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WO2014179144A1 - Fungicidal heterocyclic compounds - Google Patents

Fungicidal heterocyclic compounds Download PDF

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Publication number
WO2014179144A1
WO2014179144A1 PCT/US2014/035245 US2014035245W WO2014179144A1 WO 2014179144 A1 WO2014179144 A1 WO 2014179144A1 US 2014035245 W US2014035245 W US 2014035245W WO 2014179144 A1 WO2014179144 A1 WO 2014179144A1
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Prior art keywords
och
ring
alkyl
haloalkyl
alkoxy
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French (fr)
Inventor
Robert James Pasteris
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EIDP Inc
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EI Du Pont de Nemours and Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—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
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
    • A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
    • A01N47/38—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N< containing the group >N—CO—N< where at least one nitrogen atom is part of a heterocyclic ring; Thio analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention relates to certain heterocyclic compounds, their N-oxides, salts and compositions, and methods of their use as fungicides.
  • U.S. Patent Application U.S. 2011/0172230 discloses urea compounds and their use for the treatment of diseases associated with fatty acid amide hydrolase.
  • This invention is directed to compounds of Formula 1 (including all stereoisomers), N-oxides, and salts thereof, agricultural compositions containing them and their use as fungicides: wherein
  • E is a radical selected from the group consistin of
  • X i a radical selected from the group consisting of
  • Z 1 is a saturated, partially unsaturated or fully unsaturated chain containing 1- to
  • G is a phenyl ring, a 5- to 6-membered heteroaromatic ring, a 3- to 6-membered
  • Z 2 is a direct bond or a saturated, partially unsaturated or fully unsaturated chain
  • Q is a phenyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 3 substituents independently selected from R 9a ; or
  • Q is a 5- to 6-membered heteroaromatic ring or an 8- to 11-membered heteroaromatic bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and 1 to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, each ring or ring system optionally substituted with up to 3 substituents independently selected from R 9a on carbon atom ring members and R 9 ⁇ on nitrogen atom ring members; or
  • Q is a 3- to 7-membered nonaromatic carbocyclic ring, a 5- to 7-membered
  • a 1 is O, S, C(R 12 ) 2 , N(R 13 ), -OC(R 12 ) 2 -, -SC(R 12 ) 2 - or -N(R 13 )C(R 12 ) 2 -, wherein the bond projecting to the left is connected to the nitrogen atom, and the bond projecting to the right is connected to the carbon atom in Formula 1; W is O or S;
  • R 1 is an optionally substituted phenyl ring, an optionally substituted naphthalenyl ring system or an optionally substituted 5- to 6-membered hetero aromatic ring; or cyano, Ci -Cg alkyl, Ci -Cg haloalkyl, C2-Cg alkenyl, C2-Cg haloalkenyl, C2-Cg alkynyl, C2-Cg haloalkynyl, C3-Cg cycloalkyl, C3-Cg halocycloalkyl, C4-C10 alkylcycloalkyl, C4-C10 cycloalkylalkyl, C4-C10 halocycloalkylalkyl, C5-C10 alkylcycloalkylalkyl, C2-Cg alkoxyalkyl, C2-Cg haloalkoxyalkyl, C4-C10 cycloalkoxyalkyl, C3-C10 alkoxy
  • haloalkoxycarbonylalkyl Ci -Cg alkoxy, Ci -Cg haloalkoxy, C2-Cg alkenyloxy, C2-Cg haloalkenyloxy, C2-Cg alkynyloxy, C3-Cg haloalkynyloxy, C3-Cg cycloalkoxy, C3-Cg halocycloalkoxy, C4-C10 cycloalkylalkoxy, C2-Cg alkoxyalkoxy, C2-Cg alkylcarbonyloxy, C2-Cg haloalkylcarbonyloxy, Ci -Cg alkylthio, Ci -Cg haloalkylthio, C3-Cg cycloalkylthio, Ci -Cg alkylamino, Ci -Cg haloalkylamino, C2-Cg dialkylamino, C2-Cg halodialkylamino, C3-Cg
  • R 3 is H, cyano, halogen, hydroxy, -C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or
  • alkylsulfonylalkyl Ci -C4 alkoxy, Ci -C4 haloalkoxy, C2-C4 alkylcarbonyloxy, C2-C4 haloalkylcarbonyloxy, C2-C5 alkoxycarbonyloxy, C2-C5
  • haloalkylcarbonyl C2-C5 alkoxycarbonyl, C2-C5 alkylaminocarbonyl or C3-C5 dialkylaminocarbonyl;
  • R 5 is H, C r C 3 alkyl or C r C 3 haloalkyl
  • each R 6 is independently cyano, halogen, hydroxy, Ci -C4 alkyl, Ci -C4 haloalkyl,
  • each R 7a and R 7c is independently cyano, halogen, hydroxy, Ci -C4 alkyl, Ci -C4
  • each R 7b and R 7d is independently cyano, Ci -C4 alkyl, Ci -C4 haloalkyl, Ci -C4 alkoxy,
  • each R 8a is independently cyano, halogen, hydroxy, Ci -C3 alkyl, Ci -C3 haloalkyl or
  • each R 8 ⁇ is independently Ci -C3 alkyl, Ci -C3 haloalkyl, C2-C4 alkylcarbonyl or
  • R 9a is independently amino, cyano, halogen, hydroxy, nitro, SF 5 , C ⁇ -Cg alkyl, C j -Cg haloalkyl, C2-Cg alkenyl, C2-Cg haloalkenyl, C2-Cg alkynyl, C2-Cg haloalkynyl, C2-Cg cyanoalkyl, C ⁇ -Cg hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C4-C10 cycloalkylalkyl, C4-C10 alkylcycloalkyl, C5-C10 alkylcycloalkylalkyl, C ⁇ -C ⁇ cycloalkylcycloalkyl, Cz Cg halocycloalkoxyalkyl, C4-C8 cycloalkenyloxyalkyl, C4-C8 hal
  • dialkylaminocarbonyl C3-C6 alkoxy(alkyl)aminocarbonyl, C3-C6
  • each R 9a is independently a phenyl ring or a naphthalenyl ring system, each optionally substituted with up to 3 substituents independently selected from cyano, halogen, C1 -C2 alkyl, C 1 -C2 haloalkyl, C1-C2 alkoxy and C1 -C2 haloalkoxy; or each R 9a is independently a 5- to 6-membered heteroaromatic ring containing ring members selected from carbon atoms and 1 to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, the ring optionally substituted with up to 3 substituents independently selected from cyano, halogen, Ci -C2 alkyl, Ci -C2 haloalkyl, C1-C2 alkoxy and Ci -C2 haloalkoxy on carbon atom ring members and
  • each R 9a is independently a 3- to 7-membered nonaromatic ring containing ring
  • each R 9b is independently cyano, Ci -C3 alkyl, Ci -C3 haloalkyl, Ci -C3 alkoxy, C2-C3 alkylcarbonyl, C2-C3 alkoxycarbonyl or C3-C6 cycloalkyl;
  • alkylsulfonylalkyl C3-C5 alkoxycarbonylalkyl, C1 -C4 alkoxy, C1 -C4
  • haloalkoxy C 1 -C4 alkylthio, C1 -C4 haloalkylthio, C1 -C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, Ci -C4 alkylsulfonyl, Ci -C4 haloalkylsulfonyl, C2-C4 alkylcarbonyl, C2-C4 haloalkylcarbonyl, C2-C5 alkoxycarbonyl, C2-C5 alkylaminocarbonyl or C3-C5 dialkylaminocarbonyl;
  • R 1 1 is H, C r C 4 alkyl, C r C 4 haloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 haloalkenyl, C3-C4 alkynyl, C2-C4 haloalkynyl, C2-C4 alkoxyalkyl, C2-C4 alkylthioalkyl, C2-C4 alkylsulfinylalkyl, C2-C4 alkylsulfonylalkyl, C3-C5 alkoxycarbonylalkyl, C1 -C4 alkylsulfonyl, C1 -C4 haloalkylsulfonyl, C2-C4 alkylcarbonyl, C2-C4
  • haloalkylcarbonyl C2-C5 alkoxycarbonyl, C2-C5 alkylaminocarbonyl or C3-C5 dialkylaminocarbonyl;
  • each R 12 is independently H, Ci -C3 alkyl or Ci -C3 haloalkyl;
  • R 1 is H, cyano, Ci -C4 alkyl, Ci -C4 haloalkyl, C2-C4 alkoxyalkyl, C2-C4
  • alkylthioalkyl C1 -C4 alkylsulfonyl, C1 -C4 haloalkylsulfonyl, C2-C4 alkylcarbonyl, C2-C4 haloalkylcarbonyl, C2-C4 alkoxycarbonyl, C2-C4 alkylaminocarbonyl or C3-C5 dialkylaminocarbonyl; or
  • R 13 and R 3 are taken together with the atoms to which they are attached to form a 5- to 7-membered partially saturated ring containing ring members selected from carbon atoms and up to 3 heteroatoms independently selected from up to 1 O, up to 1 S and up to 1 N atom, the ring optionally substituted with up to 3 substituents independently selected from cyano, halogen, nitro, Ci -C2 alkyl, Ci -C2 haloalkyl, Ci -C2 alkoxy and Ci -C2 haloalkoxy on carbon atom ring members and cyano, Ci -C2 alkyl and Ci -C2 alkoxy on nitrogen atom ring members;
  • each R 14 and R 15 is independently H, Ci -C3 alkyl, Ci -C3 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, benzyl or phenyl;
  • each R 16 is independently Ci -C3 alkyl, Ci -C3 haloalkyl, C2-C4 alkenyl, C3-C6
  • each R 17 is a phenyl ring, a naphthalenyl ring system or a 5- to 6-membered
  • heteroaromatic ring each ring or ring system optionally substituted with up to 3 substituents independently selected from halogen, cyano, nitro, Ci -C2 alkyl, Ci -C2 haloalkyl, Ci -C2 alkoxy and Ci -C2 haloalkoxy on carbon atom ring members and cyano, Ci -C2 alkyl and Ci -C2 alkoxy on nitrogen atom ring members;
  • each R 18 is independently H, Ci -C3 alkyl, Ci -C3 haloalkyl or benzyl;
  • each R 19 is independently H, Ci -C3 alkyl, Ci -C3 haloalkyl, C3-C6 cycloalkyl, C4-C6 cycloalkylalkyl, C4-C6 alkylcycloalkyl, C4-C6 haloalkylcycloalkyl, C2-C4 alkoxyalkyl, C2-C4 haloalkoxyalkyl, benzyl or phenyl;
  • each R 20 is independently H, cyano, Ci -Cg alkyl, Ci -Cg haloalkyl, C3-C8 cycloalkyl,
  • Ci -Cg alkoxy Ci -Cg haloalkoxy
  • Ci -Cg alkylamino Ci -Cg alkylamino
  • n 0, 1 or 2;
  • heterocyclic ring a monosubstituted 2-pyridinyl ring, a monosubstituted 3-pyridinyl ring, a monosubstituted pyrazinyl ring, an unsubstituted phenyl ring or a monosubstituted phenyl ring;
  • this invention pertains to a compound selected from compounds of Formula 1 (including all stereoisomers) and N-oxides and salts thereof.
  • This invention also relates to a fungicidal composition
  • a fungicidal composition comprising (a) a compound of the invention (i.e. in a fungicidally effective amount); and (b) at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents.
  • This invention also relates to a fungicidal composition
  • a fungicidal composition comprising (a) a compound of the invention; and (b) at least one other fungicide (e.g., at least one other fungicide having a different site of action).
  • This invention further relates to a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof, or to the plant seed, a fungicidally effective amount of a compound of the invention (e.g., as a composition described herein).
  • This invention also relates to a composition
  • a composition comprising a compound of Formula 1, an N-oxide, or a salt thereof, and at least one invertebrate pest control compound or agent.
  • 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.
  • 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.
  • plant includes members of Kingdom Plantae, particularly seed plants (Spermatopsida), at all life stages, including young plants (e.g., germinating seeds developing into seedlings) and mature, reproductive stages (e.g., plants producing flowers and seeds).
  • Portions of plants include geotropic members typically growing beneath the surface of the growing medium (e.g., soil), such as roots, tubers, bulbs and corms, and also members growing above the growing medium, such as foliage (including stems and leaves), flowers, fruits and seeds.
  • seedling used either alone or in a combination of words means a young plant developing from the embryo of a seed.
  • the term “broadleaf used either alone or in words such as “broadleaf crop” means dicot or dicotyledon, a term used to describe a group of angiosperms characterized by embryos having two cotyledons.
  • a molecular fragment i.e. radical
  • a series of atom symbols e.g., C, H, N, O, S
  • the point or points of attachment may be explicitly indicated by a hyphen ("-").
  • alkyl used either alone or in compound words such as “alkylthio” or “haloalkyl” includes straight-chain and branched alkyl, such as, methyl, ethyl, n-propyl, /-propyl, and the different butyl, pentyl and hexyl isomers.
  • Alkenyl includes straight-chain and 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 and 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.
  • Alkylene denotes a straight-chain or branched alkanediyl.
  • alkylene examples include CH 2 , CH 2 CH 2 , CH(CH 3 ), CH 2 CH 2 CH 2 , CH 2 CH(CH 3 ), and the different butylene isomers.
  • Alkoxy includes, for example, methoxy, ethoxy, n-propyloxy, z ' -propyloxy, and the different butoxy, pentoxy and hexyloxy isomers.
  • Alkynyloxy includes straight-chain and branched alkynyloxy moieties.
  • alkynyloxy examples include HC ⁇ CCH 2 0, CH 3 C ⁇ CCH 2 0 and CH 3 C ⁇ CCH 2 CH 2 0.
  • Alkoxyalkoxy denotes straight-chain or branched alkoxy substitution on a straight-chain or branched alkoxy.
  • alkoxyalkoxy examples include CH 3 OCH 2 0, CH 3 OCH 2 (CH 3 )CHCH 2 0 and (CH 3 ) 2 CHOCH 2 CH 2 0.
  • alkylsulfonyloxy denotes alkylsulfonyl attached to and linked through an oxygen atom.
  • alkylaminocarbonyloxy denotes a straight-chain or branched alkylaminocarbonyl attached to and linked through an oxygen atom.
  • dialkylaminocarbonyloxy examples include
  • alkylthio includes straight-chain and branched alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers.
  • Alkynylthio denotes straight-chain or branched alkynyl attached to and linked through a sulfur atom such as HC ⁇ CCH 2 S, CH 3 C ⁇ CCH 2 S and CH 3 C ⁇ CCH 2 CH 2 S.
  • alkoxyalkylthio denotes alkoxyalkyl attached to and linked through a sulfur atom.
  • alkoxyalkylthio examples include CH 3 OCH 2 S, CH 3 OCH 2 CH 2 S, CH 3 CH 2 OCH 2 S, (CH 3 ) 2 CHCH 2 OCH 2 S and CH 3 CH 2 OCH 2 CH 2 S.
  • alkylamino includes an NH radical substituted with a straight-chain or branched alkyl group.
  • alkylamino examples include CH 3 CH 2 NH, CH 3 CH 2 CH 2 NH and (CH 3 ) 2 CHCH 2 NH.
  • dialkylamino examples include (CH 3 ) 2 N, (CH 3 CH 2 CH 2 ) 2 N and CH 3 CH 2 (CH 3 )N.
  • Alkynylamino includes an NH radical substituted with straight-chain or branched alkynyl.
  • alkynylamino examples include CH ⁇ CHNH, CH ⁇ CHCH 2 NH and CH 3 C ⁇ CCH 2 NH.
  • Alkoxyamino includes straight-chain or branched alkoxy attached to and linked through an NH radical. Examples of “alkoxyamino” include CH 3 CH(CH 3 )ONH, CH 3 CH 2 CHONH, and
  • Alkylsulfonylamino denotes an NH radical substituted with alkylsulfonyl.
  • Alkylsulfonylamino denotes an NH radical substituted with alkylsulfonyl.
  • Alkoxyalkyl denotes alkoxy substitution on alkyl.
  • alkoxyalkyl include CH 3 OCH 2 , CH 3 OCH 2 CH 2 , CH 3 CH 2 OCH 2 , CH 3 CH 2 CH 2 CH 2 OCH 2 and CH 3 CH 2 OCH 2 CH 2 .
  • Alkoxyalkynyl denotes alkoxy substitution on straight-chain or branched alkenyl.
  • alkoxyalkynyl examples include CH 3 OC ⁇ C, CH 3 OCH 2 C ⁇ C and CH 3 CH 2 OC ⁇ CCH 2 .
  • Alkoxyalkoxyalkyl denotes alkoxyalkoxy substitution on alkyl.
  • alkoxyalkoxyalkyl examples include CH 3 OCH 2 OCH 2 CH 3 OCH 2 OCH 2 CH 2 and CH 3 CH 2 OCH 2 OCH 2 .
  • Alkylthioalkyl denotes alkylthio substitution on alkyl.
  • alkylthioalkyl include CH 3 SCH 2 , CH 3 SCH 2 CH 2 , CH 3 CH 2 SCH 2 , CH 3 CH 2 CH 2 CH 2 SCH 2 and CH 3 CH 2 SCH 2 CH 2 ;
  • alkylsulfmylalkyl and “alkylsulfonylalkyl” include the corresponding sulfoxides and sulfones, respectively.
  • Alkylaminoalkyl denotes alkylamino substitution on alkyl.
  • alkylaminoalkyl include CH 3 NHCH 2 , CH 3 NHCH 2 CH 2 , CH 3 CH 2 NHCH 2 , CH 3 CH 2 CH 2 CH 2 NHCH 2 and CH 3 CH 2 NHCH 2 CH 2 .
  • dialkylaminoalkyl include ((CH 3 ) 2 CH)) 2 NCH 2 , (CH 3 CH 2 CH 2 ) 2 NCH 2 and CH 3 CH 2 (CH 3 )NCH 2 CH 2 .
  • Cyanoalkyl denotes an alkyl group substituted with one cyano group.
  • Examples of “cyanoalkyl” include NCCH 2 , NCCH 2 CH 2 and CH 3 CH(CN)CH 2 .
  • Hydroxyalkyl denotes an alkyl group substituted with one hydroxy group. Examples of “hydroxyalkyl” include HOCH 2 CH 2 , CH 3 CH 2 (OH)CH and HOCH 2 CH 2 CH 2 CH 2 .
  • Trialkylsilyl includes 3 branched and/or straight-chain alkyl radicals attached to and linked through a silicon atom, such as trimethylsilyl, triethylsilyl and tert-butyldimethylsilyl.
  • the term “trialkylsilyloxy” denotes trialkylsilyl attached to and linked through an oxygen atom, such as triethylsilyloxy and tert-butyldimethylsilyloxy.
  • Cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • cycloalkylalkyl denotes cycloalkyl substitution on an alkyl moiety. Examples of “cycloalkylalkyl” include cyclopropylmethyl, cyclopentylethyl, and other cycloalkyl moieties bonded to a straight-chain or branched alkyl group.
  • alkylcycloalkyl denotes alkyl substitution on a cycloalkyl moiety and includes, for example, ethylcyclopropyl, z-propylcyclobutyl, methylcyclopentyl and methylcyclohexyl.
  • Cycloalkenyl includes groups such as cyclopentenyl and cyclohexenyl as well as groups with more than one double bond such as 1,3- or 1,4-cyclohexadienyl.
  • cycloalkoxy denotes cycloalkyl attached to and linked through an oxygen atom such as cyclopentyloxy and cyclohexyloxy.
  • cycloalkylthio denotes cycloalkyl attached to and linked through a sulfur atom such as cyclopropylthio and cyclopentylthio.
  • cycloalkoxyalkyl denotes cycloalkoxy substitution on an alkyl moiety. Examples of “cycloalkoxyalkyl” include cyclopropyloxymethyl, cyclo- pentyloxyethyl, and other cycloalkoxy groups bonded to a straight-chain or branched alkyl moiety.
  • Cycloalkylalkoxy denotes cycloalkyl substitution on an alkoxy moiety.
  • Examples of “cycloalkylalkoxy” include cyclopropylmethoxy, cyclopentylethoxy, and other cycloalkyl groups bonded to a straight-chain or branched alkoxy moiety.
  • Alkylcycloalkylalkyl denotes an alkyl group substituted with alkylcycloalkyl.
  • alkylcycloalkylalkyl include methylcyclohexylmethyl and ethylcycloproylmethyl.
  • cycloalkylcycloalkyl denotes cycloalkyl substitution on another cycloalkyl ring, wherein each cycloalkyl ring independently has from 3 to 6 carbon atom ring members.
  • cycloalkylcycloalkyl examples include cyclopropylcyclopropyl (such as ⁇ , ⁇ -bicyclopropyl-l-yl, l,l'-bicyclopropyl-2-yl), cyclohexylcyclopentyl (such as 4- cyclopentylcyclohexyl) and cyclohexylcyclohexyl (such as ⁇ , ⁇ -bicyclohexyl-l-yl), and the different cis- and trans-cycloalkylcycloalkyl isomers, (such as (li?,25)-l,l'-bicyclopropyl-2- yl and (li?,2i?)-l,l'-bicyclopropyl-2-yl).
  • cyclopropylcyclopropyl such as ⁇ , ⁇ -bicyclopropyl-l-yl, l,l'-bicyclopropyl-2-yl
  • Cycloalkylamino denotes an NH radical substituted with cycloalkyl.
  • Examples of “cycloalkylamino” include cyclopropylamino and cyclohexylamino.
  • the term “cyclo- alkylaminoalkyl” denotes cycloalkylamino substitution on an alkyl group.
  • Examples of “cycloalkylaminoalkyl” include cyclopropylaminomethyl, cyclopentylaminoethyl, and other cycloalkylamino moieties bonded to a straight-chain or branched alkyl group.
  • 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, F 2 CH, C1CH 2 , CF 3 CH 2 and CF 3 CC1 2 .
  • haloalkenyl is defined analogously to the term “haloalkyl”.
  • haloalkynyl include HC ⁇ CCHC1, CF 3 C ⁇ C, CC1 3 C ⁇ C and FCH 2 C ⁇ CCH 2 .
  • haloalkoxy examples include CF 3 0, CC1 3 CH 2 0, F 2 CHCH 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.
  • haloalkylamino examples include CF 3 (CH 3 )CHNH, (CF 3 ) 2 CHNH and CH 2 C1CH 2 NH.
  • halocycloalkyl examples include 2-chlorocyclopropyl, 2-fluorocyclobutyl, 3-bromocyclopentyl and 4-chorocyclohexyl.
  • halodialkyl either alone or in compound words such as “halodialkylamino" means at least one of the two alkyl groups is substituted with at least one halogen atom, and independently each halogenated alkyl group may be partially or fully substituted with halogen atoms which may be the same or different.
  • halodialkylamino include (BrCH 2 CH 2 ) 2 N and BrCH 2 CH 2 (ClCH 2 CH 2 )N.
  • Hydroxyalkyl denotes an alkyl group substituted with one hydroxy group.
  • Examples of “hydroxyalkyl” include HOCH 2 CH 2 , CH 3 CH 2 (OH)CH and HOCH 2 CH 2 CH 2 CH 2 .
  • Trialkylsilyl includes 3 branched and/or straight-chain alkyl radicals attached to and linked through a silicon atom, such as trimethylsilyl, triethylsilyl and tert-butyldimethylsilyl.
  • C ⁇ -C 3 alkylsulfonyl designates methylsulfonyl through propylsulfonyl
  • C 2 alkoxyalkyl designates CH 3 OCH 2
  • C 3 alkoxyalkyl designates, for example, CH 3 OCH 2 CH 2 or CH 3 CH 2 OCH 2
  • C4 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 .
  • unsubstituted in connection with a group such as a ring or ring system means the group does not have any substituents other than its one or more attachments to the remainder of Formula 1.
  • optionally substituted means that the number of substituents can be zero. Unless otherwise indicated, optionally substituted groups may be substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. Commonly, the number of optional substituents (when present) ranges from 1 to 3.
  • the term “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted” or with the term “(un)substituted.”
  • the term “optionally substituted” without recitation of number or identity of possible substituents e.g., phenyl and naphthalenyl as defined in R 1 and R 4 ) refers to groups which are unsubstituted or have at least one non-hydrogen substituent that does not extinguish the biological activity possessed by the unsubstituted analog.
  • the number of optional substituents may be restricted by an expressed limitation.
  • the phrase "optionally substituted with up to 3 substituents independently selected from R 9a on carbon atom ring members” means that 0, 1, 2 or 3 substituents can be present (if the number of potential connection points allows).
  • a range is specified for the number of substituents (e.g., p being an integer from 0 to 3 in Exhibit 2) and the range exceeds the number of positions available for the substituents on a ring (e.g., 2 positions available for (R 9a ) p on Q-5 in Exhibit 2), the actual higher end of the range is recognized to be the number of available positions.
  • a "ring” or “ring system” as a component of Formula 1 is carbocyclic or heterocyclic.
  • the term “ring system” denotes two or more connected rings.
  • the term “bicyclic ring system” denotes a ring system consisting of two rings sharing two or more common atoms. In a “fused bicyclic ring system” the common atoms are adjacent, and therefore the rings share two adjacent atoms and a bond connecting them. In a “bridged bicyclic ring system” the common atoms are not adjacent (i.e. there is no bond between the bridgehead atoms).
  • a "bridged bicyclic ring system” can be formed by bonding a segment of one or more atoms to nonadjacent ring members of a ring.
  • aromatic indicates that each ring atom is essentially in the same plane and has a / ⁇ -orbital perpendicular to the ring plane, and that (4n + 2) ⁇ electrons, where n is a positive integer, are associated with the ring to comply with Huckel's rule
  • carbocyclic ring denotes a ring 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". "Saturated carbocyclic” refers to a ring having a backbone consisting of carbon atoms linked to one another by single bonds; unless otherwise specified, the remaining carbon valences are occupied by hydrogen atoms.
  • partially unsaturated ring or “partially unsaturated heterocycle” refers to a ring which contains unsaturated ring atoms and one or more double bonds but which is not aromatic, for example a 4,5-dihydro-lH-pyrazol-l-yl ring.
  • nonaromatic includes rings that are fully saturated as well as partially or fully unsaturated, provided that the rings are not aromatic.
  • heterocyclic ring denotes a ring wherein at least one of the atoms forming the ring backbone is other than carbon.
  • a heterocyclic ring can be a saturated, partially unsaturated, or fully unsaturated ring.
  • a fully unsaturated heterocyclic ring satisfies Huckel's rule, then said ring is also called a “heteroaromatic ring” or “aromatic heterocyclic ring”.
  • saturated heterocyclic ring refers to a heterocyclic ring containing only single bonds between ring members.
  • heterocyclic ring system or “heteroaromatic bicyclic ring system” denote a ring wherein at least one of the atoms forming the ring backbone is other than carbon and at least one ring is aromatic. Unless otherwise indicated, heterocyclic rings and heteroaromatic ring systems can be attached through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.
  • the wavy bond between the nitrogen atom and the atom represented by A 1 designates a single bond and the geometry about the adjacent double (i.e. the bond linking the nitrogen atom to the substituents R 2 and R 3 ) is either cis-(Z), trans-(E), or a mixture thereof.
  • X is a radical selected from the group consisting X 1 , X 2 , X 3 and X 4 , provided that when X is X 1 , E is E-l and A is NH, then R 1 is other than an unsubstituted heterocyclic ring, a monosubstituted 2-pyridinyl ring, a monosubstituted 3-pyridinyl ring, a monosubstituted pyrazinyl ring, an unsubstituted phenyl ring or a monosubstituted phenyl ring.
  • X is a radical selected from the group consisting X 1 , X 2 , X 3 and X 4 , provided that when X is X 2 , Z 1 is CH, E is E-l and A is NH, then R 1 is other than an unsubstituted 3-pyridinyl ring, an unsubstituted pyrazinyl ring or monosubstituted pyrazinyl ring.
  • Z 1 is denoted as a chain consisting of a series of atoms wherein alternative points of attachment are possible (e.g., Z 1 is OCH2CH2 or NOCH 2 )
  • Z 1 is OCH2CH2 or NOCH 2
  • Z 2 is denoted as a radical wherein alternative bonds of attachment are possible (e.g., Z 2 is CH)
  • the ring members selected from up to 2 O, up to 2 S and up to 4 N are optional, because the number of heteroatom ring members may be zero.
  • the ring or ring system is carbocyclic. If at least one heteroatom ring member is present, the ring or ring system is heterocyclic.
  • the nitrogen atom ring members may be oxidized as N-oxides, because compounds relating to Formula 1 also include N-oxide derivatives.
  • R 2 and R 3 may be taken together with the carbon atom to which they are attached to form a 3- to 7-membered ring.
  • This 3- to 7-membered ring includes as a ring member the carbon atom to which the substituents R 2 and R 3 are attached.
  • the other 2 to 6 ring members are selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 2 N atoms.
  • the heteroatoms are optional, because the number of heteroatom ring members may be zero.
  • the ring is carbocyclic. If at least one heteroatom ring member is present, the ring is heterocyclic.
  • the ring is optionally substituted with up to 4 substituents independently selected from cyano, halogen, -C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy and C1-C2 haloalkoxy on carbon atom ring members and cyano, C1-C2 alkyl and C1-C2 alkoxy on nitrogen atom ring members.
  • the nitrogen atom ring members may be oxidized as N-oxides, because compounds relating to Formula 1 also include N-oxide derivatives.
  • R 3 and R 13 may be taken together with the linking atoms to which they are directly attached to form a 5- to 7-membered partially unsaturated ring.
  • the other 2 to 4 ring members of the ring are selected from up to 1 O, up to 1 S and up to 1 N atom. In this definition the ring members selected from up to 1 O, up to 1 S and up to 1 N atom are optional, because the number of heteroatom ring members may be zero.
  • the ring is optionally substituted with up to 3 substituents independently selected from cyano, halogen, nitro, C1-C2 alkyl, -C2 haloalkyl, -C2 alkoxy and -C2 haloalkoxy on carbon atom ring members and cyano, C 1 -C2 alkyl and C 1 -C2 alkoxy on nitrogen atom ring members.
  • substituents independently selected from cyano, halogen, nitro, C1-C2 alkyl, -C2 haloalkyl, -C2 alkoxy and -C2 haloalkoxy on carbon atom ring members and cyano, C 1 -C2 alkyl and C 1 -C2 alkoxy on nitrogen atom ring members.
  • These optional substituents are attached to available carbon and nitrogen atom ring members in the portion of the ring provided by R 3 and R 13 .
  • the nitrogen atom ring members may be oxidized as N-
  • Compounds of Formula 1 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.
  • Compounds of Formula 1 may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form.
  • Compounds of Formula 1 comprise mixtures of conformational isomers.
  • compounds of Formula 1 include compounds that are enriched in one conformer relative to others.
  • the compounds of the present invention include N-oxide derivatives of Formula 1.
  • N-oxide derivatives of Formula 1 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 of electrons for oxidation to the oxide; one skilled in the art will recognize those nitrogen-containing heterocycles which can form N-oxides.
  • tertiary amines can form N-oxides.
  • N-oxides of heterocycles and tertiary amines are very well known by one skilled in the art including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane.
  • MCPBA peroxy acids
  • alkyl hydroperoxides such as tert-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.
  • Formula 1 includes all crystalline and noncrystalline 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).
  • 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 to 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.
  • Embodiments of the present invention as described in the Summary of the Invention include those described below.
  • Formula 1 includes stereoisomers, 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 E is E-l .
  • Embodiment 2 A compound of Formula 1 wherein E is E-2.
  • Embodiment 3 A compound of Formula 1 or any one of Embodiments 1 through 2 wherein X is X 1 , X 2 or X 4 .
  • Embodiment 4 A compound of Embodiment 3 wherein X is X 1 or X 2 .
  • Embodiment 5 A compound of Embodiment 3 wherein X is X 1 or X 4 .
  • Embodiment 6 A compound of Embodiment 4 wherein X is X 2 .
  • Embodiment 7 A compound of Embodiment 4 wherein X is X 1 .
  • Embodiment 8 A compound of Formula 1 or any one of Embodiments 1 through 7 wherein X is X 2 or X 3 .
  • Embodiment 10 A compound of Embodiment 9 wherein Z 1 is O, S, NH, CH 2 ,
  • Embodiment 13 A compound of Embodiment 12 wherein Z 1 is O, OCH 2 , CH 2 0 or CH 2 .
  • Embodiment 14 A compound of Formula 1 or any one of Embodiments 1 through 13 wherein G is selected from G-1 through G-91 in Exhibit 1.
  • each R 8c is independently selected from H and R 8a ;
  • R 8d is selected from H and R 8b .
  • Embodiment 15 A compound of Embodiment 14 wherein G is selected from G-1
  • Embodiment 15 a A compound of Embodiment 14 wherein G is selected from G-1,
  • Embodiment 16 A compound of Embodiment 15 wherein G is selected from G-78 through G-90.
  • Embodiment 17 A compound of Embodiment 15 wherein G is selected from G-1, G-7,
  • Embodiment 18 A compound of Embodiment 15 wherein G is selected from G-1, G-8,
  • Embodiment 19 A compound of Embodiment 18 wherein G is selected from G-l,
  • G-56, G-68, G-70 and G-71 are examples of G-56, G-68, G-70 and G-71.
  • Embodiment 19a A compound of Embodiment 18 wherein G is selected from G-56,
  • Embodiment 20 A compound of Embodiment 19 wherein G is G-l .
  • Embodiment 21 A compound of Embodiment 19 wherein G is G-56.
  • Embodiment 22 A compound of Embodiment 19 wherein G is G-68.
  • Embodiment 23 A compound of Embodiment 19 wherein G is G-70.
  • Embodiment 24 A compound of Embodiment 19 wherein G is G-71.
  • Embodiment 26 A compound of Embodiment 25 wherein Z 2 is a direct bond, O, S, NH, CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , OCH 2 , CH 2 0, OCH 2 CH 2 , CH 2 CH 2 0, CH 2 OCH 2 , SCH 2 , CH 2 S, SCH 2 CH 2 , CH 2 CH 2 S, NHCH 2 , CH 2 NH,
  • Embodiment 28 A compound of Embodiment 27 wherein Z 2 is a direct bond, O, S, NH, OCH 2 , CH 2 0, SCH 2 , CH 2 S, NHCH 2 or CH 2 NH, each optionally substituted with up to 1 substituent selected from R 7c on a carbon atom and R 7 ⁇ on a nitrogen atom.
  • Embodiment 29 A compound of Embodiment 28 wherein Z 2 is O, S, NH, OCH 2 ,
  • Embodiment 30 A compound of Embodiment 28 wherein Z 2 is a direct bond.
  • Embodiment 31 A compound of Formula 1 or any one of Embodiments 1 through 30 wherein Q is selected from Q-l through Q-107 in Exhibit 2.
  • R 9c is selected from H
  • R 9b R 9b ; and p is 0, 1, 2 or 3.
  • Embodiment 32 A compound of Embodiment 31 wherein Q is selected from Q-1,
  • Embodiment 33 A compound of Embodiment 32 wherein Q is selected from Q-1,
  • Embodiment 34 A compound of Embodiment 33 wherein Q is selected from Q-45,
  • Embodiment 35 A compound of Embodiment 34 wherein Q is selected from Q-45,
  • Embodiment 36 A compound of Embodiment 35 wherein Q is selected from Q-45,
  • Embodiment 37 A compound of Embodiment 36 wherein Q is selected from Q-45,
  • Embodiment 38 A compound of Embodiment 37 wherein Q is Q-45.
  • Embodiment 39 A compound of any one of Embodiments 31 through 38 wherein p is
  • Embodiment 40 A compound of Embodiment 39 wherein p is 0.
  • Embodiment 41 A compound of Embodiment 39 wherein p is 2.
  • Embodiment 42 A compound of Formula 1 or any one of Embodiments 1 through 41 wherein A is CH(R 10 ) or N(R! l ).
  • Embodiment 43 A compound of Embodiment 42 wherein A is CH2 or NH.
  • Embodiment 44 A compound of Embodiment 42 wherein A is CH(R 10 ).
  • Embodiment 45 A compound of Embodiment 44 wherein A is CH2.
  • Embodiment 46 A compound of Embodiment 42 wherein A is N(R! !).
  • Embodiment 47 A compound of Embodiment 46 wherein A is NH.
  • Embodiment 48 A compound of Formula 1 or any one of Embodiments 1 or 47
  • a 1 is O, S, C(R 12 ) 2 , N(R 13 ) or -OC(R 12 ) 2 -, wherein the bond projecting to the left is connected to the nitrogen atom, and the bond projecting to the right is connected to the carbon atom in Formula 1.
  • Embodiment 49 A compound of Embodiment 48 wherein A 1 is O, S or N(R 13 ).
  • Embodiment 50 A compound of Embodiment 49 wherein A 1 is O or N(R 13 ).
  • Embodiment 51 A compound of Formula 1 or any of Embodiments 1 through 50
  • Embodiment 52 A compound of Formula 1 or any one of Embodiments 1 through 51 wherein R 1 is an optionally substituted phenyl ring, an optionally substituted naphthalenyl ring system or an optionally substituted 5- to 6-membered heteroaromatic ring; or cyano, C ⁇ -Cg alkyl, C ⁇ -Cg haloalkyl, C2-Cg alkenyl,
  • haloalkylthioalkyl C2-Cg alkylsulfinylalkyl, C2-Cg alkylsulfonylalkyl, C2-Cg alkylaminoalkyl, C2-Cg haloalkylaminoalkyl, C3-C10 dialkylaminoalkyl, C 4 -C10 cycloalkylaminoalkyl, C3-Cg alkoxycarbonylalkyl, C3-Cg
  • haloalkoxycarbonylalkyl C ⁇ -Cg alkoxy, C ⁇ -Cg haloalkoxy, C2-Cg alkenyloxy, C2-Cg haloalkenyloxy, C2-Cg alkynyloxy, C3-Cg haloalkynyloxy, C3-Cg cycloalkoxy, C3-Cg halocycloalkoxy, C 4 -C10 cycloalkylalkoxy, C2-Cg alkoxyalkoxy, C2-Cg alkylcarbonyloxy, C2-Cg haloalkylcarbonyloxy, Ci -Cg alkylthio, C ⁇ -Cg haloalkylthio, C3-Cg cycloalkylthio, C ⁇ -Cg alkylamino, C2-Cg dialkylamino, C2-Cg alkylcarbonylamino, C3-C10 trialkylsilyl, pyrrolidinyl
  • Embodiment 53 A compound of Embodiment 52 wherein R 1 is cyano, C ⁇ -Cg alkyl, C ⁇ -Cg haloalkyl, C2-Cg alkenyl, C2-Cg haloalkenyl, C2-Cg alkynyl, C2-Cg haloalkynyl, C3-Cg cycloalkyl, C2-Cg alkoxyalkyl, C2-Cg haloalkoxyalkyl, C2-Cg alkylthioalkyl, C2-Cg haloalkylthioalkyl, C2-Cg alkylsulfmylalkyl, C2-Cg alkylsulfonylalkyl, C2-Cg alkylaminoalkyl, C3-C10 dialkylaminoalkyl, C ⁇ -Cg alkoxy, C ⁇ -Cg haloalkoxy, C2-Cg alkylcarbonyloxy, C2-Cg
  • haloalkylcarbonyloxy C ⁇ -Cg alkylthio, C ⁇ -Cg alkylamino, C2-Cg dialkylamino, C2-Cg alkylcarbonylamino, C3-C10 trialkylsilyl, pyrrolidinyl, piperidinyl or morpholinyl.
  • Embodiment 54 A compound of Embodiment 53 wherein R 1 is C2-C5 alkyl, C2-C5 haloalkyl, C2-C5 alkenyl, C2-C5 haloalkenyl, C2-C5 alkoxyalkyl, C2-Cg haloalkoxyalkyl, C2-C5 alkylthioalkyl, C2-Cg haloalkylthioalkyl, C2-C5 alkylaminoalkyl, C2-C5 alkoxy, C2-C5 haloalkoxy, C2-Cg alkylcarbonyloxy, C2-Cg haloalkylcarbonyloxy, C2-C5 alkylthio, C2-C5 alkylamino or C2-C5 alkylcarbonylamino .
  • Embodiment 55 A compound of Embodiment 54 wherein R 1 is C3-C5 haloalkyl, C3-C5 haloalkenyl, C3-C5 haloalkoxyalkyl, C3-C5 haloalkylthioalkyl, C2-C4 haloalkoxy or C2-C3 haloalkylcarbonyloxy.
  • Embodiment 56 A compound of Embodiment 55 wherein R 1 is C4 haloalkyl, C4
  • Embodiment 57 A compound of Formula 1 or any one of Embodiments 1 through 56 wherein when R 1 is an optionally substituted phenyl ring, an optionally substituted naphthalenyl ring system or an optionally substituted 5- to
  • each ring and ring system are independently selected from R 21 a on carbon atom ring members and R 21 ⁇ on nitrogen atom ring members;
  • each R 21 a is independently amino, cyano, halogen, hydroxy, nitro, C ⁇ -Cg alkyl, C j -Cg haloalkyl, C2-Cg alkenyl, C2-Cg haloalkenyl, C2-Cg alkynyl, C2-Cg haloalkynyl, -C4 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C4-C10 cycloalkylalkyl, C4-C10 alkylcycloalkyl, C5-C10 alkylcycloalkylalkyl, C2-C4 alkoxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C2-C6
  • alkylcarbonylthio C1-C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 haloalkylsulfonyl, C 1-C4 alkylamino, C2-Cg dialkylamino, C3-C6 cycloalkylamino, C2-C4 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl or C L-33--CL-66 t trriiaalikKyylissiiliyyli;; aannda
  • each R 21b is independently C ⁇ -Cg alkyl, C ⁇ -Cg haloalkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C3-C6 haloalkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl or C2-C4 alkoxyalkyl.
  • Embodiment 58 A compound of Embodiment 57 wherein R 1 is selected from U-1 through U-50 in Exhibit 3.
  • Embodiment 59 A compound of Embodiment 58 wherein R 1 is selected from U-l through U-5, U-8, U-l 1, U-13, U-15, U-20 through U-28, U-31, U-36 through U-39 and U-50.
  • Embodiment 60 A compound of Embodiment 59 wherein R 1 is selected from U-l through U-3, U-5, U-8, U-l 1, U-13, U-20, U-22, U-23, U-25 through U-28, U-36 through U-39 and U-50.
