H), 2.91 (t, 2H).
145 8.62 (d, IH), 8.39 (s, IH), 7.83 (s, IH), 7.74 (br s, IH), 7.70 (dd, IH), 7.21 (d, 2H), 6.80 (d, 2H), 5.36 (m, IH), 3.96 (t, 2H), 3.86 (m, 2H), 3.31 (m, 2H), 2.91 (t, 2H). 146 8.62 (d, IH), 8.39 (s, IH), 7.83 (s, IH), 7.70 (dd, IH), 7.67 (br s, IH), 7.35 (d, 2H), 6.75 (d, 2H), 5.36 (m, IH), 3.95 (t, 2H), 3.86 (m, 2H), 3.30 (m, 2H), 2.91 (t, 2H).
147 8.70 (d, IH), 8.62 (d, IH), 8.30 (br s, IH), 7.76 (s, IH), 7.61 (dd, IH), 7.22 (d, 2H), 6.82 (d, 2H), 5.31 (m, IH), 4.40 (m, IH), 3.88 (m, 2H), 3.34 (ddd, 2H), 2.77 (ddd, 2H), 1.27 (d, 3H).
148 8.62 (d, IH), 8.38 (s, IH), 7.82 (s, IH), 7.69 (dd, IH), 7.75-7.60 (br s, IH), 7.20 (d, 2H), 6.80 (d, 2H), 5.32 (m, IH), 4.37 (m, IH), 3.82 (m, 2H), 3.26 (ddd, 2H), 2.74 (ddd, 2H), 1.24 (d, 3H).
149 8.99 (s, IH), 8.62 (d, IH), 8.24 (br s, IH), 7.75 (s, IH), 7.60 (dd, IH), 7.22 (d, 2H), 6.82 (d, 2H), 5.31 (m, IH), 4.40 (m, IH), 3.88 (m, 2H), 3.35 (ddd, 2H), 2.77 (ddd, 2H), 1.27 (d, 3H).
150 8.99 (s, IH), 8.62 (d, IH), 8.27 (br s, IH), 7.77 (s, IH), 7.62 (dd, IH), 6.96 (t, 2H), 6.83 (m, 2H), 5.35 (m, IH), 3.98 (t, 2H), 3.92 (m, 2H), 3.43 (m, 2H), 2.95 (t, 2H).
151 8.99 (s, IH), 8.62 (d, IH), 8.28 (br s, IH), 7.77 (s, IH), 7.62 (dd, IH), 7.23 (d, 2H), 6.82 (d, 2H), 5.34 (m, IH), 3.99 (t, 2H), 3.91 (m, 2H), 3.43 (m, 2H), 2.95 (t, 2H).
152 8.99 (s, IH), 8.62 (d, IH), 8.27 (br s, IH), 7.77 (s, IH), 7.62 (dd, IH), 7.37 (d, 2H), 6.77 (d, 2H), 5.35 (m, IH), 3.99 (t, 2H), 3.91 (m, 2H), 3.42 (m, 2H), 2.95 (t, 2H).
153 8.71 (d, IH), 8.62 (d, IH), 8.33 (br s, IH), 7.78 (s, IH), 7.63 (d, IH), 7.23 (d, 2H), 6.82 (d, 2H), 5.35 (m, IH), 4.00 (t, 2H), 3.92 (m, 2H), 3.42 (br m, 2H), 2.95 (t, 2H).
154 8.71 (d, IH), 8.62 (d, IH), 8.33 (br s, IH), 7.77 (s, IH), 7.62 (dd, IH), 7.37 (d, 2H), 6.78 (d, 2H), 5.34 (m, IH), 3.99 (t, 2H), 3.92 (m, 2H), 3.41 (m, 2H), 2.95 (t, 2H).
155 8.71 (d, IH), 8.62 (d, IH), 8.35 (br s, IH), 7.78 (s, IH), 7.63 (dd, IH), 6.97 (t, 2H), 6.83 (m, 2H), 5.35 (m, IH), 3.99 (t, 2H), 3.92 (m, 2H), 3.43 (m, 2H), 2.95 (t, 2H).
156 8.66 (d, IH), 8.62 (d, IH), 8.29 (br s, IH), 7.76 (d, IH), 7.61 (dd, IH), 7.37 (d, 2H), 6.78 (d, 2H), 5.34 (m, IH), 3.99 (t, 2H), 3.92 (m, 2H), 3.40 (m, 2H), 2.95 (t, 2H).
157 8.66 (d, IH), 8.62 (d, IH), 8.31 (br s, IH), 7.77 (s, IH), 7.62 (dd, IH), 7.23 (d, 2H), 6.82 (d, 2H), 5.35 (m, IH), 3.99 (t, 2H), 3.93 (m, 2H), 3.41 (m, 2H), 2.95 (t, 2H).
158 8.66 (d, IH), 8.62 (d, IH), 8.31 (br s, IH), 7.77 (s, IH), 7.62 (dd, IH), 6.97 (t, 2H), 6.83 (m, 2H), 5.35 (m, IH), 3.98 (t, 2H), 3.93 (m, 2H), 3.41 (m, 2H), 2.95 (t, 2H).
159 8.95 (s, IH), 8.61 (d, IH), 8.21 (br s, IH), 7.75 (s, IH), 7.60 (dd, IH), 7.22 (d, 2H), 6.82 (d, 2H), 5.31 (m, IH), 4.40 (m, IH), 3.89 (ddd, 2H), 3.35 (ddd, 2H), 2.77 (ddd, 2H), 1.27 (d, 3H).
160 9.03 (s, IH), 8.62 (d, IH), 8.27 (br s, IH), 7.76 (s, IH), 7.62 (dd, IH), 7.22 (d, 2H), 6.82 (d, 2H), 5.40 (m, IH), 4.41 (m, IH), 3.91 (m, 2H), 3.38 (ddd, 2H), 2.78 (m, 2H), 1.27 (d, 3H).
161 8.84 (s, IH), 8.62 (d, IH), 8.23 (br s, IH), 7.75 (s, IH), 7.60 (d, IH), 7.22 (d, 2H), 6.82 (d, 2H), 5.32 (m, IH), 4.40 (m, IH), 3.89 (m, 2H), 3.35 (m, 2H), 2.77 (m, 2H), 1.27 (d, 3H). 162 8.66 (d, IH), 8.62 (d, IH), 8.28 (br s, IH), 7.76 (s, IH), 7.61 (dd, IH), 7.22 (d, 2H), 6.82 (d, 2H), 5.31 (m, IH), 4.40 (m, IH), 3.89 (m, 2H), 3.34 (ddd, 2H), 2.78 (ddd, 2H), 1.27 (d, 3H).
163 8.84 (d, IH), 8.63 (d, IH), 8.40 (br s, IH), 7.77 (s, IH), 7.61 (dd, IH), 7.37 (d, IH), 7.21 (d, 2H), 6.84 (d, 2H), 5.37 (m, IH), 4.21 (m, IH), 3.94 (t, IH), 3.88 (t, IH), 3.33 (dd, IH), 3.28 (dd, IH), 2.78 (m, 2H), 1.68 (m, 2H), 0.95 (t, 3H).
164 8.96 (s, IH), 8.62 (d, IH), 8.22 (br s, IH), 7.75 (s, IH), 7.61 (dd, IH), 7.37 (d, 2H), 6.78 (d, 2H), 5.34 (m, IH), 3.99 (t, 2H), 3.92 (m, 2H), 3.40 (m, 2H), 2.95 (t, 2H).