  • Embodiment 61 A compound of Embodiment 60 wherein R 1 is selected from U-l through U-3, U-l 1, U-13, U-20, U-22, U-23, U-36 through U-39 and U-50.
  • Embodiment 62 A compound of Embodiment 61 wherein R 1 is selected from U-l,
  • Embodiment 63 A compound of Embodiment 62 wherein R 1 is U-l .
  • Embodiment 64 A compound of Embodiment 62 wherein R 1 is U-20.
  • Embodiment 65 A compound of Embodiment 62 wherein R 1 is U-50.
  • Embodiment 66 A compound of any one of Embodiments 58 through 65 wherein k is 0, 1 or 2.
  • Embodiment 67 A compound of Embodiment 66 wherein k is 2.
  • Embodiment 68 A compound of any one of Embodiments 57 through 67 wherein each
  • R 21 a is independently halogen, C ⁇ -Cg alkyl, C ⁇ -Cg haloalkyl or C2-C4
  • Embodiment 69 A compound of Embodiment 68 wherein each R 21 a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or C2-C3 alkoxyalkyl.
  • Embodiment 70 A compound of Embodiment 69 wherein each R 21 a is independently halogen, methyl or C1-C2 haloalkyl.
  • Embodiment 71 A compound of Embodiment 70 wherein each R 21 a is independently halogen, methyl, CF 3 or CF 2 H.
  • Embodiment 72 A compound of Embodiment 71 wherein each R 21 a is independently methyl, CF 3 or CF 2 H.
  • Embodiment 73 A compound of any one of Embodiments 57 through 72 wherein each R 21b is independently -C3 alkyl.
  • Embodiment 74 A compound of Formula 1 or any one of Embodiments 1 through 73 wherein R 2 when taken alone (i.e. not taken together with R 3 ) is H, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, C2-C4 alkoxyalkyl, C2-C4 alkylthioalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C2-C4 alkenyloxy, C2-C4 haloalkenyloxy, C2-C4 alkynyloxy, C3-C4 haloalkynyloxy, C2-C4 alkoxyalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, C1-C4 alkylamin
  • Embodiment 75 A compound of Embodiment 74 wherein R 2 when taken alone is H, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C2-C3 alkenyl, C2-C3 haloalkenyl, C2-C3 alkynyl, C2-C3 haloalkynyl, C1-C3 alkoxy or C1-C3 haloalkoxy.
  • Embodiment 76 A compound of Embodiment 75 wherein R 2 when taken alone is H, C r C 3 alkyl or C r C 3 haloalkyl.
  • Embodiment 77 A compound of Embodiment 76 wherein R 2 when taken alone is H,
  • Ci -C3 alkyl trifluoromethyl or CF3CH2-.
  • Embodiment 78 A compound of Embodiment 77 wherein R 2 when taken alone is methyl, trifluoromethyl or CF3CH2-.
  • Embodiment 79 A compound of Formula 1 or any one of Embodiments 1 through 78 wherein R 2 is taken alone.
  • Embodiment 80 A compound of Formula 1 or any one of Embodiments 1 through 79 wherein R 3 when taken alone (i.e. not taken together with R 2 ) is H, C1-C3 alkyl,
  • Ci -C3 haloalkyl or C1-C3 alkoxy Ci -C3 haloalkyl or C1-C3 alkoxy.
  • Embodiment 81 A compound of Embodiment 80 wherein R 3 when taken alone is H,
  • Embodiment 82 A compound of Embodiment 81 wherein R 3 when taken alone is H,
  • Embodiment 83 A compound of Embodiment 82 wherein R 3 when taken alone is H, methyl or trifluoromethyl.
  • Embodiment 84 A compound of Formula 1 or any one of Embodiments 1 through 83 wherein R 3 is taken alone.
  • Embodiment 86 A compound of Formula 1 or any one of Embodiments 1 through 85 wherein R 4 is an optionally substituted phenyl ring, an optionally substituted naphthalenyl ring system or an optionally substituted 5- to 6-membered heteroaromatic ring; or H, cyano, hydroxy, Ci -C3 alkyl, Ci -C3 haloalkyl, C2-C3 alkenyl, C2-C3 haloalkenyl, C2-C3 alkynyl, C2-C3 haloalkynyl, C 1 -C3 alkoxy, C1 -C3 haloalkoxy, C2-C3 alkylcarbonyloxy, C2-C3 haloalkylcarbonyloxy, C1 -C3 alkylthio, Ci -C3 haloalkylthio, C2-C3 alkylcarbonyl or C2-C3 haloalkylcarbonyl.
  • R 4 is
  • Embodiment 88 A compound of Embodiment 87 wherein R 4 is H, cyano, hydroxy,
  • Embodiment 89 A compound of Embodiment 88 wherein R 4 is H, cyano, methyl,
  • Embodiment 90 A compound of Embodiment 89 wherein R 4 is H or methyl.
  • Embodiment 91 A compound of Embodiment 90 wherein R 4 is H.
  • Embodiment 92 A compound of Formula 1 or any one of Embodiments 1 through 91 wherein when R 4 is an optionally substituted phenyl ring, an optionally substituted naphthalenyl ring system or an optionally substituted 5- to
  • each ring and ring system are independently selected from R 22a on car b on atom ring members and R 22 ⁇ on nitrogen atom ring members;
  • each R 22a is independently amino, cyano, halogen, hydroxy, nitro, Ci -Cg alkyl,
  • Ci -Cg haloalkyl C2-Cg alkenyl, C2-Cg haloalkenyl, C2-Cg alkynyl, C2-Cg haloalkynyl, Ci -C4 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C4-C10 cycloalkylalkyl, C4-C10 alkylcycloalkyl, C5-C10
  • alkylcycloalkylalkyl C2-C4 alkoxyalkyl, C 1 -C4 alkoxy, C1 -C4 haloalkoxy,
  • each R 22b is independently Ci -Cg alkyl, Ci -Cg haloalkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C3-C6 haloalkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl or C2-C4 alkoxyalkyl.
  • Embodiment 93 A compound of Formula 1 or any one of Embodiments 1 through 92 wherein when R 4 is an optionally substituted phenyl ring, an optionally substituted naphthalenyl ring system or an optionally substituted 5- to 6-membered heteroaromatic ring, then R 4 is other than optionally substituted naphthalenyl.
  • Embodiment 94 A compound of Formula 1 or any one of Embodiments 1 through 93 wherein when R 4 is an optionally substituted phenyl ring or an optionally substituted 5- to 6-membered heteroaromatic ring, then R 4 is a ring selected from L-1 through L-11 in Exhibit 4.
  • g 0, 1, 2 or 3.
  • Embodiment 95 A compound of any one of Embodiments 92 through 94 wherein each
  • R 22a is independently halogen, C1-C2 alkyl, Ci -C2 haloalkyl or Ci -C2 alkoxy.
  • Embodiment 96 A compound of Embodiment 95 wherein each R22a j s independently
  • Embodiment 97 A compound of Embodiment 96 wherein each R22a j s independently
  • Embodiment 98 A compound of Formula 1 or any one of Embodiments 1 through 97 wherein R 5 is H or Ci -C2 alkyl.
  • Embodiment 99 A compound of Embodiment 98 wherein R 5 is H.
  • Embodiment 100 A compound of Formula 1 or any one of Embodiments 1 through 99 wherein each R 6 is independently cyano, hydroxy, methyl or methoxy.
  • Embodiment 101 A compound of Embodiment 100 wherein each R 6 is methyl.
  • Embodiment 102 A compound of Formula 1 or any one of Embodiments 1 through 101 wherein n is 0 or 1.
  • Embodiment 103 A compound of Embodiment 102 wherein n is 0.
  • Embodiment 104 A compound of Formula 1 or any one of Embodiments 1 through 103 wherein each R 7a and R 7c is independently halogen, Ci -C4 alkyl or Ci -C4 alkoxy.
  • Embodiment 105 A compound of Embodiment 104 wherein each R 7a and R 7c is
  • Embodiment 106 A compound of Formula 1 or any one of Embodiments 1 through 105 wherein each R 7 ⁇ and R 7 ⁇ is independently Ci -C4 alkyl.
  • Embodiment 107 A compound of Embodiment 106 wherein each R 7 ⁇ and R 7 ⁇ is
  • Embodiment 108 A compound of Formula 1 or any one of Embodiments 1 through 107 wherein each R 8a is independently halogen or C1-C3 alkyl.
  • Embodiment 109 A compound of Embodiment 108 wherein each R 8a is methyl.
  • Embodiment 110 A compound of Formula 1 or any one of Embodiments 1 through 109 wherein each R 8 ⁇ is methyl.
  • Embodiment 111 A compound of Formula 1 or any one of Embodiments 1 through 110 wherein G is unsubstituted except for its attachments to Z 1 and Z 2 .
  • Embodiment 112 A compound of Formula 1 or any one of Embodiments 1 through 111 wherein each R 9a is independently amino, cyano, halogen, C ⁇ -Cg alkyl, C ⁇ -Cg haloalkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-C6 cycloalkyl, C3-C6
  • halocycloalkyl C4-C10 cycloalkylalkyl, C2-C4 alkoxyalkyl, C1 -C4 alkoxy,
  • alkylcarbonyloxy C1 -C4 alkylthio, C1 -C4 alkylsulfonyl, C1 -C4 alkylamino, C2-Cg dialkylamino, C2-C4 alkylcarbonyl, C2-Cg alkoxycarbonyl, C2-Cg alkylaminocarbonyl or C3-C8 dialkylaminocarbonyl; or phenyl optionally substituted with up to 3 substituents independently selected from halogen, Ci -C2 alkyl, C1-C2 haloalkyl and C1 -C2 alkoxy.
  • Embodiment 113 A compound of Embodiment 112 wherein each R 9a is independently halogen, Ci -Cg alkyl, Ci -Cg haloalkyl, Ci -Cg alkoxy, C3-C4 alkenyloxy or C3-C4 alkynyloxy.
  • Embodiment 115 A compound of Embodiment 114 wherein each R 9a is independently CI, F, methyl or halomethyl.
  • Embodiment 116 A compound of Embodiment 115 wherein each R 9a is independently
  • Embodiment 116a A compound of Embodiment 116 wherein each R 9a is F.
  • Embodiment 117. A compound of Formula 1 or any one of Embodiments 1 through 116 wherein each R 9b is independently C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 alkylcarbonyl or C2-C3 alkoxycarbonyl.
  • Embodiment 119 A compound of Formula 1 or Embodiments 1 through 118 wherein
  • Ci -C4 alkoxy or C2-C5 alkoxycarbonyl Ci -C4 alkoxy or C2-C5 alkoxycarbonyl.
  • Embodiment 120 A compound of Embodiment 119 wherein R 10 is H, cyano, halogen, hydroxy, methyl or methoxy.
  • Embodiment 121 A compound of Embodiment 120 wherein R 10 is H.
  • Embodiment 122 A compound of Formula 1 or Embodiments 1 through 121 wherein
  • Embodiment 123 A compound of Embodiment 122 wherein R 1 1 is H.
  • Embodiment 124 A compound of Formula 1 or any one of Embodiments 1 through 123 wherein each R 12 is independently H or methyl.
  • Embodiment 125 A compound of Embodiment 124 wherein each R 12 is H.
  • Embodiment 126 A compound of Formula 1 or any one of Embodiments 1 through 125 wherein R 13 when taken alone (i.e. not taken together with R 3 ) is H, Ci -C2 alkyl,
  • Embodiment 127 A compound of Embodiment 126 wherein R 13 when taken alone is H or C r C 2 alkyl.
  • Embodiment 128 A compound of Embodiment 127 wherein R 13 when taken alone is H or methyl.
  • Embodiment 129 A compound of Formula 1 or any one of Embodiments 1 through 128 wherein R 13 is taken alone.
  • Embodiment 130 A compound of Formula 1 or any one of Embodiments 1 through 129 wherein s and f are both 0.
  • Embodiments of this invention 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 unless further defined in the Embodiments.
  • embodiments of this invention including Embodiments 1-130 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 1-130 are illustrated by:
  • Embodiment Al A compound of Formula 1 wherein
  • E is E-l;
  • X is X 1 or X 2 ;
  • Z 1 is O, S, NH, CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , OCH 2 , CH 2 0, OCH 2 CH 2 , CH 2 CH 2 0, CH 2 OCH 2 , SCH 2 , CH 2 S, SCH 2 CH 2 , CH 2 CH 2 S,
  • G is selected from G-l, G-9, G-12, G-15, G-19, G-22, G-30, G-36, G-46 through G-48, G-55, G-56 and G-68 through G-71 shown in Exhibit 1 wherein the bond projecting to the left is connected to Z 1 , and the bond projecting to the right is connected to Z 2 ; each R 8c is independently selected from H and R 8a ; and R 8d is selected from H and R 8 ⁇ .
  • Z 2 is a direct bond, O, S, NH, CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , OCH 2 , CH 2 0, OCH 2 CH 2 , CH 2 CH 2 0, CH 2 OCH 2 , SCH 2 , CH 2 S, SCH 2 CH 2 ,
  • Q is selected from Q-45, Q-63, Q-70, Q-71, Q-72 and Q-84 shown in Exhibit 2 wherein the bond projecting to the left is connected to Z 2 ;
  • R 9c is selected from H and R 9b ; and
  • p is 0, 1, 2 or 3;
  • A is CH(R 10 ) or N(R n );
  • W is O
  • R 1 is selected from U-1, U-20 and U-50 shown in Exhibit 3 wherein the bond projecting to the left is connected to A and k is 0, 1, 2 or 3;
  • each R 21a is independently halogen, C1-C3 alkyl, -C3 haloalkyl or C 2 -C3 alkoxyalkyl;
  • each R 6 is independently cyano, hydroxy, methyl or methoxy
  • each R 7a and R 7c is independently halogen, -C4 alkyl or C1-C4 alkoxy; each R 7b and R 7d is independently C1-C4 alkyl;
  • each R 8a is independently halogen or C1-C3 alkyl
  • each R 9a is independently halogen, C ⁇ -Cg alkyl, C ⁇ -Cg haloalkyl, C ⁇ -Cg alkoxy, C3-C4 alkenyloxy or C3-C4 alkynyloxy;
  • R 9b is C r C 3 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 alkylcarbonyl or C 2 -C 3 alkoxycarbonyl;
  • R 10 is H, cyano, halogen, hydroxy, methyl or methoxy
  • Embodiment A2 A compound of Embodiment Al wherein
  • G is selected from G-l, G-56, G-68, G-70 and G-71;
  • G is unsubstituted except for its attachments to Z 1 and Z 2 ;
  • Z 2 is a direct bond, O, S, NH, OCH 2 , CH 2 0, SCH 2 , CH 2 S, NHCH 2 or
  • Q is Q-45
  • p 0, 1 or 2;
  • A is CH 2 or NH
  • R 1 is U-l
  • each R 21a is independently halogen, methyl or C ⁇ -C 2 haloalkyl
  • k 0, 1 or 2;
  • n 0;
  • each R 7a and R 7c is methyl
  • each R 7 ⁇ and R 7 ⁇ is methyl
  • Embodiment A3 A compound of Embodiment A2 wherein
  • X is X 1 ;
  • Z 1 is O, OCH 2 , CH 2 0 or CH 2 ;
  • G is selected from G-56, G-68 and G-70;
  • Z 2 is O, S, NH, OCH 2 , CH 2 0, NHCH 2 or CH 2 NH;
  • A is CH 2 ;
  • each R 21a is independently halogen, methyl, CF 3 or CF 2 H;
  • each R 9a is independently is independently CI, F, methyl or halomethyl.
  • Embodiment A4 A compound of Formula 1 wherein
  • X i a radical selected from the group consisting of
  • G is selected from the group consisting of
  • each R 8c is H
  • each R 9a is independently CI, F or CH 3 ;
  • A is CH 2 ;
  • W is O
  • each R 21a is independently halogen, methyl or C ⁇ -C 2 haloalkyl; and n is 0;
  • Z 1 and Z 2 are each independently a chain containing up to 3-atoms, then the sum of atoms in Z 1 and Z 2 is 1, 2, 3 or 4; and when X is X 2 , then Z 1 is linked to X through carbon or nitrogen.
  • Embodiment A5 A compound of Embodiment A4 wherein
  • X is X 1 ;
  • Z 1 is O or OCH 2 ;
  • G is G-l. G-70 or G-77;
  • Z 2 is direct bond, O, S, OCH 2 , CH 2 0, NHCH 2 , NHCH(CH 3 ) or
  • p 0 or 2;
  • R 9a is F
  • each R 21a is independently methyl or C ⁇ -C 2 haloalkyl.
  • Specific embodiments include compounds of Formula 1 selected from the consisting of: 1 -[4-[[6-[(2,6-difluorophenyl)methoxy]-3-pyridazinyl]oxy]- 1 -piperidinyl]-2- [5-methyl-3-(trifluoromethyl)- lH-pyrazol- 1 -yljethanone,
  • This invention provides a fungicidal composition
  • a fungicidal composition comprising a compound of Formula 1 (including all stereoisomers, N-oxides, and salts thereof), and at least one other fungicide.
  • a compound of Formula 1 including all stereoisomers, N-oxides, and salts thereof
  • at least one other fungicide are compositions comprising a compound corresponding to any of the compound embodiments described above.
  • This invention provides a fungicidal composition
  • a fungicidal composition comprising a compound of Formula 1 (including all stereoisomers, N-oxides, and salts thereof) (i.e. in a fungicidally effective amount), and at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents.
  • a compound of Formula 1 including all stereoisomers, N-oxides, and salts thereof
  • additional component selected from the group consisting of surfactants, solid diluents and liquid diluents.
  • This invention provides a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof, or to the plant seed, a fungicidally effective amount of a compound of Formula 1 (including all stereoisomers, N-oxides, and salts thereof).
  • a compound of Formula 1 including all stereoisomers, N-oxides, and salts thereof.
  • embodiments of such methods are methods comprising applying a fungicidally effective amount of a compound corresponding to any of the compound embodiments describe above.
  • the compounds are applied as compositions of this invention.
  • Typical acid scavengers include amine bases such as triethylamine, N,N-diisopropylethylamine and pyridine.
  • Other scavengers include hydroxides such as sodium and potassium hydroxide and carbonates such as sodium carbonate and potassium carbonate.
  • Acid chlorides of Formula 2 can be prepared from the corresponding acids using a wide variety of well-known conditions published in the chemistry literature.
  • a dehydrative coupling reagent such as N,N-dicyclohexylcarbodiimide, l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or O-benzotriazol-l-y
  • Polymer-supported reagents are again useful in this method, such as polymer-bound N-cyclohexylcarbodiimide.
  • the method of Scheme 2 is typically conducted at a temperature between about 0-40 °C in a solvent such as dichloromethane or acetonitrile and in the presence of a base such as triethylamine or N,N- diisopropylethylamine.
  • a solvent such as dichloromethane or acetonitrile
  • a base such as triethylamine or N,N- diisopropylethylamine.
  • RiCF ⁇ COOH wherein R 1 is linked to the acetic acid moiety through a heteroatom can be prepared by reacting the corresponding compound of formula R l H with a haloacetic acid or ester in the presence of base; see, for example, U.S. 4,084,955.
  • Example 2 illustrates the preparation of a compound of Formula 4.
  • the reaction is carried out in the presence of a base such as sodium hydride, potassium carbonate or triethylamine and a solvent such as tetrahydrofuran, N,N-dimethylformamide or acetonitrile at a temperature between about 0 to 80 °C.
  • Compounds of Formula 6 wherein A is CH(R 10 ) can be prepared by reacting an amine of Formula 3 with an a-halocarboxylic acid halide or a-halocarboxylic acid (or its anhydride), using conditions analogous to those described for the amide-forming reactions in Schemes 1 and 2.
  • A is CH(R 10 ) or and R 1 is linked to A through a heteroatom
  • compounds of Formula lb (Formula 1 wherein E is E-1, A is NH(R 10 ) and R 10 is H) can also be prepared by reaction of an amine of Formula 8 with a compound of Formula 9 wherein Y 2 is CI or lH-imidazol-l-yl.
  • Y 2 is CI
  • the reaction is typically carried out in the presence of an acid scavenger such as an amine base (e.g., triethylamine, N,N-diisopropylethylamine and pyridine).
  • an acid scavenger such as an amine base (e.g., triethylamine, N,N-diisopropylethylamine and pyridine).
  • Other scavengers include hydroxides such as sodium and potassium hydroxide and carbonates such as sodium carbonate and potassium carbonate.
  • Compounds of Formula 9 wherein Y 2 is CI can be prepared from amines of Formula 3 by treatment with phosgene (W is O) or thiophosgene (W is S), or their equivalents.
  • Compounds of Formula 9 wherein Y 2 is lH-imidazol-l-yl can be prepared from amines of Formula 3 by treatment with 1 , ⁇ -carbonyldiimidazole (W is O) or ⁇ , ⁇ -thiocarbonyldiimidazole (W is S) according to general methods known to one skilled in the art.
  • Acid chlorides of Formula 10 can be prepared from the corresponding acids using a wide variety of well-known conditions published in the chemistry literature.
  • Acids of Formula 11 are known and can be prepared by methods known to one skilled in the art.
  • Example 3 illustrates the preparation of a compound of Formula 11.
  • compounds of Formula lc (Formula 1 wherein E is E-2) wherein A 1 is O, S or N(R 13 ) and W is O can be prepared by reacting a compound of Formula 12 with a haloacetamide of Formula 13 wherein Y 1 is CI, Br or I.
  • the reaction is carried out in the presence of a base such as sodium hydride or potassium carbonate and a solvent such as tetrahydrofuran, N,N-dimethylformamide or acetonitrile typically at a temperature between 0 to 80 °C.
  • Haloacetamide compounds of Formula 13 can be prepared by reacting an amine of Formula 3 with an a-halocarboxylic acid halide or an a-halocarboxylic acid or its anhydride, analogous to the amide-forming reactions described in Schemes 1 and 2, respectively.
  • a 1 is wherein Y 1 is CI, Br or I wherein A 1 is O, S or
  • compounds of Formula lc (Formula 1 wherein E is E-2) wherein A 1 is -OC(R 12 ) , -SC(R 12 ) 2 - or -N(R 13 )C(R 12 ) , R 5 is H and W is O can be prepared by a base-catalyzed condensation reaction of a compound of Formula 12 with an ⁇ , ⁇ -unsaturated amide of Formula 14.
  • a 1 in Formula 12 and C(R 12 )2 in Formula 14 form A 1 in Formula lc.
  • the reaction is carried out in the presence of a base such as sodium or potassium hydroxide, sodium hydride or potassium carbonate and in a solvent such as tetrahydrofuran, N,N-dimethylformamide, ethanol or acetonitrile typically at a temperature between about 0 to 80 °C.
  • a base such as sodium or potassium hydroxide, sodium hydride or potassium carbonate
  • a solvent such as tetrahydrofuran, N,N-dimethylformamide, ethanol or acetonitrile typically at a temperature between about 0 to 80 °C.
  • the ⁇ , ⁇ -unsaturated amides of Formula 14 can be prepared by coupling the corresponding ⁇ , ⁇ -unsaturated acids or acid chlorides with amines of Formula 3 using conditions analogous to those described for Schemes 1 and 2.
  • Compounds of Formula lc (Formula 1 wherein E is E-2) wherein W is O can be prepared by reacting a compound of Formula 15 with a compound of Formula 16 as illustrated in Scheme 10. The reaction is carried out in a solvent such as ethanol, tetrahydrofuran or water, and optionally in the presence of an acid catalyst such as acetic acid, hydrochloric acid or sulfuric acid. Acid salts of Formula 16 can also be used in this method, preferably in the presence of at least one molar equivalent of an acid scavenger such as pyridine or triethylamine. Typical acids used to form salts with amines include hydrochloric acid, oxalic acid and trifluoroacetic acid.
  • Compounds of Formula 15 are known and can be prepared by methods known to one skilled in the art.
  • Compounds of Formula 16 can be prepared directly or by deprotection of the corresponding N-protected compounds of Formula 16.
  • the choice and use of a suitable N-protected nitrogen function will be apparent to one skilled in the art; for representative examples see T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991.
  • the N-protected compounds of Formula 16 can be prepared by methods analogous to those already described for Schemes 1, 2, 3, and 4.
  • compounds of Formula 1 can be prepared by reacting a compound of Formula 17 with a compound of Formula 18 wherein Z a and are suitable functional groups which under the appropriate reaction conditions will allow the construction of the various Z 1 groups.
  • suitable functional groups include, but are not limited to, ionizable hydrogen, carbonyl, aldehyde, ketone, ester, acid, acid chloride, amine, alcohol, thiol, hydrazine, oxime, olefin, acetylene, halide, alkyl halide, methanesulfonate, trifluoromethanesulfonate, boronic acid, boronate, and the like.
  • a base such as potassium carbonate
  • Example 2 illustrates the preparation of a compound of Formula 17.
  • compounds of Formula 1 can also be prepared by reacting a compound of Formula 19 with a compound of Formula 20 wherein Z c and Z ⁇ are suitable functional groups which under the appropriate reaction conditions will allow the construction of the various Z 2 groups.
  • Suitable functional groups include, but are not limited to, ionizable hydrogen, carbonyl, aldehyde, ketone, ester, acid, acid chloride, amine, alcohol, thiol, hydrazine, oxime, olefin, acetylene, halide, alkyl halide, methanesulfonate, trifluoromethanesulfonate, boronic acid, boronate, and the like.
  • compounds of Formula 1 wherein Z 2 is O can be prepared by reacting a compound of Formula 19 wherein Z c is halogen with a compound of Formula 20 wherein Z ⁇ is hydroxy in the presence of a strong base such as sodium hydride, while treatment with a compound of Formula 20 wherein Z ⁇ is a hydroxymethyl will give a compound of Formula 1 wherein Z 2 is -OCH2-.
  • a strong base such as sodium hydride
  • Intermediate compounds of Formula 20 are known and can be prepared by methods known to one skilled in the art.
  • Example 2 illustrates the method of Scheme 11
  • Example 5 illustrates the method of Scheme 12.
  • One skilled in the art can easily determine how to select an appropriate compound of Formulae 17 and 18 or Formulae 19 and 20 to construction the desired Z 1 and Z 2 groups, respectively.
  • compounds of Formula 18 can be prepared by reacting a compound of Formula 21 with a compound of Formula 22 wherein Y a and are suitable functional groups which under the appropriate reaction conditions will allow the construction of the heterocyclic ring G and the chain Z 2 .
  • Suitable functional groups include, but are not limited to, hydroxy, thiol, amine, carbonyl, aldehyde, ester, acid, acid chloride, amide, thioamide, cyano, halide, alkyl halide, and the like.
  • the synthetic literature describes many general methods for forming heterocyclic rings which can be readily adapted to prepare compounds of the present method; see, for example, Heterocyclic Compounds, Vol. 5, R. C.
  • Example 1 illustrates the method of Scheme 13.
  • One skilled in the art can easily determine how to select an appropriate compound of Formula 21 and Formula 22 to construct the desired G-Z 2 moiety.
  • Compounds of Formula 23 can be prepared by methods analogous to those described in Scheme 11 and Scheme 12 above wherein the group E is replaced by PG. Also, Example 1 (Step E), Example 3 (Step A) and Example 4 (Step C) illustrate the preparation of a compound of Formula 23.
  • Step A Preparation of 1,3 -difluoro-2-(2-propen-l-yloxy)benzene
  • Step B Preparation of ethyl 5-[(2,6-difluorophenoxy)methyl]-4,5-dihydro-3- isoxazolecarboxylate
  • Step D Preparation of 3-(chloromethyl)-5-[(2,6-difluorophenoxy)methyl]-4,5- dihydroisoxazole
  • Step E Preparation of 1,1-dimethylethyl 4-[[5-[(2,6-difluorophenoxy)methyl]-4,5- dihydro-3-isoxazolyl]methyl]- 1 -piperazinecarboxylate
  • Step F Preparation of l-[4-[[5-[(2,6-difluorophenoxy)methyl]-4,5-dihydro-3- isoxazolyl]methyl]- 1 -piperazinyl]-2-[5-methyl-3-(trifluoromethyl)- 1H- pyrazol- 1 -yljethanone
  • reaction mixture was diluted with dichloromethane, washed with aqueous hydrochloric acid (1 N) and aqueous sodium hydroxide (1 N), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound, a compound of the present invention, as a tan solid (198 mg).
  • Step B Preparation of l-(4-hydroxy-l-piperidinyl)-2-[5-methyl-3-(trifluoromethyl)- lH-pyrazol- 1 -yljethanone
  • Step D Preparation of l-[4-[[6-[(2,6-difluorophenyl)methoxy]-3-pyridazinyl]oxy]-l- piperidinyl] -2-[5 -methyl-3 -(trifluoromethyl)- lH-pyrazol- 1 -yl] ethanone
  • sodium hydride 60% dispersion in mineral oil, 60 mg, 1.5 mmol
  • N,N-dimethylformamide (7 mL) at 0 °C was added portionwise l-(4-hydroxy-l-piperidinyl)- 2-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]ethanone (i.e.
  • Step A Preparation of 1 , 1 -dimethylethyl 4-[[6-[(2,6-diflurophenyl)methoxy]-3- pyridazinyljoxy- 1 -piperidinecarboxylate
  • Step B Preparation of 2-[[2,2,2-trifluoro-l-methylethylidene)amino]oxy]acetic acid To a mixture of O-(carboxymethyl)hydroxylamine hemihydrochloride (4.38 g,
  • Step C Preparation of 1,1,1 -trifluoro-2-propanone O-[2-[4-[[6-[(2,6- difluorophenyl)methoxy] -3 -pyridazinyljoxy] - 1 -piperidinyl] -2- oxoethyljoxime
  • Step B) the product of Step B) (29 mg, 0.16 mmol), N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (30.67 mg, 0.16 mmol), 1 -hydroxy- lH-benzotriazole (about 2 mg, 0.015 mmol) and triethylamine (42 uL, 0.3 mmol) in dichloromethane (2 mL) was stirred for 16 h at room temperature. The reaction mixture was diluted with dichloromethane, washed with aqueous hydrochloric acid (1 N), saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated under reduced pressure.
  • the resulting material was purified by medium pressure liquid chromatography on silica gel (4 g) (0 to 100% gradient of ethyl acetate in hexanes as eluant) to give the title compound (24 mg), a compound of the present invention.
  • Step B Preparation of 3-chloro-6-[(2,6-difluorophenoxy)methyl]pyridazine
  • reaction mixture was diluted with water; the solid precipitate was collected by filtration, washed with water and dried to give the title compound as a light brown solid (1.73 g).
  • Step C Preparation of 1 , 1 -dimethylethyl 4-[[6-[(2,6-difiuorophenoxy)methyl]-3- pyridazinyljoxy]- 1 -piperidinecarboxylate
  • N,N-dimethylformamide (7 mL) was added 4-hydroxy-l-piperidinecarboxylic acid- 1,1- dimethylethyl ester (1.39 g, 6.9 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was stirred for 1 h at 60 °C, cooled to room temperature and 3-chloro-6-[(2,6- difluorophenoxy)methyl]pyridazine (i.e. the product of Step B) (1.77 g, 6.9 mmol) in N,N- dimethylformamide (5 mL) was added dropwise.
  • 3-chloro-6-[(2,6- difluorophenoxy)methyl]pyridazine i.e. the product of Step B
  • the reaction mixture was stirred for 16 h at 55 °C, and then saturated aqueous sodium bicarbonate was added and the resulting mixture was extracted with diethyl ether. The organic extract was washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by medium pressure liquid chromatography on a silica gel (0 to 60% gradient of ethyl acetate in hexanes as eluant) to give of the title compound (170 mg).
  • Step D Preparation of l-[4-[[6-[(2,6-difluorophenoxy)methyl]-3-pyridazinyl]oxy]-l- piperidinyl] -2-[5 -methyl-3 -(trifluoromethyl)- lH-pyrazol- 1 -yl] ethanone
  • 1,1-dimethylethyl 4-[[6-[(2,6-difluorophenoxy)methyl]-3- pyridazinyl]oxy]-l-piperidinecarboxylate i.e.
  • Step B Preparation of l-[4-[[6-(2,6-difluorophenoxy)-3-pyridazinyl]methoxy]-l- piperidinyl] -2-[5 -methyl-3 -(trifluoromethyl)- lH-pyrazol- 1 -yl] ethanone
  • n means normal, i means iso, c means cyclo, Me means methyl, MeO means methoxy, MeS means methylthio, Et means ethyl, EtO means ethoxy, c-Pr means cyclopropyl, Bu means butyl, c-Bu means cyclobutyl, z ' -BuO means isobutoxy, CN means cyano, Ph means phenyl and NO2 means nitro.
  • the present disclosure also includes Tables 1-A through 1-AY, each of which are constructed the same as Table 1 above except that the row heading in Table 1 (i.e. "A is CH 2 , W is O, X a is CH, Z 1 is O and Z 2 is OCH 2 ”) is replaced with the respective row headings shown below.
  • Table 1-A the row heading is "A is NH, W is O, X a is CH, Z 1 is O and Z 2 is OCH2" and R 1 is as defined in Table 1 above.
  • the first entry in Table 1-A specifically discloses 4-[[6-[(2,6-difluorophenyl)methoxy]-3-pyridazinyl]oxy- N-phenyl-l-piperidinecarboxamide.
  • Tables 1-B through 1-AY are constructed similarly.
  • A is NH, W is O, X a is CH, Z 1 is O and Z 2 is OCH 2 .
  • A is CH 2 , W is O, X a is N, Z 1 is CH 2 and Z 2 is OCH 2 .
  • A is NH, W is O, X a is N, Z 1 is CH 2 and Z 2 is OCH 2 .
  • A is NH, W is O, X a is CH, Z 1 is O and Z 2 is CH 2 0.
  • A is CH 2 , W is S, X a is CH, Z 1 is O and Z 2 is OCH 2 .
  • A is NH, W is S, X a is CH, Z 1 is O and Z 2 is OCH 2 .
  • A is NH, W is S, X a is N, Z 1 is CH 2 and Z 2 is OCH 2 .
  • A is CH 2 , W is O, X a is CH, Z 1 is O and Z 2 is O.
  • A is NH, W is O, X a is CH, Z 1 is O and Z 2 is O.
  • l-O A is NH, W is O, X a is N, Z 1 is CH 2 and Z 2 is O.
  • A is CH 2 , W is O, X a is CH, Z 1 is O and Z 2 is S.
  • A is NH, W is O, X a is CH, Z 1 is O and Z 2 is S.
  • A is CH 2 , W is O, X a is N, Z 1 is CH 2 and Z 2 is S.
  • A is NH, W is O, X a is N, Z 1 is CH 2 and Z 2 is S.
  • A is CH 2 , W is O, X a is CH, Z 1 is O and Z 2 is NH.
  • A is NH, W is O, X a is CH, Z 1 is O and Z 2 is NH.
  • W A is NH
  • W is O
  • X a is N
  • Z 1 is CH 2
  • Z 2 is NH
  • X A is CH 2 , W is O, X a is CH, Z 1 is O and Z 2 is NHCH 2 .
  • A is NH, W is O, X a is CH, Z 1 is O and Z 2 is NH CH 2 .
  • A is CH 2 , W is O, X a is N, Z 1 is CH 2 and Z 2 is NHCH 2 .
  • A is NH, W is O, X a is N, Z 1 is CH 2 and Z 2 is NHCH 2 .
  • A is CH 2 , W is O, X a is CH, Z 1 is OCH 2 and Z 2 is OCH 2 .
  • A is CH 2 , w is o, X a is CH, is OCH 2 and Z 2 is S.
  • 1-AF A is CH 2 , w is o, X a is CH, is OCH 2 and Z 2 is NH.
  • 1-AG A is CH 2 , w is o, X a is CH, is OCH 2 and Z 2 is NHCH 2 .
  • 1-AH A is CH 2 , w is o, X a is CH, is CH 2 0 and Z 2 is OCH 2 .
  • A is CH 2 , w is o, X a is CH, is CH 2 0 and Z 2 is O.
  • 1-AK A is CH 2 , w is o, X a is CH, is CH 2 0 and Z 2 is S.
  • A is CH 2 , w is o, X a is CH, is CH 2 0 and Z 2 is NH.
  • 1-AM A is CH 2 , w is o, X a is CH, is CH 2 0 and Z 2 is NHCH 2 .
  • 1-AT A is CH 2 , w is o, X a is CH, is CH 2 and Z 2 is OCH 2 .
  • A is CH 2 , w is o, X a is CH, is CH 2 and Z 2 is O.
  • A is CH 2 , w is o, X a is CH, is CH 2 and Z 2 is S.
  • AX A is CH 2 , w is o, X a is CH, is CH 2 and Z 2 is NH.
  • A is CH 2 , w is o, X a is CH, is CH 2 and Z 2 is NHCH 2 .
  • A is CH 2 , W is O, Z 1 is CH 2 and Z 2 is OC3 ⁇ 4.
  • A is CH 2 , W is O, Z 1 is CH 2 and Z 2 is OC3 ⁇ 4.
  • the present disclosure also includes Tables 2-A through 2-Y, each of which are constructed the same as Table 2 above except that the row heading in Table 2 (i.e. "A is CH 2 , W is O, Z 1 is CH 2 and Z 2 is OCH 2 ”) is replaced with the respective row headings shown below.
  • Table 2-A the row heading is "A is NH, W is O, Z 1 is CH 2 and Z 2 is OCH 2 " and R 1 is as defined in Table 2 above.
  • Table 2-A specifically discloses 5-[[6-[(2,6-dif uorophenyl)methoxy]-3-pyridazinyl]methyl]hexahydro- N-phenylpyrrolo[3,4-c]pyrrol-2(lH)-carboxamide.
  • Tables 2-B through 2-Y are constructed similarly.
  • 2-A A is NH, W is O, Z 1 is CH 2 and Z 2 is OCH 2 .
  • 2-B A is CH 2 , W is S, Z 1 is CH 2 and Z 2 is OCH 2 .
  • 2-C A is NH, W is S, Z 1 is CH 2 and Z 2 is OC3 ⁇ 4.
  • 2-D A is CH 2 , W is O, Z 1 is CH 2 and Z 2 is CH 2 0.
  • 2-E A is NH, W is O, Z 1 is CH 2 and Z 2 is C3 ⁇ 40.
  • 2-F A is CH 2 , W is O, Z 1 is CH 2 and Z 2 is O.
  • 2-H A is CH 2 , W is O, Z 1 is CH 2 and Z 2 is S.
  • A is NH, W is O, Z 1 is CH 2 and Z 2 is S.
  • 2-J A is CH 2 , W is O, Z 1 is CH 2 and Z 2 is NH.
  • 2-K A is NH, W is O, Z 1 is CH 2 and Z 2 is NH.
  • 2-L A is CH 2 , W is O, Z 1 is CH 2 and Z 2 is NHC3 ⁇ 4.
  • 2-M A is NH, W is O, Z 1 is CH 2 and Z 2 is NHC3 ⁇ 4.
  • A is CH 2 , W is O, Z 1 is O and Z 2 is OCH 2 .
  • A is CH 2 , W is O, Zl is O and Z 2 is OCH 2 .
  • the present disclosure also includes Tables 3-A through 3-Y, each of which are constructed the same as Table 3 above except that the row heading in Table 3 (i.e. "A is CH 2 , W is O, Z 1 is O and Z 2 is OCH 2 ") is replaced with the respective row headings shown below.
  • Table 3-A the row heading is "A is NH, W is O, Z 1 is O and Z 2 is OCH 2 " and R 1 is as defined in Table 3 above.
  • the first entry in Table 3-A specifically discloses 3-[[6-[(2,6-difluorophenyl)methoxy]-3-pyridazinyl]oxy]-N-phenyl-l-azetidine- carboxamid.
  • Tables 3-B through 3-Y are constructed similarly.
  • A is NH, W is O, Z 1 is O and Z 2 is OCH 2 .
  • A is CH 2 , W is S, Z 1 is O and Z 2 is OCH 2 .
  • 3-C A is NH, W is S, Z 1 is O and Z 2 is OCH 2 .
  • 3-D A is CH 2 , W is O, Z 1 is O and Z 2 is C3 ⁇ 40.
  • 3-E A is NH, W is O, Z 1 is O and Z 2 is CH 2 0.
  • A is CH 2 , W is O, Z 1 is O and Z 2 is O.
  • 3-G A is NH, W is O, Z 1 is O and Z 2 is O.
  • A is CH 2 , W is O, Z 1 is O and Z 2 is S.
  • A is NH, W is O, Z 1 is O and Z 2 is S.
  • 3-J A is CH 2 , W is O, Z 1 is O and Z 2 is NH.
  • 3-K A is NH, W is O, Z 1 is O and Z 2 is NH.
  • A is CH 2 , W is O, Z 1 is O and Z 2 is NHCH 2 .
  • A is NH
  • W is O
  • Z 1 is O
  • Z 2 is NHCH 2 .
  • A is CH 2 , W is S, Z 1 is OCH 2 and Z 2 is OCH 2 .
  • A is NH, W is S, Z 1 is OCH 2 and Z 2 is OCH 2 .
  • A is CH 2 , W is O, Z 1 is OCH 2 and Z 2 is CH 2 0.
  • A is NH, W is O, Z 1 is OCH 2 and Z 2 is CH 2 0.
  • A is CH 2 , W is O, Z 1 is OCH 2 and Z 2 is O.
  • A is NH, W is O, Z 1 is OCH 2 and Z 2 is O.
  • A is CH 2 , W is O, Z 1 is OCH 2 and Z 2 is S.
  • A is NH, W is O, Z 1 is OCH 2 and Z 2 is S.
  • A is CH 2 , W is O, Z 1 is OCH 2 and Z 2 is NH.
  • A is NH
  • W is O
  • Z 1 is OCH 2
  • Z 2 is NH
  • A is CH 2 , W is O, Z 1 is OCH 2 and Z 2 is NHC3 ⁇ 4.
  • A is NH
  • W is O
  • Z 1 is OCH 2
  • Z 2 is NHCH 2 .
  • X a is CH, Z 1 is O and Z 2 is OC3 ⁇ 4.
  • the present disclosure also includes Tables 4-A through 4-AH, each of which are constructed the same as Table 4 above except that the row heading in Table 4 (i.e. "X a is CH, Z 1 is O and Z 2 is OCH 2 ”) is replaced with the respective row headings shown below.
  • Table 4-A the row heading is "X a is N, Z 1 is CH 2 and Z 2 is OCH 2 " and R 2 , R 3 , A 1 , R 4 , R 5 and W are as defined in Table 4 above.