165 8.96 (s, IH), 8.62 (d, IH), 8.21 (br s, IH), 7.75 (s, IH), 7.61 (dd, IH), 7.23 (d, 2H), 6.82 (d, 2H), 5.34 (m, IH), 3.99 (t, 2H), 3.92 (m, 2H), 3.40 (dd, 2H), 2.94 (t, 2H).
166 8.96 (s, IH), 8.62 (d, IH), 8.22 (br s, IH), 7.75 (s, IH), 7.61 (dd, IH), 6.96 (t, 2H), 6.83 (m, 2H), 5.34 (m, IH), 3.98 (t, 2H), 3.92 (m, 2H), 3.41 (m, 2H), 2.94 (t, 2H).
167 8.85 (s, IH), 8.62 (dd, IH), 8.23 (br s, IH), 7.76 (m, IH), 7.61 (dd, IH), 7.37 (d, 2H), 6.78 (d, 2H), 5.35 (m, IH), 3.99 (t, 2H), 3.92 (m, 2H), 3.40 (m, 2H), 2.95 (t, 2H).
168 8.85 (s, IH), 8.62 (dd, IH), 8.24 (br s, IH), 7.76 (m, IH), 7.61 (dd, IH), 7.23 (d, 2H), 6.82 (d, 2H), 5.35 (m, IH), 3.99 (t, 2H), 3.92 (m, 2H), 3.41 (m, 2H), 2.95 (t, 2H).
169 8.85 (s, IH), 8.62 (d, IH), 8.25 (br s, IH), 7.76 (m, IH), 7.62 (dd, IH), 6.97 (t, 2H), 6.83 (m, 2H), 5.35 (m, IH), 3.98 (t, 2H), 3.92 (m, 2H), 3.41 (m, 2H), 2.95 (t, 2H).
170 9.04 (s, IH), 8.63 (d, IH), 8.28 (br s, IH), 7.77 (s, IH), 7.63 (dd, IH), 7.23 (d, 2H), 6.82 (d, 2H), 5.43 (m, IH), 4.00 (t, 2H), 3.94 (m, 2H), 3.44 (m, 2H), 2.96 (t, 2H).
171 8.62 (s, IH), 8.59 (d, IH), 8.46 (br s, IH), 8.06(d, IH), 7.76 (s, IH), 7.62 (dd, IH), 7.50 (dd, IH), 6.72 (s, IH), 6.65 (d, IH), 5.23 (m, IH), 4.83 (m, IH), 3.84 (m, 2H), 3.36 (dd, IH), 3.29 (dd, IH), 2.84 (dd, IH), 2.74 (dd, IH), 1.29 (d, 3H).
172 8.84 (d, IH), 8.63 (d, IH), 8.48 (br s, IH), 8.07 (d, IH), 7.79 (s, IH), 7.64 (d, IH), 7.50 (dd, IH), 7.37 (d, IH), 6.65 (d, IH), 5.39 (m, IH), 5.24 (m, IH), 3.91 (m, 2H), 3.36 (dd, IH), 3.30 (dd, IH), 2.84 (dd, IH), 2.74 (dd, IH), 1.30 (d, 3H).
173 8.65 (s, IH), 8.61 (d, IH), 8.40 (br s, IH), 8.05 (d, IH), 7.76 (s, IH), 7.62 (dd, IH), 7.37 (d, IH), 7.10 (dd, IH), 6.73 (s, IH), 4.88 (m, IH), 4.04 (m, 2H), 3.92 (m, 2H), 3.41 (m, 2H), 2.98 (dd, 2H).
174 8.84 (d, IH), 8.63 (d, IH), 8.48 (br s, IH), 7.79 (s, IH), 7.64 (dd, IH), 7.38 (d, IH), 7.36 (d, IH), 6.99 (d, IH), 5.43 (m, IH), 4.55 (dd, 2H), 3.96 (m, 2H), 3.39 (m, 2H), 3.03 (dd, 2H).
175 8.64 (s, IH), 8.60 (d, IH), 8.42 (br s, IH), 8.05 (d, IH), 7.76 (s, IH), 7.62 (dd, IH), 7.23 (d, IH), 7.18 (dd, IH), 6.73 (s, IH), 4.88 (m, IH), 4.05 (m, 2H), 3.92 (m, 2H), 3.40 (m, 2H), 2.98 (dd, 2H).
176 8.64 (s, IH), 8.60 (d, IH), 8.43 (br s, IH), 7.77 (s, IH), 7.63 (dd, IH), 7.37 (d, IH), 6.98 (d, IH), 6.73 (s, IH), 4.88 (m, IH), 4.55 (m, 2H), 3.92 (m, 2H), 3.38 (m, 2H), 3.02 (dd, 2H). 177 8.85 (d, IH), 8.63 (d, IH), 8.44 (br s, IH), 8.05 (d, IH), 7.78 (s, IH), 7.64 (dd, IH), 7.39 (d, IH), 7.21 (m, 2H), 5.42 (m, IH), 4.05 (dd, 2H), 3.96 (m, 2H), 3.41 (m, 2H), 2.98 (dd, 2H).
178 8.85 (d, IH), 8.63 (d, IH), 8.45 (br s, IH), 8.05 (d, IH), 7.79 (s, IH), 7.64 (dd, IH), 7.38 (m, 2H), 7.11 (dd, IH), 5.42 (m, IH), 4.05 (dd, 2H), 3.98 (m, 2H), 3.43 (m, 2H), 2.98 (dd, 2H).
179 8.84 (d, IH), 8.63 (dd, IH), 8.39 (br s, IH), 7.77 (dd, IH), 7.61 (dd, IH), 7.37 (d, IH), 7.22 (m, 2H), 6.82 (m, 2H), 5.38 (m, IH), 4.40 (m, IH), 3.96 (m, IH), 3.91 (m, IH), 3.36 (m, IH), 3.22 (m, IH), 2.80 (dd, IH), 2.75 (dd, IH), 1.28 (d, 3H).
180 8.89 (d, IH), 8.61 (d, IH), 8.16 (br s, IH), 7.75 (s, IH), 7.60 (dd, IH), 7.22 (m, 2H), 6.82 (m, 2H), 5.26 (m, IH), 4.40 (m, IH), 3.90 (m, IH), 3.86 (m, IH), 3.37 (m, IH), 3.33 (m, IH), 2.79 (dd, IH), 2.74 (dd, IH), 1.27 (d, 3H).
181 8.89 (d, IH), 8.61 (d, IH), 8.23 (br s, IH), 7.77 (s, IH), 7.62 (dd, IH), 7.23 (d, 2H), 6.82 (d, 2H), 5.30 (m, IH), 3.99 (t, 2H), 3.90 (m, 2H), 3.42 (m, 2H), 2.94 (t, 2H).
182 8.65 (s, IH), 8.61 (d, IH), 8.44 (br s, IH), 8.16 (s, IH), 7.77 (s, IH), 7.63 (m, 2H), 6.74 (s, IH), 6.66 (d, 1H),4.87 (m, IH), 4.33 (m, 2H), 3.89 (m, 2H), 3.37 (m, 2H), 2.95 (dd, 2H).
183 8.84 (d, IH), 8.63 (d, IH), 8.47 (br s, IH), 8.17( s, 1H),7.80 (s, IH), 7.64 (m, 2H), 7.38 (d, IH), 6.69 (d, IH), 5.42 (m, IH), 4.34 (t, 2H), 3.94 (m, 2H), 3.38 (m, 2H), 2.94 (t, 2H)
184 8.64 (s, IH), 8.61 (d, IH), 8.41 (br s, IH), 8.19 (d, IH), 7.76 (s, IH), 7.63 (dd, IH), 6.82 (d, IH) 6.74 (m, 2H), 4.88 (m, IH), 4.07 (dd, 2H), 3.92 (m, 2H), 3.39 (m, 2H), 2.98 (dd, 2H).
185 8.85 (d, IH), 8.63 (d, IH), 8.43 (br s, IH), 8.19 (d, IH), 7.78 (s, IH), 7.64 (dd, IH), 7.39 (d, IH), 6.84 (dd, IH), 6.75 (dd, IH), 5.42 (m, IH), 4.07 (dd, 2H), 3.97 (m, 2H), 3.40 (m, 2H), 2.98 (dd, 2H).
186 8.59 (m, 3H), 8.44 (s, 2H), 7.78 (s, IH), 7.64 (dd, IH), 6.72 (s, IH), 4.86 (m, IH), 4.41 (t, 2H), 3.87 (m, 2H), 3.43 (m, 2H), 2.97 (t, 2H).
187 8.83 (d, IH), 8.63 (d, IH), 8.56 (br s, IH), 8.44 (s, 2H), 7.80 (s, IH), 7.64 (dd, IH), 7.36 (d, IH), 5.42 (m, IH), 4.40 (t, 2H), 3.93 (m, 2H), 3.42 (m, 2H), 2.97 (t, 2H).
188 8.65 (d, IH), 8.52 (s, IH), 8.48 (br s, IH), 7.76 (s, IH), 7.61 (dd, IH), 7.21 (m, 2H), 6.81 (m, 2H), 5.51 (m, IH), 4.41 (m, IH), 3.95 (m, IH), 3.90 (m, IH), 3.46 (m, IH), 3.42 (m, IH), 2.81 (dd, IH), 2.77 (dd, IH), 1.27 (d, 3H).
189 8.83 (d, IH), 8.61 (d, IH), 8.39 (s, IH), 7.93 (s, IH), 7.65 (dd, IH), 7.37 (d, IH), 7.22 (m, 2H), 6.82 (m, 2H), 5.38 (m, IH), 4.40 (m, IH), 3.95 (m, IH), 3.91 (m, IH), 3.37 (m, IH), 3.32 (m, IH), 2.80 (dd, IH), 2.75 (dd, IH), 1.28 (d, 3H).
190 8.84 (d, IH), 8.61 (d, IH), 8.41 (s, IH), 7.94 (s, IH), 7.66 (dd, IH), 7.38 (d, IH), 7.23 (m, 2H), 6.82 (d, 2H), 5.42 (m, IH), 3.99 (t, 2H), 3.96 (m, 2H), 3.40 (m, 2H), 2.95 (t, 2H).
191 8.84 (d, IH), 8.61 (d, IH), 8.42 (s, IH), 7.94 (s, IH), 7.66 (d, IH), 7.38 (d, IH), 6.96 (t, 2H), 6.83 (m, 2H), 5.42 (m, IH), 4.00-3.94 (m, 4H), 3.41 (m, 2H), 2.95 (t, 2H). 192 8.86 (d, IH), 8.46 (d, IH), 8.43 (s, IH), 7.59 (m, IH), 7.40 (s, IH), 7.38 (d, IH), 7.22 (m, 2H), 6.82 (m, 2H), 5.39 (m, IH), 4.40 (m, IH), 3.95 (m, IH), 3.91 (m, IH), 3.36 (m, IH),
3.32 (m, IH), 2.80 (dd, IH), 2.75 (dd, IH), 1.28 (d, 3H).
193 8.87 (d, IH), 8.47 (d, IH), 8.43 (s, IH), 7.60 (m, IH), 7.40 (s, IH), 7.38 (d, IH), 7.23 (m, 2H), 6.82 (d, 2H), 5.42 (m, IH), 3.99 (t, 2H), 3.97 (m, 2H), 3.40 (m, 2H), 2.95 (t, 2H).
194 8.87 (d, IH), 8.47 (d, IH), 8.44 (s, IH), 7.61 (m, IH), 7.40 (m, IH), 7.38 (d, IH), 6.96 (t, 2H), 6.83 (m, 2H), 5.42 (m, IH), 4.00-3.95 (m, 4H), 3.40 (m, 2H), 2.95 (t, 2H).
195 8.91 (s, IH), 8.88 (d, IH), 8.77 (s, IH), 8.70 (d, IH), 7.79 (d, IH), 7.37 (d, IH), 7.21 (m, 2H), 6.82 (m, 2H), 5.40 (m, IH), 4.39 (m, IH), 3.93 (m, IH), 3.89 (m, IH), 3.30 (m, IH), 3.26 (m, IH), 2.78 (dd, IH), 2.73 (dd, IH), 1.27 (d, 3H).
196 8.85 (d, IH), 8.58 (s, IH), 8.48 (d, IH), 7.60 (d, IH), 7.37 (d, IH), 7.21 (m, 2H), 6.81 (m, 2H), 5.39 (m, IH), 4.38 (m, IH), 3.92 (m, IH), 3.87 (m, IH), 3.31 (m, IH), 3.27 (m, IH), 2.78 (dd, IH), 2.72 (dd, IH), 1.27 (d, 3H).
197 8.86 (d, IH), 8.58 (s, IH), 8.48 (d, IH), 7.60 (d, IH), 7.38 (d, IH), 7.22 (m, 2H), 6.81 (d, 2H), 5.42 (m, IH), 3.97 (t, 2H), 3.93 (m, 2H), 3.34 (m, 2H), 2.92 (t, 2H).
198 8.86 (d, IH), 8.58 (s, IH), 8.48 (d, IH), 7.61 (d, IH), 7.38 (d, IH), 6.96 (t, 2H), 6.82 (m, 2H), 5.43 (m, IH), 3.96 (t, 2H), 3.93 (m, 2H), 3.35 (m, 2H), 2.92 (t, 2H).
199 8.90 (s, IH), 8.89 (d, IH), 8.78 (s, IH), 8.70 (d, IH), 7.79 (d, IH), 7.38 (d, IH), 6.96 (t, 2H), 6.83 (m, 2H), 5.43 (m, IH), 3.98-3.94 (m, 4H), 3.33 (m, 2H), 2.92 (t, 2H).
200 8.90 (s, IH), 8.89 (d, IH), 8.78 (s, IH), 8.70 (d, IH), 7.79 (d, IH), 7.38 (d, IH), 7.22 (m, 2H), 6.82 (d, 2H), 5.43 (m, IH), 4.00-3.93 (m, 4H), 3.33 (m, 2H), 2.93 (t, 2H).
201 8.98 (d, IH), 8.85 (d, IH), 8.53 (s, IH), 8.14 (s, IH), 7.91 (d, IH), 7.39 (d, IH), 7.22 (m, 2H), 6.82 (m, 2H), 5.40 (m, IH), 4.40 (m, IH), 3.94 (m, IH), 3.90 (m, IH), 3.37 (m, IH),
3.33 (m, IH), 2.80 (dd, IH), 2.75 (dd, IH), 1.28 (d, 3H).
202 9.12 (d, IH), 8.86 (d, IH), 8.43 (d, IH), 7.96 (t, IH), 7.36 (d, IH), 7.22 (m, 2H), 6.84 (m, 2H), 5.40 (m, IH), 4.41 (m, IH), 3.98 (m, IH), 3.94 (m, IH), 3.33 (m, IH), 3.29 (m, IH), 2.82 (dd, IH), 2.76 (dd, IH), 1.29 (d, 3H).