  • Table 4-A specifically discloses 2-propanone 0-[2-[4-[[6-[(2,6-difluorophenyl)methoxy]-3- pyridazinyljmethyl] - 1 -piperazinyl] -2-oxoethyl] Tables 4-B through 4-AH are constructed similarly.
  • 4-A X a is N, Z 1 is CH 2 and Z 2 is OCH 2 .
  • 4-R X a is CH, Z is CH 2 0 and Z 2 is CH 2 0.
  • 4-B X a is CH, Z 1 is O and Z 2 is CH 2 0.
  • 4-S X a is CH, Z is CH 2 0 and Z 2 is O.
  • 4-C X a is N, Z 1 is CH 2 and Z 2 is CH 2 0.
  • 4-T X a is CH, Z is CH 2 0 and Z 2 is S.
  • 4-D X a is N, Z 1 is CH 2 and Z 2 is O.
  • 4-U X a is CH, Z is CH 2 0 and Z 2 is NH.
  • 4-E X a is CH, Z 1 is O and Z 2 is S.
  • 4-V X a is CH, Z is CH 2 0 and Z 2 is NHCH 2 .
  • 4-F X a is N, Z 1 is CH 2 and Z 2 is S.
  • 4-G X a is CH, Z 1 is O and Z 2 is NH.
  • 4-H X a is N, Z 1 is CH 2 and Z 2 is NH.
  • 4-1 X a is CH, Z 1 is O and Z 2 is NHCH 2 .
  • 4-J X a is N, Z 1 is CH 2 and Z 2 is NHCH 2 .
  • 4-K X a is CH, Z 1 is OCH 2 and Z 2 is OCH 2 .
  • 4-L X a is CH, Z 1 is OCH 2 and Z 2 is CH 2 0.
  • 4-AC X a is CH, Z is CH 2 and Z 2 is OCH 2 .
  • 4-M X a is CH, Z 1 is OCH 2 and Z 2 is O.
  • 4-AD X a is CH, Z is CH 2 and Z 2 is CH 2 0.
  • 4-N X a is CH, Z 1 is OCH 2 and Z 2 is S.
  • 4-AE X a is CH, Z is CH 2 and Z 2 is O.
  • 4-0 X a is CH, Z 1 is OCH 2 and Z 2 is NH. 4-AF X a is CH, Z is CH 2 and Z 2 is S.
  • 4-P X a is CH, Z 1 is OCH 2 and Z 2 is NHCH 2 .
  • 4-AG X a is CH, Z is CH 2 and Z 2 is NH.
  • 4-Q X a is CH, Z 1 is CH 2 0 and Z 2 is OCH 2 .
  • 4-AH X a is CH, Z is CH 2 and Z 2 is NHCH 2 .
  • Z! is CH 2 and Z 2 is OC3 ⁇ 4.
  • CH 3 CH 3 -N(Me)CH 2 - H H o Z! is CH 2 and Z 2 is OCH 2 .
  • the present disclosure also includes Tables 5-A through 5-K, each of which are constructed the same as Table 5 above except that the row heading in Table 5 (i.e. "Z 1 is CH 2 and Z 2 is OCH 2 ") is replaced with the respective row headings shown below.
  • Table 5-A the row heading is "Z is CH 2 and Z 2 is CH 2 0" and R 2 , R 3 , A 1 , R 4 , R 5 and W are as defined in Table 5 above.
  • Table 5-A specifically discloses 2-propanone 0-[2-[5-[[6-[(2,6-dif uorophenoxy)methyl]-3-pyridazinyl]methyl]- hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl]-2-oxoethyl]oxime.
  • Tables 5-B through 5-K are constructed similarly.
  • 5-A Z 1 is CH 2 and Z 2 is CH 2 0.
  • 5-B Z 1 is CH 2 and Z 2 is O.
  • 5-C Z 1 is CH 2 and Z 2 is S.
  • 5-E Z 1 is CH 2 and Z 2 is NH CH 2 .
  • Z 1 is O and Z 2 is OCH 2 .

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Abstract

Disclosed are compounds of Formula 1, including all geometric and stereoisomers, N-oxides, and salts thereof, wherein E, X, Z1, G, Z2 and Q are as defined in the disclosure. Also disclosed are compositions containing the compounds of Formula 1 and methods for controlling plant disease caused by a fungal pathogen comprising applying an effective amount of a compound or a composition of the invention.

Description

TITLE
FUNGICIDAL HETEROCYCLIC COMPOUNDS
FIELD OF THE INVENTION
This invention relates to certain heterocyclic compounds, their N-oxides, salts and compositions, and methods of their use as fungicides.
BACKGROUND OF THE INVENTION
The control of plant diseases caused by fungal plant pathogens is extremely important in achieving high crop efficiency. Plant disease damage to ornamental, vegetable, field, cereal, and fruit crops can cause significant reduction in productivity and thereby result in increased costs to the consumer. Many products are commercially available for these purposes, but the need continues for new compounds which are more effective, less costly, less toxic, environmentally safer or have different sites of action.
PCT Patent Publications WO 2008/013925, WO 2008/091580, WO 2009/094407 and WO 2012/082580 disclose azocyclic amide derivatives and their use as fungicides.
U.S. Patent Application U.S. 2011/0172230 discloses urea compounds and their use for the treatment of diseases associated with fatty acid amide hydrolase.
SUMMARY OF THE INVENTION
This invention is directed to compounds of Formula 1 (including all stereoisomers), N-oxides, and salts thereof, agricultural compositions containing them and their use as fungicides:
Figure imgf000002_0001
wherein
E is a radical selected from the group consistin of
Figure imgf000002_0002
X i a radical selected from the group consisting of
Figure imgf000002_0003
X1 X XJ x^ wherein the bond projecting to the left is connected to E, and the bond projecting to the right is connected to Z1;
Z1 is a saturated, partially unsaturated or fully unsaturated chain containing 1- to
3-atoms selected from up to 3 carbon, up to 1 O, up to 1 S and up to 2 N, wherein up to 1 carbon atom is selected from C(=0) and C(=NOH), the chain optionally substituted with up to 2 substituents independently selected from R7a on carbon atoms and R b on nitrogen atoms;
G is a phenyl ring, a 5- to 6-membered heteroaromatic ring, a 3- to 6-membered
nonaromatic heterocyclic ring or a 3- to 6-membered nonaromatic carbocyclic ring, each ring optionally substituted with up to 3 substituents independently selected from R8a on carbon atom ring members and R8^ on nitrogen atom ring members;
Z2 is a direct bond or a saturated, partially unsaturated or fully unsaturated chain
containing 1- to 3-atoms selected from up to 3 carbon, up to 1 O, up to 1 S and up to 2 N, wherein up to 2 carbon atoms are independently selected from C(=0) and C(=NOH), the chain optionally substituted with up to 2 substituents independently selected from R7c on carbon atoms and R d on nitrogen atoms;
Q is a phenyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 3 substituents independently selected from R9a; or
Q is a 5- to 6-membered heteroaromatic ring or an 8- to 11-membered heteroaromatic bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and 1 to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, each ring or ring system optionally substituted with up to 3 substituents independently selected from R9a on carbon atom ring members and R9^ on nitrogen atom ring members; or
Q is a 3- to 7-membered nonaromatic carbocyclic ring, a 5- to 7-membered
nonaromatic heterocyclic ring or an 8- to 11-membered nonaromatic bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, wherein up to 3 carbon atom ring members are independently selected from C(=0) and C(=S), and the sulfur atom ring members are independently selected from S(=O)s(=NR20)f, each ring or ring system optionally substituted with up to 3 substituents independently selected from R9a on carbon atom ring members and R9^ on nitrogen atom ring members;
A is CH(R10), N(Rn) or C(=0);
A1 is O, S, C(R12)2, N(R13), -OC(R12)2-, -SC(R12)2- or -N(R13)C(R12)2-, wherein the bond projecting to the left is connected to the nitrogen atom, and the bond projecting to the right is connected to the carbon atom in Formula 1; W is O or S;
R1 is an optionally substituted phenyl ring, an optionally substituted naphthalenyl ring system or an optionally substituted 5- to 6-membered hetero aromatic ring; or cyano, Ci -Cg alkyl, Ci -Cg haloalkyl, C2-Cg alkenyl, C2-Cg haloalkenyl, C2-Cg alkynyl, C2-Cg haloalkynyl, C3-Cg cycloalkyl, C3-Cg halocycloalkyl, C4-C10 alkylcycloalkyl, C4-C10 cycloalkylalkyl, C4-C10 halocycloalkylalkyl, C5-C10 alkylcycloalkylalkyl, C2-Cg alkoxyalkyl, C2-Cg haloalkoxyalkyl, C4-C10 cycloalkoxyalkyl, C3-C10 alkoxyalkoxyalkyl, C2-Cg alkylthioalkyl, C2-Cg haloalkylthioalkyl, C2-Cg alkylsulfinylalkyl, C2-Cg alkylsulfonylalkyl, C2-Cg alkylaminoalkyl, C2-Cg haloalkylaminoalkyl, C3-C10 dialkylaminoalkyl, C4-C10 cycloalkylaminoalkyl, C3-Cg alkoxycarbonylalkyl, C3-Cg
haloalkoxycarbonylalkyl, Ci -Cg alkoxy, Ci -Cg haloalkoxy, C2-Cg alkenyloxy, C2-Cg haloalkenyloxy, C2-Cg alkynyloxy, C3-Cg haloalkynyloxy, C3-Cg cycloalkoxy, C3-Cg halocycloalkoxy, C4-C10 cycloalkylalkoxy, C2-Cg alkoxyalkoxy, C2-Cg alkylcarbonyloxy, C2-Cg haloalkylcarbonyloxy, Ci -Cg alkylthio, Ci -Cg haloalkylthio, C3-Cg cycloalkylthio, Ci -Cg alkylamino, Ci -Cg haloalkylamino, C2-Cg dialkylamino, C2-Cg halodialkylamino, C3-Cg cycloalkylamino, C2-Cg alkylcarbonylamino, C2-Cg haloalkylcarbonylamino, Ci -Cg alkylsulfonylamino, Ci -Cg haloalkylsulfonylamino, C3-C10 trialkylsilyl, pyrrolidinyl, piperidinyl or morpholinyl;
R2 is H, amino, cyano, halogen, -CH(=0), -C(=0)OH, -C(=0)NH2, CrC6 alkyl, Cj-Cg haloalkyl, C2-Cg alkenyl, C2-Cg haloalkenyl, C2-Cg alkynyl, C2-Cg haloalkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C4-C6 alkylcycloalkyl, C4-C6 cycloalkylalkyl, C4-C6 halocycloalkylalkyl, C3-C6 cycloalkenyl, C3-C6 halocycloalkenyl, C2-C6 alkoxyalkyl, C2-C6 alkylthioalkyl, C2-C6
alkylsulfinylalkyl, C2-C6 alkylsulfonylalkyl, C2-C6 alkylaminoalkyl, C2-C6 haloalkylaminoalkyl, C3-C6 dialkylaminoalkyl, C^-C^ alkoxy, C^-C^ haloalkoxy, C2-Cg alkenyloxy, C2-Cg haloalkenyloxy, C2-Cg alkynyloxy, C3-C6 haloalkynyloxy, C3-C6 cycloalkoxy, C3-C6 halocycloalkoxy, C2-Cg
alkoxyalkoxy, C2-C6 alkylcarbonyloxy, C2-C6 haloalkylcarbonyloxy, C^-C^ alkylthio, C^-C^ haloalkylthio, C3-C6 cycloalkylthio, C^-C^ alkylamino, C^-C^ haloalkylamino, C2-C6 dialkylamino, C2-C6 halodialkylamino, C3-C6 cycloalkylamino, C^-C^ alkylsulfonylamino, C^-C^ haloalkylsulfonylamino, C2-C6 alkylcarbonylamino, C2-C6 haloalkylcarbonylamino, C2-C6
alkylcarbonyl, C2-Cg haloalkylcarbonyl, C4-C6 cycloalkylcarbonyl, C2-Cg alkoxycarbonyl, C4-C6 cycloalkoxycarbonyl, C5-C6 cycloalkylalkoxycarbonyl, C2-C6 alkylaminocarbonyl or C3-C6 dialkylaminocarbonyl; R3 is H, cyano, halogen, hydroxy, -C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or
C1 -C3 haloalkoxy; or
R2 and R3 are taken together with the carbon atom to which they are attached to form a 3- to 7-membered ring containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 2 N atoms, wherein up to 3 carbon atom ring members are independently selected from C(=0) and C(=S), and the sulfur atom ring members are independently selected from S(=O)s(=NR20)f, the ring optionally substituted with up to 4 substituents independently selected from cyano, halogen, C 1 -C2 alkyl, C1 -C2 haloalkyl, Ci -C2 alkoxy and Ci -C2 haloalkoxy on carbon atom ring members and cyano, Ci -C2 alkyl and Ci -C2 alkoxy on nitrogen atom ring members;
R4 is an optionally substituted phenyl ring, an optionally substituted naphthalenyl ring system or an optionally substituted 5- to 6-membered heteroaromatic ring; or H, cyano, halogen, hydroxy, -CH(=0), C1 -C4 alkyl, C 1 -C4 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, C2-C4 alkoxyalkyl, C2-C4 alkylthioalkyl, C2-C4 alkylsulfinylalkyl, C2-C4
alkylsulfonylalkyl, Ci -C4 alkoxy, Ci -C4 haloalkoxy, C2-C4 alkylcarbonyloxy, C2-C4 haloalkylcarbonyloxy, C2-C5 alkoxycarbonyloxy, C2-C5
alkylaminocarbonyloxy, C3-C5 dialkylaminocarbonyloxy, C 1 -C4 alkylthio,
C1 -C4 haloalkylthio, C1 -C4 alkylsulfinyl, C1 -C4 haloalkylsulfinyl, C 1 -C4 alkylsulfonyl, C1 -C4 haloalkylsulfonyl, C2-C4 alkylcarbonyl, C2-C4
haloalkylcarbonyl, C2-C5 alkoxycarbonyl, C2-C5 alkylaminocarbonyl or C3-C5 dialkylaminocarbonyl;
R5 is H, CrC3 alkyl or CrC3 haloalkyl;
each R6 is independently cyano, halogen, hydroxy, Ci -C4 alkyl, Ci -C4 haloalkyl,
C2-C4 alkenyl or Ci -C4 alkoxy; or
two R6 are taken together as Ci -C4 alkylene or C2-C4 alkenylene to form a bridged or fused ring system;
each R7a and R7c is independently cyano, halogen, hydroxy, Ci -C4 alkyl, Ci -C4
haloalkyl, Ci -C4 alkoxy or Ci -C4 haloalkoxy;
each R7b and R7d is independently cyano, Ci -C4 alkyl, Ci -C4 haloalkyl, Ci -C4 alkoxy,
C2-C4 alkylcarbonyl or C2-C4 alkoxycarbonyl;
each R8a is independently cyano, halogen, hydroxy, Ci -C3 alkyl, Ci -C3 haloalkyl or
C1 -C3 alkoxy;
each R8^ is independently Ci -C3 alkyl, Ci -C3 haloalkyl, C2-C4 alkylcarbonyl or
C2-C4 alkoxycarbonyl; R9a is independently amino, cyano, halogen, hydroxy, nitro, SF5, C^-Cg alkyl, Cj-Cg haloalkyl, C2-Cg alkenyl, C2-Cg haloalkenyl, C2-Cg alkynyl, C2-Cg haloalkynyl, C2-Cg cyanoalkyl, C^-Cg hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C4-C10 cycloalkylalkyl, C4-C10 alkylcycloalkyl, C5-C10 alkylcycloalkylalkyl, C^-C^ cycloalkylcycloalkyl, Cz Cg halocycloalkoxyalkyl, C4-C8 cycloalkenyloxyalkyl, C4-C8 halocycloalkenyloxyalkyl, C5-C8 cycloalkylalkylaminoalkyl, C2-C6 alkoxyalkyl, C2-C6 alkoxyhaloalkyl, C2-C6 haloalkoxyhaloalkyl, C3-C6 dialkoxyalkyl, C3-C6 alkoxyalkenyl, C3-C6 alkoxyalkynyl, C3-C6 alkoxycarbonylalkyl, C3-C6 halodialkylammoalkyl, C^-C^ alkoxy, C^-Cg haloalkoxy, C3-C6 alkenyloxy, C3-C6 haloalkenyloxy, C3-C6 alkynyloxy, C2-Cg haloalkynyloxy, C2-C6 alkoxyhaloalkoxy, C2-C6
haloalkoxyalkoxy, C2-C6 haloalkoxyhaloalkoxy, C^-C^ alkylsulfonyloxy, C^-C^ haloalkylsulfonyloxy, C2-C6 alkylcarbonyloxy, C3-C6 alkenylcarbonyloxy, C3-C6 haloalkenylcarbonyloxy, C4-C8 halocycloalkylcarbonyloxy, C3-C6 alkoxycarbonylalkoxy, C2-C6 alkylthiocarbonyloxy, C3-C6 trialkylsilyloxy, C5-C10 trialkylsilylalkynyloxy, C^-Cg alkylthio, C^-Cg haloalkylthio, C2-Cg alkenylthio, C2-C6 alkynylthio, C2-C6 alkoxy alkylthio, C2-C6 alkylcarbonylthio, C^-Cg alkylsulfmyl, C^-Cg haloalkylsulfinyl, C^-Cg alkylsulfonyl, C^-Cg haloalkylsulfonyl, C^-C^ alkylamino, C^-C^ haloalkylamino, C2-C6
dialkylamino, C2-C6 halodialkylamino, C2-C6 alkenylamino, C2-C6
alkynylamino, C3-C6 cycloalkylamino, C4-C8 cycloalkylalkylamino, C^-C^ alkoxyamino, C^-C^ haloalkoxyamino, C2-C6 alkylcarbonylamino, C2-C6 haloalkylcarbonylamino, C2-C6 alkoxy carbonylamino, C2-C6
haloalkoxycarbonylamino, C3-C6 alkylcarbonyl(alkyl)amino, C3-C6
haloalkylcarbonyl(alkyl)amino, C3-C6 alkoxy carbonyl(alkyl)amino, C2-C6 alkylaminocarbonylamino, C3-C6 dialkylamino carbonylamino, C3-C6 alkylaminocarbonylalkylamino C2-C6 alkylamino(thiocarbonyl)amino, C3-C6 dialkylamino(thiocarbonyl)amino, C2-C6 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 haloalkoxycarbonyl, C2-C6 alkylaminocarbonyl, C3-C6
dialkylaminocarbonyl, C3-C6 alkoxy(alkyl)aminocarbonyl, C3-C6
alkoxyalkylcarbonyl, C3-C6 alkoxyalkoxycarbonyl, C2-C6 alkylthiocarbonyl, C2- C^ alkylsulfonylaminocarbonyl, C2-C6 haloalkylsulfonylaminocarbonyl, C3-C6 trialkylsilyl, -S(=0)ONR14R15, -S(=0)ONHC≡N, -NHC≡N, -NHC(=0)H, -N=C(R16)2, -N(R14)S(=0)OR17, -CH(=0), -C(=0)OH, -C(=0)NH2,
-C(=0)NHC≡N, -C(=S)NR14R15, -OS(=0)OR17, -OC(=S)NR14R15,
-OC(=S)SR16 or -C(=NOR18)R19; or each R9a is independently a phenyl ring or a naphthalenyl ring system, each optionally substituted with up to 3 substituents independently selected from cyano, halogen, C1 -C2 alkyl, C 1 -C2 haloalkyl, C1-C2 alkoxy and C1 -C2 haloalkoxy; or each R9a is independently a 5- to 6-membered heteroaromatic ring containing ring members selected from carbon atoms and 1 to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, the ring optionally substituted with up to 3 substituents independently selected from cyano, halogen, Ci -C2 alkyl, Ci -C2 haloalkyl, C1-C2 alkoxy and Ci -C2 haloalkoxy on carbon atom ring members and cyano, Ci -C2 alkyl and Ci -C2 alkoxy on nitrogen atom ring members; or
each R9a is independently a 3- to 7-membered nonaromatic ring containing ring
members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, wherein up to 3 carbon atom ring members are independently selected from C(=0) and C(=S), the ring optionally substituted with up to 3 substituents independently selected from cyano, halogen, C1 -C2 alkyl, C 1 -C2 haloalkyl, C1 -C2 alkoxy and C1 -C2 haloalkoxy on carbon atom ring members and cyano, Ci -C2 alkyl and Ci -C2 alkoxy on nitrogen atom ring members;
each R9b is independently cyano, Ci -C3 alkyl, Ci -C3 haloalkyl, Ci -C3 alkoxy, C2-C3 alkylcarbonyl, C2-C3 alkoxycarbonyl or C3-C6 cycloalkyl;
R10 is H, cyano, halogen, hydroxy, -CH(=0), C1 -C4 alkyl, C 1 -C4 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, C2-C4 alkoxyalkyl, C2-C4 alkylthioalkyl, C2-C4 alkylsulfinylalkyl, C2-C4
alkylsulfonylalkyl, C3-C5 alkoxycarbonylalkyl, C1 -C4 alkoxy, C1 -C4
haloalkoxy, C 1 -C4 alkylthio, C1 -C4 haloalkylthio, C1 -C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, Ci -C4 alkylsulfonyl, Ci -C4 haloalkylsulfonyl, C2-C4 alkylcarbonyl, C2-C4 haloalkylcarbonyl, C2-C5 alkoxycarbonyl, C2-C5 alkylaminocarbonyl or C3-C5 dialkylaminocarbonyl;
R1 1 is H, CrC4 alkyl, CrC4 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C3-C4 alkynyl, C2-C4 haloalkynyl, C2-C4 alkoxyalkyl, C2-C4 alkylthioalkyl, C2-C4 alkylsulfinylalkyl, C2-C4 alkylsulfonylalkyl, C3-C5 alkoxycarbonylalkyl, C1 -C4 alkylsulfonyl, C1 -C4 haloalkylsulfonyl, C2-C4 alkylcarbonyl, C2-C4
haloalkylcarbonyl, C2-C5 alkoxycarbonyl, C2-C5 alkylaminocarbonyl or C3-C5 dialkylaminocarbonyl;
each R12 is independently H, Ci -C3 alkyl or Ci -C3 haloalkyl;
R1 is H, cyano, Ci -C4 alkyl, Ci -C4 haloalkyl, C2-C4 alkoxyalkyl, C2-C4
alkylthioalkyl, C1 -C4 alkylsulfonyl, C1 -C4 haloalkylsulfonyl, C2-C4 alkylcarbonyl, C2-C4 haloalkylcarbonyl, C2-C4 alkoxycarbonyl, C2-C4 alkylaminocarbonyl or C3-C5 dialkylaminocarbonyl; or
R13 and R3 are taken together with the atoms to which they are attached to form a 5- to 7-membered partially saturated ring containing ring members selected from carbon atoms and up to 3 heteroatoms independently selected from up to 1 O, up to 1 S and up to 1 N atom, the ring optionally substituted with up to 3 substituents independently selected from cyano, halogen, nitro, Ci -C2 alkyl, Ci -C2 haloalkyl, Ci -C2 alkoxy and Ci -C2 haloalkoxy on carbon atom ring members and cyano, Ci -C2 alkyl and Ci -C2 alkoxy on nitrogen atom ring members;
each R14 and R15 is independently H, Ci -C3 alkyl, Ci -C3 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, benzyl or phenyl;
each R16 is independently Ci -C3 alkyl, Ci -C3 haloalkyl, C2-C4 alkenyl, C3-C6
cycloalkyl, benzyl or phenyl;
each R17 is a phenyl ring, a naphthalenyl ring system or a 5- to 6-membered
heteroaromatic ring, each ring or ring system optionally substituted with up to 3 substituents independently selected from halogen, cyano, nitro, Ci -C2 alkyl, Ci -C2 haloalkyl, Ci -C2 alkoxy and Ci -C2 haloalkoxy on carbon atom ring members and cyano, Ci -C2 alkyl and Ci -C2 alkoxy on nitrogen atom ring members;
each R18 is independently H, Ci -C3 alkyl, Ci -C3 haloalkyl or benzyl;
each R19 is independently H, Ci -C3 alkyl, Ci -C3 haloalkyl, C3-C6 cycloalkyl, C4-C6 cycloalkylalkyl, C4-C6 alkylcycloalkyl, C4-C6 haloalkylcycloalkyl, C2-C4 alkoxyalkyl, C2-C4 haloalkoxyalkyl, benzyl or phenyl;
each R20 is independently H, cyano, Ci -Cg alkyl, Ci -Cg haloalkyl, C3-C8 cycloalkyl,
C3-C8 halocycloalkyl, Ci -Cg alkoxy, Ci -Cg haloalkoxy, Ci -Cg alkylamino,
Ci -Cg haloalkylamino, C2-Cg dialkylamino or phenyl; and
n is 0, 1 or 2;
provided that:
(a) that the sum of s and f is 0, 1 or 2 in each instance of S(=O)s(=NR20)f;
(b) when Z1 and Z2 are each independently a chain containing 1- to 3 -atoms, then the sum of atoms in Z1 and Z2 is 1, 2, 3 or 4;
(c) when A is C(=0) or CH(R10) and R10 is hydroxy, then R1 is linked through a carbon atom to A;
(d) when X is X2 or X3, then Z1 is linked to X through carbon, nitrogen or C(=NOH);
(e) when X is X1, E is E-l and A is NH, then R1 is other than an unsubstituted
heterocyclic ring, a monosubstituted 2-pyridinyl ring, a monosubstituted 3-pyridinyl ring, a monosubstituted pyrazinyl ring, an unsubstituted phenyl ring or a monosubstituted phenyl ring; and
(f) when X is X2, Z1 is CH, E is E-l and A is NH, then R1 is other than an
unsubstituted 3-pyridinyl ring, an unsubstituted pyrazinyl ring or monosubstituted pyrazinyl ring.
More particularly, this invention pertains to a compound selected from compounds of Formula 1 (including all stereoisomers) and N-oxides and salts thereof.
This invention also relates to a fungicidal composition comprising (a) a compound of the invention (i.e. in a fungicidally effective amount); and (b) at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents.
This invention also relates to a fungicidal composition comprising (a) a compound of the invention; and (b) at least one other fungicide (e.g., at least one other fungicide having a different site of action).
This invention further relates to a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof, or to the plant seed, a fungicidally effective amount of a compound of the invention (e.g., as a composition described herein).
This invention also relates to a composition comprising a compound of Formula 1, an N-oxide, or a salt thereof, and at least one invertebrate pest control compound or agent.
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 the present disclosure and claims, "plant" includes members of Kingdom Plantae, particularly seed plants (Spermatopsida), at all life stages, including young plants (e.g., germinating seeds developing into seedlings) and mature, reproductive stages (e.g., plants producing flowers and seeds). Portions of plants include geotropic members typically growing beneath the surface of the growing medium (e.g., soil), such as roots, tubers, bulbs and corms, and also members growing above the growing medium, such as foliage (including stems and leaves), flowers, fruits and seeds.
As referred to herein, the term "seedling", used either alone or in a combination of words means a young plant developing from the embryo of a seed.
As referred to herein, the term "broadleaf used either alone or in words such as "broadleaf crop" means dicot or dicotyledon, a term used to describe a group of angiosperms characterized by embryos having two cotyledons.
Generally when a molecular fragment (i.e. radical) is denoted by a series of atom symbols (e.g., C, H, N, O, S) the implicit point or points of attachment will be easily recognized by those skilled in the art. In some instances herein, particularly when alternative points of attachment are possible, the point or points of attachment may be explicitly indicated by a hyphen ("-").
In the above recitations, the term "alkyl", used either alone or in compound words such as "alkylthio" or "haloalkyl" includes straight-chain and branched alkyl, such as, methyl, ethyl, n-propyl, /-propyl, and the different butyl, pentyl and hexyl isomers. "Alkenyl" includes straight-chain and 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 and 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. "Alkylene" denotes a straight-chain or branched alkanediyl. Examples of "alkylene" include CH2, CH2CH2, CH(CH3), CH2CH2CH2, CH2CH(CH3), and the different butylene isomers. "Alkenylene" denotes a straight-chain or branched alkenediyl containing one olefmic bond. Examples of "alkenylene" include CH=CH, CH2CH=CH and CH=C(CH3).
"Alkoxy" includes, for example, methoxy, ethoxy, n-propyloxy, z'-propyloxy, and the different butoxy, pentoxy and hexyloxy isomers. "Alkenyloxy" includes straight-chain and branched alkenyl attached to and linked through an oxygen atom. Examples of "alkenyloxy" include H2C=CHCH20, CH3CH=CHCH20 and (CH3)2C=CHCH20. "Alkynyloxy" includes straight-chain and branched alkynyloxy moieties. Examples of "alkynyloxy" include HC≡CCH20, CH3C≡CCH20 and CH3C≡CCH2CH20. "Alkoxyalkoxy" denotes straight-chain or branched alkoxy substitution on a straight-chain or branched alkoxy. Examples of "alkoxyalkoxy" include CH3OCH20, CH3OCH2(CH3)CHCH20 and (CH3)2CHOCH2CH20. The term "alkylsulfonyloxy" denotes alkylsulfonyl attached to and linked through an oxygen atom. Examples of "alkylsulfonyloxy" include CH3S(=0)20 and CH3CH2S(=0)20. The term "alkylcarbonyloxy" denotes a straight-chain or branched alkyl bonded to a C(=0)0 moiety. Examples of "alkylcarbonyloxy" include CH3CH2C(=0)0 and (CH3)2CHC(=0)0. The term "alkenylcarbonyloxy" denotes a straight-chain or branched alkenyl bonded to a C(=0)0 moiety. Examples of "alkenylcarbonyloxy" include H2C=CHCH2C(=0)0, CH3CH=CHCH2C(=0)0 and (CH3)2C=CHCH2C(=0)0. Examples of "alkoxycarbonyloxy" include CH3CH2CH2OC(=0)0 and (CH3)2CHOC(=0)0. The term "alkoxycarbonylalkoxy" denotes alkoxycarbonyl substitution on straight-chain or branched alkoxy. Examples of "alkoxycarbonylalkoxy" include CH3CH2OC(=0)CH2CH20 and CH3CH2CH(CH3)OC(=0)CH20. The term "alkylaminocarbonyloxy" denotes a straight-chain or branched alkylaminocarbonyl attached to and linked through an oxygen atom. Examples of "alkylaminocarbonyloxy" include (CH3)2CHCH2NHC(=0)0 and CH3CH2NHC(=0)0. Examples of "dialkylaminocarbonyloxy" include
CH3CH2CH2(CH3)NC(=0)0 and (CH3)2NC(=0)0. Examples of "alkylthiocarbonyloxy" include CH3SC(=0)0, CH3CH2CH2SC(=0)0 and (CH3)2CHSC(=0)0.
The term "alkylthio" includes straight-chain and branched alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers. "Alkenylthio" denotes straight-chain or branched alkenyl attached to and linked through a sulfur atom such as CH2=CHS, CH2=CHCH2S and CH3CH=CHS. "Alkynylthio" denotes straight-chain or branched alkynyl attached to and linked through a sulfur atom such as HC≡CCH2S, CH3C≡CCH2S and CH3C≡CCH2CH2S. "Alkylsulfmyl" includes both enantiomers of an alkylsulfmyl group. Examples of "alkylsulfmyl" include CH3S(=0), CH3CH2S(=0), CH3CH2CH2S(=0), (CH3)2CHS(=0), and the different butylsulfmyl, pentylsulfmyl and hexylsulfmyl isomers. Examples of "alkylsulfonyl" include CH3S(=0)2, CH3CH2S(=0)2, CH3CH2CH2S(=0)2, (CH3)2CHS(=0)2, and the different butylsulfonyl, pentylsulfonyl and hexylsulfonyl isomers. The term "alkoxyalkylthio" denotes alkoxyalkyl attached to and linked through a sulfur atom. Examples of "alkoxyalkylthio" include CH3OCH2S, CH3OCH2CH2S, CH3CH2OCH2S, (CH3)2CHCH2OCH2S and CH3CH2OCH2CH2S. "Alkylcarbonylthio" denotes a straight-chain or branched alkylcarbonyl attached to and linked through a sulfur atom. Examples of "alkylcarbonylthio" include CH3C(=0)S, CH3CH2CH2C(=0)S and (CH3)2CHC(=0)S.
The term "alkylamino" includes an NH radical substituted with a straight-chain or branched alkyl group. Examples of "alkylamino" include CH3CH2NH, CH3CH2CH2NH and (CH3)2CHCH2NH. Examples of "dialkylamino" include (CH3)2N, (CH3CH2CH2)2N and CH3CH2(CH3)N. "Alkenylamino" includes an NH radical substituted with straight-chain or branched alkenyl. Examples of "alkenylamino" include CH2=CHNH, CH2=CHCH2NH and CH3CH=CH2NH. "Alkynylamino" includes an NH radical substituted with straight-chain or branched alkynyl. Examples of "alkynylamino" include CH≡CHNH, CH≡CHCH2NH and CH3C≡CCH2NH. "Alkoxyamino" includes straight-chain or branched alkoxy attached to and linked through an NH radical. Examples of "alkoxyamino" include CH3CH(CH3)ONH, CH3CH2CHONH, and
(CH3)2CHCH(CH3)ONH. The term "alkylcarbonylamino" denotes alkyl bonded to a C(=0)NH moiety. Examples of "alkylcarbonylamino" include CH3CH2C(=0)NH and CH3CH2CH2C(=0)NH. The term "alkoxycarbonylamino" denotes alkoxy bonded to a C(=0)NH moiety. Examples of "alkoxycarbonylamino" include CH3OC(=0)NH and CH3CH2OC(=0)NH. "Alkylsulfonylamino" denotes an NH radical substituted with alkylsulfonyl. Examples of "alkylsulfonylamino" include CH3CH2S(=0)2NH and (CH3)2CHS(=0)2NH. The term "alkylaminocarbonylamino" denotes alkylamino bonded to a C(=0)NH moiety. Examples of "alkylaminocarbonylamino" include CH3CH2NHC(=0)NH and (CH3)2CHNHC(=0)NH. "Alkylsulfonylamino" denotes an NH radical substituted with alkylsulfonyl. Examples of "alkylsulfonylamino" include CH3CH2S(=0)2NH and (CH3)2CHS(=0)2NH. "Alkylamino(thiocarbonyl)amino" denotes a straight-chain or branched alkylamino group bonded to a C(=S)NH moiety. Examples of "alkylamino(thiocarbonyl)amino" include CH3CH2NHC(=S)NH, CH3CH2CH2NHC(=S)NH and (CH3)2CHNHC(=S)NH.
"Alkylcarbonyl" denotes a straight-chain or branched alkyl group 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- and pentoxycarbonyl isomers. "Alkoxyalkylcarbonyl" denotes a straight-chain or branched alkoxyalkyl bonded to a C(=0) moiety. Examples of "alkoxyalkylcarbonyl" include CH30CH2C(=0), CH3OCH2CH2C(=0) and (CH3)2CHOCH2CH2C(=0). "Alkoxyalkoxycarbonyl" denotes a straight-chain or branched alkoxyalkoxy bonded to a C(=0) moiety. Examples of "alkoxyalkoxycarbonyl" include CH3OCH2OC(=0) and (CH3)2CHOCH2CH2OC(=0). "Alkylthiocarbonyl" denotes a straight-chain or branched alkylthio group bonded to a C(=0) moiety. Examples of "alkylthiocarbonyl" include CH3SC(=0), CH3CH2CH2SC(=0) and (CH3)2CHSC(=0). Examples of "alkylaminocarbonyl" include CH3NHC(=0), CH3CH2NHC(=0), CH3CH2CH2NHC(=0), (CH3)2CHNHC(=0), and the different butylamino- and pentylaminocarbonyl isomers. Examples of "dialkylaminocarbonyl" include (CH3)2NC(=0), (CH3CH2)2NC(=0), CH3CH2(CH3)NC(=0),
(CH3)2CH(CH3)NC(=0) and CH3CH2CH2(CH3)NC(=0).
"Alkoxyalkyl" denotes alkoxy substitution on alkyl. Examples of "alkoxyalkyl" include CH3OCH2, CH3OCH2CH2, CH3CH2OCH2, CH3CH2CH2CH2OCH2 and CH3CH2OCH2CH2. "Alkoxyalkenyl" denotes alkoxy substitution on straight-chain or branched alkenyl. Examples of "alkoxyalkenyl" include CH3OCH=CH, CH3OCH2CH=CH, CH3CH2OCH=C(CH3) and CH3CH2OCH=CH2. "Alkoxyalkynyl" denotes alkoxy substitution on straight-chain or branched alkenyl. Examples of "alkoxyalkynyl" include CH3OC≡C, CH3OCH2C≡C and CH3CH2OC≡CCH2. "Alkoxyalkoxyalkyl" denotes alkoxyalkoxy substitution on alkyl. Examples of "alkoxyalkoxyalkyl" include CH3OCH2OCH2 CH3OCH2OCH2CH2 and CH3CH2OCH2OCH2. The term "alkoxycarbonylalkyl" denotes alkoxycarbonyl substitution on alkyl. Examples of "alkoxycarbonylalkyl" include CH3CH2OC(=0)CH2, (CH3)2CHCH2OC(=0)CH2 and CH3OC(=0)CH2CH2.
"Alkylthioalkyl" denotes alkylthio substitution on alkyl. Examples of "alkylthioalkyl" include CH3SCH2, CH3SCH2CH2, CH3CH2SCH2, CH3CH2CH2CH2SCH2 and CH3CH2SCH2CH2; "alkylsulfmylalkyl" and "alkylsulfonylalkyl" include the corresponding sulfoxides and sulfones, respectively.
"Alkylaminoalkyl" denotes alkylamino substitution on alkyl. Examples of
"alkylaminoalkyl" include CH3NHCH2, CH3NHCH2CH2, CH3CH2NHCH2, CH3CH2CH2CH2NHCH2 and CH3CH2NHCH2CH2. Examples of "dialkylaminoalkyl" include ((CH3)2CH))2NCH2, (CH3CH2CH2)2NCH2 and CH3CH2(CH3)NCH2CH2.
"Cyanoalkyl" denotes an alkyl group substituted with one cyano group. Examples of "cyanoalkyl" include NCCH2, NCCH2CH2 and CH3CH(CN)CH2. "Hydroxyalkyl" denotes an alkyl group substituted with one hydroxy group. Examples of "hydroxyalkyl" include HOCH2CH2, CH3CH2(OH)CH and HOCH2CH2CH2CH2. "Trialkylsilyl" includes 3 branched and/or straight-chain alkyl radicals attached to and linked through a silicon atom, such as trimethylsilyl, triethylsilyl and tert-butyldimethylsilyl. The term "trialkylsilyloxy" denotes trialkylsilyl attached to and linked through an oxygen atom, such as triethylsilyloxy and tert-butyldimethylsilyloxy.
"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 a straight-chain or branched alkyl group. The term "alkylcycloalkyl" denotes alkyl substitution on a cycloalkyl moiety and includes, for example, ethylcyclopropyl, z-propylcyclobutyl, methylcyclopentyl and methylcyclohexyl. "Cycloalkenyl" includes groups such as cyclopentenyl and cyclohexenyl as well as groups with more than one double bond such as 1,3- or 1,4-cyclohexadienyl.
The term "cycloalkoxy" denotes cycloalkyl attached to and linked through an oxygen atom such as cyclopentyloxy and cyclohexyloxy. The term "cycloalkylthio" denotes cycloalkyl attached to and linked through a sulfur atom such as cyclopropylthio and cyclopentylthio. The term "cycloalkoxyalkyl" denotes cycloalkoxy substitution on an alkyl moiety. Examples of "cycloalkoxyalkyl" include cyclopropyloxymethyl, cyclo- pentyloxyethyl, and other cycloalkoxy groups bonded to a straight-chain or branched alkyl moiety. "Cycloalkylalkoxy" denotes cycloalkyl substitution on an alkoxy moiety. Examples of "cycloalkylalkoxy" include cyclopropylmethoxy, cyclopentylethoxy, and other cycloalkyl groups bonded to a straight-chain or branched alkoxy moiety.
"Alkylcycloalkylalkyl" denotes an alkyl group substituted with alkylcycloalkyl. Examples of "alkylcycloalkylalkyl" include methylcyclohexylmethyl and ethylcycloproylmethyl. The term "cycloalkylcycloalkyl" denotes cycloalkyl substitution on another cycloalkyl ring, wherein each cycloalkyl ring independently has from 3 to 6 carbon atom ring members. Examples of cycloalkylcycloalkyl include cyclopropylcyclopropyl (such as Ι,Γ-bicyclopropyl-l-yl, l,l'-bicyclopropyl-2-yl), cyclohexylcyclopentyl (such as 4- cyclopentylcyclohexyl) and cyclohexylcyclohexyl (such as Ι,Γ-bicyclohexyl-l-yl), and the different cis- and trans-cycloalkylcycloalkyl isomers, (such as (li?,25)-l,l'-bicyclopropyl-2- yl and (li?,2i?)-l,l'-bicyclopropyl-2-yl).
"Cycloalkylamino" denotes an NH radical substituted with cycloalkyl. Examples of "cycloalkylamino" include cyclopropylamino and cyclohexylamino. The term "cyclo- alkylaminoalkyl" denotes cycloalkylamino substitution on an alkyl group. Examples of "cycloalkylaminoalkyl" include cyclopropylaminomethyl, cyclopentylaminoethyl, and other cycloalkylamino moieties bonded to a straight-chain or branched alkyl group.
"Cycloalkylcarbonyl" denotes cycloalkyl bonded to a C(=0) group including, for example, cyclopropylcarbonyl and cyclopentylcarbonyl. The term "cycloalkoxycarbonyl" means cycloalkoxy bonded to a C(=0) group, for example, cyclopropyloxycarbonyl and cyclopentyloxycarbonyl. "Cycloalkylalkoxycarbonyl" denotes cycloalkylalkoxy bonded to a C(=0) group. Examples of "cycloalkylalkoxycarbonyl" include cyclopropylethoxycarbonyl and cyclopentylmethoxycarbonyl.