203 10.29 (s, IH), 8.95 (d, IH), 8.86 (d, IH), 8.14 (d, IH), 7.36 (d, IH), 7.22 (m, 2H), 6.84 (m, 2H), 5.40 (m, IH), 4.42 (m, IH), 4.03-3.94 (m, 2H), 3.41-3.33 (m, 2H), 2.86-2.74 (m, 2H), 1.30 (d, 3H).
204 9.13 (br d, IH), 8.87 (d, IH), 8.44 (d, IH), 7.96 (t, IH), 7.38 (d, IH), 7.23 (m, 2H), 6.84 (d, 2H), 5.43 (m, IH), 4.04-3.98 (m, 4H), 3.36 (m, 2H), 2.97 (t, 2H).
205 9.70 (s, IH), 8.62 (d, IH), 8.35 (br s, IH), 7.79 (s, IH), 7.64 (dd, IH), 7.22 (m, 2H), 6.95 (s, IH), 6.82 (m, 2H), 5.00 (m, IH), 4.42 (m, IH), 3.94 (t, IH), 3.90 (t, IH), 3.44 (dd, IH), 3.40 (dd, IH), 2.83-2.77 (m, 2H), 1.27 (d, 3H).
206 10.42 (s, IH), 9.38 (d, IH), 9.08 (d, IH), 8.92 (d, IH), 8.21 (dd, IH), 7.36 (d, IH), 7.22 (m, 2H), 6.85 (m, 2H), 5.39 (m, IH), 4.41 (m, IH), 4.00 (m, 2H), 3.38 (dd, IH), 3.34 (dd, IH), 2.83 (dd, IH), 2.77 (dd, IH), 1.29 (d, 3H). 207 10.44 (s, IH), 9.38 (d, IH), 9.08 (d, IH), 8.93 (d, IH), 8.21 (dd, IH), 7.37 (d, IH), 7.23 (m, 2H), 6.84 (d, 2H), 5.43 (m, IH), 4.04 (m, 2H), 4.01 (t, 2H), 3.41 (m, 2H), 2.98 (t, 2H).
208 8.65 (s, IH), 8.61 (d, IH), 8.45 (br s, IH), 7.95 (d,lH), 7.77 (s, IH), 7.63 (d, IH), 7.33 (m,
IH), 6.74 (s, IH), 6.72 (dd, IH), 4.87 (m, IH), 4.32 (t, 2H), 3.89 (m, 2H), 3.36 (m, 2H), 2.95 (t, 2H).
209 8.85 (d, IH), 8.62 (d, IH), 8.45 (br s, IH), 7.95 (d, IH), 7.79 (s, IH), 7.63 (d, IH), 7.38 (m,
IH), 7.33 (m, IH), 6.73 (dd, IH), 5.42 (m, IH), 4.32 (t, 2H), 3.94 (m, 2H), 3.39 (m, 2H), 2.94 (t, 2H).
210 8.59 (d, IH), 8.52 (br s, IH), 8.42 (d, IH), 7.77 (s, IH), 7.62 (dd, IH), 7.21 (m, 2H), 6.80 (m, 2H), 6.66 (d, IH), 4.82 (m, IH), 4.39 (m, IH), 3.85 (m, 2H), 3.37 (dd, IH), 3.32 (dd, IH), 2.82-2.74 (m, 2H), 1.26 (d, 3H).
211 8.59 (d, IH), 8.51 (br s, IH), 8.41 (d, IH), 7.77 (s, IH), 7.61 (dd, IH), 7.21 (m, 2H), 6.80 (m, 3H), 6.66 (d, IH), 4.82 (m, IH), 4.39 (m, IH), 3.85 (m, 2H), 3.36 (dd, IH), 3.31 (dd, IH), 2.82-2.74 (m, 2H), 1.26 (d, 3H).
212 8.65 (d, IH), 8.64 (s, IH), 8.50 (br s, IH), 7.76 (s, IH), 7.61 (dd, IH), 7.21 (m, 2H), 6.81 (m, 2H), 5.50 (m, IH), 4.41 (m, IH), 3.94 (m, IH), 3.88 (m, IH), 3.44 (m, 2H), 2.84-2.74 (m, 2H), 1.27 (d, 3H).
213 9.39 (br s, IH), 8.59 (d, IH), 8.48 (s, IH), 7.87 (s, IH), 7.72 (d, IH), 7.49 (d, IH), 7.40 (dd, IH), 7.27 (d, 2H), 7.22 (d, 2H), 6.40 (d, IH), 6.00 (dt, IH), 3.81 (m, IH), 3.58 (m, 2H), 3.21-3.12 (m, 4H).
214 8.58 (s, IH), 7.91 (s, IH), 7.85 (d, IH), 7.76 (d, IH), 7.27 (s, 4H), 7.06 (d, IH), 6.48 (d,
IH), 6.09 (dt, IH), 5.85 (br s, IH), 4.65 (m, IH), 3.70 (m, 2H), 3.29(d, 2H), 3.22 (m, 2H).
215 8.28 (d, IH), 7.55 (d, IH), 7.36 (s, IH), 7.29 (m, 4H), 7.25 (d, IH), 7.03 (d, IH), 6.51 (d,
IH), 6.14 (dt, IH), 5.21 (m, IH), 3.83 (m, 2H), 3.39 (s, 3H), 3.30 (m, 2H), 3.2-2.8 (br m, 2H).
216 8.61 (d, IH), 8.49 (br s, IH), 8.15 (s, IH), 7.80 (s, IH), 7.66 (dd, IH), 7.28 (s, 4H), 6.50 (d,
IH), 6.13 (dt, IH), 5.38 (m, IH), 3.82 (m, 2H), 3.38-3.3 l(m, 4H).
217 8.61 (d, IH), 8.45 (br s, IH), 8.06 (s, IH), 7.79 (s, IH), 7.65 (dd, IH), 7.28 (s, 4H), 6.49 (d,
IH), 6.13 (dt, IH), 5.37 (m, IH), 3.81 (m, 2H), 3.36-3.30(m, 4H).
218 8.61 (d, IH), 8.32 (br s, IH), 7.76 (s, IH), 7.63 (dd, IH), 7.27 (s, 4H), 6.49 (d, IH), 6.12 (dt, IH), 5.34 (m, IH), 3.81 (m, 2H), 3.3 l(m, 4H).
219 8.85 (d, IH), 8.64 (d, IH), 8.40 (br s, IH), 7.79 (s, IH), 7.63 (d, IH), 7.39 (d, IH), 7.12 (d, 2H), 6.54 (d, 2H), 5.40 (m, IH), 3.91 (t, 2H), 3.27 (br s, 2H), 3.09 (br m, 2H), 2.81 (br m, 2H).
220 8.26 (d, IH), 7.53 (d, IH), 7.34 (s, IH), 7.25 (d, IH), 7.22 (m, 2H), 7.02 (d, IH), 6.83 (m, 2H), 5.18 (m, IH), 4.39 (m, IH), 3.87 (m, 2H), 3.39 (s, 3H), 3.3-2.8 (m, 2H), 2.77 (dd, IH), 2.72 (dd, IH), 1.28 (d, 3H). 221 8.85 (d, 1H), 8.64 (d, 1H), 8.40 (br s, 1H), 7.78 (s, 1H), 7.62 (dd, 1H), 7.38 (d, 1H), 7.16 (d, 2H), 6.62 (d, 2H), 5.39 (m, 1H), 3.88 (m, 2H), 3.34 (t, 2H), 3.28 (m, 2H), 2.93 (s, 3H), 2.74 (t, 2H).