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, F2CH, C1CH2, CF3CH2 and CF3CC12. The terms "haloalkenyl", "haloalkynyl" "haloalkoxy", "haloalkylthio", "haloalkylamino", "haloalkylsulfmyl", "haloalkylsulfonyl", "halocycloalkyl", and the like, are defined analogously to the term "haloalkyl". Examples of "haloalkenyl" include C12C=CHCH2 and CF3CH2CH=CHCH2. Examples of "haloalkynyl" include HC≡CCHC1, CF3C≡C, CC13C≡C and FCH2C≡CCH2. Examples of "haloalkoxy" include CF30, CC13CH20, F2CHCH2CH20 and CF3CH20. Examples of "haloalkylthio" include CC13S, CF3S, CC13CH2S and C1CH2CH2CH2S. Examples of "haloalkylamino" include CF3(CH3)CHNH, (CF3)2CHNH and CH2C1CH2NH. Examples of "haloalkylsulfmyl" include CF3S(=0), CC13S(=0), CF3CH2S(=0) and CF3CF2S(=0). Examples of "haloalkylsulfonyl" include CF3S(=0)2, CC13S(=0)2, CF3CH2S(=0)2 and CF3CF2S(=0)2. Examples of "halocycloalkyl" include 2-chlorocyclopropyl, 2-fluorocyclobutyl, 3-bromocyclopentyl and 4-chorocyclohexyl. The term "halodialkyl", either alone or in compound words such as "halodialkylamino", means at least one of the two alkyl groups is substituted with at least one halogen atom, and independently each halogenated alkyl group may be partially or fully substituted with halogen atoms which may be the same or different. Examples of "halodialkylamino" include (BrCH2CH2)2N and BrCH2CH2(ClCH2CH2)N.
"Hydroxyalkyl" denotes an alkyl group substituted with one hydroxy group. Examples of "hydroxyalkyl" include HOCH2CH2, CH3CH2(OH)CH and HOCH2CH2CH2CH2.
"Trialkylsilyl" includes 3 branched and/or straight-chain alkyl radicals attached to and linked through a silicon atom, such as trimethylsilyl, triethylsilyl and tert-butyldimethylsilyl.
The total number of carbon atoms in a substituent group is indicated by the " -Cj" prefix where i and j are numbers from 1 to 12. For example, C^-C3 alkylsulfonyl designates methylsulfonyl through propylsulfonyl; C2 alkoxyalkyl designates CH3OCH2; C3 alkoxyalkyl designates, for example, 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.
The term "unsubstituted" in connection with a group such as a ring or ring system means the group does not have any substituents other than its one or more attachments to the remainder of Formula 1. The term "optionally substituted" means that the number of substituents can be zero. Unless otherwise indicated, optionally substituted groups may be substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. Commonly, the number of optional substituents (when present) ranges from 1 to 3. As used herein, the term "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted" or with the term "(un)substituted." The term "optionally substituted" without recitation of number or identity of possible substituents (e.g., phenyl and naphthalenyl as defined in R1 and R4) refers to groups which are unsubstituted or have at least one non-hydrogen substituent that does not extinguish the biological activity possessed by the unsubstituted analog.
The number of optional substituents may be restricted by an expressed limitation. For example, the phrase "optionally substituted with up to 3 substituents independently selected from R9a on carbon atom ring members" means that 0, 1, 2 or 3 substituents can be present (if the number of potential connection points allows). When a range is specified for the number of substituents (e.g., p being an integer from 0 to 3 in Exhibit 2) and the range exceeds the number of positions available for the substituents on a ring (e.g., 2 positions available for (R9a)p on Q-5 in Exhibit 2), the actual higher end of the range is recognized to be the number of available positions.
When a compound is substituted with a substituent bearing a subscript that indicates the number of said substituents can vary (e.g., (R6)n wherein n is 0 to 2), then said substituents are independently selected from the group of defined substituents, unless otherwise indicated. When a variable group is shown to be optionally attached to a position, for example (R6)n wherein n may be 0, then hydrogen may be at the position even if not recited in the definition of the variable group.
Naming of substituents in the present disclosure uses recognized terminology providing conciseness in precisely conveying to those skilled in the art the chemical structure. For sake of conciseness, locant descriptors may be omitted.
Unless otherwise indicated, a "ring" or "ring system" as a component of Formula 1 (e.g., R9a and R2 and R3 taken together) is carbocyclic or heterocyclic. The term "ring system" denotes two or more connected rings. The term "bicyclic ring system" denotes a ring system consisting of two rings sharing two or more common atoms. In a "fused bicyclic ring system" the common atoms are adjacent, and therefore the rings share two adjacent atoms and a bond connecting them. In a "bridged bicyclic ring system" the common atoms are not adjacent (i.e. there is no bond between the bridgehead atoms). A "bridged bicyclic ring system" can be formed by bonding a segment of one or more atoms to nonadjacent ring members of a ring. The term "ring member" refers to an atom (e.g., C, O, N or S) or other moiety (e.g., C(=0), C(=S) or S(=O)s(=NR20)f) forming the backbone of a ring or ring system. The term "aromatic" indicates that each ring atom is essentially in the same plane and has a /^-orbital perpendicular to the ring plane, and that (4n + 2) π electrons, where n is a positive integer, are associated with the ring to comply with Huckel's rule
The term "carbocyclic ring" denotes a ring 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". "Saturated carbocyclic" refers to a ring having a backbone consisting of carbon atoms linked to one another by single bonds; unless otherwise specified, the remaining carbon valences are occupied by hydrogen atoms.
As used herein, the term "partially unsaturated ring" or "partially unsaturated heterocycle" refers to a ring which contains unsaturated ring atoms and one or more double bonds but which is not aromatic, for example a 4,5-dihydro-lH-pyrazol-l-yl ring. The term "nonaromatic" includes rings that are fully saturated as well as partially or fully unsaturated, provided that the rings are not aromatic.
The terms "heterocyclic ring", "heterocycle" or "heterocyclic ring system" denote a ring wherein at least one of the atoms forming the ring backbone is other than carbon. Unless otherwise indicated, a heterocyclic ring can be a saturated, partially unsaturated, or fully unsaturated ring. When a fully unsaturated heterocyclic ring satisfies Huckel's rule, then said ring is also called a "heteroaromatic ring" or "aromatic heterocyclic ring". "Saturated heterocyclic ring" refers to a heterocyclic ring containing only single bonds between ring members. The terms "heteroaromatic ring system" or "heteroaromatic bicyclic ring system" denote a ring wherein at least one of the atoms forming the ring backbone is other than carbon and at least one ring is aromatic. Unless otherwise indicated, heterocyclic rings and heteroaromatic ring systems can be attached through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.
The wavy bond between the nitrogen atom and the atom represented by A1 designates a single bond and the geometry about the adjacent double (i.e. the bond linking the nitrogen atom to the substituents R2 and R3) is either cis-(Z), trans-(E), or a mixture thereof.
As described above, X is a radical selected from the group consisting X1, X2, X3 and X4, provided that when X is X2 or X3, then Z1 is linked to X through carbon, nitrogen or C(=NOH). Thus, this definition does not include the possibility of Z1 being linked to X2 or X3 through oxygen, sulfur or C(=0).
As described above, X is a radical selected from the group consisting X1, X2, X3 and X4, provided that when X is X1, E is E-l and A is NH, then R1 is other than an unsubstituted heterocyclic ring, a monosubstituted 2-pyridinyl ring, a monosubstituted 3-pyridinyl ring, a monosubstituted pyrazinyl ring, an unsubstituted phenyl ring or a monosubstituted phenyl ring. In this definition the term "unsubstituted" in connection with a ring means that the ring does not have any substituents other than its one attachment to the remainder of Formula 1; and the term "monosubstituted" in connection with a ring means that the ring has one non-hydrogen substituent, in addition to its one attachment to the remainder of Formula 1.
As described above, X is a radical selected from the group consisting X1, X2, X3 and X4, provided that when X is X2, Z1 is CH, E is E-l and A is NH, then R1 is other than an unsubstituted 3-pyridinyl ring, an unsubstituted pyrazinyl ring or monosubstituted pyrazinyl ring. In this definition the term "unsubstituted" in connection with a ring means that the ring does not have any substituents other than its one attachment to the remainder of Formula 1; and the term "monosubstituted" in connection with a ring means that the ring has one non-hydrogen substituent, in addition to its one attachment to the remainder of Formula 1.
As described above, Z1 is a saturated, partially unsaturated or fully unsaturated chain containing 1- to 3-atoms selected from up to 3 carbon, up to 1 O, up to 1 S and up to 2 N, wherein up to 1 carbon atom is selected from C(=0) and C(=NOH), the chain optionally substituted with up to 2 substituents independently selected from R7a on carbon atoms and R7^ on nitrogen atoms. When Z1 is denoted as a chain consisting of a series of atoms wherein alternative points of attachment are possible (e.g., Z1 is OCH2CH2 or NOCH2), then the atom on the left is connected to X and the atom on the right is connected to G in Formula 1 (i.e. X-OCH2CH2-G and X=NOCH2-G). When Z1 is denoted as a radical wherein alternative bonds of attachment are possible (e.g., Z1 is CH), then both configurations are allowed (i.e. X=CH-G or X-CH=G), unless otherwise indicated.
As described above, Z2 is {inter alia) a saturated, partially unsaturated or fully unsaturated chain containing 1- to 3-atoms selected from up to 3 carbon, up to 1 O, up to 1 S and up to 2 N, wherein up to 2 carbon atoms are independently selected from C(=0) and C(=NOH), the chain optionally substituted with up to 2 substituents independently selected from R7c on carbon atoms and R d on nitrogen atoms. When Z2 is denoted as a chain consisting of a series of atoms wherein alternative points of attachment are possible (e.g., Z2 is CH2CH2O or NNHCH2), then the atom on the left is connected to G and the atom on the right is connected to Q in Formula 1 (i.e. G-CH2CH20-Q and G=NNHCH2-Q). When Z2 is denoted as a radical wherein alternative bonds of attachment are possible (e.g., Z2 is CH), then both configurations are allowed (i.e. G=CH-Q or G-CH=Q), unless otherwise indicated.
As noted above, Q is (inter alia) a 3- to 7-membered nonaromatic carbocyclic ring, a 5- to 7-membered nonaromatic heterocyclic ring or an 8- to 11-membered nonaromatic bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, wherein up to 3 carbon atom ring members are independently selected from C(=0) and C(=S), and the sulfur atom ring members are independently selected from S(=O)s(=NR20)f, each ring or ring system optionally substituted with up to 3 substituents independently selected from R9a on carbon and R9^ on nitrogen atom ring members. In this definition the ring members selected from up to 2 O, up to 2 S and up to 4 N are optional, because the number of heteroatom ring members may be zero. When no heteroatom ring members are present, the ring or ring system is carbocyclic. If at least one heteroatom ring member is present, the ring or ring system is heterocyclic. The definition of S(=O)s(=NR20)f allows up to 2 sulfur ring members, which can be oxidized sulfur moieties (e.g., S(=0) or S(=0)2) or unoxidized sulfur atoms (i.e. when s and f are both zero). The nitrogen atom ring members may be oxidized as N-oxides, because compounds relating to Formula 1 also include N-oxide derivatives. The up to 3 carbon atom ring members selected from C(=0) and C(=S) are in addition to the up to 4 heteroatoms selected from up to 2 O, up to 2 S and up to 4 N atoms.
As described above, A is CH(R10), N(Rn) or C(=0), provided that when A is C(=0) or CH(R10) and R10 is hydroxy, then R1 is linked through a carbon atom to A. Thus, this definition does not include the possibility of "-R1-C(=0)-" or "-R1-CH(OH)-" wherein R1 is connected via a nitrogen atom.
As noted above, R2 and R3 may be taken together with the carbon atom to which they are attached to form a 3- to 7-membered ring. This 3- to 7-membered ring includes as a ring member the carbon atom to which the substituents R2 and R3 are attached. The other 2 to 6 ring members are selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 2 N atoms. In this definition the heteroatoms are optional, because the number of heteroatom ring members may be zero. When no heteroatom ring members are present, the ring is carbocyclic. If at least one heteroatom ring member is present, the ring is heterocyclic. The ring is optionally substituted with up to 4 substituents independently selected from cyano, halogen, -C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy and C1-C2 haloalkoxy on carbon atom ring members and cyano, C1-C2 alkyl and C1-C2 alkoxy on nitrogen atom ring members. The nitrogen atom ring members may be oxidized as N-oxides, because compounds relating to Formula 1 also include N-oxide derivatives.
As described above, R3 and R13 may be taken together with the linking atoms to which they are directly attached to form a 5- to 7-membered partially unsaturated ring. Thus, the 5- to 7-membered ring includes as a ring member the carbon atom to which R3 is directly attached, the nitrogen atom in Formula 1 depicted as "=N~" and the nitrogen atom to which R13 is directly attached. The other 2 to 4 ring members of the ring are selected from up to 1 O, up to 1 S and up to 1 N atom. In this definition the ring members selected from up to 1 O, up to 1 S and up to 1 N atom are optional, because the number of heteroatom ring members may be zero. The ring is optionally substituted with up to 3 substituents independently selected from cyano, halogen, nitro, C1-C2 alkyl, -C2 haloalkyl, -C2 alkoxy and -C2 haloalkoxy on carbon atom ring members and cyano, C1 -C2 alkyl and C1 -C2 alkoxy on nitrogen atom ring members. These optional substituents (when present) are attached to available carbon and nitrogen atom ring members in the portion of the ring provided by R3 and R13. The nitrogen atom ring members may be oxidized as N-oxides, because compounds relating to Formula 1 also include N-oxide derivatives.
Compounds of Formula 1 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. Compounds of Formula 1 may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form.
Compounds of Formula 1 can exist as one or more conformational isomers due to restricted rotation about an amide bond (e.g., C(=W)-N) in Formula 1. Compounds of Formula 1 comprise mixtures of conformational isomers. In addition, compounds of Formula 1 include compounds that are enriched in one conformer relative to others.
Molecular depictions drawn herein follow standard conventions for depicting stereochemistry. To indicate stereoconfiguration, bonds rising from the plane of the drawing and towards the viewer are denoted by solid wedges where the broad end of the wedge is attached to the atom rising from the plane of the drawing towards the viewer. Bonds going below the plane of the drawing and away from the viewer are denoted by dashed wedges where the narrow end of the wedge is attached to the atom further away from the viewer. Constant width lines indicate bonds with a direction opposite or neutral relative to bonds shown with solid or dashed wedges; constant width lines also depict bonds in molecules or parts of molecules in which no particular stereoconfiguration is intended to be specified.
One skilled in the art recognizes that, compounds of Formula 1 can exist in equilibrium with one or more of its respective tautomeric counterparts. Unless otherwise indicated, reference to a compound by one tautomer description is to be considered to include all tautomers. For example, when E is E2 and R3 is hydroxy, then reference to the tautomeric form depicted by Formula l1 also includes the tautomeric form depicted by Formula I2.
Figure imgf000020_0001
The compounds of the present invention include N-oxide derivatives of Formula 1. 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 of electrons for oxidation to the oxide; one skilled in the art will recognize those nitrogen-containing heterocycles which can form N-oxides. One skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for the preparation of N-oxides of heterocycles and tertiary amines are very well known by one skilled in the art including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-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.
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 plant diseases caused by fungal plant pathogens (i.e. are agriculturally suitable). 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.
Compounds selected from Formula 1, stereoisomers, N-oxides, and salts thereof, typically exist in more than one form, therefore Formula 1 includes all crystalline and noncrystalline 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 to 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.
Embodiments of the present invention as described in the Summary of the Invention include those described below. In the following Embodiments, Formula 1 includes stereoisomers, 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 E is E-l .
Embodiment 2. A compound of Formula 1 wherein E is E-2.
Embodiment 3. A compound of Formula 1 or any one of Embodiments 1 through 2 wherein X is X1 , X2 or X4.
Embodiment 4. A compound of Embodiment 3 wherein X is X1 or X2.
Embodiment 5. A compound of Embodiment 3 wherein X is X1 or X4.
Embodiment 6. A compound of Embodiment 4 wherein X is X2.
Embodiment 7. A compound of Embodiment 4 wherein X is X1.
Embodiment 8. A compound of Formula 1 or any one of Embodiments 1 through 7 wherein X is X2 or X3.
Embodiment 9. A compound of Formula 1 or any one of Embodiments 1 through 8 wherein Z1 is a saturated, partially unsaturated or fully unsaturated chain containing 1- to 3 -atoms selected from up to 3 carbon, up to 1 O, up to 1 S and up to 2 N, wherein up to 1 carbon atom is C(=0), the chain optionally substituted with up to 1 substituent selected from R7a on a carbon atom and R b on a nitrogen atom.
Embodiment 10. A compound of Embodiment 9 wherein Z1 is O, S, NH, CH2,
CH2CH2, CH2CH2CH2, OCH2, CH20, OCH2CH2, CH2CH20, CH2OCH2, SCH2, CH2S, SCH2CH2, CH2CH2S, CH2SCH2, NHCH2, CH2NH, NHCH2CH2,
CH2CH2NH, CHCH2, CHCH2CH2, NNH, NHCH2, NHN=CH, CH= NH, ON=CH, CH=NO, CH2NHO, C(=0), C(=0)CH2, CH2C(=0), C(=0)CH2CH2, CH2CH2C(=0), NHC(=0), C(=0)NH, C(=0)NHCH2 or CH2NHC(=0), each optionally substituted with up to 1 substituent selected from R7a on a carbon atom and R b on a nitrogen atom.
Embodiment 11. A compound of Embodiment 10 wherein Z1 is O, S, NH, CH2, OCH2, CH20, SCH2, CH2S, NHCH2, CH2NH, C(=0), CH2C(=0), NHC(=0),
C(=0)NH, C(=0)NHCH2 or CH2NHC(=0), each optionally substituted with up to 1 substituent selected from R7a on a carbon atom and R b on a nitrogen atom.
Embodiment 12. A compound of Embodiment 11 wherein Z1 is O, NH, CH2, OCH2, CH20, NHCH2, CH2NH, NHC(=0) or C(=0)NH, each optionally substituted with up to 1 substituent selected from R7a on a carbon atom and R b on a nitrogen atom.
Embodiment 13. A compound of Embodiment 12 wherein Z1 is O, OCH2, CH20 or CH2.
Embodiment 14. A compound of Formula 1 or any one of Embodiments 1 through 13 wherein G is selected from G-1 through G-91 in Exhibit 1.
Exhibit 1
Figure imgf000023_0001
G-9 G-10 G-l l G-12
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
G-89 G-90 G-91
wherein the bond projecting to the left is connected to Z1, and the bond projecting to the right is connected to Z2; each R8c is independently selected from H and R8a; and
R8d is selected from H and R8b.
Embodiment 15. A compound of Embodiment 14 wherein G is selected from G-1
through G-3, G-7, G-8, G-10 through G-15, G-19 through G-24, G-26 through
G-30, G-32 through G-39, G-43 through G-48, G-55 through G-59, G-64, G-65,
G-68 through G-76 and G-78 through G-90.
Embodiment 15 a. A compound of Embodiment 14 wherein G is selected from G-1,
G-9, G-12, G-15, G-19, G-22, G-30, G-36, G-46 through G-48, G-55, G-56 and
G-68 through G-71.
Embodiment 16. A compound of Embodiment 15 wherein G is selected from G-78 through G-90.
Embodiment 17. A compound of Embodiment 15 wherein G is selected from G-1, G-7,
G-8, G-11, G-15, G-19 through G-24, G-30, G-36, G-46 through G-48, G-55,
G-56 and G-68 through G-76.
Embodiment 18. A compound of Embodiment 15 wherein G is selected from G-1, G-8,
G-12, G-15, G-19, G-22, G-30, G-36, G-46 through G-48, G-56, G-57 and G-68 through G-71. Embodiment 19. A compound of Embodiment 18 wherein G is selected from G-l,
G-56, G-68, G-70 and G-71.
Embodiment 19a. A compound of Embodiment 18 wherein G is selected from G-56,
G-68 and G-70.
Embodiment 20. A compound of Embodiment 19 wherein G is G-l .
Embodiment 21. A compound of Embodiment 19 wherein G is G-56.
Embodiment 22. A compound of Embodiment 19 wherein G is G-68.
Embodiment 23. A compound of Embodiment 19 wherein G is G-70.
Embodiment 24. A compound of Embodiment 19 wherein G is G-71.
Embodiment 25. A compound of Formula 1 or any one of Embodiments 1 through 24 wherein Z2 is a direct bond or a saturated, partially unsaturated or fully unsaturated chain containing 1- to 3 -atoms selected from up to 3 carbon, up to 1 O, up to 1 S and up to 2 N, wherein up to 2 carbon atoms are C(=0), the chain optionally substituted with up to 1 substituent selected from R7c on a carbon atom and R d on a nitrogen atom.
Embodiment 26. A compound of Embodiment 25 wherein Z2 is a direct bond, O, S, NH, CH2, CH2CH2, CH2CH2CH2, OCH2, CH20, OCH2CH2, CH2CH20, CH2OCH2, SCH2, CH2S, SCH2CH2, CH2CH2S, NHCH2, CH2NH,
NHCH2CH2, CH2CH2NH, CHCHCH2, NNH, NNHCH2, NO, ONCH, CHNO, C(=0), C(=0)CH2, CH2C(=0), C(=0)CH2CH2, CH2CH2C(=0), NHC(=0),
C(=0)NH, C(=0)NHCH2, CH2NHC(=0), CH2C(=0)NH, S02NH, NHS02, S02NHCH2 or CH2NHS02, each optionally substituted with up to 1 substituent selected from R7c on a carbon atom and R7^ on a nitrogen atom.
Embodiment 27. A compound of Embodiment 26 wherein Z2 is a direct bond, O, S, NH, CH2, OCH2, CH20, SCH2, CH2S, NHCH2, CH2NH, NHC(=0) or
C(=0)NH, each optionally substituted with up to 1 substituent selected from R7c on a carbon atom and R7^ on a nitrogen atom.
Embodiment 28. A compound of Embodiment 27 wherein Z2 is a direct bond, O, S, NH, OCH2, CH20, SCH2, CH2S, NHCH2 or CH2NH, each optionally substituted with up to 1 substituent selected from R7c on a carbon atom and R7^ on a nitrogen atom.
Embodiment 29. A compound of Embodiment 28 wherein Z2 is O, S, NH, OCH2,
CH20, NHCH2 or CH2NH.
Embodiment 30. A compound of Embodiment 28 wherein Z2 is a direct bond.
Embodiment 31. A compound of Formula 1 or any one of Embodiments 1 through 30 wherein Q is selected from Q-l through Q-107 in Exhibit 2.
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000031_0002
Figure imgf000031_0003
Q-74 Q-75 Q-76
Figure imgf000032_0001
Q-92 Q-93 Q-94
Figure imgf000033_0001
Q-107
wherein the bond projecting to the left is connected to Z2; R9c is selected from H and
R9b; and p is 0, 1, 2 or 3.
Embodiment 32. A compound of Embodiment 31 wherein Q is selected from Q-1,
Q-20, Q-32, Q-33, Q-34, Q-45, Q-46, Q-47, Q-60 through Q-73, Q-76 through
Q-79, Q-84 through Q-94 and Q-98 through Q-107.
Embodiment 33. A compound of Embodiment 32 wherein Q is selected from Q-1,
Q-45, Q-63, Q-64, Q-65, Q-68, Q-69, Q-70, Q-71, Q-72, Q-73, Q-76, Q-78,
Q-79, Q-84, Q-85, Q-98, Q-99, Q-100, Q-101 and Q-103 through Q-107. Embodiment 34. A compound of Embodiment 33 wherein Q is selected from Q-45,
Q-63, Q-64, Q-65, Q-68, Q-69, Q-70, Q-71, Q-72, Q-84, Q-85 and Q-103 through Q-107. Embodiment 35. A compound of Embodiment 34 wherein Q is selected from Q-45,
Q-63, Q-65, Q-70, Q-71, Q-72, Q-84 and Q-85.
Embodiment 36. A compound of Embodiment 35 wherein Q is selected from Q-45,
Q-63, Q-65, Q-70, Q-71, Q-72 and Q-84.
Embodiment 37. A compound of Embodiment 36 wherein Q is selected from Q-45,
Q-63, Q-70, Q-71, Q-72 and Q-84.
Embodiment 38. A compound of Embodiment 37 wherein Q is Q-45.
Embodiment 39. A compound of any one of Embodiments 31 through 38 wherein p is
0, 1 or 2.
Embodiment 40. A compound of Embodiment 39 wherein p is 0.
Embodiment 41. A compound of Embodiment 39 wherein p is 2.
Embodiment 42. A compound of Formula 1 or any one of Embodiments 1 through 41 wherein A is CH(R10) or N(R! l).
Embodiment 43. A compound of Embodiment 42 wherein A is CH2 or NH.
Embodiment 44. A compound of Embodiment 42 wherein A is CH(R10).
Embodiment 45. A compound of Embodiment 44 wherein A is CH2.
Embodiment 46. A compound of Embodiment 42 wherein A is N(R! !).
Embodiment 47. A compound of Embodiment 46 wherein A is NH.
Embodiment 48. A compound of Formula 1 or any one of Embodiments 1 or 47
wherein A1 is O, S, C(R12)2, N(R13) or -OC(R12)2-, wherein the bond projecting to the left is connected to the nitrogen atom, and the bond projecting to the right is connected to the carbon atom in Formula 1.
Embodiment 49. A compound of Embodiment 48 wherein A1 is O, S or N(R13).
Embodiment 50. A compound of Embodiment 49 wherein A1 is O or N(R13).
Embodiment 51. A compound of Formula 1 or any of Embodiments 1 through 50
wherein W is O.
Embodiment 52. A compound of Formula 1 or any one of Embodiments 1 through 51 wherein R1 is an optionally substituted phenyl ring, an optionally substituted naphthalenyl ring system or an optionally substituted 5- to 6-membered heteroaromatic ring; or cyano, C^-Cg alkyl, C^-Cg haloalkyl, C2-Cg alkenyl,
C2-Cg haloalkenyl, C2-Cg alkynyl, C2-Cg haloalkynyl, C3-Cg cycloalkyl, C2-Cg alkoxyalkyl, C2-Cg haloalkoxyalkyl, C2-Cg alkylthioalkyl, C2-Cg
haloalkylthioalkyl, C2-Cg alkylsulfinylalkyl, C2-Cg alkylsulfonylalkyl, C2-Cg alkylaminoalkyl, C2-Cg haloalkylaminoalkyl, C3-C10 dialkylaminoalkyl, C4-C10 cycloalkylaminoalkyl, C3-Cg alkoxycarbonylalkyl, C3-Cg
haloalkoxycarbonylalkyl, C^-Cg alkoxy, C^-Cg haloalkoxy, C2-Cg alkenyloxy, C2-Cg haloalkenyloxy, C2-Cg alkynyloxy, C3-Cg haloalkynyloxy, C3-Cg cycloalkoxy, C3-Cg halocycloalkoxy, C4-C10 cycloalkylalkoxy, C2-Cg alkoxyalkoxy, C2-Cg alkylcarbonyloxy, C2-Cg haloalkylcarbonyloxy, Ci -Cg alkylthio, C^-Cg haloalkylthio, C3-Cg cycloalkylthio, C^-Cg alkylamino, C2-Cg dialkylamino, C2-Cg alkylcarbonylamino, C3-C10 trialkylsilyl, pyrrolidinyl, piperidinyl or morpholinyl.
Embodiment 53. A compound of Embodiment 52 wherein R1 is cyano, C^-Cg alkyl, C^-Cg haloalkyl, C2-Cg alkenyl, C2-Cg haloalkenyl, C2-Cg alkynyl, C2-Cg haloalkynyl, C3-Cg cycloalkyl, C2-Cg alkoxyalkyl, C2-Cg haloalkoxyalkyl, C2-Cg alkylthioalkyl, C2-Cg haloalkylthioalkyl, C2-Cg alkylsulfmylalkyl, C2-Cg alkylsulfonylalkyl, C2-Cg alkylaminoalkyl, C3-C10 dialkylaminoalkyl, C^-Cg alkoxy, C^-Cg haloalkoxy, C2-Cg alkylcarbonyloxy, C2-Cg
haloalkylcarbonyloxy, C^-Cg alkylthio, C^-Cg alkylamino, C2-Cg dialkylamino, C2-Cg alkylcarbonylamino, C3-C10 trialkylsilyl, pyrrolidinyl, piperidinyl or morpholinyl.
Embodiment 54. A compound of Embodiment 53 wherein R1 is C2-C5 alkyl, C2-C5 haloalkyl, C2-C5 alkenyl, C2-C5 haloalkenyl, C2-C5 alkoxyalkyl, C2-Cg haloalkoxyalkyl, C2-C5 alkylthioalkyl, C2-Cg haloalkylthioalkyl, C2-C5 alkylaminoalkyl, C2-C5 alkoxy, C2-C5 haloalkoxy, C2-Cg alkylcarbonyloxy, C2-Cg haloalkylcarbonyloxy, C2-C5 alkylthio, C2-C5 alkylamino or C2-C5 alkylcarbonylamino .
Embodiment 55. A compound of Embodiment 54 wherein R1 is C3-C5 haloalkyl, C3-C5 haloalkenyl, C3-C5 haloalkoxyalkyl, C3-C5 haloalkylthioalkyl, C2-C4 haloalkoxy or C2-C3 haloalkylcarbonyloxy.
Embodiment 56. A compound of Embodiment 55 wherein R1 is C4 haloalkyl, C4
haloalkenyl, C3 haloalkoxyalkyl or C3 haloalkoxy.
Embodiment 57. A compound of Formula 1 or any one of Embodiments 1 through 56 wherein when R1 is an optionally substituted phenyl ring, an optionally substituted naphthalenyl ring system or an optionally substituted 5- to
6-membered heteroaromatic ring, then the optional substituents on each ring and ring system are independently selected from R21 a on carbon atom ring members and R21^ on nitrogen atom ring members;
each R21 a is independently amino, cyano, halogen, hydroxy, nitro, C^-Cg alkyl, Cj-Cg haloalkyl, C2-Cg alkenyl, C2-Cg haloalkenyl, C2-Cg alkynyl, C2-Cg haloalkynyl, -C4 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C4-C10 cycloalkylalkyl, C4-C10 alkylcycloalkyl, C5-C10 alkylcycloalkylalkyl, C2-C4 alkoxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C2-C6
alkylcarbonyloxy, 1-C4 alkylthio, C1-C4 haloalkylthio, C2-C6
alkylcarbonylthio, C1-C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 haloalkylsulfonyl, C 1-C4 alkylamino, C2-Cg dialkylamino, C3-C6 cycloalkylamino, C2-C4 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl or C L-33--CL-66 t trriiaalikKyylissiiliyyli;; aannda
each R21b is independently C^-Cg alkyl, C^-Cg haloalkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C3-C6 haloalkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl or C2-C4 alkoxyalkyl.
Embodiment 58. A compound of Embodiment 57 wherein R1 is selected from U-1 through U-50 in Exhibit 3.
Exhibit 3
Figure imgf000036_0001
U-6 U-7 U-8
Figure imgf000036_0002
-10 U-l l U-12
Figure imgf000036_0003
U-21 U-22 U-23 U-24
Figure imgf000037_0001
U-41 U-42 U-43 U-44
Figure imgf000037_0002
U-45 U-46 U-47 U-48 (R21a)k
Figure imgf000037_0003
U-49 U-50
wherein the bond projecting to the left is connected to A; R21c is selected from H and R21b;andkis 0, 1,2 or 3. Embodiment 59. A compound of Embodiment 58 wherein R1 is selected from U-l through U-5, U-8, U-l 1, U-13, U-15, U-20 through U-28, U-31, U-36 through U-39 and U-50.
Embodiment 60. A compound of Embodiment 59 wherein R1 is selected from U-l through U-3, U-5, U-8, U-l 1, U-13, U-20, U-22, U-23, U-25 through U-28, U-36 through U-39 and U-50.
Embodiment 61. A compound of Embodiment 60 wherein R1 is selected from U-l through U-3, U-l 1, U-13, U-20, U-22, U-23, U-36 through U-39 and U-50. Embodiment 62. A compound of Embodiment 61 wherein R1 is selected from U-l,
U-20 and U-50.
Embodiment 63. A compound of Embodiment 62 wherein R1 is U-l .
Embodiment 64. A compound of Embodiment 62 wherein R1 is U-20.
Embodiment 65. A compound of Embodiment 62 wherein R1 is U-50.
Embodiment 66. A compound of any one of Embodiments 58 through 65 wherein k is 0, 1 or 2.
Embodiment 67. A compound of Embodiment 66 wherein k is 2.
Embodiment 68. A compound of any one of Embodiments 57 through 67 wherein each
R21 a is independently halogen, C^-Cg alkyl, C^-Cg haloalkyl or C2-C4
alkoxyalkyl.
Embodiment 69. A compound of Embodiment 68 wherein each R21 a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or C2-C3 alkoxyalkyl.
Embodiment 70. A compound of Embodiment 69 wherein each R21 a is independently halogen, methyl or C1-C2 haloalkyl.
Embodiment 71. A compound of Embodiment 70 wherein each R21 a is independently halogen, methyl, CF3 or CF2H.
Embodiment 72. A compound of Embodiment 71 wherein each R21 a is independently methyl, CF3 or CF2H.
Embodiment 73. A compound of any one of Embodiments 57 through 72 wherein each R21b is independently -C3 alkyl.
Embodiment 74. A compound of Formula 1 or any one of Embodiments 1 through 73 wherein R2 when taken alone (i.e. not taken together with R3) is H, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, C2-C4 alkoxyalkyl, C2-C4 alkylthioalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C2-C4 alkenyloxy, C2-C4 haloalkenyloxy, C2-C4 alkynyloxy, C3-C4 haloalkynyloxy, C2-C4 alkoxyalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, C1-C4 alkylamino, C1-C4 haloalkylamino, C2-C4 dialkylamino, C2-C4
halodialkylamino C2-C4 alkylcarbonyl, C2-C4 haloalkylcarbonyl or C2-C4 alkoxy carbonyl. Embodiment 75. A compound of Embodiment 74 wherein R2 when taken alone is H, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C2-C3 alkenyl, C2-C3 haloalkenyl, C2-C3 alkynyl, C2-C3 haloalkynyl, C1-C3 alkoxy or C1-C3 haloalkoxy.
Embodiment 76. A compound of Embodiment 75 wherein R2 when taken alone is H, CrC3 alkyl or CrC3 haloalkyl.
Embodiment 77. A compound of Embodiment 76 wherein R2 when taken alone is H,
Ci -C3 alkyl, trifluoromethyl or CF3CH2-.
Embodiment 78. A compound of Embodiment 77 wherein R2 when taken alone is methyl, trifluoromethyl or CF3CH2-.
Embodiment 79. A compound of Formula 1 or any one of Embodiments 1 through 78 wherein R2 is taken alone.
Embodiment 80. A compound of Formula 1 or any one of Embodiments 1 through 79 wherein R3 when taken alone (i.e. not taken together with R2) is H, C1-C3 alkyl,
Ci -C3 haloalkyl or C1-C3 alkoxy.
Embodiment 81. A compound of Embodiment 80 wherein R3 when taken alone is H,
CrC3 alkyl or CrC3 haloalkyl.
Embodiment 82. A compound of Embodiment 81 wherein R3 when taken alone is H,
Ci -C2 alkyl or trifluoromethyl.
Embodiment 83. A compound of Embodiment 82 wherein R3 when taken alone is H, methyl or trifluoromethyl.
Embodiment 84. A compound of Formula 1 or any one of Embodiments 1 through 83 wherein R3 is taken alone.
Embodiment 85. A compound of Formula 1 or any one of Embodiments 1 through 84 wherein when R2 and R3 are taken together with the carbon atom to which they are attached to form a ring, said ring is a 3- to 6-membered ring containing ring members selected from carbon atoms and up to 2 heteroatoms independently selected from up to 2 O, up to 2 S and up to 2 N, wherein up to 1 carbon atom ring member is selected from C(=0) and C(=S), the ring optionally substituted with up to 3 substituents independently selected from cyano, halogen, Ci -C2 alkyl, C1-C2 haloalkyl, Ci -C2 alkoxy and Ci -C2 haloalkoxy on carbon atom ring members and cyano, Ci -C2 alkyl and Ci -C2 alkoxy on nitrogen atom ring members.
Embodiment 86. A compound of Formula 1 or any one of Embodiments 1 through 85 wherein R4 is an optionally substituted phenyl ring, an optionally substituted naphthalenyl ring system or an optionally substituted 5- to 6-membered heteroaromatic ring; or H, cyano, hydroxy, Ci -C3 alkyl, Ci -C3 haloalkyl, C2-C3 alkenyl, C2-C3 haloalkenyl, C2-C3 alkynyl, C2-C3 haloalkynyl, C1 -C3 alkoxy, C1 -C3 haloalkoxy, C2-C3 alkylcarbonyloxy, C2-C3 haloalkylcarbonyloxy, C1 -C3 alkylthio, Ci -C3 haloalkylthio, C2-C3 alkylcarbonyl or C2-C3 haloalkylcarbonyl. Embodiment 87. A compound of Embodiment 86 wherein R4 is H, cyano, hydroxy,
C1-C3 alkyl, C1-C3 haloalkyl, C2-C3 alkenyl, C2-C3 haloalkenyl, C2-C3 alkynyl, C2-C3 haloalkynyl, C1-C3 alkoxy, C1 -C3 haloalkoxy, C2-C3 alkylcarbonyloxy
C1 -C3 alkylthio, C 1 -C3 haloalkylthio, C2-C3 haloalkylcarbonyloxy, C2-C3 alkylcarbonyl or C2-C3 haloalkylcarbonyl.
Embodiment 88. A compound of Embodiment 87 wherein R4 is H, cyano, hydroxy,
C1 -C3 alkyl, C 1 -C3 haloalkyl, C1-C3 alkoxy, C1 -C3 haloalkoxy, C 1 -C3 alkylthio, i -C3 haloalkylthio, C2-C3 alkylcarbonyloxy or C2-C3 haloalkylcarbonyloxy.
Embodiment 89. A compound of Embodiment 88 wherein R4 is H, cyano, methyl,
CH3O- or CH3C(=0)0-.
Embodiment 90. A compound of Embodiment 89 wherein R4 is H or methyl.
Embodiment 91. A compound of Embodiment 90 wherein R4 is H.
Embodiment 92. A compound of Formula 1 or any one of Embodiments 1 through 91 wherein when R4 is an optionally substituted phenyl ring, an optionally substituted naphthalenyl ring system or an optionally substituted 5- to
6-membered heteroaromatic ring, then the optional substituents on each ring and ring system are independently selected from R22a on carbon atom ring members and R22^ on nitrogen atom ring members;
each R22a is independently amino, cyano, halogen, hydroxy, nitro, Ci -Cg alkyl,
Ci -Cg haloalkyl, C2-Cg alkenyl, C2-Cg haloalkenyl, C2-Cg alkynyl, C2-Cg haloalkynyl, Ci -C4 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C4-C10 cycloalkylalkyl, C4-C10 alkylcycloalkyl, C5-C10
alkylcycloalkylalkyl, C2-C4 alkoxyalkyl, C 1 -C4 alkoxy, C1 -C4 haloalkoxy,
C2-Cg alkylcarbonyloxy, Ci -C4 alkylthio Ci -C4 haloalkylthio, C2-Cg alkylcarbonylthio, C 1 -C4 alkylsulfinyl, C1 -C4 haloalkylsulfinyl, C1 -C4 alkylsulfonyl, Ci -C4 haloalkylsulfonyl, Ci -C4 alkylamino, C2-Cg dialkylamino, C3-C6 cycloalkylamino, C2-C4 alkylcarbonyl, C2-Cg alkoxycarbonyl, C2-Cg alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl or
C3-C6 trialkylsilyl; and
each R22b is independently Ci -Cg alkyl, Ci -Cg haloalkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C3-C6 haloalkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl or C2-C4 alkoxyalkyl.
Embodiment 93. A compound of Formula 1 or any one of Embodiments 1 through 92 wherein when R4 is an optionally substituted phenyl ring, an optionally substituted naphthalenyl ring system or an optionally substituted 5- to 6-membered heteroaromatic ring, then R4 is other than optionally substituted naphthalenyl.
Embodiment 94. A compound of Formula 1 or any one of Embodiments 1 through 93 wherein when R4 is an optionally substituted phenyl ring or an optionally substituted 5- to 6-membered heteroaromatic ring, then R4 is a ring selected from L-1 through L-11 in Exhibit 4.
Exhibit 4
Figure imgf000041_0001
L-9 L-10 L-l l
wherein g is 0, 1, 2 or 3.
Embodiment 95. A compound of any one of Embodiments 92 through 94 wherein each
R22a is independently halogen, C1-C2 alkyl, Ci -C2 haloalkyl or Ci -C2 alkoxy. Embodiment 96. A compound of Embodiment 95 wherein each R22a js independently
CI, Br, I, Ci -C2 alkyl, trifluoromethyl or methoxy.
Embodiment 97. A compound of Embodiment 96 wherein each R22a js independently
CI, Br, Ci -C2 alkyl or trifluoromethyl.
Embodiment 98. A compound of Formula 1 or any one of Embodiments 1 through 97 wherein R5 is H or Ci -C2 alkyl.
Embodiment 99. A compound of Embodiment 98 wherein R5 is H.
Embodiment 100. A compound of Formula 1 or any one of Embodiments 1 through 99 wherein each R6 is independently cyano, hydroxy, methyl or methoxy.
Embodiment 101. A compound of Embodiment 100 wherein each R6 is methyl.
Embodiment 102. A compound of Formula 1 or any one of Embodiments 1 through 101 wherein n is 0 or 1.
Embodiment 103. A compound of Embodiment 102 wherein n is 0. Embodiment 104. A compound of Formula 1 or any one of Embodiments 1 through 103 wherein each R7a and R7c is independently halogen, Ci -C4 alkyl or Ci -C4 alkoxy.
Embodiment 105. A compound of Embodiment 104 wherein each R7a and R7c is
methyl.
Embodiment 106. A compound of Formula 1 or any one of Embodiments 1 through 105 wherein each R7^ and R7^ is independently Ci -C4 alkyl.
Embodiment 107. A compound of Embodiment 106 wherein each R7^ and R7^ is
methyl.
Embodiment 108. A compound of Formula 1 or any one of Embodiments 1 through 107 wherein each R8a is independently halogen or C1-C3 alkyl.
Embodiment 109. A compound of Embodiment 108 wherein each R8a is methyl.
Embodiment 110. A compound of Formula 1 or any one of Embodiments 1 through 109 wherein each R8^ is methyl.
Embodiment 111. A compound of Formula 1 or any one of Embodiments 1 through 110 wherein G is unsubstituted except for its attachments to Z1 and Z2.
Embodiment 112. A compound of Formula 1 or any one of Embodiments 1 through 111 wherein each R9a is independently amino, cyano, halogen, C^-Cg alkyl, C^-Cg haloalkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-C6 cycloalkyl, C3-C6
halocycloalkyl, C4-C10 cycloalkylalkyl, C2-C4 alkoxyalkyl, C1 -C4 alkoxy,
C1 -C4 haloalkoxy, C3-C4 alkenyloxy, C3-C4 alkynyloxy, C2-Cg
alkylcarbonyloxy, C1 -C4 alkylthio, C1 -C4 alkylsulfonyl, C1 -C4 alkylamino, C2-Cg dialkylamino, C2-C4 alkylcarbonyl, C2-Cg alkoxycarbonyl, C2-Cg alkylaminocarbonyl or C3-C8 dialkylaminocarbonyl; or phenyl optionally substituted with up to 3 substituents independently selected from halogen, Ci -C2 alkyl, C1-C2 haloalkyl and C1 -C2 alkoxy.
Embodiment 113. A compound of Embodiment 112 wherein each R9a is independently halogen, Ci -Cg alkyl, Ci -Cg haloalkyl, Ci -Cg alkoxy, C3-C4 alkenyloxy or C3-C4 alkynyloxy.
Embodiment 114. A compound of Embodiment 113 wherein each R9a is independently halogen, CrC2 alkyl, CrC2 haloalkyl, CrC2 alkoxy, H2C=CHCH20- or HC≡CCH20-.
Embodiment 115. A compound of Embodiment 114 wherein each R9a is independently CI, F, methyl or halomethyl.
Embodiment 116. A compound of Embodiment 115 wherein each R9a is independently
CL F or CH3.
Embodiment 116a. A compound of Embodiment 116 wherein each R9a is F. Embodiment 117. A compound of Formula 1 or any one of Embodiments 1 through 116 wherein each R9b is independently C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 alkylcarbonyl or C2-C3 alkoxycarbonyl.
Embodiment 118. A compound of Embodiment 117 wherein each R9^ is independently methyl, CH3C(=0) or CH3OC(=0).
Embodiment 119. A compound of Formula 1 or Embodiments 1 through 118 wherein
R10 is H, cyano, halogen, hydroxy, CH(=0), Ci -C4 alkyl, Ci -C4 haloalkyl,
Ci -C4 alkoxy or C2-C5 alkoxycarbonyl.
Embodiment 120. A compound of Embodiment 119 wherein R10 is H, cyano, halogen, hydroxy, methyl or methoxy.
Embodiment 121. A compound of Embodiment 120 wherein R10 is H.
Embodiment 122. A compound of Formula 1 or Embodiments 1 through 121 wherein
R1 1 is H, methyl, CH3C(=0) or CH3OC(=0).
Embodiment 123. A compound of Embodiment 122 wherein R1 1 is H.
Embodiment 124. A compound of Formula 1 or any one of Embodiments 1 through 123 wherein each R12 is independently H or methyl.
Embodiment 125. A compound of Embodiment 124 wherein each R12 is H.
Embodiment 126. A compound of Formula 1 or any one of Embodiments 1 through 125 wherein R13 when taken alone (i.e. not taken together with R3) is H, Ci -C2 alkyl,
Ci-C2 haloalkyl, CH3C(=0), CF3C(=0) or CH3OC(=0).
Embodiment 127. A compound of Embodiment 126 wherein R13 when taken alone is H or CrC2 alkyl.
Embodiment 128. A compound of Embodiment 127 wherein R13 when taken alone is H or methyl.
Embodiment 129. A compound of Formula 1 or any one of Embodiments 1 through 128 wherein R13 is taken alone.
Embodiment 130. A compound of Formula 1 or any one of Embodiments 1 through 129 wherein s and f are both 0.
Embodiments of this invention, including Embodiments 1-130 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 unless further defined in the Embodiments. In addition, embodiments of this invention, including Embodiments 1-130 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 1-130 are illustrated by:
Embodiment Al . A compound of Formula 1 wherein
E is E-l; X is X1 or X2;
Z1 is O, S, NH, CH2, CH2CH2, CH2CH2CH2, OCH2, CH20, OCH2CH2, CH2CH20, CH2OCH2, SCH2, CH2S, SCH2CH2, CH2CH2S,
CH2SCH2, NHCH2, CH2NH, NHCH2CH2, CH2CH2NH, CHCH2, CHCH2CH2, NNH, NNHCH2, NHN=CH, CH=NNH, ON=CH, CH=NO, CH2NHO, C(=0), C(=0)CH2, CH2C(=0), C(=0)CH2CH2, CH2CH2C(=0), NHC(=0), C(=0)NH, C(=0)NHCH2 or
CH2NHC(=0), each optionally substituted with up to 1 substituent selected from R7a on a carbon atom and R b on a nitrogen atom;
G is selected from G-l, G-9, G-12, G-15, G-19, G-22, G-30, G-36, G-46 through G-48, G-55, G-56 and G-68 through G-71 shown in Exhibit 1 wherein the bond projecting to the left is connected to Z1, and the bond projecting to the right is connected to Z2; each R8c is independently selected from H and R8a; and R8d is selected from H and R8^.
Z2 is a direct bond, O, S, NH, CH2, CH2CH2, CH2CH2CH2, OCH2, CH20, OCH2CH2, CH2CH20, CH2OCH2, SCH2, CH2S, SCH2CH2,
CH2CH2S, NHCH2, CH2NH, NHCH2CH2, CH2CH2NH, CHCHCH2, NNH, NNHCH2, NO, ONCH, CHNO, C(=0), C(=0)CH2, CH2C(=0), C(=0)CH2CH2, CH2CH2C(=0), NHC(=0), C(=0)NH, C(=0)NHCH2, CH2NHC(=0), CH2C(=0)NH, S02NH, NHS02, S02NHCH2 or CH2NHS02, each optionally substituted with up to 1 substituent selected from R7c on a carbon atom and R d on a nitrogen atom;
Q is selected from Q-45, Q-63, Q-70, Q-71, Q-72 and Q-84 shown in Exhibit 2 wherein the bond projecting to the left is connected to Z2; R9c is selected from H and R9b; and p is 0, 1, 2 or 3;
A is CH(R10) or N(Rn);
W is O;
R1 is selected from U-1, U-20 and U-50 shown in Exhibit 3 wherein the bond projecting to the left is connected to A and k is 0, 1, 2 or 3;
each R21a is independently halogen, C1-C3 alkyl, -C3 haloalkyl or C2-C3 alkoxyalkyl;
each R6 is independently cyano, hydroxy, methyl or methoxy;
each R7a and R7c is independently halogen, -C4 alkyl or C1-C4 alkoxy; each R7b and R7d is independently C1-C4 alkyl;
each R8a is independently halogen or C1-C3 alkyl;
each R9a is independently halogen, C^-Cg alkyl, C^-Cg haloalkyl, C^-Cg alkoxy, C3-C4 alkenyloxy or C3-C4 alkynyloxy; R9b is CrC3 alkyl, C3-C6 cycloalkyl, C2-C3 alkylcarbonyl or C2-C3 alkoxycarbonyl;
R10 is H, cyano, halogen, hydroxy, methyl or methoxy; and
R1 1 is H, methyl, CH3C(=0) or CH3OC(=0).
Embodiment A2. A compound of Embodiment Al wherein
Z1 is O, NH, CH2, OCH2, CH20, NHCH2, CH2NH, NHC(=0) or C(=0)NH, each optionally substituted with up to 1 substituent selected from R7a on a carbon atom and R7^ on a nitrogen atom;
G is selected from G-l, G-56, G-68, G-70 and G-71;
G is unsubstituted except for its attachments to Z1 and Z2;
Z2 is a direct bond, O, S, NH, OCH2, CH20, SCH2, CH2S, NHCH2 or
CH2NH, each optionally substituted with up to 1 substituent selected from R7c on a carbon atom and R d on a nitrogen atom;
Q is Q-45;
p is 0, 1 or 2;
A is CH2 or NH;
R1 is U-l;
each R21a is independently halogen, methyl or C^-C2 haloalkyl;
k is 0, 1 or 2;
n is 0;
each R7a and R7c is methyl;
each R7^ and R7^ is methyl; and
each R9a is independently halogen, C}-C2 alkyl, Cj-C2 haloalkyl, C}-C2 alkoxy, H2C=CHCH20- or HC≡CCH20-.
Embodiment A3. A compound of Embodiment A2 wherein
X is X1;
Z1 is O, OCH2, CH20 or CH2;
G is selected from G-56, G-68 and G-70;
Z2 is O, S, NH, OCH2, CH20, NHCH2 or CH2NH;
A is CH2;
each R21a is independently halogen, methyl, CF3 or CF2H; and
each R9a is independently is independently CI, F, methyl or halomethyl. Embodiment A4. A compound of Formula 1 wherein
E is
Figure imgf000046_0001
X i a radical selected from the group consisting of
Figure imgf000046_0002
X1 X2 X4 wherein the bond projecting to the left is connected to E, and the bond projecting to the right is connected to Z1;
Z1 is O, CH2, OCH2, CH20, C(=0), NHC(=0), C(=0)NHCH2,
CH2NHC(=0) or NOCH2;
G is selected from the group consisting of
Figure imgf000046_0003
Figure imgf000046_0004
G-70 G-72 G-77
wherein the bond projecting to the left is connected to Z1, and the bond projecting to the right is connected to Z2;
each R8c is H;
Z2 is direct bond, O, S, NH, CH2, OCH2, CH20, NHCH2, NHCH(CH3), N(CH3)CH(CH3) or C(=0)N(CH3); Q is
Figure imgf000047_0001
Q-45
wherein the bond projecting to the left is connected to Z2; p is 0, 1, 2 or 3;
each R9a is independently CI, F or CH3;
A is CH2;
W is O;
R1 is
Figure imgf000047_0002
U-1
wherein the bond projecting to the left is connected to A; k is 0, 1, 2 or 3;
each R21a is independently halogen, methyl or C}-C2 haloalkyl; and n is 0;
provided that:
when Z1 and Z2 are each independently a chain containing up to 3-atoms, then the sum of atoms in Z1 and Z2 is 1, 2, 3 or 4; and when X is X2, then Z1 is linked to X through carbon or nitrogen.
Embodiment A5. A compound of Embodiment A4 wherein
X is X1;
Z1 is O or OCH2;
G is G-l. G-70 or G-77;
Z2 is direct bond, O, S, OCH2, CH20, NHCH2, NHCH(CH3) or
N(CH3)CH(CH3);
p is 0 or 2;
R9a is F;
k is 2; and
each R21a is independently methyl or C^-C2 haloalkyl.
Specific embodiments include compounds of Formula 1 selected from the consisting of: 1 -[4-[[6-[(2,6-difluorophenyl)methoxy]-3-pyridazinyl]oxy]- 1 -piperidinyl]-2- [5-methyl-3-(trifluoromethyl)- lH-pyrazol- 1 -yljethanone,
1 -[4-[[6-[[(2,6-difluorophenyl)methyl]amino]-3-pyridazinyl]oxy]- 1 - piperidinyl] -2-[5 -methyl-3 -(trifluoromethyl)- lH-pyrazol- 1 -yl] ethanone, 1 -[4-[[6-methyl[(li?)- 1 -phenylethyl]amino]-3-pyridazinyl]oxy]- 1 - piperidinyl] -2-[5 -methyl-3 -(trifluoromethyl)- lH-pyrazol- 1 -yl] ethanone, 1,1,1 -trifluoro-2-propanone 0-[2-[4-[[6-[(2,6-difluorophenyl)methoxy]-3- pyridazinyl]oxy]-l-piperidinyl]-2-oxoethyl]oxime,
1 -[4-[[6-[(2,6-difluorophenoxy)methyl]-3-pyridazinyl]oxy]- 1 -piperidinyl]-2- [5 -methyl-3 -(trifluoromethyl)- lH-pyrazol- 1 -yl]ethanone,
1 -[4-[[6-[(2,6-difluorophenyl)amino]-3-pyridazinyl]oxy]- 1 -piperidinyl]-2-[5- methy 1-3 -(trifluoromethyl)- lH-pyrazol- 1 -yl]ethanone,
2-[5-methyl-3-(trifluoromethyl)- lH-pyrazol- 1 -yl]-l -[4-[[6-[[(li?)-l - phenylethyl] amino] -3 -pyridazinyl]oxy] - 1 -piperidinyl] ethanone,
l-[4-[[6-[(2,6-difluorophenyl)thio]-3-pyridazinyl]oxy]-l-piperidinyl]-2-[5- methy 1-3 -(trifluoromethyl)- lH-pyrazol- 1 -yl]ethanone and
l-[4-[[6-(2,6-difluorophenoxy)-3-pyridazinyl]oxy]-l-piperidinyl]-2-[5- methy 1-3 -(trifluoromethyl)- lH-pyrazol- 1 -yl]ethanone.
This invention provides a fungicidal composition comprising a compound of Formula 1 (including all stereoisomers, N-oxides, and salts thereof), and at least one other fungicide. Of note as embodiments of such compositions are compositions comprising a compound corresponding to any of the compound embodiments described above.
This invention provides a fungicidal composition comprising a compound of Formula 1 (including all stereoisomers, N-oxides, and salts thereof) (i.e. in a fungicidally effective amount), and at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents. Of note as embodiments of such compositions are compositions comprising a compound corresponding to any of the compound embodiments described above.
This invention provides a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof, or to the plant seed, a fungicidally effective amount of a compound of Formula 1 (including all stereoisomers, N-oxides, and salts thereof). Of note as embodiments of such methods are methods comprising applying a fungicidally effective amount of a compound corresponding to any of the compound embodiments describe above. Of particular note are embodiments where the compounds are applied as compositions of this invention.
One or more of the following methods and variations as described in Schemes 1-14 can be used to prepare the compounds of Formula 1. The definitions of E, X, Z1, G, Z2, Q, A, A1, W, R1, R2, R3, R4, R5, R7a, R7b, R10, R1 1 and R12 in the compounds of Formulae 1- 23 below are as defined above in the Summary of the Invention unless otherwise noted. Compounds of Formulae la-lc are various subsets of the compounds of Formula 1, and all substituents for Formulae la-lc are as defined above for Formula 1 unless otherwise noted.
As shown in Scheme 1, compounds of Formula la (Formula 1 wherein E is E-l) wherein A is CH(R10) or C(=0), W is O and X is linked to C=W through a N atom can be prepared by coupling an acid chloride of Formula 2 with an amine of Formula 3 in the presence of an acid scavenger. Typical acid scavengers include amine bases such as triethylamine, N,N-diisopropylethylamine and pyridine. Other scavengers include hydroxides such as sodium and potassium hydroxide and carbonates such as sodium carbonate and potassium carbonate. In certain cases the addition of a polymer-supported acid scavenger such as polymer-bound N,N-diisopropylethylamine and polymer-bound 4-dimethylaminopyridine promotes reactivity. Acid salts of the Formula 3 amines can also be used in this reaction, provided that at least 2 equivalents of the acid scavenger is present. Typical acids used to form salts with amines include hydrochloric acid, oxalic acid and trifluoroacetic acid. The method of Scheme 1 is illustrated by Example 4 (Step D).
Acid chlorides of Formula 2 can be prepared from the corresponding acids using a wide variety of well-known conditions published in the chemistry literature.
Scheme 1
Figure imgf000049_0001
to H through a N atom C(=0), W is O and X is
linked to C=W through a N atom
As shown in Scheme 2, compounds of Formula la (Formula 1 wherein E is E-l) wherein A is CH(R10) or C(=0), W is O and X is linked to C=W through a N atom can also be prepared by coupling an amine of Formula 3 (or its acid salt) with an acid of Formula 4 in the presence of a dehydrative coupling reagent such as N,N-dicyclohexylcarbodiimide, l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or O-benzotriazol-l-yl-N,N,N',N- tetramethyluronium hexafluorophosphates. Polymer-supported reagents are again useful in this method, such as polymer-bound N-cyclohexylcarbodiimide. The method of Scheme 2 is typically conducted at a temperature between about 0-40 °C in a solvent such as dichloromethane or acetonitrile and in the presence of a base such as triethylamine or N,N- diisopropylethylamine. For conditions and variations of this reaction see Example 1 (Step F) and Example 3 (Step C) of the present invention and PCT Patent Publication WO 2009/094445 Example 6 (Step D), Example 7, and Example 8. The acids of Formula 4 are known and can be prepared by methods known to one skilled in the art. For example, RiCF^COOH wherein R1 is linked to the acetic acid moiety through a heteroatom can be prepared by reacting the corresponding compound of formula RlH with a haloacetic acid or ester in the presence of base; see, for example, U.S. 4,084,955. R!C ^COOH wherein R1 is linked to the acetic acid moiety through a carbon atom can be prepared from the corresponding compound of formula R1CH2 -halogen by displacement of the halogen with cyanide followed by hydrolysis; see, for example, Adachi, Yuki Gosei Kagaku Kyokaishi 1969, 27(9), 875-876; or from R1C(=0)CH3 using Willgerodt-Kindler reaction conditions; see, for example, Darabi et al, Tetrahedron Letters 1999, 40(42), 7549- 7552 and Alam et al, Synthetic Communications 2003, 55(1), 59-63 and references cited therein; or from R^ r or R1! by palladium-catalyzed coupling with tert-butyl acetate or diethyl malonate followed by ester hydrolysis; see, for example, Buchwald et al, J. Am. Chem. Soc. 2001, 725(33), 7996-8002 and Hartwig et al, J. Am. Chem. Soc. 2002, 124(42), 12557-12565. Also Example 2 (Step A) illustrates the preparation of a compound of Formula 4.
Scheme 2
R 1^ Z^
Figure imgf000050_0001
wherein X is linked wherein A is CH(R ) or to H through a N atom C(=0), W is O and X is
linked to C=W through a N atom
One skilled in the art will recognize that the methods of Schemes 1 and 2 can result in mixtures when certain functionalities are present in the compound of Formula 3 (e.g., when a second NH group is present). In these instances, incorporation of a protection/deprotection sequence or standard separation methods can be employed to isolate the desired product.
As the synthetic literature includes many amide-forming methods, the synthetic procedures of Schemes 1 and 2 are simply representative examples of a wide variety of methods useful for the preparation of compounds of Formula 1.
As shown in Scheme 3, compounds of Formula la (Formula 1 wherein E is E-l) wherein A is CH(R10) or C(=0), W is O and R1 is linked to A through a heteroatom can be prepared by reaction of a compound of Formula 5 with a compound of Formula 6 wherein Y1 is CI, Br or I. The reaction is carried out in the presence of a base such as sodium hydride, potassium carbonate or triethylamine and a solvent such as tetrahydrofuran, N,N-dimethylformamide or acetonitrile at a temperature between about 0 to 80 °C.
Compounds of Formula 5 are known and can be prepared by methods known in the art; see, for example, Dayagi et al., in The Chemistry of the Carbon-Nitrogen Double Bond, ed. Patei, Interscience, New York 1970; Sandler et al, Organic Functional Group Preparations, Academic Press, New York 1972, 3, 372 and Hilgetag et al, Preparative Organic Chemistry, John Wiley & Sons, New York 1972, 504-515. Compounds of Formula 6 wherein A is CH(R10) can be prepared by reacting an amine of Formula 3 with an a-halocarboxylic acid halide or a-halocarboxylic acid (or its anhydride), using conditions analogous to those described for the amide-forming reactions in Schemes 1 and 2. Compounds of Formula 6 wherein A is C(=0) can be prepared by reacting an amine of Formula 3 and oxalyl chloride by methods well-known in the art.
Scheme 3
Figure imgf000051_0001
wherein R1 is linked to wherein Y1 is CI, Br wherein A is CH(R10 ) or C(=0), W is O
H through a heteroatom or I, A is CH(R10) or and R1 is linked to A through a heteroatom
C(=0) and W is O
As depicted in Scheme 4, compounds of Formula lb (Formula 1 wherein E is E-1, A is NH(R10) and R10 is H) wherein X is linked to C=W through a N atom can be prepared by reacting an amine of Formula 3 with an isocyanate or isothiocyanate of Formula 7 to obtain compounds of Formula lb wherein W is O or S, respectively. The reaction is typically carried out at an ambient temperature in an aprotic solvent such as dichloromethane or acetonitrile. For conditions and variations of this reaction see, for example, PCT Patent Publication WO 2009/094445 Example 1 (Step C), Example 4, and Example 5.
Scheme 4
Figure imgf000051_0002
7
wherein X is linked wherein X is linked to to H through a N atom c=w through a N atom
As shown in Scheme 5, compounds of Formula lb (Formula 1 wherein E is E-1, A is NH(R10) and R10 is H) can also be prepared by reaction of an amine of Formula 8 with a compound of Formula 9 wherein Y2 is CI or lH-imidazol-l-yl. When Y2 is CI, the reaction is typically carried out in the presence of an acid scavenger such as an amine base (e.g., triethylamine, N,N-diisopropylethylamine and pyridine). Other scavengers include hydroxides such as sodium and potassium hydroxide and carbonates such as sodium carbonate and potassium carbonate. Compounds of Formula 9 wherein Y2 is CI can be prepared from amines of Formula 3 by treatment with phosgene (W is O) or thiophosgene (W is S), or their equivalents. Compounds of Formula 9 wherein Y2 is lH-imidazol-l-yl can be prepared from amines of Formula 3 by treatment with 1 , Γ-carbonyldiimidazole (W is O) or Ι,Γ-thiocarbonyldiimidazole (W is S) according to general methods known to one skilled in the art.
Scheme 5
Figure imgf000052_0001
wherein Y is CI or
l_f/-imidazol- 1 -yl
As shown in Scheme 6, compounds of Formula lc (Formula 1 wherein E is E-2) wherein W is O and X is linked to C=W through a N atom can be prepared by coupling an acid chloride of Formula 10 with an amine of Formula 3 in the presence of an acid scavenger, analogous to the method described in Scheme 1. Acid chlorides of Formula 10 can be prepared from the corresponding acids using a wide variety of well-known conditions published in the chemistry literature.
Scheme 6
Figure imgf000052_0002
10
lc
wherein X is linked . .
to H through a N atom wherein W is O and X is linked to C=W through a N atom
In an alternate method, as depicted in Scheme 7, compounds of Formula lc (Formula 1 wherein E is E-2) wherein W is O and X is linked to C=W through a N atom can be prepared by coupling an acid of Formula 11 with an amine of Formula 3 (or its acid salt) in the presence of a dehydrative coupling reagent analogous to the method described in Scheme 2. Acids of Formula 11 are known and can be prepared by methods known to one skilled in the art. For leading references see, for example, Paquette et al, Journal of Medicinal & Pharmaceutical Chemistry 1962, 5, 464-77; Van Dijk et al., Journal of Medicinal Chemistry 1977, 20(9), 1199-206; Balsamo et al, Journal of Medicinal Chemistry 1989, 32(6), 1398- 1401 and references sited therein, and U.S. 4,584,014. Also Example 3 (Step B) illustrates the preparation of a compound of Formula 11. Scheme 7
Figure imgf000053_0001
As the synthetic literature includes many amide-forming methods, the methods of Schemes 6 and 7 are simply representative examples of a wide variety of methods useful for the preparation of Formula 1 compounds.
As shown in Scheme 8, compounds of Formula lc (Formula 1 wherein E is E-2) wherein A1 is O, S or N(R13) and W is O can be prepared by reacting a compound of Formula 12 with a haloacetamide of Formula 13 wherein Y1 is CI, Br or I. The reaction is carried out in the presence of a base such as sodium hydride or potassium carbonate and a solvent such as tetrahydrofuran, N,N-dimethylformamide or acetonitrile typically at a temperature between 0 to 80 °C.
Compounds of Formula 12 are known and can be prepared by methods known in the art; see, for example, Dayagi et al., in The Chemistry of the Carbon-Nitrogen Double Bond, ed. S. Patei, Interscience, New York 1970; Sandler et al, Organic Functional Group Preparations, Academic Press, New York 1972, 3, 372 and Hilgetag et al, Preparative Organic Chemistry, John Wiley & Sons, New York 1972, 504-515. Haloacetamide compounds of Formula 13 can be prepared by reacting an amine of Formula 3 with an a-halocarboxylic acid halide or an a-halocarboxylic acid or its anhydride, analogous to the amide-forming reactions described in Schemes 1 and 2, respectively.
Scheme 8
Figure imgf000053_0002
wherein A1 is wherein Y1 is CI, Br or I wherein A1 is O, S or
O, S, or N(R13) N(R13) and W is O
As depicted in Scheme 9, compounds of Formula lc (Formula 1 wherein E is E-2) wherein A1 is -OC(R12) , -SC(R12)2- or -N(R13)C(R12) , R5 is H and W is O can be prepared by a base-catalyzed condensation reaction of a compound of Formula 12 with an α,β-unsaturated amide of Formula 14. In this method A1 in Formula 12 and C(R12)2 in Formula 14 form A1 in Formula lc. The reaction is carried out in the presence of a base such as sodium or potassium hydroxide, sodium hydride or potassium carbonate and in a solvent such as tetrahydrofuran, N,N-dimethylformamide, ethanol or acetonitrile typically at a temperature between about 0 to 80 °C. The α,β-unsaturated amides of Formula 14 can be prepared by coupling the corresponding α,β-unsaturated acids or acid chlorides with amines of Formula 3 using conditions analogous to those described for Schemes 1 and 2.
Scheme 9
Figure imgf000054_0001
W is O
Compounds of Formula lc (Formula 1 wherein E is E-2) wherein W is O can be prepared by reacting a compound of Formula 15 with a compound of Formula 16 as illustrated in Scheme 10. The reaction is carried out in a solvent such as ethanol, tetrahydrofuran or water, and optionally in the presence of an acid catalyst such as acetic acid, hydrochloric acid or sulfuric acid. Acid salts of Formula 16 can also be used in this method, preferably in the presence of at least one molar equivalent of an acid scavenger such as pyridine or triethylamine. Typical acids used to form salts with amines include hydrochloric acid, oxalic acid and trifluoroacetic acid. The reaction of amines with carbonyl compounds is well known see, for example, Dayagi et al. in The Chemistry of the Carbon- Nitrogen Double Bond, ed. S. Patei, Interscience, New York 1970; Sandler et al, Organic Functional Group Preparations, Academic Press, New York 1972, 3, 372 and Hilgetag et al, Preparative Organic Chemistry, John Wiley & Sons, New York 1972, 504-515.
Compounds of Formula 15 are known and can be prepared by methods known to one skilled in the art. Compounds of Formula 16 can be prepared directly or by deprotection of the corresponding N-protected compounds of Formula 16. The choice and use of a suitable N-protected nitrogen function will be apparent to one skilled in the art; for representative examples see T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991. The N-protected compounds of Formula 16 can be prepared by methods analogous to those already described for Schemes 1, 2, 3, and 4.
Scheme 10
Figure imgf000054_0002
15 16 lc
wherein W is O
As shown in Scheme 11, compounds of Formula 1 can be prepared by reacting a compound of Formula 17 with a compound of Formula 18 wherein Za and are suitable functional groups which under the appropriate reaction conditions will allow the construction of the various Z1 groups. Suitable functional groups include, but are not limited to, ionizable hydrogen, carbonyl, aldehyde, ketone, ester, acid, acid chloride, amine, alcohol, thiol, hydrazine, oxime, olefin, acetylene, halide, alkyl halide, methanesulfonate, trifluoromethanesulfonate, boronic acid, boronate, and the like. For example, compounds of Formula 1 wherein Z1 is CH2 can be prepared by reacting a compound of Formula 17 wherein Za is an ionizable nitrogen-bound hydrogen (i.e. ionizable hydrogen atom bound to a nitrogen ring member of X2 or X3) with a base such as potassium carbonate followed by treatment with a compound of Formula 18 wherein T is a methyl halide (e.g., CICH2-), while treatment with a compound of Formula 18 wherein T is a haloketone (e.g., C1CH2C(=0)-) will give a compound of Formula 1 wherein Z1 is -CH2C(=0)-, which can be reduced to give a compound of Formula 1 wherein Z1 is -CH2CH(OH)-. Compounds of Formula 1 wherein Z1 is O can be prepared by reacting a compound of Formula 17 wherein Za is a hydroxy group attached to an X1 or X4 ring with a strong base such as sodium hydride followed by treatment with a compound of Formula 18 wherein T is a halogen, while treatment with a compound of Formula 18 wherein T is a methyl halide or a haloketone will give a compound of Formula 1 wherein Z1 is -OCH2- or -OCH2C(=0)-, respectively. Compounds of Formula 1 wherein Z1 is -C(R7a)=NO- can be prepared by reacting a compound of Formula 17 wherein Za is an aldehyde or ketone with a compound of Formula 18 wherein T is an aminooxy group. Compounds of Formula 1 wherein Z1 is -NR7^C(=0)- can be prepared by reacting a compound of Formula 17 wherein Za is an amine with a compound of Formula 18 wherein T is an acid chloride in the presence of a base. Compounds of Formula 1 wherein Z1 is -SCH2CH2- can be prepared by reacting a compound of Formula 17 wherein Za is SH with a compound of Formula 18 wherein T is 2-iodoethyl in the presence of a base, which can be subsequent oxidized to give a compound of Formula 1 wherein Z1 is -S(=0)CH2CH2- or -S(=0)2CH2CH2-.
Intermediate compounds of Formula 17 are known and can be prepared by methods known to one skilled in the art. Also Example 2 (Step B) illustrates the preparation of a compound of Formula 17.
wherein Z
Figure imgf000055_0001
group for construction of the functional group for construction
desired Z 1 group of the desired Z 1 group
As shown in Scheme 12, compounds of Formula 1 can also be prepared by reacting a compound of Formula 19 with a compound of Formula 20 wherein Zc and Z^ are suitable functional groups which under the appropriate reaction conditions will allow the construction of the various Z2 groups. Suitable functional groups include, but are not limited to, ionizable hydrogen, carbonyl, aldehyde, ketone, ester, acid, acid chloride, amine, alcohol, thiol, hydrazine, oxime, olefin, acetylene, halide, alkyl halide, methanesulfonate, trifluoromethanesulfonate, boronic acid, boronate, and the like. For example, compounds of Formula 1 wherein Z2 is O can be prepared by reacting a compound of Formula 19 wherein Zc is halogen with a compound of Formula 20 wherein Z^ is hydroxy in the presence of a strong base such as sodium hydride, while treatment with a compound of Formula 20 wherein Z^ is a hydroxymethyl will give a compound of Formula 1 wherein Z2 is -OCH2-. Reaction of a compound of Formula 19 wherein Zc is hydroxy with a strong base such as sodium hydride, followed by treatment with a compound of Formula 20 wherein Z^ is methyl halide (e.g., C1CH2-) or haloketone (e.g., C1CH2C(=0)-) will give a compound of Formula 1 wherein Z2 is -OCH2- or -OCH2(C=0)-, respectively. Compounds of Formula 1 wherein Z2 is -C(=0)N(R7^)- can be prepared by reacting a compound of Formula 19 wherein Zc is an acid moiety with a compound of Formula 20 wherein Z^ is an amino group in the presence of a coupling reagent, while treatment with a compound of Formula 20 wherein Z^ is aminomethyl will give a compound of Formula 1 wherein Z2 is -C(=0)N(R7b)CH2-. Compounds of Formula 1 wherein Z2 is -NR7bC(=0)- can be prepared by reacting a compound of Formula 19 wherein Zc is an amino group with a compound of Formula 20 wherein Z^ is an acid chloride in the presence of a base. Compounds of Formula 1 wherein Z2 is -CH2S- can be prepared by reacting a compound of Formula 19 wherein Zc is methyl halide (e.g., C1CH2-) with a compound of Formula 20 wherein Zd is SH in the presence of a base, which can be subsequent oxidized to give a compound of Formula 1 wherein Z2 is -CH2S(=0)C- or -CH2S(=0)2-. Intermediate compounds of Formula 20 are known and can be prepared by methods known to one skilled in the art.
Scheme 12
wherein Zc
Figure imgf000056_0001
group for construction of the functional group for construction
2 2
desired Z group of the desired Z group As the synthetic literature describes many general methods for forming saturated, partially unsaturated or fully unsaturated 1- to 3-membered chains consisting of carbon atoms and heteroatoms such as the Z1 and Z2 chains of the present invention, the synthetic methods of Schemes 11 and 12 are simply representative examples of a wide variety of methods useful for the preparation of compounds of Formula 1. For representative references; see, for example, Comprehensive Organic Functional Group Transformations, Vol. 1, 2, 3 and 5, A. R. Katritzky editor, Pergamon Press, New York, 1995; Vogel's Textbook of Practical Organic Chemistry, 5th Ed., pp 470-823, Longman Group, London, 1989; and Advanced Organic Chemistry, 4th Ed. Jerry March, Wiley, New York 1992. Also, Example 2 (Step D) illustrates the method of Scheme 11; and Example 5 (Step B) illustrates the method of Scheme 12. One skilled in the art can easily determine how to select an appropriate compound of Formulae 17 and 18 or Formulae 19 and 20 to construction the desired Z1 and Z2 groups, respectively.
One skilled in the art will recognize that the method of Scheme 12 can be performed when the substituent E-X-Z n Formula 19 is replaced with T thus providing a compound of Formula 18, which can be reacted with a compound of Formula 17 as described in Scheme 11. Example 1 (Step D), Example 2 (Step C) and Example 4 (Step B) illustrate this method for preparing a compound of Formula 18.
Alternatively, as shown in Scheme 13, compounds of Formula 18 can be prepared by reacting a compound of Formula 21 with a compound of Formula 22 wherein Ya and are suitable functional groups which under the appropriate reaction conditions will allow the construction of the heterocyclic ring G and the chain Z2. Suitable functional groups include, but are not limited to, hydroxy, thiol, amine, carbonyl, aldehyde, ester, acid, acid chloride, amide, thioamide, cyano, halide, alkyl halide, and the like. The synthetic literature describes many general methods for forming heterocyclic rings which can be readily adapted to prepare compounds of the present method; see, for example, Heterocyclic Compounds, Vol. 5, R. C. Elderfield, Ed., Wiley, New York. 1957, which describes methods for preparing benzofused oxazoles, thiazoles and imidazoles; Comprehensive Heterocyclic Chemistry, Vol. 4-6, A. R. Katritzky and C. W. Rees editors, Pergamon Press, New York, 1984; Comprehensive Heterocyclic Chemistry II, Vol. 2-4, A. R. Katritzky, C. W. Rees, and E. F. Scriven editors, Pergamon Press, New York, 1996; and the series, The Chemistry of Heterocyclic Compounds, E. C. Taylor, editor, Wiley, New York. Also, Example 1 (Step B) illustrates the method of Scheme 13. One skilled in the art can easily determine how to select an appropriate compound of Formula 21 and Formula 22 to construct the desired G-Z2 moiety. Scheme 13
Figure imgf000058_0001
21 22 18
wherein Ya is a suitable wherein Y^ is a suitable
functional group for functional group for
construction of the construction of the
desired herterocyclic desired herterocyclic ring
2 2
ring and Z chain and Z chain
As shown in Scheme 14, compounds of Formula 23 wherein PG is an amine protecting group can be deprotected to provide amines of Formula 3. A wide array of amine protecting groups are suitable for the method of Scheme 14; see, for example, T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991. The choice of the appropriate protecting groups will be apparent to one skilled in the art. After deprotection, the amine of Formula 3 can be isolated as its acid salt or the free amine by general methods known in the art. Example 1 (Step F), Example 3 (Step C) and Example 4 (Step D) illustrate the method of Scheme 14.
Scheme 14
PG. ^Zi .zl 71 72
( , Q deprotec •ttiinomn η " ^. ^ , ^
X G Q
23 3
wherein PG is an amine protecting
group attached to the nitrogen
atom in the X ring
Compounds of Formula 23 can be prepared by methods analogous to those described in Scheme 11 and Scheme 12 above wherein the group E is replaced by PG. Also, Example 1 (Step E), Example 3 (Step A) and Example 4 (Step C) illustrate the preparation of a compound of Formula 23.
Numerous other methods for preparation of compounds of Formula 1 and useful intermediates for their preparation exist in the art and are well-known to one skilled in the art. For representative procedures relevant to constructing rings X1 through X4; see, for example, Comprehensive Heterocyclic Chemistry, Vol. 3 and 7, A. R. Katritzky and C. W. Rees editors, Pergamon Press, New York, 1984; Comprehensive Heterocyclic Chemistry II, Vol. 6 and 9, A. R. Katritzky, C. W. Rees, and E. F. Scriven editors, Pergamon Press, New York, 1996; and the series, The Chemistry of Heterocyclic Compounds, E. C. Taylor, editor, Wiley, New York. For specific examples see methods outlined PCT Patent Publication WO 2011/085170. It is recognized by one skilled in the art that various functional groups can be converted into others to provide different compounds of Formula 1. For example, conversion of compounds of Formula 1 wherein W is O to the corresponding compounds wherein W is S can be accomplished using a variety of standard thiating reagents such as phosphorus pentasulfide or 2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4- disulfide (Lawesson's reagent).
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, Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). One skilled in the art will recognize that, in some cases, after the introduction of a given reagent as it is depicted in any individual scheme, it may be necessary to perform additional routine synthetic steps not described in detail to complete the synthesis of compounds of Formula 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.
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. Steps in the following 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. ¾ NMR spectra are reported in ppm downfield from tetramethylsilane in CDCI3 unless otherwise noted; "s" means singlet, "d" means doublet, "t" means triplet, "m" means multiplet, and "br s" means broad singlet. EXAMPLE 1
Preparation of 1 -[4-[[5-[(2,6-difluorophenoxy)methyl]-4,5-dihydro-3-isoxazolyl]methyl]- 1 - piperazinyl]-2- [5 -methyl-3 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl] ethanone (Compound 35)
Step A: Preparation of 1,3 -difluoro-2-(2-propen-l-yloxy)benzene
To a mixture of potassium carbonate (15.2 g, 0.11 mol) in acetone (75 mL) was added 2,6-difluorophenol (13.0 g, 0.10 mol) followed by allyl bromide (12.1 g, 0.10 mol), dropwise. Additional acetone (25 mL) was added to the reaction mixture and the mixture was stirred at room temperature overnight. The reaction mixture was heated at 50 °C for 1 h, cooled and filtered. The solids collected were washed with acetone and the combined filtrate and washings were concentrated under reduced pressure. The resulting oil was dissolved in petroleum ether (100 mL), washed with aqueous sodium hydroxide (10%), water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a colorless oil (15.6 g).
in NMR (CDCI3): δ 4.64 (m, 2H), 5.25 (m, 1H), 5.36 (m, 1H), 6.03-6.08 (m, 1H), 6.86-6.97 (m, 3H).
Step B: Preparation of ethyl 5-[(2,6-difluorophenoxy)methyl]-4,5-dihydro-3- isoxazolecarboxylate
To a mixture of l,3-difluoro-2-(2-propen-l-yloxy)benzene (i.e. the product of Step A) (3.40 g, 20 mmol) and ethyl 2-chloro-2-(hydroxyimino)acetate (3.03 g, 20 mmol) in ethyl acetate (100 mL) was added sodium bicarbonate (5.0 g, 60 mmol). The reaction mixture was stirred at room temperature for eight days, and then filtered, washing with ethyl acetate. The combined filtrate and washings were concentrated under reduced pressure to give the title compound as a light yellow oil (5.57 g).
!H NMR (CDCI3): δ 3.7 (t, 3H), 3.64 (m, 2H), 4.29 (m, 2H), 4.36 (m, 2H), 5.10 (m, 1H), 6.86-6.97 (m, 3H).
Step C: Preparation of 5-[(2,6-difluorophenoxy)methyl]-4,5-dihydro-3- isoxazolemethanol
A mixture of ethyl 5-[(2,6-difluorophenoxy)methyl]-4,5-dihydro-3- isoxazolecarboxylate (i.e. the product of Step B) (3.57 g, 12.5 mmol) in ethanol (25 mL) was cooled to 0 °C and sodium borohydride (0.76 g, 20 mmol) was added portionwise over 15 minutes. The reaction mixture was allowed to warm to room temperature, stirred for 20 h, and then concentrated under reduced pressure. The resulting material was acidified with aqueous hydrochloric acid (1 N) while maintaining the temperature at about 0 °C. The resulting mixture was extracted with ethyl acetate and the organic extract was washed with aqueous sodium bicarbonate and aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a colorless oil (2.7 g).
!H NMR (CDCI3): δ 2.04 (br s, 1H), 3.22 (m, 2H), 4.19-4.38 (m, 2H), 4.46 (s, 2H), 4.80- 5.00 (m, 1H), 6.85-7.00 (m, 3H).
Step D: Preparation of 3-(chloromethyl)-5-[(2,6-difluorophenoxy)methyl]-4,5- dihydroisoxazole
To a mixture of 5-[(2,6-difluorophenoxy)methyl]-4,5-dihydro-3-isoxazolemethanol) (i.e. the product of Step C) (2.50 g, 10.3 mmol) in dichloromethane (30 mL) was added thionyl chloride (1.5 mL, 20 mmol). The reaction mixture was stirred at room temperature for 16 h, and then concentrated under reduced pressure. The resulting material was filtered through a pad of silica gel with the aid of ethyl acetate, and the filtrate was concentrated under reduced pressure to give an amber oil (2.55 g). The oil was purified by medium pressure liquid chromatography on silica gel (40 g) (0 to 30% gradient of ethyl acetate in hexanes as eluant) to provide the title compound as an amber oil (2.3 g).
!H NMR (CDCI3): δ 3.24-3.35 (m, 2H), 4.19-4.25 (m, 2H), 4.30-4.40 (m, 2H), 4.90-5.10 (m, 1H), 6.85-7.00 (m, 3H).
Step E: Preparation of 1,1-dimethylethyl 4-[[5-[(2,6-difluorophenoxy)methyl]-4,5- dihydro-3-isoxazolyl]methyl]- 1 -piperazinecarboxylate
A mixture of 3-(chloromethyl)-5-[(2,6-difluorophenoxy)methyl]-4,5-dihydroisoxazole (i.e. the product of Step D) (0.52 g, 2.0 mmol), 1,1-dimethylethyl ester 1-piperazinecarboxylic acid, (0.37 g, 2.0 mmol) and potassium carbonate (0.40 g, 2.9 mmol) in acetonitrile (10 mL) was heated at 45 °C for 6 days, cooled, and stirred at room temperature overnight. The reaction mixture was partitioned between water and diethyl ether and the organic phase was separated. The organic phase was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as an amber oil (0.78 g).