222 8.27 (d, 1H), 7.54 (d, 1H), 7.35 (s, 1H), 7.25 (d, 1H), 7.23 (m, 2H), 7.03 (d, 1H), 6.83 (m, 2H), 5.21 (m, 1H), 3.98 (t, 2H), 3.92 (t, 2H), 3.39 (s, 3H), 3.3-2.8 (br m, 2H), 2.92 (t, 2H).
223 8.60 (d, 1H), 8.48 (br s, 1H), 8.14 (s, 1H), 7.79 (s, 1H), 7.65 (d, 1H), 7.22 (m, 2H), 6.82 (m, 2H), 5.36 (m, 1H), 4.41 (m, 1H), 3.89 (t, 1H), 3.84 (t, 1H), 3.44-3.33 (br m, 2H), 2.83-2.73 (m, 21H), 1.26 (d, 3H).
224 8.60 (d, 1H), 8.40 (br s, 1H), 7.75 (s, 1H), 7.62 (dd, 1H), 7.21 (m, 2H), 6.80 (m, 2H), 5.30 (m, 1H), 4.39 (m, 1H), 3.85 (m, 2H), 3.36 (m, 1H), 3.31 (m, 1H), 2.79 (dd, 1H), 2.73 (m, 1H), 1.26 (d, 3H).
225 9.32 (br s, 1H), 8.81 (d, 1H), 8.59 (d, 1H), 7.83 (s, 1H), 7.69 (d, 1H), 7.35 (d, 1H), 7.26
(obscured, 2H), 7.19 (d, 2H), 6.43 (d, 1H), 6.12 (m, 1H), 5.42 (m, 1H), 3.16 (d, 2H), 2.71 (m, 2H), 2.47 (m, 1H), 1.92 (m, 2H), 1.74 (m, 1H), 1.26 (m, 2H).
226 8.84 (d, 1H), 8.63 (d, 1H), 8.51 (s, 1H), 7.76 (s, 1H), 7.62 (d, 1H), 7.35 (d, 1H), 7.30 (AB d, 4H), 6.52 (d, 1H), 6.30 (m, 1H), 5.35 (m, 1H), 3.25 (br s, 2H), 2.88 (br s, 2H), 2.51 (br s, 2H), 2.21 (br s, 2H), 1.98 (br s, 2H).
227 8.82 (d, 1H), 8.74 (br s, 1H), 8.59 (d, 1H), 7.80 (s, 1H), 7.65 (d, 1H), 7.36 (d, 1H), 7.28 (s, 4H), 6.52 (d, 1H), 6.27 (m, 1H), 5.64 (m, 1H), 3.32 (m, 2H), 3.10 (m, 2H), 2.80 (m, 1H), 2.52 (m, 1H), 2.42 (m, 1H), 2.08 (m, 1H).
a NMR data are in ppm downfield from tetramethylsilane. Couplings are designated by (s)-singlet, (d)-doublet, (t)-triplet, (m)-multiplet, (dd)-doublet of doublets, (dt)-doublet of triplets, (td)-triplet of doublets, (br s)-broad singlet, (br t)-broad triplet.
BIOLOGICAL EXAMPLES OF THE INVENTION TEST A
For evaluating control of diamondback moth (Plutella xylostella) the test unit consisted of a small open container with a 12-14-day-old radish plant inside. This was pre-infested with ~50 neonate larvae that were dispensed into the test unit via corn cob grits using a bazooka inoculator. The larvae moved onto the test plant after being dispensed into the test unit.
Test compounds were formulated using a solution containing 10% acetone, 90% water and 300 ppm X-77® Spreader Lo-Foam Formula non-ionic surfactant containing alkylarylpolyoxyethylene, free fatty acids, glycols and isopropanol (Loveland Industries, Inc. Greeley, Colorado, USA). The formulated compounds were applied in 1 mL of liquid through a SUJ2 atomizer nozzle with 1/8 JJ custom body (Spraying Systems Co. Wheaton, Illinois, USA) positioned 1.27 cm (0.5 inches) above the top of each test unit. Test compounds were sprayed at 250 and/or 50 ppm and replicated three times. After spraying of the formulated test compound, each test unit was allowed to dry for 1 h and then a black, screened cap was placed on top. The test units were held for 6 days in a growth chamber at 25 °C and 70% relative humidity. Plant feeding damage was then visually assessed based on foliage consumed.
Of the compounds of Formula 1 tested, the following provided very good to excellent levels of control efficacy (40% or less feeding damage and/or 100% mortality at 250 ppm: compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19, 20, 23, 24, 25, 26, 28, 29, 30, 31, 35, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 50, 51, 52, 53, 54, 55, 57, 58, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 77, 78, 79, 80, 82, 83, 84, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135 and 214.
Of the compounds of Formula 1 tested, the following provided very good to excellent levels of control efficacy (40% or less feeding damage and/or 100% mortality) at 50 ppm: compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 16, 17, 20, 21, 22, 23, 25, 26, 29, 31, 35, 38, 40, 43, 45, 47, 48, 50, 51, 52, 55, 57, 58, 59, 60, 61, 62, 63, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 78, 80, 81, 82, 84, 85, 86, 87, 88, 89, 90, 91, 92, 94, 95, 96, 97, 98, 99, 101, 103, 104, 106, 107, 109, 110, 111, 112, 113, 114, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 143, 144, 145, 146, 147, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 172, 173, 174, 175, 176, 177, 179, 180, 181, 182, 183, 189, 190, 191, 192, 193, 194, 201, 205, 208, 209, 213, 214, 215, 217, 218, 219, 220, 221, 222, 223, 224, 226 and 227.
TEST B
For evaluating control of fall armyworm (Spodoptera frugiperda) the test unit consisted of a small open container with a 4-5-day-old maize (corn) plant inside. This was pre -infested (using a core sampler) with 10-15 1 -day-old larvae on a piece of insect diet.
Test compounds were formulated and sprayed at 250 and/or 50 ppm as described for Test A. The applications were replicated three times. After spraying, the test units were maintained in a growth chamber at 25 °C and 70% relative humidity and then visually rated as described for Test A.
Of the compounds of Formula 1 tested, the following provided very good to excellent levels of control efficacy (40% or less feeding damage and/or 100% mortality) at 250 ppm: compounds 1, 2, 3, 8, 9, 10, 12, 13, 14, 16, 17, 20, 23, 24, 25, 26, 50, 51, 52, 57, 58, 65, 66, 67, 68, 69, 70, 71, 72, 73, 77, 78, 79, 80, 82, 83, 84, 112, 113, 114, 115, 117, 118, 119, 120, 121, 122, 123, 125, 126, 127, 129, 130, 131, 132, 133 and 134.
Of the compounds of Formula 1 tested, the following provided very good to excellent levels of control efficacy (40% or less feeding damage and/or 100% mortality) at 50 ppm: compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 16, 17, 20, 21, 22, 23, 25, 26, 31, 52, 57, 58, 59, 60, 66, 68, 69, 71, 72, 73, 81, 82, 84, 85, 86, 87, 88, 89, 90, 91, 92, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 106, 107, 109, 110, 111, 112, 113, 114, 115, 118, 119, 120, 121, 122, 123, 127, 130, 131, 136, 137, 139, 143, 146, 147, 150, 151, 152, 153, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 172, 178, 179, 180, 181, 183, 189, 190, 191, 192, 193, 201, 205, 209, 210, 215, 216, 217, 219, 220, 221, 222, 223, 224, 226 and 227.