!H NMR (CDCI3): δ 1.46 (s, 9H), 2.38-2.48 (m, 4H), 3.10-3.25 (m, 2H), 3.28 (s, 2H), 3.40-
3.47 (m 4 H), 4.15-4.22 (m, 2H), 4.85-4.95 (m, 1H), 6.85-7.00 (m, 3H).
Step F: Preparation of l-[4-[[5-[(2,6-difluorophenoxy)methyl]-4,5-dihydro-3- isoxazolyl]methyl]- 1 -piperazinyl]-2-[5-methyl-3-(trifluoromethyl)- 1H- pyrazol- 1 -yljethanone
To a mixture of 4-[[5-[(2,6-difluorophenoxy)methyl]-4,5-dihydro-3- isoxazolyl]methyl]-l -piperazinecarboxylate (i.e. the product of Step E) (0.78 g, 1.9 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1.0 mL). The reaction mixture was stirred at room temperature for 3 days, and then concentrated under reduced pressure. The resulting material was dissolved in ethyl acetate, washed with aqueaous sodium bicarbonate and aqueaous saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give l-[[5-[(2,6-difluorophenoxy)methyl]-4,5- dihydro-3-isoxazolyl]methylpiperazine as an amber oil (0.44 g).
A mixture of l-[[5-[(2,6-difluorophenoxy)methyl]-4,5-dihydro-3- isoxazolyl]methylpiperazine (0.147 g, 0.47 mmol), 5-methyl-3-(trifluoromethyl)-lH- pyrazole-1 -acetic acid, (104 mg, 0.5 mmol), N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (150 mg, 0.78 mmol), 1 -hydroxy- lH-benzotriazole (about 2 mg) and triethylamine (75 uL, 0.53 mmol) in dichloromethane (10 mL) was vortexed at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with aqueous hydrochloric acid (1 N) and aqueous sodium hydroxide (1 N), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound, a compound of the present invention, as a tan solid (198 mg).
lH NMR (CDCI3): δ 2.31 (s, 3H), 2.45-2.55 (m, 4H), 3.10-3.25 (m, 2H), 3.31 (s, 2H), 3.52- 3.70 (m, 4 H), 4.15-4.28 (m, 2H), 4.87-4.94 (m, 1H), 4.95 (s, 2H), 6.33 (s, 1H), 6.85-7.00 (m, 3H).
EXAMPLE 2
Preparation of 1 -[4-[[6-[(2,6-difluorophenyl)methoxy]-3-pyridazinyl]oxy]- 1 -piperidinyl]-2-
[5-methyl-3-(trifluoromethyl)- lH-pyrazol- 1 -yljethanone (Compound 13) Step A: Preparation of 5-methyl-3-(trifluoromethyl)-lH-pyrazole-l -acetyl chloride
A mixture of 5-methyl-3-(trifluoromethyl)-lH-pyrazole-l -acetic acid (5.2 g, 25 mmol) in dichloromethane (70 mL) and N,N-dimethylformamide (2 drops) was cooled to 0 °C and oxalyl chloride (4.76 g, 37.5 mmol) in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at room temperature for 16 h, and then concentrated under reduced pressure to give the title compound as a slightly yellowish solid (5.64 g).
!H NMR (CDC13): δ 6.38 (s, 1H), 5.27 (s, 2H), 2.31 (s, 3H).
Step B: Preparation of l-(4-hydroxy-l-piperidinyl)-2-[5-methyl-3-(trifluoromethyl)- lH-pyrazol- 1 -yljethanone
A mixture of 4-hydroxypiperidine (10.1 g, 0.1 mol) and triethylamine (13.06 ml, 0.15 mol) in dichloromethane (120 mL) was cooled to 0 °C, and then 5-methyl-3- (trifluoromethyl)-lH-pyrazole-l -acetyl chloride (i.e. the product of Step A) (22.66 g, 0.1 mole) in dichloromethane (100 mL) was added dropwise. The reaction mixture was stirred for 16 h at room temperature, and then filtered, washing with dichloromethane. The combined filtrate and washings were concentrated under reduced pressure. The resulting material was dissolved in methanol (200 mL) and aqueous sodium hydroxide (I N) (100 mL), stirred for 2 to 3 h, and then aqueous hydrochloric acid (1 N) (100 mL) was added. The methanol was removed under reduced pressure and the resulting mixture was extracted with ethyl acetate. The organic extract was washed with aqueous hydrochloric acid (1 N), saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a white solid (16.4 g).
!H NMR (CDCI3): δ 6.33 (s, 1H), 4.97 (s, 2H), 3.92-4.02 (m, 2H), 3.74-3.83 (m, 1H), 3.3- 3.4 (m, 2H), 2.3 (s, 3H), 1.9-1.95 (m, 3H), 1.46-1.58 (m, 2H).
Step C: Preparation of 3-chloro-6-[(2,6-difluorophenyl)methoxypyridazine
To a mixture of sodium hydride (60% dispersion in mineral oil, 960 mg, 24 mmol) in tetrahydrofuran (20 mL) was added dropwise 2,6-difluorobenzenemethanol (1.15 g, 8 mmol) in tetrahydrofuran (4 mL). The reaction mixture was heat at 60 °C and stirred for 1 h, and then 3,6-dichloropyridazine (3.58 g, 24 mmol) in tetrahydrofuran (10 mL) was added dropwise. The reaction mixture was stirred for 4 h at 55 °C, cooled, and saturated aqueous sodium bicarbonate (10 mL) was added. The tetrahydrofuran was removed under reduced pressure and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered concentrated under reduced pressure. Water was added to the resulting material and the solid precipitate was collected by filtration, washed with water and dried to give the title compound (1.69 g).
!H NMR (CDCI3): δ 7.32-7.41 (m, 2H), 6.92-7.02 (m, 3H), 5.62 (s, 2H).
Step D: Preparation of l-[4-[[6-[(2,6-difluorophenyl)methoxy]-3-pyridazinyl]oxy]-l- piperidinyl] -2-[5 -methyl-3 -(trifluoromethyl)- lH-pyrazol- 1 -yl] ethanone To a mixture of sodium hydride (60% dispersion in mineral oil, 60 mg, 1.5 mmol) in N,N-dimethylformamide (7 mL) at 0 °C was added portionwise l-(4-hydroxy-l-piperidinyl)- 2-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]ethanone (i.e. the product of Step B) (349 mg, 1.2 mmol). The reaction mixture was allowed to warm to room temperature, stirred for 1 h, and then 3-chloro-6-[(2,6-difluorophenyl)methoxypyridazine (i.e. the product of Step C) (256 mg, 1 mmol) was added portionwise and stirring was continued for 16 h at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by medium pressure liquid chromatography on a silica gel (0 to 100% gradient of ethyl acetate in hexanes as eluant) to give the title compound (41 mg), a compound of the present invention. !H NMR (CDCI3): δ 7.3-7.4 (m, 1H), 6.9-7.0 (m, 4H), 6.33 (s, 1H), 5.53 (s, 2H), 5.4-5.5 (m, 1H), 4.95-5.04 (m, 2H), 3.77-4.02 (m, 2H), 3.44-3.52 (m, 2H), 2.32 (s, 3H), 2.03-2.21 (m, 2H), 1.80-1.91 (m, 2H). EXAMPLE 3
Preparation of 1,1,1 -trifluoro-2-propanone O-[2-[4-[[6-[(2,6-difluorophenyl)methoxy]-3- pyridazinyl]oxy]-l-piperidinyl]-2-oxoethyl]oxime (Compound 16)
Step A: Preparation of 1 , 1 -dimethylethyl 4-[[6-[(2,6-diflurophenyl)methoxy]-3- pyridazinyljoxy- 1 -piperidinecarboxylate
To a mixture of sodium hydride (60% dispersion in mineral oil, 180 mg, 4.5 mmol) in N,N-dimethylformamide (7 mL) was added 4-hydroxy-l-piperidinecarboxylic acid- 1,1- dimethylethyl ester (603.81 mg, 3 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was stirred for 1 h at 60 °C, cooled to room temperature and 3-chloro-6-[(2,6- difluorophenyl)methoxypyridazine (i.e. the product of Example 2, Step C) (768 mg, 3 mmol) in N,N-dimethylformamide (5 mL) was added dropwise. The reaction mixture stirred for 16 h at 55 °C, after which time saturated aqueous sodium bicarbonate was added and the resulting mixture was extracted with diethyl ether. The organic extract was washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by medium pressure liquid chromatography on a silica gel (0 to 60% gradient of ethyl acetate in hexanes as eluant) to give the title compound (110 mg). !H NMR (CDCI3): δ 7.3-7.4 (m, 1H), 6.92-6.97 (m, 4H), 5.53 (s, 2H), 5.31-5.40 (m, 1H), 3.77-3.90 (m, 2H), 3.2-3.3 (m, 2H), 2.04-2.14 (m, 2H), 1.69-1.81 (m, 2H).
Step B: Preparation of 2-[[2,2,2-trifluoro-l-methylethylidene)amino]oxy]acetic acid To a mixture of O-(carboxymethyl)hydroxylamine hemihydrochloride (4.38 g,
20 mmol) in tetrahydrofuran (25 mL) at 0 °C was added l,l,l-trifluoro-2-propanone (5.6 g, 50 mmol). The reaction mixture was allowed to slowly warm to room temperature and stirred for 24 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a white powder.
!H NMR (CDCI3): δ 2.07 (s, 3H), 4.80 (s, 2H).
Step C: Preparation of 1,1,1 -trifluoro-2-propanone O-[2-[4-[[6-[(2,6- difluorophenyl)methoxy] -3 -pyridazinyljoxy] - 1 -piperidinyl] -2- oxoethyljoxime
To a mixture of 1,1 -dimethylethyl 4-[[6-[(2,6-diflurophenyl)methoxy]-3- pyridazinyljoxy- 1 -piperidinecarboxylate (i.e. the product of Step A) (129 mg, 0.31 mmol) in methanol (2 mL) was added hydrogen chloride (2 M in diethyl ether) (1.55 ml, 3.1 mmol). The reaction mixture was stirred for 2.5 h at room temperature. The resulting solid precipitate was collected by filtration, washed with cold diethyl ether and dried to give 3- [(2,6-difluorophenyl)methoxy]-6-(4-piperidinyloxy)pyridazine hydrochloride as a white powder (45 mg).
A mixture of 3-[(2,6-difluorophenyl)methoxy]-6-(4-piperidinyloxy)pyridazine hydrochloride (45 mg, 0.13 mmol), 2-[[2,2,2-trifluoro-l-methylethylidene)amino]oxy]acetic acid (i.e. the product of Step B) (29 mg, 0.16 mmol), N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (30.67 mg, 0.16 mmol), 1 -hydroxy- lH-benzotriazole (about 2 mg, 0.015 mmol) and triethylamine (42 uL, 0.3 mmol) in dichloromethane (2 mL) was stirred for 16 h at room temperature. The reaction mixture was diluted with dichloromethane, washed with aqueous hydrochloric acid (1 N), saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by medium pressure liquid chromatography on silica gel (4 g) (0 to 100% gradient of ethyl acetate in hexanes as eluant) to give the title compound (24 mg), a compound of the present invention.
1Η NMR (CDC13): δ 7.3-7.4 (m, 1Η), 6.93-6.97 (m, 4Η), 5.54 (s, 2Η), 5.40-5.49 (m, 1Η), 4.9 (s, 2Η), 3.99-4.08 (m, 1Η), 3.65-3.71 (m, 1Η), 3.42-3.51 (m, 1Η), 3.32-3.42 (m, 1Η), 2.09-2.20 (m, 2Η), 2.087 (s, 3Η), 1.8-1.9 (m, 2Η).
EXAMPLE 4
Preparation of 1 -[4-[[6-[(2,6-difluorophenoxy)methyl]-3-pyridazinyl]oxy]- 1 -piperidinyl]-2- [5-methyl-3-(trifiuoromethyl)-lH-pyrazol-l-yl]ethanone (Compound 17)
Step A: Preparation of 3-(bromomethyl)-6-chloro-pyridazine
A mixture of 3-chloro-6-methylpyridazine (5.14 g, 40 mmol), N-bromosuccinimide
(7.19 g, 10.1 mmol) and 2,2'-azobis(2-methylpropionitrile) (657 mg, 4 mmol) in carbon tetrachloride (100 mL) was heated at reflux overnight. The reaction mixture was cooled and filtered, washing with carbon tetrachloride. The combined filtrate and washings were concentrated under reduced pressure. The resulting material was purified by medium pressure liquid chromatography on silica gel (0 to 50% gradient of ethyl acetate in hexanes as eluant) to give the title compound an oil (1.59 g).
!H NMR ^DC^): δ 7.65-7.67 (m, 1H), 7.55-7.57 (m, 1H), 4.72 (s, 2H).
Step B: Preparation of 3-chloro-6-[(2,6-difluorophenoxy)methyl]pyridazine
A mixture of 3-(bromomethyl)-6-chloro-pyridazine (i.e. the product of Step A) (1.59 g,
7.66 mmol), 2,6-difiuorophenol (996.5 mg, 7.66 mmol) and potassium carbonate (1.59 g,
11.5 mmol) in N,N-dimethylformamide (5 mL) was stirred for 16 h at room temperature.
The reaction mixture was diluted with water; the solid precipitate was collected by filtration, washed with water and dried to give the title compound as a light brown solid (1.73 g).
!H NMR (CDCI3): δ 7.90-7.92 (m, 1H), 7.60-7.62 (m, 1H), 6.99-7.07 (m, 1H), 6.90-6.98 (m,
2H), 5.49 (s, 2H).
Step C : Preparation of 1 , 1 -dimethylethyl 4-[[6-[(2,6-difiuorophenoxy)methyl]-3- pyridazinyljoxy]- 1 -piperidinecarboxylate
To a mixture of sodium hydride (60% dispersion in mineral oil, 414 mg, 10.3 mmol) in
N,N-dimethylformamide (7 mL) was added 4-hydroxy-l-piperidinecarboxylic acid- 1,1- dimethylethyl ester (1.39 g, 6.9 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was stirred for 1 h at 60 °C, cooled to room temperature and 3-chloro-6-[(2,6- difluorophenoxy)methyl]pyridazine (i.e. the product of Step B) (1.77 g, 6.9 mmol) in N,N- dimethylformamide (5 mL) was added dropwise. The reaction mixture was stirred for 16 h at 55 °C, and then saturated aqueous sodium bicarbonate was added and the resulting mixture was extracted with diethyl ether. The organic extract was washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by medium pressure liquid chromatography on a silica gel (0 to 60% gradient of ethyl acetate in hexanes as eluant) to give of the title compound (170 mg).
!H NMR (CDCI3): δ 7.8 (d, 1H), 6.94-7.05 (m, 2H), 6.86-6.93 (m, 2H), 5.44-5.52 (m, 1H), 5.38 (s, 2H), 3.73-3.84 (m, 2H), 3.21-3.31 (m, 2H), 2.03-2.14 (m, 2H), 1.70-1.82 (m, 2H), 1.48 (s, 9H).
Step D: Preparation of l-[4-[[6-[(2,6-difluorophenoxy)methyl]-3-pyridazinyl]oxy]-l- piperidinyl] -2-[5 -methyl-3 -(trifluoromethyl)- lH-pyrazol- 1 -yl] ethanone To a mixture of 1,1-dimethylethyl 4-[[6-[(2,6-difluorophenoxy)methyl]-3- pyridazinyl]oxy]-l-piperidinecarboxylate (i.e. the product of Step C) (180 mg, 0.43 mmol) in methanol (2 mL) was added hydrogen chloride (2 M in diethyl ether) (2.15 ml, 4.3 mmol). The reaction mixture was stirred for 4 h at room temperature, and then concentrated under reduced pressure to give 3-[(2,6-difluorophenoxy)methyl]-6-(4-piperidinyloxy)pyridazine hydrochloride.
A mixture of 3-[(2,6-difluorophenoxy)methyl]-6-(4-piperidinyloxy)pyridazine hydrochloride (0.43 mmol) and triethylamine (176 uL, 1.3 mmol) in dichloromethane (5 mL) was cooled to 0 °C and (5-methyl-3-(trifluoromethyl)-lH-pyrazole-l -acetyl chloride (i.e. the product of Example 2, Step A) (118 mg, 0.52 mmol) in dichloromethane (2 mL) was added dropwise. The reaction mixture was stirred at room temperature for 16 h, and then diluted with dichloromethane. The resulting mixture was washed with aqueous hydrochloric acid (1 N), saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (186 mg), a compound of the present invention.
in NMR (CDCI3): δ 7.90-7.91 (d, 1H), 7.05-7.06 (d, 1H), 6.86-7.01 (m, 3H), 6.33 (s, 1H), 5.51-6.01 (m, 1H), 5.38 (s, 2H), 4.93-5.02 (m, 2H), 3.96-4.00 (m, 1H), 3.79-3.84 (m, 1H), 3.43-3.58 (m, 2H), 2.31 (s, 3H), 2.08-2.20 (m, 2H), 1.80-1.91 (m, 2H). EXAMPLE 5
Preparation of l-[4-[[6-(2,6-difluorophenoxy)-3-pyridazinyl]methoxy]-l-piperidinyl]-2-[5- methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]ethanone (Compound 22) Step A: Preparation of 1 -[4-[(6-chloro-3-pyridazinyl)methoxy]- 1 -piperidinyl]-2-[5- methyl-3-(trifluoromethyl)- lH-pyrazol- 1 -yljethanone
To a mixture of sodium hydride (60% dispersion in mineral oil, 52 mg, 1.3 mmol) in tetrahydrofuran (2 mL) was added l-(4-hydroxy-l-piperidinyl)-2-[5-methyl-3- (trifluoromethyl)-lH-pyrazol-l-yl]ethanone (i.e. the product of Example 2, Step B) (291.28 mg, 1 mmol). The reaction mixture was stirred at room temperature for 30 minutes, and then heat at 55 °C for 30 minutes. A solution of 3-(bromomethyl)-6-chloro-pyridazine (i.e. the product of Example 4, Step A) (170 mg, 0.82 mmol) in a mixture of tetrahydrofuran and N,N-dimethylformamide (2 mL, 2:1) was added to the reaction mixture and stirring was continued for 16 h at 55 °C. The reaction mixture was concentrated under reduced pressure, partitioned between water and ethyl acetate and the organic layer was separated. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by medium pressure liquid chromatography on a silica gel (0 to 100% gradient of ethyl acetate in hexanes as eluent) to give the title compound (43 mg).
!H NM (CDCI3): δ 7.63-7.66 (m, 1H), 7.53-7.56 (m, 1H), 6.33 (s, 1H), 4.97 (s, 2H), 4.87 (s, 2H), 3.81-3.89 (m, 1H), 3.73-3.80 (m, 2H), 3.39-3.55 (m, 2H), 2.31 (s, 3H).
Step B: Preparation of l-[4-[[6-(2,6-difluorophenoxy)-3-pyridazinyl]methoxy]-l- piperidinyl] -2-[5 -methyl-3 -(trifluoromethyl)- lH-pyrazol- 1 -yl] ethanone A mixture of l-[4-[(6-chloro-3-pyridazinyl)methoxy]-l-piperidinyl]-2-[5-methyl-3- (trifluoromethyl)-lH-pyrazol-l-yl]ethanone (i.e. the product of Step A) (69 mg, 0.17 mmol), 2,6-difluorophenol (44.23 mg, 0.34 mmol) and potassium carbonate (69 mg, 0.5 mmol) was irradiated in a microwave for 1 h at 150 °C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by medium pressure liquid chromatography on silica gel (4 g) (0 to 100% gradient of ethyl acetate in hexanes as eluent) to give the title compound (22 mg), a compound of the present invention.
in NMR (CDCI3): δ 7.7.70-7.72 (m, 1H), 7.38-7.40 (m, 1H), 7.17-7.24 (m, 1H), 6.99-7.08 (m, 2H), 6.32 (m, 1H), 4.96 (s, 2H), 4.8 (s, 2H), 3.80-3.88 (m, 1H), 3.72-3.99 (m, 2H), 3.36- 3.45 (m, 2H), 2.31 (s, 3H), 1.83-1.92 (m, 2H), 1.62-1.71 (m, 2H).
By the procedures described herein together with methods known in the art, the following compounds of Tables 1 to 12 can be prepared. The following abbreviations are used in the Tables which follow: n means normal, i means iso, c means cyclo, Me means methyl, MeO means methoxy, MeS means methylthio, Et means ethyl, EtO means ethoxy, c-Pr means cyclopropyl, Bu means butyl, c-Bu means cyclobutyl, z'-BuO means isobutoxy, CN means cyano, Ph means phenyl and NO2 means nitro.
In Tables 7, 8, 1 1 and 12 under the column heading "E" is an entry selected from E-la
Figure imgf000068_0001
-lg E-lh E-li E-lj
Figure imgf000068_0002
E-2c E-2d Table 1
Figure imgf000069_0001
Figure imgf000070_0001
The present disclosure also includes Tables 1-A through 1-AY, each of which are constructed the same as Table 1 above except that the row heading in Table 1 (i.e. "A is CH2, W is O, Xa is CH, Z1 is O and Z2 is OCH2") is replaced with the respective row headings shown below. For example, in Table 1-A the row heading is "A is NH, W is O, Xa is CH, Z1 is O and Z2 is OCH2" and R1 is as defined in Table 1 above. Thus, the first entry in Table 1-A specifically discloses 4-[[6-[(2,6-difluorophenyl)methoxy]-3-pyridazinyl]oxy- N-phenyl-l-piperidinecarboxamide. Tables 1-B through 1-AY are constructed similarly.
Table Row Heading
1-A A is NH, W is O, Xa is CH, Z1 is O and Z2 is OCH2.
1-B A is CH2, W is O, Xa is N, Z 1 is CH2 and Z2 is OCH2.
1-C A is NH, W is O, Xa is N, Z1 is CH2 and Z2 is OCH2.
1 -D A is CH2, W is O, Xa is CH, Z 1 is O and Z2 is CH20.
1-E A is NH, W is O, Xa is CH, Z1 is O and Z2 is CH20.
1 -F A is CH2, W is O, Xa is N, Z 1 is CH2 and Z2 is CH20.
1 -G A is NH, W is O, Xa is N, Z 1 is CH2 and Z2 is CH20.
1-H A is CH2, W is S, Xa is CH, Z1 is O and Z2 is OCH2.
1-1 A is NH, W is S, Xa is CH, Z1 is O and Z2 is OCH2.
1 - J A is CH2, W is S, Xa is N, Z 1 is CH2 and Z2 is OCH2.
1-K A is NH, W is S, Xa is N, Z1 is CH2 and Z2 is OCH2.
1-L A is CH2, W is O, Xa is CH, Z1 is O and Z2 is O.
1-M A is NH, W is O, Xa is CH, Z1 is O and Z2 is O.
1 -N A is CH2, W is O, Xa is N, Z 1 is CH2 and Z2 is O.
l-O A is NH, W is O, Xa is N, Z1 is CH2 and Z2 is O.
1-P A is CH2, W is O, Xa is CH, Z1 is O and Z2 is S.
1-Q A is NH, W is O, Xa is CH, Z1 is O and Z2 is S.
1-R A is CH2, W is O, Xa is N, Z1 is CH2 and Z2 is S.
1-S A is NH, W is O, Xa is N, Z1 is CH2 and Z2 is S.
1-T A is CH2, W is O, Xa is CH, Z1 is O and Z2 is NH.
1-U A is NH, W is O, Xa is CH, Z1 is O and Z2 is NH.
1 -V A is CH2, W is O, Xa is N, Z 1 is CH2 and Z2 is NH.
1 - W A is NH, W is O, Xa is N, Z 1 is CH2 and Z2 is NH.
1-X A is CH2, W is O, Xa is CH, Z1 is O and Z2 is NHCH2.
1-Y A is NH, W is O, Xa is CH, Z1 is O and Z2 is NH CH2.
1-Z A is CH2, W is O, Xa is N, Z1 is CH2 and Z2 is NHCH2.
1-AA A is NH, W is O, Xa is N, Z1 is CH2 and Z2 is NHCH2.
1-AB A is CH2, W is O, Xa is CH, Z1 is OCH2 and Z2 is OCH2.
1 -AC A is CH2, W is O, Xa is CH, Z 1 is OCH2 and Z2 is CH20.
1 -AD A is CH2, W is O, Xa is CH, Z 1 is OCH2 and Z2 is O. Table Row Heading
1-AE A is CH2, w is o, Xa is CH, is OCH2 and Z2 is S.
1-AF A is CH2, w is o, Xa is CH, is OCH2 and Z2 is NH.
1-AG A is CH2, w is o, Xa is CH, is OCH2 and Z2 is NHCH2.
1-AH A is CH2, w is o, Xa is CH, is CH20 and Z2 is OCH2.
1-AI A is CH2, w is o, Xa is CH, is CH20 and Z2 is CH20.
1-AJ A is CH2, w is o, Xa is CH, is CH20 and Z2 is O.
1-AK A is CH2, w is o, Xa is CH, is CH20 and Z2 is S.
1-AL A is CH2, w is o, Xa is CH, is CH20 and Z2 is NH.
1-AM A is CH2, w is o, Xa is CH, is CH20 and Z2 is NHCH2.
1-AN A is CH2, w is o, Xa is CH, is C=ONH and Z2 is OCH2.
1-AO A is CH2, w is o, Xa is CH, is C=ONH and Z2 is CH20.
1-AP A is CH2, w is o, Xa is CH, is C=ONH and Z2 is O.
1-AQ A is CH2, w is o, Xa is CH, is C=ONH and Z2 is S.
1-AR A is CH2, w is o, Xa is CH, is C=ONH and Z2 is NH.
1-AS A is CH2, w is o, Xa is CH, is C=ONH and Z2 is NHCH2.
1-AT A is CH2, w is o, Xa is CH, is CH2 and Z2 is OCH2.
1-AU A is CH2, w is o, Xa is CH, is CH2 and Z2 is CH20.
1-AV A is CH2, w is o, Xa is CH, is CH2 and Z2 is O.
1-AW A is CH2, w is o, Xa is CH, is CH2 and Z2 is S.
1-AX A is CH2, w is o, Xa is CH, is CH2 and Z2 is NH.
1-AY A is CH2, w is o, Xa is CH, is CH2 and Z2 is NHCH2.
Table 2
Figure imgf000072_0001
A is CH2, W is O, Z1 is CH2 and Z2 is OC¾. A is CH2, W is O, Z1 is CH2 and Z2 is OC¾.
Rl Rl
Ph z-BuO
2-Me-Ph CF3CH2OCH2
2-MeO-Ph 3-Et-Ph
2-Cl-Ph 3-CF3-Ph
2-Br-Ph 3-CN-Ph
2-EtO-Ph 3-N02-Ph
2-MeS-Ph 2,5-di-Cl-Ph CH2, W is O, Z1 is CH2 and Z2 is OCH2. A is CH2, W is O, Z1 is CH2 and Z2 is OCH2. Rl Rl
3-Cl-Ph 5-Br-2-Cl-Ph
3-Br-Ph 2-Cl-5-Me-Ph
3-I-Ph 2-MeO-5-CF3-Ph 3-Me-Ph 2,5-di-Et-Ph
2-Cl-5-CF3-Ph 3 -Me- 1 /-pyrazol- 1 -yl
2,5-di-Br-Ph 3- Cl-l//-pyrazol-l-yl 2-Br-5-Me-Ph 3 -Br- l /-pyrazol- 1 -yl
2-Br-5-CF3-Ph 3-CF3-l /-pyrazol-l-yl
5-Cl-2-Me-Ph 3 ,5-di-Me- l/f-pyrazol- 1 -yl 5-Br-2-Me-Ph 3 -Cl-5-Me- l#-pyrazol- 1 -yl 2,5-di-Me-Ph 3 -Br-5-Me- l /-pyrazol- 1 -yl 2-Me-5-CF3-Ph 5-MeO-3-Me- l//-pyrazol- 1 -yl 5-CN-2-Me-Ph 3 , 5 -di-Et- 1 /-pyrazol- 1 -yl
2-Me-5-N02-Ph 5-Et-3-CF3- l#-pyrazol- 1 -yl 5-Cl-2-MeO-Ph 2,5-di-Me-3-furyl
5-Br-2-MeO-Ph 2,5-di-Me-3-thienyl
2-MeO-5-Me-Ph 2,5-di-Cl-3-thienyl
3 -Et-5-Me- l /-pyrazol- 1 -yl 1.4- di-Me- 1 /-pyrrol- 3 -yl
5 -Me-3 -CF3 - 1 / -pyrazol- 1 -yl 1 ,4-di-Me- l//-pyrazol-3-yl 5-Me-3-CF3CF2-l/ -pyrazol- l-yl l,3-di-Me-4- l//-pyrazol-4-yl
5-C1-3 -Me- ltf-pyrazol- 1 -yl 2,5-di-Me-4-oxazolyl
3,5-di-Cl-l /-pyrazol-l -yl 2.5- di-Me-4-thiazolyl
5-CI-3-CF3- ltf-pyrazol- 1 -yl 3.6- di-Me-2-pyridinyl
5-Br-3 -Me- l#-pyrazol- 1 -yl 2,5-di-Me-3-pyridinyl
3 ,5-di-Br- l /-pyrazol- 1 -yl 2.5- di-Me-4-pyridinyl
5-Br-3-CF3-l#-pyrazol- l-yl 3.6- di-Cl-2-pyridinyl
3- CHF2-l -pyrazol- l-yl 2,5-di-Cl-3-pyridinyl
3-CHF2-5-Me-l/ -pyrazol-l -yl 2.5- di-Cl-4-pyridinyl
3 ,5-bis-(CHF2)- ltf-pyrazol- 1 -yl 4-Br-3 -pyridazinyl
3,5-di-Me-2-thienyl 4- CF3 -2-pyrimidinyl
3,5-di-Cl-2-thienyl 3.6- di-Me-2-pyrazinyl
3,5-di-Me-2-furyl 2.5- di-Me-4-pyrimidinyl
4- Me-2-CF3-5-thiazolyl 4-MeO-5-pyrimidinyl
4-Me-2-CF3-5-oxazolyl 3.6- di-Me-4-pyridazinyl l-Me-4-CF3- l/ -imidazol-2-yl l-Me-4-CF3- l//-imidazol-2-yl
2,4-di-Me-li/-pyrrol-l -yl 3,5-bis-(CF3)-l//-pyrazol-l-yl CH2, W is O, Z1 is CH2 and Z2 is OCH2. A is CH2, W is O, Z1 is CH2 and Z2 is OCH2 Rl Rl
1 -Me-3 -CF3 - l /-pyrazol-5-yl 3-CI-5-CF3- ltf-pyrazol- 1 -yl 3-Br-5-CF3-l /-pyrazol- l-yl 3,5-bis-(CHF20)-l#-pyrazol-l-yl 3 -Me-5 -CF3 - 1 / -pyrazol- 1 -yl 3,5-di-MeO- l /-pyrazol- 1 -yl 3-MeO-5-CF3-l/ -pyrazol- l-yl 5-EtO-3-Me- l/f-pyrazol- 1 -yl
3,5-di-Br- l -pyrazol- 1 -yl 5-EtO-3-CF3-l /-pyrazol-l-yl 5-MeO-3 -Me- li -pyrazol- 1 -yl 3 ,5-di-Br- IH- 1 ,2,4-triazol- 1 -yl 5-MeO-3 -CF3 - ltf-pyrazol- 1 -yl 3-Cl-5-Me-l /-l,2,4-triazol-l-yl 3,5-di-Cl-l /-l,2,4-triazol-l-yl 3-Br-5-Me-l /-l,2,4-triazol-l-yl 3-Me-5-Cl- IH- 1 ,2,4-triazol- 1 -yl 3-CF3 -5-Cl- IH- 1 ,2,4-triazol- 1 -yl
3-Me-5-Br- IH- 1 ,2,4-triazol- 1 -yl 3-CF3 -5-Br- IH- 1 ,2,4-triazol- 1 -yl
3-CI-5-CF3 - IH- 1 ,2,4-triazol- 1 -yl 3 ,5-bis-(CF3)- IH- 1 ,2,4-triazol- 1 -yl 3-Br-5-CF3- \H- 1 ,2,4-triazol- 1 -yl CF3OCH2CH2
«-Bu MeOCH2CH20
(Me)2CHCH2CH2 CF3CH2CH20 CH3C(Me)=CHCH2 CF3CH2C(=0)0
HC≡CCH2 CH2=CHCH20 CF3CH2CH2CH2 CH3CH2CH2S C12C=CHCH2 CF3CH2CH2S 2-CF3-c-Pr CF3CH2CH2NH
The present disclosure also includes Tables 2-A through 2-Y, each of which are constructed the same as Table 2 above except that the row heading in Table 2 (i.e. "A is CH2, W is O, Z1 is CH2 and Z2 is OCH2") is replaced with the respective row headings shown below. For example, in Table 2-A the row heading is "A is NH, W is O, Z1 is CH2 and Z2 is OCH2" and R1 is as defined in Table 2 above. Thus, the first entry in Table 2-A specifically discloses 5-[[6-[(2,6-dif uorophenyl)methoxy]-3-pyridazinyl]methyl]hexahydro- N-phenylpyrrolo[3,4-c]pyrrol-2(lH)-carboxamide. Tables 2-B through 2-Y are constructed similarly.
Table Row Heading
2-A A is NH, W is O, Z1 is CH2 and Z2 is OCH2.
2-B A is CH2, W is S, Z1 is CH2 and Z2 is OCH2.
2-C A is NH, W is S, Z1 is CH2 and Z2 is OC¾.
2-D A is CH2, W is O, Z1 is CH2 and Z2 is CH20.
2-E A is NH, W is O, Z1 is CH2 and Z2 is C¾0.
2-F A is CH2, W is O, Z 1 is CH2 and Z2 is O.
2-G A is H, W is O, Z1 is CHo and Z2 is O. Table Row Heading
2-H A is CH2, W is O, Z1 is CH2 and Z2 is S.
2-1 A is NH, W is O, Z1 is CH2 and Z2 is S.
2-J A is CH2, W is O, Z1 is CH2 and Z2 is NH.
2-K A is NH, W is O, Z1 is CH2 and Z2 is NH.
2-L A is CH2, W is O, Z1 is CH2 and Z2 is NHC¾.
2-M A is NH, W is O, Z1 is CH2 and Z2 is NHC¾.
2-N A is CH2, W is S, Z1 is CH2C=0 and Z2 is OC¾.
2-0 A is NH, W is S, Z1 is C¾C=0 and Z2 is OC¾.
2-P A is CH2, W is O, Z1 is CH2C=0 and Z2 is C¾0.
2-Q A is NH, W is O, Z1 is C¾C=0 and Z2 is C¾0.
2-R A is CH2, W is O, Z1 is CH2C=0 and Z2 is O.
2-S A is NH, W is O, Z1 is C¾C=0 and Z2 is O.
2-T A is CH2, W is O, Z1 is CH2C=0 and Z2 is S.
2-U A is NH, W is O, Z1 is C¾C=0 and Z2 is S.
2-V A is CH2, W is O, Z1 is CH2C=0 and Z2 is NH.
2-W A is NH, W is O, Z1 is C¾C=0 and Z2 is NH.
2-X A is CH2, W is O, Z1 is CH2C=0 and Z2 is NHC¾.
2-Y A is NH, W is O, Z1 is C¾C=0 and Z2 is NHC¾.
Table 3
Figure imgf000075_0001
A is CH2, W is O, Z1 is O and Z2 is OCH2. A is CH2, W is O, Zl is O and Z2 is OCH2.
Rl Rl
Ph z-BuO
2-Me-Ph CF3CH2OCH2
2-MeO-Ph 3-Et-Ph
2-Cl-Ph 3-CF3-Ph
2-Br-Ph 3-CN-Ph
2-EtO-Ph 3-N02-Ph
2-MeS-Ph 2,5-di-Cl-Ph
3-Cl-Ph 5-Br-2-Cl-Ph
3-Br-Ph 2-Cl-5-Me-Ph
3-I-Ph 2-MeO-5-CF3-Ph A is CH2, W is O, Z1 is O and Z2 is OC¾. A is CH2, W is O, Z1 is O and Z2 is OCH2. Rl Rl
3-Me-Ph 2,5-di-Et-Ph
2-Cl-5-CF3-Ph 3 -Me- 1 f-pyrazol- 1 -yl 2,5-di-Br-Ph 3- Cl-l#-pyrazol-l-yl 2-Br-5-Me-Ph 3 -Br- 1 /-pyrazol- 1 -yl 2-Br-5-CF3-Ph 3-CF3-l /-pyrazol-l-yl 5-Cl-2-Me-Ph 3,5-di-Me-l /-pyrazol-l-yl 5-Br-2-Me-Ph 3 -Cl-5-Me- l#-pyrazol- 1 -yl 2,5-di-Me-Ph 3 -Br-5-Me- 1 f-pyrazol- 1 -yl 2-Me-5-CF3-Ph 5-MeO-3 -Me- l#-pyrazol- 1 -yl 5-CN-2-Me-Ph 3 , 5 -di-Et- l /-pyrazol- 1 -yl 2-Me-5-N02-Ph 5-Et-3-CF3- ltf-pyrazol- 1 -yl 5-Cl-2-MeO-Ph 2,5-di-Me-3-furyl 5-Br-2-MeO-Ph 2,5-di-Me-3-thienyl
2-MeO-5-Me-Ph 2,5-di-Cl-3-thienyl
3 -Et-5-Me- l#-pyrazol- 1 -yl 1.4- di-Me-l -pyrrol-3-yl 5-Me-3-CF3-l#-pyrazol-l-yl 1 ,4-di-Me- l /-pyrazol-3-yl 5-Me-3-CF3CF2-l /-pyrazol-l-yl 1 ,3 -di-Me-4- l#-pyrazol-4-yl 5-C1-3 -Me- ltf-pyrazol- 1 -yl 2 , 5 -di-Me-4-oxazolyl 3,5-di-Cl-l#-pyrazol-l-yl 2.5- di-Me-4-thiazolyl 5-CI-3-CF3- l//-pyrazol- 1 -yl 3.6- di-Me-2-pyridinyl 5-Br-3 -Me- li/-pyrazol- 1 -yl 2,5-di-Me-3-pyridinyl 3 ,5-di-Br- l f-pyrazol- 1 -yl 2.5- di-Me-4-pyridinyl 5-Br-3-CF3- ltf-pyrazol- 1 -yl 3.6- di-Cl-2-pyridinyl
3- CHF2-l /-pyrazol-l-yl 2,5-di-Cl-3-pyridinyl 3-CHF2-5-Me-l /-pyrazol-l-yl 2.5- di-Cl-4-pyridinyl 3,5-bis-(CHF2)-l#-pyrazol- l-yl 4-Br-3 -pyridazinyl
3,5-di-Me-2-thienyl 4 -C F 3 - 2 -pyrimidinyl 3,5-di-Cl-2-thienyl 3.6- di-Me-2-pyrazinyl 3,5-di-Me-2-furyl 2.5- di-Me-4-pyrimidinyl
4- Me-2-CF3-5-thiazolyl 4- MeO-5-pyrimidinyl 4-Me-2-CF3-5-oxazolyl 3.6- di-Me-4-pyridazinyl
1 -Me-4-CF3 - l /-imidazol-2-yl 1 -Me-4-CF3 - l#-imidazol-2-yl
2,4-di-Me-l /-pyrrol- l-yl 3,5-bis-(CF3)-l /-pyrazol-l-yl 1 -Me-3 -CF3 - ltf-pyrazol-5-yl 3-CI-5-CF3- ltf-pyrazol- 1 -yl 3-Br-5-CF3- l//-pyrazol- 1 -yl 3,5-bis-(CHF20)-l//-pyrazol- l-yl 3 -Me-5 -CF3 - 1 tf-pyrazol- 1 -yl 3,5-di-MeO- l /-pyrazol- 1 -yl A is CH2, W is O, Z1 is O and Z2 is OC¾. CH2, W is O, Z1 is O and Z2 is OCH2.
Rl Rl
3 -MeO-5-CF3 - ltf-pyrazol- 1 -yl 5-EtO-3 -Me- l /-pyrazol- 1 -yl
3 ,5-di-Br- l /-pyrazol- 1 -yl 5-EtO-3-CF3-l#-pyrazol-l-yl 5-MeO-3 -Me- l /-pyrazol- 1 -yl 3 ,5-di-Br- IH- 1 ,2,4-triazol- 1 -yl 5-MeO-3 -CF3 - ltf-pyrazol- 1 -yl 3-Cl-5-Me-l /-l,2,4-triazol-l-yl 3,5-di-Cl-l /-l,2,4-triazol-l-yl 3-Br-5-Me-l /-l,2,4-triazol-l-yl 3-Me-5-Cl- IH- 1 ,2,4-triazol- 1 -yl 3-CF3 -5-Cl- IH- 1 ,2,4-triazol- 1 -yl 3-Me-5-Br- IH- 1 ,2,4-triazol- 1 -yl 3-CF3 -5-Br- IH- 1 ,2,4-triazol- 1 -yl 3-CI-5-CF3 - IH- 1 ,2,4-triazol- 1 -yl 3 ,5-bis-(CF3)- IH- 1 ,2,4-triazol- 1 -yl 3 -Br-5-CF3 - IH- 1 ,2,4-triazol- 1 -yl CF3OCH2CH2
«-Bu MeOCH2CH20
(Me)2CHCH2CH2 CF3CH2CH20 CH3C(Me)=CHCH2 CF3CH2C(=0)0
HC≡CCH2 CH2=CHCH20 CF3CH2CH2CH2 CH3CH2CH2S C12C=CHCH2 CF3CH2CH2S 2-CF3-c-Pr CF3CH2CH2NH
The present disclosure also includes Tables 3-A through 3-Y, each of which are constructed the same as Table 3 above except that the row heading in Table 3 (i.e. "A is CH2, W is O, Z1 is O and Z2 is OCH2") is replaced with the respective row headings shown below. For example, in Table 3-A the row heading is "A is NH, W is O, Z1 is O and Z2 is OCH2" and R1 is as defined in Table 3 above. Thus, the first entry in Table 3-A specifically discloses 3-[[6-[(2,6-difluorophenyl)methoxy]-3-pyridazinyl]oxy]-N-phenyl-l-azetidine- carboxamid. Tables 3-B through 3-Y are constructed similarly.
Table Row Heading
3-A A is NH, W is O, Z1 is O and Z2 is OCH2.
3-B A is CH2, W is S, Z1 is O and Z2 is OCH2.
3-C A is NH, W is S, Z1 is O and Z2 is OCH2.
3-D A is CH2, W is O, Z1 is O and Z2 is C¾0.
3-E A is NH, W is O, Z1 is O and Z2 is CH20.
3-F A is CH2, W is O, Z1 is O and Z2 is O.
3-G A is NH, W is O, Z1 is O and Z2 is O.
3-H A is CH2, W is O, Z1 is O and Z2 is S.
3-1 A is NH, W is O, Z1 is O and Z2 is S.
3-J A is CH2, W is O, Z1 is O and Z2 is NH.
3-K A is NH, W is O, Z1 is O and Z2 is NH. Row Heading
A is CH2, W is O, Z1 is O and Z2 is NHCH2.
A is NH, W is O, Z1 is O and Z2 is NHCH2.
A is CH2, W is S, Z1 is OCH2 and Z2 is OCH2.
A is NH, W is S, Z1 is OCH2 and Z2 is OCH2.
A is CH2, W is O, Z1 is OCH2 and Z2 is CH20.
A is NH, W is O, Z1 is OCH2 and Z2 is CH20.
A is CH2, W is O, Z1 is OCH2 and Z2 is O.
A is NH, W is O, Z1 is OCH2 and Z2 is O.
A is CH2, W is O, Z1 is OCH2 and Z2 is S.
A is NH, W is O, Z1 is OCH2 and Z2 is S.
A is CH2, W is O, Z1 is OCH2 and Z2 is NH.
A is NH, W is O, Z1 is OCH2 and Z2 is NH.
A is CH2, W is O, Z1 is OCH2 and Z2 is NHC¾.
A is NH, W is O, Z1 is OCH2 and Z2 is NHCH2.
Table 4
Figure imgf000078_0001
Xa is CH, Z1 is O and Z2 is OC¾.
R2 R3 A1 R4 R5 W
CH3 CH3 o H H o
CH3 CH3 s H H o
CH3 CH3 NH H H o
CH3 CH3 N(Me) H H o
CH3 CH3 CH2 H H o
CH3 CH3 -OCH2- H H o
CH3 CH3 -SCH2- H H o
CH3 CH3 NHCH2 H H o
CH3 CH3 -N(Me)CH2- H H o
CH3 CH3 O CH3 H o
CH3 CH3 O CH3 CH3 o
CH3 CH3 o H H s
CF3 H o H H o
CF3 H s H H o Xa is CH, Z1 is O and Z2 is OCH2.
R2 R3 A1 R4 R5 W
CF3 H NH H H o
CF3 H N(Me) H H o
CF3 H CH2 H H o
CF3 H -OCH2- H H o
CF3 H -SCH2- H H o
CF3 H -NHCH2- H H o
CF3 H -N(Me)CH2- H H o
CF3 CH3 O H H o
CF3 CH3 s H H o
CF3 CH3 NH H H o
CF3 CH3 N(Me) H H o
CF3 CH3 CH2 H H o
CF3 CH3 -OCH2- H H o
CF3 CH3 -SCH2- H H o
CF3 CH3 -NHCH2- H H o
CF3 CH3 -N(Me)CH2- H H o
CF3 H O CH3 H o
CF3 CH3 O H CH3 o
CF3CH2 H o H H o
CF3CH2 CH3 o H H o
CH3CH2 H o H H o
CH3CH2 CH3 o H H o
CH3 H o H H o
CHF2 H o H H o
CHF2 CH3 o H H o
CHF2 CHF2 o H H o
CH3 CH2CH(Me)N- H H o
CF3 CH2CH(Me)N- H H o
The present disclosure also includes Tables 4-A through 4-AH, each of which are constructed the same as Table 4 above except that the row heading in Table 4 (i.e. "Xa is CH, Z1 is O and Z2 is OCH2") is replaced with the respective row headings shown below. For example, in Table 4-A the row heading is "Xa is N, Z1 is CH2 and Z2 is OCH2" and R2, R3, A1, R4, R5 and W are as defined in Table 4 above. Thus, the first entry in Table 4-A specifically discloses 2-propanone 0-[2-[4-[[6-[(2,6-difluorophenyl)methoxy]-3- pyridazinyljmethyl] - 1 -piperazinyl] -2-oxoethyl] Tables 4-B through 4-AH are constructed similarly.
Table Row Heading Table Row Heading
4-A Xa is N, Z1 is CH2 and Z2 is OCH2. 4-R Xa is CH, Z is CH20 and Z2 is CH20. 4-B Xa is CH, Z1 is O and Z2 is CH20. 4-S Xa is CH, Z is CH20 and Z2 is O.
4-C Xa is N, Z1 is CH2 and Z2 is CH20. 4-T Xa is CH, Z is CH20 and Z2 is S.
4-D Xa is N, Z1 is CH2 and Z2 is O. 4-U Xa is CH, Z is CH20 and Z2 is NH. 4-E Xa is CH, Z1 is O and Z2 is S. 4-V Xa is CH, Z is CH20 and Z2 is NHCH2. 4-F Xa is N, Z1 is CH2 and Z2 is S. 4-W Xa is CH, Z is C=ONH and Z2 is OCH2. 4-G Xa is CH, Z1 is O and Z2 is NH. 4-X Xa is CH, Z is C=ONH and Z2 is CH20. 4-H Xa is N, Z1 is CH2 and Z2 is NH. 4-Y Xa is CH, Z is C=ONH and Z2 is O. 4-1 Xa is CH, Z1 is O and Z2 is NHCH2. 4-Z Xa is CH, Z is C=ONH and Z2 is S.
4-J Xa is N, Z1 is CH2 and Z2 is NHCH2. 4-AA Xa is CH, Z is C=ONH and Z2 is NH. 4-K Xa is CH, Z1 is OCH2 and Z2 is OCH2. 4-AB Xa is CH, Z is C=ONH and Z2 is NHCH2. 4-L Xa is CH, Z1 is OCH2 and Z2 is CH20. 4-AC Xa is CH, Z is CH2 and Z2 is OCH2. 4-M Xa is CH, Z1 is OCH2 and Z2 is O. 4-AD Xa is CH, Z is CH2 and Z2 is CH20. 4-N Xa is CH, Z1 is OCH2 and Z2 is S. 4-AE Xa is CH, Z is CH2 and Z2 is O.
4-0 Xa is CH, Z1 is OCH2 and Z2 is NH. 4-AF Xa is CH, Z is CH2 and Z2 is S.
4-P Xa is CH, Z1 is OCH2 and Z2 is NHCH2. 4-AG Xa is CH, Z is CH2 and Z2 is NH.
4-Q Xa is CH, Z1 is CH20 and Z2 is OCH2. 4-AH Xa is CH, Z is CH2 and Z2 is NHCH2.
Table 5
Figure imgf000080_0001
Z! is CH2 and Z2 is OC¾.
R2 R3 Al R4 R5 W
CH3 CH3 O H H o
CH3 CH3 s H H o
CH3 CH3 NH H H o
CH3 CH3 N(Me) H H o
CH3 CH3 CH2 H H o
CH3 CH3 -OCH2- H H o
CH3 CH3 -SCH2- H H o
CH3 CH3 NHCH2 H H o
CH3 CH3 -N(Me)CH2- H H o Z! is CH2 and Z2 is OCH2.
R2 R3 A1 R4 R5 W
CH3 CH3 o CH3 H o
CH3 CH3 o CH3 CH3 o
CH3 CH3 o H H s
CF3 H o H H o
CF3 H s H H o
CF3 H NH H H o
CF3 H N(Me) H H o
CF3 H CH2 H H o
CF3 H -OCH2- H H o
CF3 H -SCH2- H H o
CF3 H -NHCH2- H H o
CF3 H -N(Me)CH2- H H o
CF3 CH3 O H H o
CF3 CH3 s H H o
CF3 CH3 NH H H o
CF3 CH3 N(Me) H H o
CF3 CH3 CH2 H H o
CF3 CH3 -OCH2- H H o
CF3 CH3 -SCH2- H H o
CF3 CH3 -NHCHo- H H o
CF3 CH3 -N(Me)CH2- H H o
CF3 H O CH3 H o
CF3 CH3 O H CH3 o
CF3CH2 H o H H o
CF3CH2 CH3 o H H o
CH3CH2 H o H H o
CH3CH2 CH3 o H H o
CH3 H o H H o
CHF2 H o H H o
CHF2 CH3 o H H o
CHF2 CHF2 o H H o
CH3 - CH2CH(Me)N- H H o
CF3 - CH2CH(Me)N- H H o
The present disclosure also includes Tables 5-A through 5-K, each of which are constructed the same as Table 5 above except that the row heading in Table 5 (i.e. "Z1 is CH2 and Z2 is OCH2") is replaced with the respective row headings shown below. For example, in Table 5-A the row heading is "Z is CH2 and Z2 is CH20" and R2, R3, A1, R4, R5 and W are as defined in Table 5 above. Thus, the first entry in Table 5-A specifically discloses 2-propanone 0-[2-[5-[[6-[(2,6-dif uorophenoxy)methyl]-3-pyridazinyl]methyl]- hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl]-2-oxoethyl]oxime. Tables 5-B through 5-K are constructed similarly.
Table Row Heading Table Row Heading
5-A Z1 is CH2 and Z2 is CH20. 5-F Z1 is CH2C=0 and Z2 is OCH2. 5-B Z1 is CH2 and Z2 is O. 5-G Z1 is CH2C=0 and Z2 is CH20. 5-C Z1 is CH2 and Z2 is S. 5-H Z1 is CH2C=O and Z2 is O.
5-D Z1 is CH2 and Z2 is NH. 5-1 Z1 is CH2C=O and Z2 is S.
5-E Z1 is CH2 and Z2 is NH CH2. 5-J Z1 is CH2C=0 and Z2 is NH.
Table 6
Figure imgf000082_0001
Z1 is O and Z2 is OCH2.
R2 R3 A1 R4 R5 W
CH3 CH3 o H H o
CH3 CH3 s H H o
CH3 CH3 NH H H o
CH3 CH3 N(Me) H H o
CH3 CH3 CH2 H H o
CH3 CH3 -OCH2- H H o
CH3 CH3 -SCH2- H H o
CH3 CH3 NHCH2 H H o
CH3 CH3 -N(Me)CH2- H H o
CH3 CH3 O CH3 H o
CH3 CH3 O CH3 CH3 o
CH3 CH3 o H H s
CF3 H o H H o
CF3 H s H H o
CF3 H NH H H o
CF3 H N(Me) H H o
CF3 H CH2 H H o Z1 is O and Z2 is OCH2.
R2 R3 A1 R4 R5 W
CF3 H -OCH2- H H o
CF3 H -SCH2- H H o
CF3 H -NHCH2- H H o
CF3 H -N(Me)CH2- H H o
CF3 CH3 O H H o
CF3 CH3 s H H o
CF3 CH3 NH H H o
CF3 CH3 N(Me) H H o
CF3 CH3 CH2 H H o
CF3 CH3 -OCH2- H H o
CF3 CH3 -SCH2- H H o
CF3 CH3 -NHCH2- H H o
CF3 CH3 -N(Me)CH2- H H o
CF3 H O CH3 H o
CF3 CH3 O H CH3 o
CF3CH2 H o H H o
CF3CH2 CH3 o H H o
CH3CH2 H o H H o
CH3CH2 CH3 o H H o
CH3 H o H H o
CHF2 H o H H o
CHF2 CH3 o H H o
CHF2 CHF2 o H H o
CH3 CH2CH(Me)N- H H o
CF3 CH2CH(Me)N- H H o
The present disclosure also includes Tables 6-A through 6-T, each of which are constructed the same as Table 6 above except that the row heading in Table 6 (i.e. "Z1 is O and Z2 is OCH2") is replaced with the respective row headings shown below. For example, in Table 6-A the row heading is "Z1 is O and Z2 is CH20" and R2, R3, A1, R4, R5 and W are as defined in Table 6 above. Thus, the first entry in Table 6-A specifically discloses 2- propanone 0-[2-[3-[[6-[(2,6-difluorophenoxy)methyl]-3-pyridazinyl]oxy]-l-azetidinyl]-2- oxoethyljoxime. Tables 6-B through 6-T are constructed similarly.
Table Row Heading Table Row Heading
6-A Z1 is O and Z2 is CH20. 6-A Z1 is O and Z2 is CH20.
6-B Z1 is O and Z2 is O. 6-B Z1 is O and Z2 is O. Table Row Heading Table Row Heading
6-C Z1 is O and Z2 is S. 6-C Z1 is O and Zs- is S.
6-D z1 is O and Z2 is NH. 6-D z1 is O and Z2 is NH.
6-E z1 is O and Z2 is NHCH2. 6-E z1 is O and Z2 is NHC¾.
6-F z1 is OCH2 and Z2 is CH20. 6-F z1 is OCH2 and Z2 is CHoO.
6-G z1 is OCH2 and Z2 is O. 6-G z1 is OCH2 and Z2 is O.
6-H z1 is OCH2 and Z2 is S. 6-H z1 is OCH2 and Z2 is S.
6-1 z1 is OCH2 and Z2 is NH. 6-1 z1 is OCH2 and Z2 is NH.
6-J z1 is OCH2 and Z2 is NHCH2. 6-J z1 is OCH2 and Z2 is NHCH2.
6-K z1 is C=ONH and Z2 is O. 6-K z1 is C=ONH and Z2 is O.
6-L z1 is C=ONH and Z2 is S. 6-L z1 is C=ONH and Z2 is S.
6-M z1 is C=ONH and Z2 is NH. 6-M z1 is C=ONH and Z2 is NH.
6-N z1 is C=ONH and Z2 is NHCH2. 6-N z1 is C=ONH and Z2 is NHCH2.
6-0 z1 is CH2 and Z2 is OCH2. 6-0 z1 is CH2 and Z2 is OCH2.
6-P z1 is CH2 and Z2 is C¾0. 6-P z1 is CH2 and Z2 is C¾0.
6-Q z1 is CH2 and Z2 is O. 6-Q z1 is CH2 and Z is O.
6-R z1 is CH2 and Z2 is S. 6-R z1 is CH2 and Z2 is S.
6-S z1 is CH2 and Z2 is NH. 6-S z1 is CH2 and Z2 is NH.
6-T z1 is CH2 and Z2 is NHC¾. 6-T z1 is CH2 and Z2 is NHCH2.
Ta le 7
Figure imgf000084_0001
In Table 7 the structures of G-1 through G-91 are shown in Exhibit 1 above. The substituents R8c and
R8d are attached to the G-ring as shown in in Exhibit 1.
E is E- la.
G R8c R8d zi Z2
G-1 CH3 - CH2 CH20
G-2 H - CH2 CH20
G-3 H H NH CH20
G-4 H - CH2 CH20
G-5 H - CH2 CH20
G-6 H CH3 CH2 CH20
G-7 - - CH2 CH20
G-8 - - CH2 CH20 E is E-la.
G R8c R8d zi Z2
G-9 - CH3 CH2 C¾0
G-10 H - CH2 CH20
G-l l H - CH2 CH20
G-12 H CH3 CH2 CH20
G-13 H CH3 C¾ CH20
G-14 H - C¾ CH20
G-15 H - C¾ CH20
G-16 H CH3 C¾ C¾0
G-17 H - C¾ C¾0
G-18 H - C¾ CH20
G-19 - CH3 C¾ CH20
G-20 - - CH2 CH20
G-21 - - C¾ CH20
G-22 H CH3 C¾ CH20
G-23 H - C¾ CH20
G-24 H - C¾ C¾0
G-25 H - C¾ C¾0
G-26 H - C¾ CH20
G-27 H - C¾ CH20
G-28 H - CH2 CH20
G-29 H - C¾ CH20
G-30 H - C¾ CH20
G-31 H - C¾ CH2
G-32 H - C¾ C¾
G-33 H - C¾ C¾
G-34 H - C¾ CH2
G-35 H - C¾ CH2
G-36 CH3 - CH2 CH20
G-37 H - C¾ CH20
G-38 H - C¾ CH20
G-39 CH3 CH3 C¾ CH20
G-40 H - C¾ C¾0
G-41 H - C¾ CH20
G-42 H CH3 C¾ CHoO
G-43 H CH3 C¾ CHoO
G-44 H - CH2 CH20 E is E-la.
G R8c R8d zi Z2
G-45 H - NH C¾0
G-46 - - CH2 C¾0
G-47 - - CH2 C¾0
G-48 - CH3 CH2 C¾0
G-49 H - C¾ C¾0
G-50 H - C¾ C¾0
G-51 H CH3 C¾ C¾0
G-52 H - C¾ C¾0
G-53 H - C¾ C¾0
G-54 H - C¾ C¾0
G-55 - - C¾ C¾0
G-56 H - C¾ C¾0
G-57 H - C¾ C¾0
G-58 H CH3 C¾ C¾0
G-59 H CH3 C¾ C¾0
G-60 H - C¾ CH2C¾CH2
G-61 H - C¾ C¾0
G-62 H - C¾ CH2CH20
G-63 H - C¾ C¾0
G-64 H - C¾ C¾0
G-65 H - C¾ C¾
G-66 H - C¾ bond
G-67 H - C¾ C¾
G-68 6-Cl - C¾ C¾0
G-69 H - C¾ C¾0
G-70 4,5-di-CH3 - C¾ C¾0
G-71 H - C¾ C¾0
G-72 H - C¾ C¾0
G-73 H - C¾ C¾0
G-74 H - C¾ C¾0
G-75 H - C¾ C¾0
G-76 - - C¾ C¾0
G-77 H - C¾ C¾0
G-78 H - C¾ C¾0
G-79 H - C¾ C¾0
G-80 H - C¾ C¾0 E is E-la.
G R8c R8d Zl Z2
G-81 H CH2 C¾0
G-82 H CH2 C¾0
G-83 H CH2 C¾0
G-84 H C¾ C¾0
G-85 H C¾ C¾0
G-86 H C¾ C¾0
G-87 H C¾ C¾0
G-88 H C¾ C¾0
G-89 H C¾ C¾0
G-90 H C¾ C¾0
G-91 H C¾ C¾0
G-70 H O C¾0
G-70 H s C¾0
G-70 H NH C¾0
G-70 H N(CH3) C¾0
G-70 H NHC=0 C¾0
G-70 H CH2NHC=0 O
G-70 H CH2OCH2 O
G-70 H NHNH C¾0
G-70 H CH2NHNH bond
G-70 H OCH2 C¾0
G-70 H SCH2 C¾0
G-70 H NHCH2 C¾0
G-70 H N(C=OCH3)CH2 O
G-70 H ON=CH O
G-70 H O s
G-70 H O SCH2
G-70 H O NH
G-70 H O NHCH2
G-70 H O CH2OCH2
G-70 H O C=ONH
G-70 H O C=ONHCH2
G-70 H O C=ON(CH3)CH2
G-70 H O CH=NO
G-70 H O ON=CH
G-70 H O ON=C(CH3) E is E-la.
G R8c R8d
G-70 H - o CH2S
G-70 H - O CH2NH
G-70 H - O CH2SCH2
G-70 H - O OCH2CH2
G-70 H - o NHS(=0)2
The present disclosure also includes Tables 7-A through 7-Q, each of which is constructed the same as Table 7 above except that the Row Heading in Table 7 (i.e. "E is E-la") is replaced with the respective row headings shown below. For example, in Table 7-A the row heading is "E is E-lb" and G, R8c R8^, Z1 and Z2 are as defined in Table 7 above. Thus, the first entry in Table 7-A specifically discloses 2-[5-chloro-3- (trifluoromethyl)- lH-pyrazol- 1 -yl] - 1 - [4-[ [4- [(2,6-difluorophenoxy)methyl]-5 -methyl-2- thiazolyl]methyl]-l-piperidinyl]ethanone. Tables 7-B and 7-Q are constructed similarly.
Table Row Heading Table Row Heading
7-A E is E-lb 7-J E is E-lk
7-B E is E-lc 7-K E is E-ll
7-C E is E-ld 7-L E is E-lm
7-D E is E-le 7-M E is E-ln
7-E E is E-lf 7-N E is E-2a
7-F E is E-lg 7-0 E is E-2b
7-G E is E-lh 7-P E is E-2c
7-Η E is E-li 7-Q E is E-2d
7-1 E is E-lj
Table 8
Figure imgf000088_0001
0 In Table 8 the structures of G-l through G-91 are shown in Exhibit 1 above. The substituents R8c and
R8d are attached to the G-ring as shown in in Exhibit 1.
E is E-la.
G R8 R8d zi Z2
G-l CH3 CH2 CH20 G-2 H CH2 CH20 G-3 H H NH CH20 E is E-la.
G R8c R8d zi Z2
G-4 H - C¾ C¾0
G-5 H - C¾ C¾0
G-6 H CH3 C¾ C¾0
G-7 - - C¾ C¾0
G-8 - - C¾ C¾0
G-9 - CH3 C¾ C¾0
G-10 H - C¾ C¾0
G-l l H - C¾ C¾0
G-12 H CH3 C¾ C¾0
G-13 H CH3 C¾ C¾0
G-14 H - C¾ C¾0
G-15 H - C¾ C¾0
G-16 H CH3 C¾ C¾0
G-17 H - C¾ C¾0
G-18 H - C¾ C¾0
G-19 - CH3 C¾ C¾0
G-20 - - C¾ C¾0
G-21 - - C¾ C¾0
G-22 H CH3 C¾ C¾0
G-23 H - C¾ C¾0
G-24 H - C¾ C¾0
G-25 H - C¾ C¾0
G-26 H - C¾ C¾0
G-27 H - C¾ C¾0
G-28 H - C¾ C¾0
G-29 H - C¾ C¾0
G-30 H - C¾ C¾0
G-31 H - C¾ C¾
G-32 H - C¾ C¾
G-33 H - C¾ C¾
G-34 H - C¾ C¾
G-35 H - C¾ C¾
G-36 CH3 - C¾ C¾0
G-37 H - C¾ C¾0
G-38 H - C¾ C¾0
G-39 CH3 CH3 C¾ C¾0 E is E-la.
G R8c R8d zi Z2
G-40 H - C¾ C¾0
G-41 H - C¾ C¾0
G-42 H CH3 C¾ C¾0
G-43 H CH3 C¾ C¾0
G-44 H - CH2 C¾0
G-45 H - NH C¾0
G-46 - - C¾ C¾0
G-47 - - C¾ C¾0
G-48 - CH3 C¾ C¾0
G-49 H - CH2 CH20
G-50 H - C¾ C¾0
G-51 H CH3 C¾ C¾0
G-52 H - C¾ C¾0
G-53 H - C¾ C¾0
G-54 H - CH2 C¾0
G-55 - - C¾ C¾0
G-56 H - C¾ C¾0
G-57 H - C¾ C¾0
G-58 H CH3 C¾ C¾0
G-59 H CH3 CH2 C¾0
G-60 H - C¾ CH2CH2CH2
G-61 H - C¾ C¾0
G-62 H - C¾ CH2CH20
G-63 H - C¾ C¾0
G-64 H - C¾ C¾0
G-65 H - CH2 CH2
G-66 H - C¾ bond
G-67 H - C¾ C¾
G-68 6-Cl - C¾ C¾0
G-69 H - C¾ C¾0
G-70 4,5-di-CH3 - CH2 C¾0
G-71 H - C¾ C¾0
G-72 H - C¾ C¾0
G-73 H - C¾ C¾0
G-74 H - C¾ C¾0
G-75 H - CH2 CH20 E is E-la.
R8c R8d zi Z2
G-76 - CH2 C¾0
G-77 H CH2 C¾0
G-78 H CH2 C¾0
G-79 H C¾ C¾0
G-80 H C¾ C¾0
G-81 H C¾ C¾0
G-82 H C¾ C¾0
G-83 H C¾ C¾0
G-84 H C¾ C¾0
G-85 H C¾ C¾0
G-86 H C¾ C¾0
G-87 H C¾ C¾0
G-88 H C¾ C¾0
G-89 H C¾ C¾0
G-90 H C¾ C¾0
G-91 H C¾ C¾0
G-70 H O C¾0
G-70 H s C¾0
G-70 H NH C¾0
G-70 H N(CH3) C¾0
G-70 H NHC=0 C¾0
G-70 H CH2NHC=0 O
G-70 H CH2OCH2 O
G-70 H NHNH C¾0
G-70 H CH2NHNH bond
G-70 H OCH2 C¾0
G-70 H SCH2 C¾0
G-70 H NHCH2 C¾0
G-70 H N(C=OCH3)CH2 O
G-70 H ON=CH O
G-70 H O s
G-70 H O SCH2
G-70 H O NH
G-70 H O NHCH2
G-70 H O CH2OCH2
G-70 H O C=ONH E is E-la.
R8c R8d Λ
G-70 H O C=ONHCH2
G-70 H O C=ON(CH3)CH2
G-70 H O CH=NO
G-70 H O ON=CH
G-70 H O ON=C(CH3)
G-70 H O c¾s
G-70 H O CH2NH
G-70 H O CH2SCH2
G-70 H O OCH2CH2
G-70 H O NHS(=0)2
The present disclosure also includes Tables 8-A through 8-Q, each of which is constructed the same as Table 8 above except that the Row Heading in Table 8 (i.e. "E is
E-la") is replaced with the respective row headings shown below. For example, in Table
8-A the row heading is "E is E-lb" and G, R8c, R8d, Z1 and Z2 are as defined in Table 8 above. Thus, the first entry in Table 8-A specifically discloses 2-[5-chloro-3- (trifluoromethyl)-lH-pyrazol-l-yl]-l-[4-[[4-[(2,6-difluorophenoxy)methyl]-5-methyl-2- thiazolyl]methyl]-l-piperazinyl]ethanone. Tables 8-B and 8-Q are constructed similarly.
Table Row Heading Table Row Heading
8-A E is E-lb. 8-J E is E-lk.
8-B E is E-lc. 8-K E is E-ll.
8-C E is E-ld. 8-L E is E-lm.
8-D E is E-le. 8-M E is E-ln.
8-E E is E-lf. 8-N E is E-2a.
8-F E is E-lg. 8-0 E is E-2b.
8-G E is E-lh. 8-P E is E-2c.
8-Η E is E-li. 8-Q E is E-2d.
8-1 E is E-lj. Table 9
Figure imgf000093_0001
In Table 9 the structures of Q-1 through Q-105 are shown in Exhibit 2 above. The substituents (R9a)j and R9c are attached to the Q-ring as shown in in Exhibit 2.
is CH and Z 1 is O. Xa is CH and Z1 is O.
Q (R9a)p R9c Z2 Q (R9a)p R9c Z2
Q-1 3 -CI - OCH2 Q-54 H oc¾
Q-2 H - OCH2 Q-55 H OCH2
Q-3 H CH3 OCH2 Q-56 H OCH2
Q-4 2-CH3 - OCH2 Q-57 H OCH2
Q-5 H - OCH2 Q-58 H OCH2
Q-6 H - OCH2 Q-59 H OCH2
Q-7 H - OCH2 Q-60 H CH2
Q-8 H - OCH2 Q-61 H CH2
Q-9 H - OCH2 Q-62 H CH2
Q- 10 H CH3 OCH2 Q-63 H CH2
Q-l l H CH3 OCH2 Q-64 H CH2
Q- 12 H CH3 OCH2 Q-65 H CH2
Q-13 H CH3 OCH2 Q-66 H CH2
Q-14 H CH3 OCH2 Q-67 H CH2
Q- 15 H - OCH2 Q-68 H CH2
Q-16 H - OCH2 Q-69 H CH2
Q- 17 H - OCH2 Q-70 H CH2
Q-18 H - OCH2 Q-71 H CH2
Q-19 H - OCH2 Q-72 H CH3 CH2
Q-20 H - OCH2 Q-73 H C¾
Q-21 H CH3 OCH2 Q-74 H CH2
Q-22 H CH3 OCH2 Q-75 H CH3 CH2
Q-23 H CH3 OCH2 Q-76 H CH2
Q-24 5-CF3 - OCH2 Q-77 H CH2
Q-25 5-Cl - OCH2 Q-78 H CH3 C¾
Q-26 H - OCH2 Q-79 H CH3 CH2 Xa is CH and Z1 is O. Xa is CH and Z1 is O.
Q R9c Z2 Q R9c
(R9a)D (R9a)p Z2
Q-27 3,5-diCH3 - oc¾ Q-80 H - CH2
Q-28 H H oc¾ Q-81 H - C¾
Q-29 H - oc¾ Q-82 H - C¾
Q-30 H - oc¾ Q-83 H - C¾
Q-31 H CH3 oc¾ Q-84 H - C¾
Q-32 H - oc¾ Q-85 H - C¾
Q-33 2-Cl - OCH2 Q-86 H CH3 C¾
Q-34 H - oc¾ Q-87 H - C¾
Q-35 H - OCH2 Q-88 H CH3 C¾
Q-36 H - oc¾ Q-89 H - C¾
Q-37 H - OCH2 Q-90 H - C¾
Q-38 H - OCH2 Q-91 H - C¾
Q-39 H - OCH2 Q-92 H CH3 C¾
Q-40 H - OCH2 Q-93 H - C¾
Q-41 H - OCH2 Q-94 H - C¾
Q-42 H - OCH2 Q-95 H CH3 OCH2
Q-43 H - OCH2 Q-96 H - OCH2
Q-44 H - OCH2 Q-97 H - OCH2
Q-46 H - OCH2 Q-98 H - C¾
Q-47 H - OCH2 Q-99 H - C¾
Q-48 H - OCH2 Q-100 H - C¾
Q-49 H - OCH2 Q-101 H - C¾
Q-50 H - OCH2 Q-102 H CH3 C¾
Q-51 H - OCH2 Q-103 3-Ph - C¾
Q-52 H - OCH2 Q-104 4-Ph - C¾
Q-53 H - OCH2 Q-105 3-Ph - C¾
The present disclosure also includes Tables 9-A through 9-E, each of which is constructed the same as Table 9 above except that the Row Heading in Table 9 (i.e. "Xa is CH and Z1 is O") is replaced with the respective row headings shown below. For example, in Table 9-A the row heading is "Xa is CH and Z1 is CH2" and Q, (R9a)p, R9c and Z2 are as defined in Table 9 above. Thus, the first entry in Table 9-A specifically discloses l-[4-[[6- [(3 -chloro-2-thienyl)methoxy] -3 -pyridazinyljmethyl] - 1 -piperidinyl] -2- [5 -methyl-3 - (trifluoromethyl)-lH-pyrazol-l-yl]ethanone. Tables 9-B and 9-E are constructed similarly.
Table Row Heading
9-A Xa is CH and Z1 is CH2. Table Row Heading
9-B Xa is CH and Z1 is OCH2.
9-C Xa is CH and Z1 is CH20.
9-D Xa is CH and Z1 is C=ONH.
9-E Xa is N and Z1 is CH2.
Table 10
Figure imgf000095_0001
In Table 10 the structures of Q-1 through Q-105 are shown in Exhibit 2 above. The substituents
(R9a)p and R9c are attached to the Q-ring as shown in in Exhibit 2.
is CH and Z 1 is O. Xa is CH and Z1 is O.
Q (R9a)p R9c Z2 Q (R9a)p R9c Z2
Q-1 3 -CI OCH2 Q-54 H OCH2
Q-2 H OCH2 Q-55 H OCH2
Q-3 H CH3 OCH2 Q-56 H OCH2
Q-4 2-CH3 OCH2 Q-57 H OCH2
Q-5 H OCH2 Q-58 H OCH2
Q-6 H OCH2 Q-59 H OCH2
Q-7 H OCH2 Q-60 H CH2
Q-8 H OCH2 Q-61 H CH2
Q-9 H OCH2 Q-62 H CH2
Q-10 H CH3 OCH2 Q-63 H CH2
Q-l l H CH3 OCH2 Q-64 H CH2
Q-12 H CH3 OCH2 Q-65 H CH2
Q-13 H CH3 OCH2 Q-66 H CH2
Q-14 H CH3 OCH2 Q-67 H CH2
Q-15 H OCH2 Q-68 H CH2
Q-16 H OCH2 Q-69 H CH2
Q-17 H OCH2 Q-70 H CH2
Q-18 H OCH2 Q-71 H CH2
Q-19 H OCH2 Q-72 H CH3 CH2
Q-20 H OCH2 Q-73 H CH2
Q-21 H CH3 OCH2 Q-74 H CH2
Q-22 H CH3 OCH2 Q-75 H CH3 CH2 Xa is CH and Z1 is O. Xa is CH and Z1 is O.
Q R9c Q R9c
(R9a)D Z2 (R9a)p Z2
Q-23 H CH3 oc¾ Q-76 H - C¾
Q-24 5-CF3 - oc¾ Q-77 H - CH2
Q-25 5-Cl - oc¾ Q-78 H CH3 C¾
Q-26 H - oc¾ Q-79 H CH3 C¾
Q-27 3,5-di-CH3 - oc¾ Q-80 H - CH2
Q-28 H H oc¾ Q-81 H - C¾
Q-29 H - OCH2 Q-82 H - C¾
Q-30 H - oc¾ Q-83 H - C¾
Q-31 H CH3 OCH2 Q-84 H - C¾
Q-32 H - OCH2 Q-85 H - C¾
Q-33 2-Cl - OCH2 Q-86 H CH3 C¾
Q-34 H - OCH2 Q-87 H - C¾
Q-35 H - OCH2 Q-88 H CH3 C¾
Q-36 H - OCH2 Q-89 H - C¾
Q-37 H - OCH2 Q-90 H - C¾
Q-38 H - OCH2 Q-91 H - C¾
Q-39 H - OCH2 Q-92 H CH3 C¾
Q-40 H - OCH2 Q-93 H - C¾
Q-41 H - OCH2 Q-94 H - C¾
Q-42 H - OCH2 Q-95 H CH3 OCH2
Q-43 H - OCH2 Q-96 H - OCH2
Q-44 H - OCH2 Q-97 H - OCH2
Q-46 H - OCH2 Q-98 H - C¾
Q-47 H - OCH2 Q-99 H - C¾
Q-48 H - OCH2 Q-100 H - C¾
Q-49 H - OCH2 Q-101 H - C¾
Q-50 H - OCH2 Q-102 H CH3 C¾
Q-51 H - OCH2 Q-103 3-Ph - C¾
Q-52 H - OCH2 Q-104 4-Ph - C¾
Q-53 H - OCH2 Q-105 3-Ph - C¾
The present disclosure also includes Tables 10-A through 10-E, each of which is constructed the same as Table 10 above except that the Row Heading in Table 10 (i.e. "Xa is CH and Z1 is O") is replaced with the respective row headings shown below. For example, in Table 10-A the row heading is "Xa is CH and Z1 is CH2" and Q, (R9a)p, R9c and Z2 are as defined in Table 10 above. Thus, the first entry in Table 10-A specifically discloses 1,1,1- trifluoro-2-propanone O-[2-[4-[[6-[(3-chloro-2-thienyl)methoxy]-3-pyridazinyl]methyl]-l- piperidinyl]-2-oxoethyl]oxime. Tables 10-B and 10-E are constructed similarly.
Table Row Heading
10-A Xa is CH and Z1 is CH2.
10-B xa is CH and Z1 is OCH2.
10-C Χ¾ is CH and Z1 is CH20.
10-D xa is CH and Z1 is C=ONH.
Figure imgf000097_0001
Table 11
E Z1 Z2
In Table 11 the structures of Q-45, Q-63, Q-64, Q-70, Q-71, Q-72 and Q-103 are shown in Exhibit 2 above. The substituents (R9a)p and R^c are attached to the Q-ring as shown in in Exhibit 2. The structures of G-70 and G-71 are shown in Exhibit 1 above. The substituent R^c attached to G-70 and G-71 , shown in Exhibit 1 , is H.
s E-la, X is χΐ and G is G-70. E is E-la, X is X1 and G is G-70.
R9c c
Q (R9a)p zi Z2 R9
Q (R9a)p zi Z2
Q-45 2-F H O O Q-45 2-Br H OCH2 SCH2
Q-45 2-Cl H O O Q-45 2-Me H OCH2 SCH2
Q-45 2-Br H O O Q-45 2,6-di-F H OCH2 SCH2
Q-45 2-Me H O O Q-45 2,6-di-Cl H OCH2 SCH2
Q-45 2,6-di-F H O O Q-45 2,6-di-Br H OCH2 SCH2
Q-45 2,6-di-Cl H O O Q-45 2,6-di-Me H OCH2 SCH2
Q-45 2,6-di-Br H O O Q-45 2,4-di-F H OCH2 SCH2
Q-45 2,6-di-Me H O O Q-45 2,4-diCl H OCH2 SCH2
Q-45 2,4-di-F H O O Q-45 2-CN H OCH2 SCH2
Q-45 2,4-di-Cl H O O Q-45 2-MeO H OCH2 SCH2
Q-45 2-CN H O O Q-45 2-CF3 H OCH2 SCH2
Q-45 2-MeO H O O Q-45 3-CF3 H OCH2 SCH2
Q-45 2-CF3 H O O Q-45 4-CF3 H OCH2 SCH2
Q-45 3-CF3 H O O Q-45 H H OCH2 SCH2
Q-45 4-CF3 H O O Q-45 2-F H OCH2 NH
Q-45 H H O O Q-45 2-Cl H OCH2 NH
Q-45 2-F H O CH20 Q-45 2-Br H OCH2 NH
Q-45 2-Cl H O CH20 Q-45 2-Me H OCH2 NH
Q-45 2-Br H O CH20 Q-45 2,6-di-F H OCH2 NH
Q-45 2-Me H O CH20 Q-45 2,6-di-Cl H OCH2 NH E is E-l a, X is X1 and G is G-70. E is E-l a, X is X1 and G is G-70.
Q (R9a)D R9c zi Z2 Q R9c
(R9a)p zi Z2
Q-45 2,6-di-F H O c¾o Q-45 2,6-di-Br H OCH2 NH
Q-45 2,6-di-Cl H O CH20 Q-45 2,6-di-Me H OCH2 NH
Q-45 2,6-di-Br H O CH20 Q-45 2,4-di-F H OCH2 NH
Q-45 2,6-di-Me H O CH20 Q-45 2,4-di-Cl H OCH2 NH
Q-45 2,4-di-F H O c¾o Q-45 2-CN H OCH2 NH
Q-45 2,4-di-Cl H O CH20 Q-45 2-MeO H OCH2 NH
Q-45 2-CN H O CH20 Q-45 2-CF3 H OCH2 NH
Q-45 2-MeO H O CH20 Q-45 3-CF3 H OCH2 NH
Q-45 2-CF3 H O CH20 Q-45 4-CF3 H OCH2 NH
Q-45 3-CF3 H O CH20 Q-45 H H OCH2 NH
Q-45 4-CF3 H O CH20 Q-45 2-F H OCH2 CH2NH
Q-45 H H O CH20 Q-45 2-Cl H OCH2 CH2NH
Q-45 2-F H O OCH2 Q-45 2-Br H OCH2 CHoNH
Q-45 2-Cl H O OCH2 Q-45 2-Me H OCH2 CH2NH
Q-45 2-Br H O OCH2 Q-45 2,6-di-F H OCH2 CH2NH
Q-45 2-Me H O OCH2 Q-45 2,6-di-Cl H OCH2 CH2NH
Q-45 2,6-di-F H O OCH2 Q-45 2,6-di-Br H OCH2 CH2NH
Q-45 2,6-di-Cl H O OCH2 Q-45 2,6-di-Me H OCH2 CH2NH
Q-45 2,6-di-Br H O OCH2 Q-45 2,4-di-F H OCH2 CH2NH
Q-45 2,6-di-Me H O OCH2 Q-45 2,4-di-Cl H OCH2 CH2NH
Q-45 2,4-di-F H O OCH2 Q-45 2-CN H OCH2 CH2NH
Q-45 2,4-di-Cl H O OCH2 Q-45 2-MeO H OCH2 CH2NH
Q-45 2-CN H O OCH2 Q-45 2-CF3 H OCH2 CH2NH
Q-45 2-MeO H O OCH2 Q-45 3-CF3 H OCH2 CH2NH
Q-45 2-CF3 H O OCH2 Q-45 4-CF3 H OCH2 CH2NH
Q-45 3-CF3 H O OCH2 Q-45 H H OCH2 CH2NH
Q-45 4-CF3 H O OCH2 Q-45 2-F H OCH2 NHCH2
Q-45 H H O OCH2 Q-45 2-Cl H OCH2 NHCH2
Q-45 2-F H O s Q-45 2-Br H OCH2 NHCH2
Q-45 2-Cl H O s Q-45 2-Me H OCH2 NHCH2
Q-45 2-Br H O s Q-45 2,6-di-F H OCH2 NHCH2
Q-45 2-Me H O s Q-45 2,6-di-Cl H OCH2 NHCH2
Q-45 2,6-di-F H O s Q-45 2,6-di-Br H OCH2 NHCH2
Q-45 2,6-di-Cl H O s Q-45 2,6-di-Me H OCH2 NHCH2
Q-45 2,6-di-Br H O s Q-45 2,4-di-F H OCH2 NHCH2
Q-45 2,6-di-Me H O s Q-45 2,4-di-Cl H OCH2 NHCH2 E is E-l a, X is X1 and G is G-70. E is E-la, X is X1 and G is G-70.