TEST C
For evaluating control of green peach aphid (Myzus persicae) through contact and/or systemic means, the test unit consisted of a small open container with a 12- 15 -day-old radish plant inside. This was pre-infested by placing on a leaf of the test plant 30-40 aphids on a piece of leaf excised from a culture plant (cut-leaf method). The aphids moved onto the test plant as the leaf piece desiccated. After pre-infestation, the soil of the test unit was covered with a layer of sand.
Test compounds were formulated and sprayed at 250 and/or 50 ppm as described for Test A. The applications were replicated three times. After spraying of the formulated test compound, each test unit was allowed to dry for 1 h and then a black, screened cap was placed on top. The test units were held for 6 days in a growth chamber at 19-21 °C and 50- 70% relative humidity. Each test unit was then visually assessed for insect mortality.
Of the compounds of Formula 1 tested, the following resulted in at least 80% mortality at 250 ppm: compounds 1, 6, 7, 11, 12, 13, 14, 16, 17, 20, 21, 22, 23, 24, 25, 40, 45, 47, 48, 50, 51, 52, 53, 57, 58, 59, 60, 61, 63, 66, 67, 68, 69, 70, 71, 72, 73, 79, 80, 85, 86, 88, 91, 94, 95, 97, 98, 103, 106, 107, 109, 110, 112, 113, 114, 116, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 129, 130, 131, 132, 133, 134, 135, 136, 137, 143, 144, 145, 147, 149, 150, 151, 152, 153, 155, 158, 160, 162, 163, 165, 166, 167, 168, 169, 170, 171, 172, 174, 178, 179, 180, 181, 182, 183, 189, 190, 191, 192, 194, 195, 201, 205, 210, 219, 221 and 227.
Of the compounds of Formula 1 tested, the following resulted in at least 80% mortality at 50 ppm: compounds 11, 16, 17, 25, 40, 45, 50, 51, 52, 58, 59, 60, 66, 67, 68, 69, 70, 71, 72, 85, 91, 103, 112, 114, 116, 119, 120, 121, 122, 123, 124, 125, 127, 130, 131, 132, 133, 134, 137, 147, 150, 152, 153, 155, 158, 168, 170, 179, 181 and 183.
TEST D
For evaluating control of the western flower thrips {Frankliniella occidentalis) through contact and/or systemic means, the test unit consisted of a small open container with a 5-7- day-old Soleil bean plant inside.
Test compounds were formulated and sprayed at 250 and/or 50 ppm, replicated three times as described for Test A. After spraying, the test units were allowed to dry for 1 hour, then 22-27 adult thrips were added to the unit, and then a black, screened cap was placed on top. The test units were held for 7 days at 25 °C and 45-55%) relative humidity. Of the compounds of Formula 1 tested, the following provided very good to excellent levels of control efficacy (30% or less plant damage and/or 100% mortality) at 250 ppm: compounds 1, 16, 17, 60, 69, 71, 85, 90, 91, 94, 95, 96, 97, 98, 101, 103, 109, 110, 111, 130, 131, 147, 162, 163, 172, 174, 177, 179, 181, 183, 187, 189, 190, 191, 192, 193, 201, 209, 215, 220, 222, 224 and 227.
Of the compounds of Formula 1 tested, the following provided very good to excellent levels of control efficacy (30% or less plant damage and/or 100% mortality) at 50 ppm: compounds 1 and 94.
TEST E
For evaluating control of potato leafhopper (Empoasca fabae) through contact and/or systemic means, the test unit consisted of a small open container with a 5-6-day-old Soleil bean plant (primary leaves emerged) inside.
Test compounds were formulated and sprayed at 250 and/or 50 ppm, replicated three times as described for Test A. After spraying, the test units were allowed to dry for 1 hour before they were post-infested with 5 potato leafhoppers (18-21 -day-old adults). A black, screened cap was placed on the top of the cylinder. The test units were held for 6 days in a growth chamber at 24 °C and 70% relative humidity. Each test unit was then visually assessed for insect mortality.
Of the compounds of Formula 1 tested, the following resulted in at least 80% mortality at 250 ppm: compounds 71, 72, 110, 136, 159, 163, 172, 179, 180, and 201.
Of the compounds of Formula 1 tested, the following resulted in at least 80% mortality at 50 ppm: compound 163.
TEST F
For evaluating control of cotton melon aphid {Aphis gossypii) through contact and/or systemic means, the test unit consisted of a small open container with a 6-7-day-old cotton plant inside. This was pre-infested with 30-40 insects on a piece of leaf according to the cut-leaf method described for Test C, and the soil of the test unit was covered with a layer of sand. Test compounds were formulated and sprayed at 250 ppm as described for Test A, replicated three times. After spraying, the test units were maintained in a growth chamber 19-21 °C and 50-70%) relative humidity and then visually rated as described for Test C.
Of the compounds of Formula 1 tested, the following resulted in at least 80% mortality at 250 ppm: compound 5.
TEST G
For evaluating control of corn planthopper (Peregrinus maidis) through contact and/or systemic means, the test unit consisted of a small open container with a 3-4 day-old corn spike inside. White sand was added to the top of the soil. Test compounds were formulated and sprayed at 250 ppm as described for Test A, replicated three times. After spraying, the test units were allowed to dry for 1 hour before they were post-infested with -15-20 nymphs (18-21 -day-old). A black, screened cap was placed on the top of the cylinder. The test units were held for 6 days in a growth chamber at 24 °C and 70% relative humidity. Each test unit was then visually assessed for insect mortality.
Of the compounds of Formula 1 tested, the following resulted in at least 80% mortality at 250 ppm: compounds 85 and 132.
In addition to Tests A-G, tests were conducted evaluating control of root knot nematode (Meloidogyne incognita), but noticeable activity against this additional invertebrate pest was not seen under the test conditions at the application rates tested.

Claims

is claimed is:
A compound sele ted from Formula 1, an N-oxide, or a salt thereof,
Figure imgf000126_0001
A1 is N or CR7;
A2 is N or CR8;
A3 is N or CR9;
A4 is N or CR10;
provided that not more than two of A1, A2, A3 and A4 are N;
T is O, S(0)k or NR36;
L is -C(R! 1)=C(R12)-, wherein the carbon atom bonded to R1 1 is also bonded to
CR R5 and the carbon atom bonded to R12 is also bonded to R6; or 1,4- diphenylene optionally substituted with up to 4 substituents independently selected from R13; or -C(R3 )(R35)-Z-, wherein the carbon atom bonded to R34 and R35 is also bonded to CR4R5 and Z is bonded to R6;
Z is O, S(0)m, NR37 or CR38R39;
R1 is a phenyl or 5- or 6-membered heteroaromatic ring optionally substituted with up to 5 substituents independently selected from R14;
R2 is H, hydroxy, Ci~C6 alkyl, Ci~C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl,
C2-C6 alkynyl, C3-C6 haloalkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl,
C5-C7 cycloalkenyl, -Cg alkoxy, C2-C6 alkoxyalkyl, -CHO, C(W!)R15,
C(0)OR16, C(0)NR17R18, S(0)pR19 or S(O)2NR20R21;
each R3 is independently halogen, cyano, C1-C4 alkyl or C1-C4 alkoxy;
R^s H or C^ alkyl;
R5 is H or CrC4 alkyl;
R6 is a phenyl or 5- or 6-membered heteroaromatic ring optionally substituted with up to 5 substituents independently selected from R22;
R7, R8, R9 and R10 are independently H, halogen, cyano, nitro, OR23, NR24R25, Cr
C6 alkyl, -Cg haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C3-C6 haloalkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl, C5-C7 cycloalkenyl, -CHO, C(W2)R26, C(0)OR27, C(0)NR28R29, S(0)qR30,
S(0)2NR28R29 or OC(0)R31; or a phenyl or 5- or 6-membered heteroaromatic ring optionally substituted with up to 5 substituents independently selected from R40; or a vicinal pair of R7 and R8, or R8 and R9, or R9 and R10, are taken together with the carbon atoms to which the pair is attached to form a fused 5- or 6-membered aromatic or nonaromatic ring containing ring members selected from carbon atoms and up to 3 heteroatoms independently selected from N, O and S;
R1 1 and R12 are independently H, halogen, C1-C2 alkyl or C1-C2 alkoxy;
each R13, R14, R22 and R40 is independently halogen, cyano, nitro, OR23, NR24R25, -Cg alkyl, -Cg haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C3-C6 haloalkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl, C5-C7 cycloalkenyl, -CHO, C(W2)R26, C(0)OR27, C(0)NR28R29, S(0)qR30,
S(0)2NR28R29 or OC(0)R31;
R15 and R16 are independently Cj-Cg alkyl, -Cg haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C3-C6 haloalkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5-C7 cycloalkenyl; or phenyl optionally substituted with up to 3 substituents independently selected from halogen, cyano, nitro, OR23, NR2 R25, C!-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, - haloalkyl, C2-C6 alkoxyalkyl, C2-C4 haloalkenyl, -CHO, C(W2)R26, C(0)OR27, C(0)NR28R29, S(0)qR30, S(0)2NR28R29 and OC(0)R31;
each R17 and R20 is independently H, Cj-Cg alkyl, Cj-Cg haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C3-C6 haloalkynyl, C3-C7 cycloalkyl, C4- C8 cycloalkylalkyl or C5-C7 cycloalkenyl; or phenyl optionally substituted with up to 3 substituents independently selected from halogen, cyano, nitro, OR23, NR2 R25, C!-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, - haloalkyl, C2-C6 alkoxyalkyl, C2-C4 haloalkenyl, -CHO, C(W2)R26, C(0)OR27, C(0)NR28R29, S(0)qR30, S(0)2NR28R29 and OC(0)R31;
each R18, R21, R24 and R29 is independently H, -Cg alkyl, C2-C6 alkenyl or C2-C6 alkynyl;
each R19, R26, R27 and R30 is independently -Cg alkyl or -Cg haloalkyl;
each R23 and R31 is independently H, C^-Cg alkyl or C^-Cg haloalkyl;
each R25, R36 and R37 is independently H, -Cg alkyl, C(0)R32 or C(0)OR33; each R28 and R32 is independently H, Ci~C6 alkyl, Ci~C6 haloalkyl, C2-C6 alkenyl,
C2-C6 haloalkenyl, C2-C6 alkynyl, C3-C6 haloalkynyl, C3-C7 cycloalkyl, C4-
Cg cycloalkylalkyl or C5-C7 cycloalkenyl;
each R33 is independently Ci~C6 alkyl, Ci~C6 haloalkyl, C2-C6 alkenyl, C2-C6
haloalkenyl, C2-C6 alkynyl, C3-C6 haloalkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5-C7 cycloalkenyl;
R34 is H, -C4 alkyl, -^ haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, -Q alkoxy or cyano;
R35 is H or methyl;
R38 is H, OH, halogen,€γ-€2 alkyl or€γ-€2 alkoxy;
R39 is selected from H, cyano and C^-C2 alkyl, and when R38 is halogen, then R39 is additionally selected from halogen; or
R38 and R39 together with the carbon atom to which said R38 and R39 are attached represent a carbonyl moiety;
W is O or S;
W1 is O or S;
each W2 is independently O or S;
k is 0, 1 or 2;
m is 0, 1 or 2;
n is an integer from 0 to 5;
p is 0, 1 or 2;
each q is independently 0, 1 or 2;
s is 1 , 2 or 3; and
t is 1 or 2;
provided that the sum of s and t is 2, 3 or 4.
2. A compound of Claim 1 wherein:
T is O;
Z is O;
R1 is a 4-pyridinyl ring substituted with 1 to 3 substituents independently selected from R14, wherein one of said substituents is located at the 2-position of the 4-pyridinyl ring;
R2 is H, methyl, C2-C5 alkoxyalkyl or C2-C4 alkoxycarbonyl;
R4 is H or C!-C4 alkyl;
R5 is H; R6 is a phenyl ring optionally substituted with up to 5 substituents independently selected from R22 or a pyridinyl ring optionally substituted with up to 4 substituents independently seleted from R22;
R7, R8, R9 and R10 are independently H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C3-C4 haloalkynyl,
C3-C6 cycloalkyl, Ci~C4 alkoxy, Cj-C/j haloalkoxy, Ci~C4 alkylthio, C1-C4 haloalkylthio or cyano, or a vicinal pair of R7 and R8, or R8 and R9, or R9 and R10, are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered aromatic or nonaromatic ring containing ring members selected from carbon atoms and up to 3 heteroatoms independently selected from
N, O and S;
R1 1 and R12 are independently H, halogen or methyl;
each R13 is halogen or methyl;
each R14 is independently halogen, Cj-C/j alkyl, Cj-C/j haloalkyl, cyano, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C3-C4 haloalkynyl, C3-C6 cycloalkyl, Cj-C/j alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio or C1-C4 haloalkylthio;
each R22 is independently halogen, cyano, Ci~C6 alkyl, Ci~C6 haloalkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, Ci~C6 alkoxy or C}-C6 haloalkoxy;
R34 is H or C!-C2 alkyl;
R 5 is H;
W is O;
n is 0;
s is 1 ; and
t is 1.
3. A compound of Claim 2 wherein:
A1 is N or CR7;
A2 is N or CR8;
A3 is N or CR9;
A4 is CR10;
L is -C(Rn)=C(R12)-, -C(R34)(R35)0- or unsubstituted diphenylene;
R1 is a 4-pyridinyl ring substituted with 1 substituent selected from R14, wherein said substituent is located at the 2-position of the 4-pyridinyl ring;
R2 is H;
R4 is H or methyl; R6 is a phenyl or pyridinyl ring substituted with 1 to 3 substituents independently selected from R22 wherein one substituent is at the para position;
R7, R8, R9 and R10 are independently H, halogen or C1-C4 haloalkyl;
R1 1 and R12 are H;
each R14 is independently halogen or C1-C4 haloalkyl;
each R22 is independently F, CI, Br, cyano, CH3, CF3, cyclopropyl, HC≡C, CH30 or CF3O; and
R3 is H or methyl.
4. A compound of Claim 3 wherein:
R6 is a phenyl or pyridinyl ring substituted at the para position with a substituent independently selected from R22 and optionally substituted at an ortho position with a substituent independently selected from R22;
R7 is H or F;
R8 and R9 are independently H, halogen or C1-C4 haloalkyl;
R10 is H or F;
each R14 is independently F, CI, Br or CF3; and
each R22 is independently F, CI, Br, CF3 or CF30.
5. A compound of Claim 4 wherein:
R6 is a phenyl ring substituted at the para position with a substituent selected from R22;
R7 is H;
R8 is H, halogen or CF3;
R9 is H, halogen or CF3;
R10 is H;
R14 is CI; and
R22 is F, CI, Br or CF3.
6. A compound of Claim 1 that is selected from the group consisting of:
2-chloro-N-[2-[[l-[(2E)-3-(4-chlorophenyl)-2-propen-l-yl]-3-azetidinyl]oxy]-
6-(trifluoromethyl)-3-pyridinyl]-4-pyridinecarboxamide,
2-chloro-N-[4,5-dichloro-2-[[l-[(2E)-3-(4-chlorophenyl)-2-propen-l-yl]- 3-azetidinyl]oxy]phenyl]-4-pyridinecarboxamide,
2-chloro-N-[6-chloro-2-[[ 1 -[(2E)-3-(4-chlorophenyl)-2-propen- 1 -yl]-3-azetidinyl]- oxy]-5 -fluoro-3 -pyridinyl] -4-pyridinecarboxamide,
2-chloro-N-[5-chloro-2-[[ 1 -[(2E)-3-(4-chlorophenyl)-2-propen- 1 -yl]-3-azetidinyl]- oxy]-6-fluoro-3 -pyridinyl] -4-pyridinecarboxamide, 2-chloro-N-[2-[[ 1 -[(2E)-3-(4-chlorophenyl)-2-propen- 1 -yl)-2-methyl-3-azetidinyl]- oxy]-6-(trifiuoromethyl)-3-pyridinyl]-4-pyridinecarboxamide, and
2-chloro-N-[6-chloro-2-[[l-[2-(4-chlorophenoxy)propyl]-3-azetidinyl]oxy]-5-fluoro-3- pyridinyl]-4-pyridinecarboxamide.
7. A compound of Claim 1 that is 2-chloro-N-[2-[[l-[(2E)-3-(4-chlorophenyl)-2- propen- 1 -yl] -3 -azetidinyljoxy] -6-(trifluoromethyl)-3 -pyridinyl] -4-pyridinecarboxamide.
8. A composition comprising a compound of Claim 1 and at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents, said composition optionally further comprising at least one additional biologically active compound or agent.
9. The composition of Claim 8 wherein the at least one additional biologically active compound or agent is selected from the group consisting of abamectin, acephate, acequinocyl, acetamiprid, acetoprole, acrinathrin, amidoflumet, amitraz, avermectin, azadirachtin, azinphos-methyl, bifenthrin, bifenazate, bistrifluron, borate, buprofezin, carbaryl, carbofuran, cartap, carzol, chlorantraniliprole, chlorfenapyr, chlorfluazuron, chlorpyrifos, chlorpyrifos-methyl, chromafenozide, clofentezin, clothianidin,
cyantraniliprole, cyflumetofen, cyfluthrin, beta-cyfluthrin, cyhalothrin, gamma-cyhalothrin, lambda-cyhalothrin, cypermethrin, alpha-cypermethrin, zeta-cypermethrin, cyromazine, deltamethrin, diafenthiuron, diazinon, dieldrin, diflubenzuron, dimefluthrin, dimehypo, dimethoate, dinotefuran, diofenolan, emamectin, endosulfan, esfenvalerate, ethiprole, etofenprox, etoxazole, fenbutatin oxide, fenothiocarb, fenoxycarb, fenpropathrin, fenvalerate, fipronil, flonicamid, flubendiamide, flucythrinate, flufenerim, flufenoxuron, fluvalinate, tau-fluvalinate, fonophos, formetanate, fosthiazate, halofenozide, hexaflumuron, hexythiazox, hydramethylnon, imidacloprid, indoxacarb, insecticidal soaps, isofenphos, lufenuron, malathion, mepyrfluthrin, metaflumizone, metaldehyde, methamidophos, methidathion, methiodicarb, methomyl, methoprene, methoxychlor, metofluthrin, monocrotophos, methoxyfenozide, nitenpyram, nithiazine, novaluron, noviflumuron, oxamyl, parathion, parathion-methyl, permethrin, phorate, phosalone, phosmet,
phosphamidon, pirimicarb, profenofos, profluthrin, propargite, protrifenbute, pymetrozine, pyrafluprole, pyrethrin, pyridaben, pyridalyl, pyrifluquinazon, pyriprole, pyriproxyfen, rotenone, ryanodine, spinetoram, spinosad, spirodiclofen, spiromesifen, spirotetramat, sulfoxaflor, sulprofos, tebufenozide, tebufenpyrad, teflubenzuron, tefluthrin, terbufos, tetrachlorvinphos, tetramethrin, tetramethylfluthrin, thiacloprid, thiamethoxam, thiodicarb, thiosultap-sodium, tolfenpyrad, tralomethrin, triazamate, trichlorfon, triflumuron, all strains of Bacillus thuringiensis, entomopathogenic bacteria, all strains of Nucleo polyhydrosis viruses, entomopathogenic viruses and entomopathogenic fungi.
10. The composition of Claim 9 wherein the at least one additional biologically active compound or agent is selected from the group consisting of abamectin, acetamiprid, acrinathrin, amitraz, avermectin, azadirachtin, bifenthrin, buprofezin, carbaryl, cartap, chlorantraniliprole, chlorfenapyr, chlorpyrifos, clothianidin, cyantraniliprole, cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, gamma-cyhalothrin, cypermethrin, alpha- cypermethrin, zeta-cypermethrin, cyromazine, deltamethrin, dieldrin, dinotefuran, diofenolan, emamectin, endosulfan, esfenvalerate, ethiprole, etofenprox, etoxazole, fenothiocarb, fenoxycarb, fenvalerate, fipronil, flonicamid, flubendiamide, flufenoxuron, fluvalinate, formetanate, hexaflumuron, hydramethylnon, imidacloprid, indoxacarb, lufenuron, mepyrfluthrin, metaflumizone, methiodicarb, methomyl, methoprene, methoxyfenozide, nitenpyram, nithiazine, novaluron, oxamyl, pymetrozine, pyrethrin, pyridaben, pyridalyl, pyriproxyfen, ryanodine, spinetoram, spinosad, spirodiclofen, spiromesifen, spirotetramat, sulfoxaflor, tebufenozide, tetramethrin, tetramethylfluthrin, thiacloprid, thiamethoxam, thiodicarb, thiosultap-sodium, tralomethrin, triazamate, triflumuron, all strains of Bacillus thuringiensis and all strains of Nucleo polyhydrosis viruses.
11. A composition for protecting an animal from an invertebrate parasitic pest comprising a parasiticidally effective amount of a compound of Claim 1 and at least one carrier.
12. A method for controlling an invertebrate pest comprising contacting the invertebrate pest or its environment with a biologically effective amount of a compound of Claim 1.
13. The method of Claim 12 wherein a plant in the environment of the invertebrate pest is contacted with the biologically effective amount of the compound of Claim 1.
14. A method for protecting a seed or a plant grown therefrom from an invertebrate pest comprising contacting the seed with a biologically effective amount of a compound of Claim 1.
15. The method of Claim 14 wherein the seed is coated with the compound of Claim
1 formulated as a composition comprising a film former or adhesive agent.
16. A treated seed comprising a compound of Claim 1 in an amount of from about 0.0001 to 1 % by weight of the seed before treatment.
PCT/US2011/044436 2010-07-20 2011-07-19 Pesticidal 3-(aryloxy)azacycloalkanes WO2012012366A1 (en)

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US10633336B2 (en) 2014-12-19 2020-04-28 The Broad Institute, Inc. Dopamine D2 receptor ligands
US10752588B2 (en) 2014-12-19 2020-08-25 The Broad Institute, Inc. Dopamine D2 receptor ligands
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JPWO2016175017A1 (en) * 2015-04-28 2018-02-22 アグロカネショウ株式会社 Novel 4-pyridinecarboxamide derivative and agricultural and horticultural agent containing this as an active ingredient
JP2020515608A (en) * 2017-03-31 2020-05-28 ダウ アグロサイエンシィズ エルエルシー Molecules with pesticidal utility, and intermediates, compositions, and processes related thereto
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