Q R9c
(R9a)o zi Z2 Q (R9a)D R9c zi Z2
Q-45 2,4-di-F H O s Q-45 2-CN H OCH2 NHCH2
Q-45 2,4-di-Cl H O s Q-45 2-MeO H OCH2 NHCH2
Q-45 2-CN H O s Q-45 2-CF3 H OCH2 NHCH2
Q-45 2-MeO H O s Q-45 3-CF3 H OCH2 NHCH2
Q-45 2-CF3 H O s Q-45 4-CF3 H OCH2 NHCH2
Q-45 3-CF3 H O s Q-45 H H OCH2 NHCH2
Q-45 4-CF3 H O s Q-45 2-F H OCH2 CH2
Q-45 H H O s Q-45 2-Cl H OCH2 CH2
Q-45 2-F H O C¾S Q-45 2-Br H OCH2 CH2
Q-45 2-Cl H O C¾S Q-45 2-Me H OCH2 CH2
Q-45 2-Br H O CH2S Q-45 2,6-di-F H OCH2 CH2
Q-45 2-Me H O CH2S Q-45 2,6-di-Cl H OCH2 CH2
Q-45 2,6-di-F H O CH2S Q-45 2,6-di-Br H OCH2 CH2
Q-45 2,6-di-Cl H O CH2S Q-45 2,6-di-Me H OCH2 CH2
Q-45 2,6-di-Br H O CH2S Q-45 2,4-di-F H OCH2 CH2
Q-45 2,6-di-Me H O CH2S Q-45 2,4-di-Cl H OCH2 CH2
Q-45 2,4-di-F H O CH2S Q-45 2-CN H OCH2 CH2
Q-45 2,4-di-Cl H O CH2S Q-45 2-MeO H OCH2 CH2
Q-45 2-CN H O CH2S Q-45 2-CF3 H OCH2 CH2
Q-45 2-MeO H O CH2S Q-45 3-CF3 H OCH2 CH2
Q-45 2-CF3 H O CH2S Q-45 4-CF3 H OCH2 CH2
Q-45 3-CF3 H O CH2S Q-45 H H OCH2 CH2
Q-45 4-CF3 H O C¾S Q-63 H H OCH2 CH2
Q-45 H H O CH2S Q-64 H H OCH2 CH2
Q-45 2-F H O SCH2 Q-70 H H OCH2 CH2
Q-45 2-Cl H O SCH2 Q-71 H H OCH2 C¾
Q-45 2-Br H O SCH2 Q-72 H H OCH2 C¾
Q-45 2-Me H O SCH2 Q-72 H Me OCH2 C¾
Q-45 2,6-di-F H O SCH2 Q-103 H H OCH2 CH2
Q-45 2,6-di-Cl H O SCH2 Q-45 2-F H CH20 O
Q-45 2,6-di-Br H O SCH2 Q-45 2-Cl H CH20 O
Q-45 2,6-di-Me H O SCH2 Q-45 2-Br H C¾0 O
Q-45 2,4-di-F H O SCH2 Q-45 2-Me H C¾0 O
Q-45 2,4-di-Cl H O SCH2 Q-45 2,6-di-F H CH20 O
Q-45 2-CN H O SCH2 Q-45 2,6-di-Cl H CHoO O
Q-45 2-MeO H 0 SCH2 Q-45 2,6-di-Br H CH20 O E is E-la, X is χΐ and G is G-70. E is E-la, X is χΐ and G is G-70.
Q (R9a)p R9c zi Z2 Q (R9a)p R9c zi Z2
Q-45 2-CF3 H O sc¾ Q-45 2,6-di-Me H CH20 O
Q-45 3-CF3 H O sc¾ Q-45 2,4-di-F H CH20 O
Q-45 4-CF3 H O sc¾ Q-45 2,4-di-Cl H CH20 O
Q-45 H H O sc¾ Q-45 2-CN H CH20 O
Q-45 2-F H O NH Q-45 2-MeO H CH20 O
Q-45 2-Cl H O NH Q-45 2-CF3 H CH20 O
Q-45 2-Br H O NH Q-45 3-CF3 H CH20 O
Q-45 2-Me H O NH Q-45 4-CF3 H CH20 O
Q-45 2,6-di-F H O NH Q-45 H H CH20 O
Q-45 2,6-di-Cl H O NH Q-45 2-F H CH20 CH20
Q-45 2,6-di-Br H O NH Q-45 2-Cl H CH20 CH20
Q-45 2,6-di-Me H O NH Q-45 2-Br H CH20 CH20
Q-45 2,4-di-F H O NH Q-45 2-Me H CH20 CH20
Q-45 2,4-di-Cl H O NH Q-45 2,6-di-F H CH20 CH20
Q-45 2-CN H O NH Q-45 2,6-di-Cl H CH20 CH20
Q-45 2-MeO H O NH Q-45 2,6-di-Br H CH20 CH20
Q-45 2-CF3 H O NH Q-45 2,6-di-Me H CH20 CH20
Q-45 3-CF3 H O NH Q-45 2,4-di-F H CH20 CH20
Q-45 4-CF3 H O NH Q-45 2,4-di-Cl H CH20 CH20
Q-45 H H O NH Q-45 2-CN H CH20 CH20
Q-45 2-F H O CH2NH Q-45 2-MeO H CH20 CH20
Q-45 2-Cl H O CH2NH Q-45 2-CF3 H CH20 CH20
Q-45 2-Br H O CH2NH Q-45 3-CF3 H CH20 CH20
Q-45 2-Me H O CH2NH Q-45 4-CF3 H CH20 CH20
Q-45 2,6-di-F H O CH2NH Q-45 H H CH20 CH20
Q-45 2,6-di-Cl H O CH2NH Q-45 2-F H CH20 OCH2
Q-45 2,6-di-Br H O CH2NH Q-45 2-Cl H CH20 OCH2
Q-45 2,6-di-Me H O CH2NH Q-45 2-Br H CH20 OCH2
Q-45 2,4-di-F H O CH2NH Q-45 2-Me H CH20 OCH2
Q-45 2,4-di-Cl H O CH2NH Q-45 2,6-di-F H CH20 OCH2
Q-45 2-CN H O CH2NH Q-45 2,6-di-Cl H CH20 OCH2
Q-45 2-MeO H O CH2NH Q-45 2,6-di-Br H CH20 OCH2
Q-45 2-CF3 H O CH2NH Q-45 2,6-di-Me H CH20 OCH2
Q-45 3-CF3 H O CH2NH Q-45 2,4-di-F H CH20 OCH2
Q-45 4-CF3 H O CH2NH Q-45 2,4-di-Cl H CH20 OCH2
Q-45 H H O CH2NH Q-45 2-CN H CH20 OCH2 E is E-la, X is X1 and G is G-70. E is E-la, X is X1 and G is G-70.
Q (R9a)D R9c zi Z2 Q (R9a)p R9c zi Z2
Q-45 2-F H O NHCH2 Q-45 2-MeO H C¾0 OCH2
Q-45 2-Cl H O NHCH2 Q-45 2-CF3 H C¾0 OCH2
Q-45 2-Br H O NHCH2 Q-45 3-CF3 H C¾0 OCH2
Q-45 2-Me H O NHCH2 Q-45 4-CF3 H C¾0 OCH2
Q-45 2,6-di-F H O NHCH2 Q-45 H H C¾0 OCH2
Q-45 2,6-di-Cl H O NHCH2 Q-45 2-F H C¾0 s
Q-45 2,6-di-Br H O NHCH2 Q-45 2-Cl H C¾0 s
Q-45 2,6-di-Me H O NHCH2 Q-45 2-Br H C¾0 s
Q-45 2,4-di-F H O NHCH2 Q-45 2-Me H C¾0 s
Q-45 2,4-di-Cl H O NHCH2 Q-45 2,6-diF H CH20 s
Q-45 2-CN H O NHCH2 Q-45 2,6-diCl H C¾0 s
Q-45 2-MeO H O NHCH2 Q-45 2,6-diBr H C¾0 s
Q-45 2-CF3 H O NHCH2 Q-45 2,6-di-Me H C¾0 s
Q-45 3-CF3 H O NHCH2 Q-45 2,4-di-F H C¾0 s
Q-45 4-CF3 H O NHCH2 Q-45 2,4-di-Cl H C¾0 s
Q-45 H H O NHCH2 Q-45 2-CN H CH20 s
Q-45 2-F H O CH2 Q-45 2-MeO H C¾0 s
Q-45 2-Cl H O CH2 Q-45 2-CF3 H C¾0 s
Q-45 2-Br H O CH2 Q-45 3-CF3 H C¾0 s
Q-45 2-Me H O CH2 Q-45 4-CF3 H C¾0 s
Q-45 2,6-di-F H O CH2 Q-45 H H C¾0 s
Q-45 2,6-di-Cl H O CH2 Q-45 2-F H C¾0 CH2S
Q-45 2,6-di-Br H O CH2 Q-45 2-Cl H C¾0 CH2S
Q-45 2,6-di-Me H O CH2 Q-45 2-Br H C¾0 CH2S
Q-45 2,4-di-F H O CH2 Q-45 2-Me H C¾0 CH2S
Q-45 2,4-di-Cl H O CH2 Q-45 2,6-di-F H C¾0 CH2S
Q-45 2-CN H O CH2 Q-45 2,6-di-Cl H C¾0 CH2S
Q-45 2-MeO H O CH2 Q-45 2,6-di-Br H C¾0 CH2S
Q-45 2-CF3 H O CH2 Q-45 2,6-di-Me H C¾0 CH2S
Q-45 3-CF3 H O CH2 Q-45 2,4-di-F H C¾0 CH2S
Q-45 4-CF3 H O CH2 Q-45 2,4-di-Cl H C¾0 CH2S
Q-45 H H O CH2 Q-45 2-CN H C¾0 CH2S
Q-63 2-F H O CH2 Q-45 2-MeO H C¾0 CH2S
Q-64 2-Cl H O CH2 Q-45 2-CF3 H C¾0 CH2S
Q-70 2-Br H O CH2 Q-45 3-CF3 H CH20 CH2S
Q-71 2-Me H O CH2 Q-45 4-CF3 H C¾0 CH2S E is E-la, X is X1 and G is G-70. E is E-la, X is X1 and G is G-70.
Q (R9a)p R9c zi Z2 Q (R9a)p R9c zi Z2
Q-72 2,6-di-F H O CH2 Q-45 H H C¾0 CH2S
Q-72 2,6-di-Cl H O CH2 Q-45 2-F H C¾0 SCH2
Q-103 2,6-di-Br H O CH2 Q-45 2-Cl H CH20 SCH2
Q-45 2,6-di-Me H oc¾ O Q-45 2-Br H C¾0 SCH2
Q-45 2,4-di-F H OCH2 O Q-45 2-Me H C¾0 SCH2
Q-45 2,4-di-Cl H oc¾ O Q-45 2,6-di-F H C¾0 SCH2
Q-45 2-CN H oc¾ O Q-45 2,6-di-Cl H C¾0 SCH2
Q-45 2-MeO H oc¾ O Q-45 2,6-di-Br H C¾0 SCH2
Q-45 2-CF3 H OCH2 O Q-45 2,6-di-Me H C¾0 SCH2
Q-45 3-CF3 H OC¾ O Q-45 2,4-di-F H C¾0 SCH2
Q-45 4-CF3 H oc¾ O Q-45 2,4-di-Cl H C¾0 SCH2
Q-45 H H oc¾ O Q-45 2-CN H C¾0 SCH2
Q-45 2-F H OCH2 O Q-45 2-MeO H C¾0 SCH2
Q-45 2-Cl H OCH2 O Q-45 2-CF3 H C¾0 SCH2
Q-45 2-Br H OCH2 O Q-45 3-CF3 H C¾0 SCH2
Q-45 2-Me H OCH2 O Q-45 4-CF3 H CH20 SCH2
Q-45 2,6-di-F H OCH2 O Q-45 H H C¾0 SCH2
Q-45 2,6-di-Cl H OCH2 O Q-45 2-F H C¾0 NH
Q-45 2,6-di-Br H OCH2 O Q-45 2-Cl H C¾0 NH
Q-45 2-F H OCH2 CH20 Q-45 2-Br H C¾0 NH
Q-45 2-Cl H OCH2 CH20 Q-45 2-Me H C¾0 NH
Q-45 2-Br H OCH2 CH20 Q-45 2,6-di-F H C¾0 NH
Q-45 2-Me H OCH2 CH20 Q-45 2,6-di-Cl H CH20 NH
Q-45 2,6-diF H OCH2 CH20 Q-45 2,6-di-Br H C¾0 NH
Q-45 2,6-diCl H OCH2 CH20 Q-45 2,6-di-Me H C¾0 NH
Q-45 2,6-di-Br H OCH2 C¾0 Q-45 2,4-di-F H C¾0 NH
Q-45 2,6-di-Me H OCH2 CH20 Q-45 2,4-di-Cl H C¾0 NH
Q-45 2,4-di-F H OCH2 CH20 Q-45 2-CN H C¾0 NH
Q-45 2,4-di-Cl H OCH2 CH20 Q-45 2-OMe H C¾0 NH
Q-45 2-CN H OCH2 CH20 Q-45 2-CF3 H C¾0 NH
Q-45 2-MeO H OCH2 CH20 Q-45 3-CF3 H C¾0 NH
Q-45 2-CF3 H OCH2 C¾0 Q-45 4-CF3 H C¾0 NH
Q-45 3-CF3 H OCH2 C¾0 Q-45 H H C¾0 NH
Q-45 4-CF3 H OCH2 CH20 Q-45 2-F H C¾0 CH2NH
Q-45 H H OCH2 CH20 Q-45 2-Cl H C¾0 CH2NH
Q-45 2-F H OCH2 OCH2 Q-45 2-Br H CH20 CH2NH E is E-la, X is X1 and G is G-70. E is E-la, X is X1 and G is G-70.
Q (R9a)p R9c zi Z2 Q (R9a)p R9c zi Z2
Q-45 2-Cl H OCH2 Q-45 2-Me H C¾0 CH2NH
Q-45 2-Br H OCH2 OCH2 Q-45 2,6-di-F H C¾0 CH2NH
Q-45 2-Me H oc¾ OCH2 Q-45 2,6-di-Cl H C¾0 CH2NH
Q-45 2,6-di-F H OCH2 OCH2 Q-45 2,6-di-Br H C¾0 CH2NH
Q-45 2,6-di-Cl H oc¾ OCH2 Q-45 2,6-di-Me H C¾0 CH2NH
Q-45 2,6-di-Br H oc¾ OCH2 Q-45 2,4-di-F H C¾0 CH2NH
Q-45 2,6-di-Me H oc¾ OCH2 Q-45 2,4-di-Cl H C¾0 CH2NH
Q-45 2,4-di-F H oc¾ OCH2 Q-45 2-CN H C¾0 CH2NH
Q-45 2,4-di-Cl H oc¾ OCH2 Q-45 2-MeO H C¾0 CH2NH
Q-45 2-CN H OCH2 OCH2 Q-45 2-CF3 H C¾0 CH2NH
Q-45 2-MeO H oc¾ OCH2 Q-45 3-CF3 H C¾0 CH2NH
Q-45 2-CF3 H OCH2 OCH2 Q-45 4-CF3 H C¾0 CH2NH
Q-45 3-CF3 H OCH2 OCH2 Q-45 H H C¾0 CH2NH
Q-45 4-CF3 H OCH2 OCH2 Q-45 2-F H C¾0 NHCH2
Q-45 H H OCH2 OCH2 Q-45 2-Cl H C¾0 NHCH2
Q-45 2-F H OCH2 s Q-45 2-Br H CH20 NHCH2
Q-45 2-Cl H OCH2 s Q-45 2-Me H C¾0 NHCH2
Q-45 2-Br H OCH2 s Q-45 2,6-di-F H C¾0 NHCH2
Q-45 2-Me H OCH2 s Q-45 2,6-di-Cl H C¾0 NHCH2
Q-45 2,6-di-F H OCH2 s Q-45 2,6-di-Br H C¾0 NHCH2
Q-45 2,6-di-Cl H OCH2 s Q-45 2,6-di-Me H C¾0 NHCH2
Q-45 2,6-di-Br H OCH2 s Q-45 2,4-di-F H C¾0 NHCH2
Q-45 2,6-di-Me H OCH2 s Q-45 2,4-di-Cl H C¾0 NHCH2
Q-45 2,4-di-F H OCH2 s Q-45 2-CN H C¾0 NHCH2
Q-45 2,4-di-Cl H OCH2 s Q-45 2-MeO H C¾0 NHCH2
Q-45 2-CN H OCH2 s Q-45 2-CF3 H C¾0 NHCH2
Q-45 2-MeO H OCH2 s Q-45 3-CF3 H C¾0 NHCH2
Q-45 2-CF3 H OCH2 s Q-45 4-CF3 H C¾0 NHCH2
Q-45 3-CF3 H OCH2 s Q-45 - H C¾0 NHCH2
Q-45 4-CF3 H OCH2 s Q-45 2-F H C¾0 CH2
Q-45 H H OCH2 s Q-45 2-Cl H C¾0 CH2
Q-45 2-F H OCH2 CH2S Q-45 2-Br H C¾0 C¾
Q-45 2-Cl H OCH2 CH2S Q-45 2-Me H C¾0 CH2
Q-45 2-Br H OCH2 CH2S Q-45 2,6-di-F H C¾0 CH2
Q-45 2-Me H OCH2 CH2S Q-45 2,6-di-Cl H CH20 CH2
Q-45 2,6-di-F H OCH2 CH2S Q-45 2,6-di-Br H C¾0 CH2 is E-la, X is χΐ and G is G-70. E is E-la, X is X^ and G is G-70.
R9c zi Z2 R9c
Q (R9a)p Q (R9a)D zi Z2
Q-45 2,6-di-Cl H oc¾ CH2S Q-45 2,6-di-Me H C¾0 C¾
Q-45 2,6-di-Br H OCH2 CH2S Q-45 2,4-di-F H CH20 CH2
Q-45 2,6-di-Me H OCH2 CH2S Q-45 2,4-diCi H C¾0 CH2
Q-45 2,4-di-F H OCH2 CH2S Q-45 2-CN H C¾0 C¾
Q-45 2,4-di-Cl H OCH2 C¾S Q-45 2-MeO H C¾0 C¾
Q-45 2-CN H OCH2 C¾S Q-45 2-CF3 H C¾0 C¾
Q-45 2-MeO H OCH2 CH2S Q-45 3-CF3 H C¾0 C¾
Q-45 2-CF3 H OCH2 CH2S Q-45 4-CF3 H C¾0 C¾
Q-45 3-CF3 H OCH2 CH2S Q-45 H H CH20 CH2
Q-45 4-CF3 H OCH2 CH2S Q-63 H H C¾0 CH2
Q-45 H H OCH2 CH2S Q-64 H H C¾0 C¾
Q-45 2-F H OCH2 SCH2 Q-70 H H C¾0 C¾
Q-45 2-Cl H OCH2 SCH2 Q-71 H H C¾0 C¾
The present disclosure also includes Tables 11 -A through 11 -AY, each of which is constructed the same as Table 11 above except that the Row Heading in Table 11 (i.e. "E is E-la, X is X1 and G is G-70") is replaced with the respective row headings shown below. For example, in Table 1 1-A the row heading is "E is E-lb, X is X1 and G is G-70" and Q, (R9a)p, R9c, Z1 and Z2 are as defined in Table 11 above. Thus, the first entry in Table 11-A specifically discloses 2-[5-chloro-3-(trifluoromethyl)-lH-pyrazol-l-yl]-l-[4-[[6-(2- fluorophenoxy)-3-pyridazinyl]oxy]-l-piperidinyl]ethanone. Tables 11-B and 11 -AY are constructed similarly.
Table Row Heading Table Row Heading
11 -A E is E-lb, X is X1 and G is G-70. 1 1-AA E is E-lb, X is X1 and G is G-71. 11-B E is E-l c, X is X1 and G is G-70. 11 -AB E is E-lc X is X1 and G is G-71. 11-C E is E-ld, X is X1 and G is G-70. 11 -AC E is E-ld, X is X1 and G is G-71. 11-D E is E-le, X is χΐ and G is G-70. 11 -AD E is E-le, X is χΐ and G is G-71. 11-E E is E-lf, X is X1 and G is G-70. 11 -AE E is E-lf, X is X1, and G is G-71. 11-F E is E- lg, X is X1 and G is G-70. 11 -AF E is E-lg, X is χΐ and G is G-71. 11-G E is E- lh, X is X1 and G is G-70. 11 -AG E is E- lh, X is X1 and G is G-71. 11 -H E is E-li, X is X1 and G is G-70. 1 1 -AH E is E-li, X is X1 and G is G-71. 11-1 E is E-lj, X is X1 and G is G-70. 11 -AI E is E-lj, X is X1 and G is G-71. 11-J E is E-lk, X is X1 and G is G-70. 11 -AJ E is E-lk, X is X1 and G is G-71. 11-K E is E-ll, X is X1 and G is G-70. 11 -AK E is E-ll, X is X1 and G is G-71. 11-L E is E-lm, X is χΐ and G is G-70. 11 -AL E is E-lm, X is χΐ and G is G-71. 11-M E is E- ln, X is χΐ and G is G-70. 11 -AM E is E-ln, X is χΐ and G is G-71. Table Row Heading Table Row Heading
11-N E is E-2a, X is and G is G-70. 11 -AN E is E-2a, X is X^ and G is G-71. l l-O E is E-2b, X is X1 and G is G-70. 11 -AO E is E-2b, X is X1 and G is G-71.
11-P E is E-2c, X is X^ and G is G-70. 11 -AP E is E-2c, X is X^ and G is G-71.
11-Q E is E-2d, X is X1 and G is G-70. 11 -AQ E is E-2d, X is X1 and G is G-71.
11-R E is E-la, X is X4 and G is G-70. 11 -AR E is E-la, X is X4 and G is G-71.
11-S E is E-ld, X is X4 and G is G-70. 11 -AS E is E-ld, X is X4 and G is G-71.
11-T E is E-lg, X is X4 and G is G-70. 11 -AT E is E-lg, X is X4 and G is G-71.
11-U E is E-lh, X is X4 and G is G-70. 11 -AU E is E-lh, X is X4 and G is G-71.
11-V E is E-lk, X is X4 and G is G-70. 11 -AV E is E-lk, X is X4 and G is G-71.
11-W E is E-ll, X is X4 and G is G-70. 11 -AW E is E-ll, X is X4 and G is G-71.
11-X E is E-2a, X is X4 and G is G-70. 11-AX E is E-2a, X is X4 and G is G-71.
11-Y E is E-2b, X is X4 and G is G-70. 11 -AY E is E-2b, X is X4 and G is G-71.
11-Z E is E-la, X is X^ and G is G-71.
Table 12
E Z1 Z2
In Table 12 the structures of Q-45, Q-63, Q-64, Q-70, Q-71, Q-72 and Q-103 are shown in Exhibit 2 above. The substituents (R9a)p and R9c are attached to the Q-ring, as shown in in Exhibit 2. The structures of G-70 and G-71 are shown in Exhibit 1 above. The substituent R8c attached to G-70 and G-71 is H.
E is E-la, X is X^ and G is G-70. E is E-la, X is X^ and G is G-
Q (R9a)„ R9c Z2 Q (R9a)n R9c Λ Z2
Q-45 2-F CH2 O Q-45 2-Me CH2 SCH2 Q-45 2-Cl CH2 O Q-45 2,6-di-F CH2 SCH2 Q-45 2-Br CH2 O Q-45 2,6-di-Cl CH2 SCH2 Q-45 2-Me CH2 O Q-45 2,6-di-Br CH2 SCH2 Q-45 2,6-di-F CH2 O Q-45 2,6-di-Me CH2 SCH2 Q-45 2,6-di-Cl CH2 O Q-45 2,4-di-F CH2 SCH2 Q-45 2,6-di-Br CH2 O Q-45 2,4-di-Cl CH2 SCH2 Q-45 2,6-di-Me CH2 O Q-45 2-CN CH2 SCH2 Q-45 2,4-di-F CH2 O Q-45 2-MeO CH2 SCH2 Q-45 2,4-di-Cl CH2 O Q-45 2- CF3 CH2 SCH2 Q-45 2-CN CH2 O Q-45 3- CF3 CH2 SCH2 Q-45 2-MeO CH2 O Q-45 4- CF3 CH2 SCH2 Q-45 2- CF3 CH2 O Q-45 H CH2 SCH2 Q-45 3- CF3 CH2 O Q-45 2-F CH2 NH E is E-la, X is X2 and G is G-70. E is E-la, X is X2 and G is G-70.
Q R9c
(R9a)p zi Z2 Q R9c
(R9a)p zi Z2
Q-45 4-CF3 - CH2 O Q-45 2-Cl - CH2 NH
Q-45 H - CH2 O Q-45 2-Br - CH2 NH
Q-45 2-F - CH2 CH20 Q-45 2-Me - CH2 NH
Q-45 2-Cl - CH2 CH20 Q-45 2,6-di-F - CH2 NH
Q-45 2-Br - CH2 CH20 Q-45 2,6-di-Cl - CH2 NH
Q-45 2-Me - CH2 CH20 Q-45 2,6-di-Br - CH2 NH
Q-45 2,6-di-F - CH2 CH20 Q-45 2,6-di-Me - CH2 NH
Q-45 2,6-di-Cl - CH2 CH20 Q-45 2,4-di-F - CH2 NH
Q-45 2,6-di-Br - CH2 CH20 Q-45 2,4-di-Cl - CH2 NH
Q-45 2,6-di-Me - CH2 CH20 Q-45 2-CN - CH2 NH
Q-45 2,4-di-F - CH2 CH20 Q-45 2-MeO - CH2 NH
Q-45 2,4-di-Cl - CH2 CH20 Q-45 2-CF3 - CH2 NH
Q-45 2-CN - CH2 CH20 Q-45 3-CF3 - CH2 NH
Q-45 2-MeO - CH2 CH20 Q-45 4-CF3 - CH2 NH
Q-45 2-CF3 - CH2 CH20 Q-45 H - CH2 NH
Q-45 3-CF3 - CH2 CH20 Q-45 2-F - CH2 CH2NH
Q-45 4-CF3 - CH2 CH20 Q-45 2-Cl - CH2 CH2NH
Q-45 H - CH2 CH20 Q-45 2-Br - CH2 CH2NH
Q-45 2-F - CH2 OCH2 Q-45 2-Me - CH2 CH2NH
Q-45 2-Cl - CH2 OCH2 Q-45 2,6-di-F - CH2 CH2NH
Q-45 2-Br - CH2 OCH2 Q-45 2,6-di-Cl - CH2 CH2NH
Q-45 2-Me - CH2 OCH2 Q-45 2,6-di-Br - CH2 CH2NH
Q-45 2,6-di-F - CH2 OCH2 Q-45 2,6-di-Me - CH2 CH2NH
Q-45 2,6-di-Cl - CH2 OCH2 Q-45 2,4-di-F - CH2 CH2NH
Q-45 2,6-di-Br - CH2 OCH2 Q-45 2,4-di-Cl - CH2 CH2NH
Q-45 2,6-di-Me - CH2 OCH2 Q-45 2-CN - CH2 CH2NH
Q-45 2,4-di-F - CH2 OCH2 Q-45 2-OMe - CH2 CH2NH
Q-45 2,4-di-Cl - CH2 OCH2 Q-45 2-CF3 - CH2 CH2NH
Q-45 2-CN - CH2 OCH2 Q-45 3-CF3 - CH2 CH2NH
Q-45 2-MeO - CH2 OCH2 Q-45 4-CF3 - CH2 CH2NH
Q-45 2-CF3 - CH2 OCH2 Q-45 H - CH2 CH2NH
Q-45 3-CF3 - CH2 OCH2 Q-45 2-F - CH2 NHCH2
Q-45 4-CF3 - CH2 OCH2 Q-45 2-Cl - CH2 NHCH2
Q-45 H - CH2 OCH2 Q-45 2-Br - CH2 NHCH2
Q-45 2-F - CH2 s Q-45 2-Me - CH2 NHCH2
Q-45 2-Cl - CH2 s Q-45 2,6-di-F - CH2 NHCH2 E is E-la, X is X2 and G is G-70. E is E-la, X is X2 and G is G-70.
Q (R9a)p R9c Z1 Z2 Q R9c
(R9a)p zi Z2
Q-45 2-Br CH2 S Q-45 2,6-di-Cl - CH2 NHCH2
Q-45 2-Me CH2 s Q-45 2,6-di-Br - CH2 NHCH2
Q-45 2,6-di-F CH2 s Q-45 2,6-di-Me - CH2 NHCH2
Q-45 2,6-di-Cl CH2 s Q-45 2,4-di-F - CH2 NHCH2
Q-45 2,6-di-Br CH2 s Q-45 2,4-di-Cl - CH2 NHCH2
Q-45 2,6-di-Me CH2 s Q-45 2-CN - CH2 NHCH2
Q-45 2,4-di-F CH2 s Q-45 2-OMe - CH2 NHCH2
Q-45 2,4-di-Cl CH2 s Q-45 2-CF3 - CH2 NHCH2
Q-45 2-CN CH2 s Q-45 3-CF3 - CH2 NHCH2
Q-45 2-MeO CH2 s Q-45 4-CF3 - CH2 NHCH2
Q-45 2-CF3 CH2 s Q-45 H - CH2 NHCH2
Q-45 3-CF3 CH2 s Q-45 2-F - CH2 CH2
Q-45 4-CF3 CH2 s Q-45 2-Cl - CH2 CH2
Q-45 H CH2 s Q-45 2-Br - CH2 CH2
Q-45 2-F CH2 CH2S Q-45 2-Me - CH2 CH2
Q-45 2-Cl CH2 CH2S Q-45 2,6-di-F - CH2 CH2
Q-45 2-Br CH2 CH2S Q-45 2,6-di-Cl - CH2 CH2
Q-45 2-Me CH2 CH2S Q-45 2,6-di-Br - CH2 CH2
Q-45 2,6-di-F CH2 CH2S Q-45 2,6-di-Me - CH2 CH2
Q-45 2,6-di-Cl CH2 CH2S Q-45 2,4-di-F - CH2 CH2
Q-45 2,6-di-Br CH2 CH2S Q-45 2,4-di-Cl - CH2 CH2
Q-45 2,6-di-Me CH2 CH2S Q-45 2-CN - CH2 CH2
Q-45 2,4-di-F CH2 CH2S Q-45 2-MeO - CH2 CH2
Q-45 2,4-di-Cl CH2 CH2S Q-45 2-CF3 - CH2 CH2
Q-45 2-CN CH2 CH2S Q-45 3-CF3 - CH2 CH2
Q-45 2-MeO CH2 CH2S Q-45 4-CF3 - CH2 CH2
Q-45 2-CF3 CH2 CH2S Q-45 H - CH2 CH2
Q-45 3-CF3 CH2 CH2S Q-63 H - CH2 CH2
Q-45 4-CF3 CH2 CH2S Q-64 H - CH2 CH2
Q-45 H CH2 CH2S Q-70 H - CH2 CH2
Q-45 2-F CH2 SCH2 Q-71 H - CH2 CH2
Q-45 2-Cl CH2 SCH2 Q-72 H H CH2 CH2
Q-45 2-Br CH2 SCH2 Q-72 H Me CH2 CH2
Q-103 H - CH2 CH2 The present disclosure also includes Tables 12-A through 12- AY, each of which is constructed the same as Table 12 above except that the Row Heading in Table 12 (i.e. "E is E-la, X is X2 and G is G-70") is replaced with the respective row headings shown below. For example, in Table 12-A the row heading is "E is E-lb, X is X2 and G is G-70" and Q, (R9a)p, R9c, Z1 and Z2 are as defined in Table 12 above. Thus, the first entry in Table 12-A specifically discloses 2-[5-chloro-3-(trifluoromethyl)-lH-pyrazol-l-yl]-l-[4-[[6-(2- fluorophenoxy)-3-pyridazinyl]methyl]-l-piperazinyl]ethanone. Tables 12-B and 12-AY are constructed similarly.
Table Row Heading Table Row Heading
12-A E is E-lb, X is X2 and G is G-70. 12-AA E is E-lb, X is X2 and G is G-71.
12-B E is E-lc, X is X2 and G is G-70. 12-AB E is E-lc, X is X2 and G is G-71.
12-C E is E-ld, X is X2 and G is G-70. 12-AC E is E-ld, X is X2 and G is G-71.
12-D E is E-le, X is X2 and G is G-70. 12-AD E is E-le, X is X2 and G is G-71.
12-E E is E-lf, X is X2 and G is G-70. 12-AE E is E-lf, X is X2 and G is G-71.
12-F E is E-lg, X is X2 and G is G-70. 12-AF E is E-lg, X is X2 and G is G-71.
12-G E is E-lh, X is X2 and G is G-70. 12-AG E is E-lh, X is X2 and G is G-71.
12-Η E is E-li, X is X2 and G is G-70. 12-AH E is E-li, X is X2 and G is G-71.
12-1 E is E-lj, X is X2 and G is G-70. 12-AI E is E-lj, X is X2 and G is G-71.
12-J E is E-lk, X is X2 and G is G-70. 12-AJ E is E-lk, X is X2 and G is G-71.
12-K E is E-ll, X is X2 and G is G-70. 12-AK E is E-ll, X is X2 and G is G-71.
12-L E is E-lm, X is X2 and G is G-70. 12-AL E is E-lm, X is X2 and G is G-71.
12-M E is E-ln, X is X2 and G is G-70. 12-AM E is E-ln, X is X2 and G is G-71.
12-N E is E-2a, X is X2 and G is G-70. 12-AN E is E-2a, X is X2 and G is G-71.
12-0 E is E-2b, X is X2 and G is G-70. 12-AO E is E-2b, X is X2 and G is G-71.
12-P E is E-2c, X is X2 and G is G-70. 12-AP E is E-2c, X is X2 and G is G-71.
12-Q E is E-2d, X is X2 and G is G-70. 12-AQ E is E-2d, X is X2 and G is G-71.
12-R E is E-la, X is X3 and G is G-70. 12-AR E is E-la, X is X3 and G is G-71.
12-S E is E-ld, X is X3 and G is G-70. 12-AS E is E-ld, X is X3 and G is G-71.
12-T E is E-lg, X is X3 and G is G-70. 12-AT E is E-lg, X is X3 and G is G-71.
12-U E is E-lh, X is X3 and G is G-70. 12-AU E is E-lh, X is X3 and G is G-71.
12-V E is E-lk, X is X3 and G is G-70. 12-AV E is E-lk, X is X3 and G is G-71.
12-W E is E-ll, X is X3 and G is G-70. 12-AW E is E-ll, X is X3 and G is G-71.
12-X E is E-2a, X is X3 and G is G-70. 12-AX E is E-2a, X is X3 and G is G-71.
12-Y E is E-2b, X is X3 and G is G-70. 12-AY E is E-2b, X is X3 and G is G-71.
12-Z E is E-la, X is X2 and G is G-71. Formulation/Utility
A compound of this invention will generally be used as a fungicidal 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 serve 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 0.001-95 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 percentages are by weight and all formulations are prepared in conventional ways. Compound numbers refer to compounds in Index Table A. 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 constructed 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 8 98.5% silica aerogel 0.5% synthetic amorphous fine silica 1.0% Example B
Wettable Powder
Compound 7 65.0% dodecylphenol polyethylene glycol ether 2.0% sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0% montmorillonite (calcined) 23.0%
Example C
Granule
Compound 4 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 20 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 8 10.0% polyoxyethylene sorbitol hexoleate 20.0%
C^-Cio fatty acid methyl ester 70.0%>
Example F
Microemulsion
Compound 7 5.0%> polyvinylpyrrolidone -vinyl acetate copolymer 30.0% alkylpolyglycoside 30.0%> glyceryl monooleate 15.0% water 20.0%
Example G
Seed Treatment
Compound 4 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%
Water-soluble and water-dispersible formulations are typically diluted with water to form aqueous compositions before application. Aqueous compositions for direct applications to the plant or portion thereof (e.g., spray tank compositions) typically at least about 1 ppm or more (e.g., from 1 ppm to 100 ppm) of the compound(s) of this invention.
The compounds of this invention are useful as plant disease control agents. The present invention therefore further comprises a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof to be protected, or to the plant seed to be protected, an effective amount of a compound of the invention or a fungicidal composition containing said compound. The compounds and/or compositions of this invention provide control of diseases caused by a broad spectrum of fungal plant pathogens in the Basidiomycete, Ascomycete, Oomycete and Deuteromycete classes. They are effective in controlling a broad spectrum of plant diseases, particularly foliar pathogens of ornamental, turf, vegetable, field, cereal, and fruit crops. These pathogens include: Oomycetes, including Phytophthora diseases such as Phytophthora infestans, Phytophthora megasperma, Phytophthora parasitica, Phytophthora cinnamomi and Phytophthora capsici, Pythium diseases such as Pythium aphanidermatum, and diseases in the Peronosporaceae family such as Plasmopara viticola, Peronospora spp. (including Peronospora tabacina and Peronospora parasitica), Pseudoperonospora spp. (including Pseudoperonospora cubensis) and Bremia lactucae; Ascomycetes, including Alternaria diseases such as Alternaria solani and Alternaria brassicae, Guignardia diseases such as Guignardia bidwell, Venturia diseases such as Venturia inaequalis, Septoria diseases such as Septoria nodorum and Septoria tritici, powdery mildew diseases such as Erysiphe spp. (including Erysiphe graminis and Erysiphe polygoni), Uncinula necatur, Sphaerotheca fuliginea, Podosphaera leucotricha and Pseudocercosporella herpotrichoides, Botrytis diseases such as Botrytis cinerea, Monilinia fructicola, Sclerotinia diseases such as Sclerotinia sclerotiorum, Sclerotinia minor, Magnaporthe grisea, and Phomopsis viticola, Helminthosporium diseases such as Helminthosporium tritici repentis and Pyrenophora teres, anthracnose diseases such as Glomerella or Colletotrichum spp. (such as Colletotrichum graminicola and Colletotrichum orbiculare), and Gaeumannomyces graminis; Basidiomycetes, including rust diseases caused by Puccinia spp. (such as Puccinia recondita, Puccinia striiformis, Puccinia hordei, Puccinia graminis and Puccinia arachidis), Hemileia vastatrix and Phakopsora pachyrhizi; other pathogens including Rutstroemia floccosum (also known as Sclerotinia homoeocarpa); Rhizoctonia spp. (such as Rhizoctonia solani); Fusarium diseases such as Fusarium roseum, Fusarium graminearum and Fusarium oxysporumVerticillium dahliae; Sclerotium rolfsii; Rynchosporium secalis; Cercosporidium personatum, Cercospora arachidicola and Cercospora beticola; Rhizopus spp. (such as Rhizopus stolonifer); Aspergillus spp. (such as Aspergillus flavus and Aspergillus parasiticus); and other genera and species closely related to these pathogens. In addition to their fungicidal activity, the compositions or combinations also have activity against bacteria such as Erwinia amylovora, Xanthomonas campestris, Pseudomonas syringae, and other related species. By controlling harmful microorganisms, the compounds of the invention are useful for improving (i.e. increasing) the ratio of beneficial to harmful microorganisms in contact with crop plants or their propagules (e.g., seeds, corns, bulbs, tubers, cuttings) or in the agronomic environment of the crop plants or their propagules.
Furthermore, the compounds of this invention are useful in treating postharvest diseases of fruits and vegetables caused by fungi and bacteria. These infections can occur before, during and after harvest. For example, infections can occur before harvest and then remain dormant until some point during ripening (e.g., host begins tissue changes in such a way that infection can progress); also infections can arise from surface wounds created by mechanical or insect injury. In this respect, the compounds of this invention can reduce losses (i.e. losses resulting from quantity and quality) due to postharvest diseases which may occur at any time from harvest to consumption. Treatment of postharvest diseases with compounds of the invention can increase the period of time during which perishable edible plant parts (e.g, fruits, seeds, foliage, stems, bulbs, tubers) can be stored refrigerated or un- refrigerated after harvest, and remain edible and free from noticeable or harmful degradation or contamination by fungi or other microorganisms. Treatment of edible plant parts before or after harvest with compounds of the invention can also decrease the formation of toxic metabolites of fungi or other microorganisms, for example, mycotoxins such as aflatoxins.
Plant disease control is ordinarily accomplished by applying an effective amount of a compound of this invention either pre- or post-infection, to the portion of the plant to be protected such as the roots, stems, foliage, fruits, seeds, tubers or bulbs, or to the media (soil or sand) in which the plants to be protected are growing. The compounds can also be applied to seeds to protect the seeds and seedlings developing from the seeds. The compounds can also be applied through irrigation water to treat plants. Control of postharvest pathogens which infect the produce before harvest is typically accomplished by field application of a compound of this invention, and in cases where infection occurs after harvest the compounds can be applied to the harvested crop as dips, sprays, fumigants, treated wraps and box liners.
Rates of application for these compounds (i.e. a fungicidally effective amount) can be influenced by factors such as the plant diseases to be controlled, the plant species to be protected, ambient moisture and temperature and should be determined under actual use conditions. One skilled in the art can easily determine through simple experimentation the fungicidally effective amount necessary for the desired level of plant disease control. Foliage can normally be protected when treated at a rate of from less than about 1 g/ha to about 5,000 g/ha of active ingredient. Seed and seedlings can normally be protected when seed is treated at a rate of from about 0.1 to about 10 g per kilogram of seed.
Compounds of this invention can also be mixed with one or more other biologically active compounds or agents including fungicides, insecticides, nematocides, bactericides, acaricides, herbicides, herbicide safeners, growth regulators such as insect molting inhibitors and rooting stimulants, chemosterilants, semiochemicals, repellents, attractants, pheromones, feeding stimulants, plant nutrients, other biologically active compounds or entomopathogenic bacteria, virus or fungi to form a multi-component pesticide giving an even broader spectrum of agricultural protection. Thus the present invention also pertains to a composition comprising a compound of Formula 1 (in a fungicidally effective amount) and at least one additional biologically active compound or agent (in a biologically effective amount) and can further comprise at least one of a surfactant, a solid diluent or a liquid diluent. The other biologically active compounds or agents can be formulated in compositions comprising at least one of a surfactant, solid or liquid diluent. For mixtures of the present invention, one or more other biologically active compounds or agents can be formulated together with a compound of Formula 1, to form a premix, or one or more other biologically active compounds or agents can be formulated separately from the compound of Formula 1, and the formulations combined together before application (e.g., in a spray tank) or, alternatively, applied in succession.
Of note is a composition which in addition to the compound of Formula 1 include at least one fungicidal compound selected from the group consisting of the classes (1) methyl benzimidazole carbamate (MBC) fungicides; (2) dicarboximide fungicides; (3) demethylation inhibitor (DMI) fungicides; (4) phenylamide fungicides; (5) amine/morpholine fungicides; (6) phospholipid biosynthesis inhibitor fungicides; (7) carboxamide fungicides; (8) hydroxy(2-amino-)pyrimidine fungicides; (9) anilinopyrimidine fungicides; (10) N-phenyl carbamate fungicides; (11) quinone outside inhibitor (Qol) fungicides; (12) phenylpyrrole fungicides; (13) quinoline fungicides; (14) lipid peroxidation inhibitor fungicides; (15) melanin biosynthesis inhibitors-reductase (MBI-R) fungicides; (16) melanin biosynthesis inhibitors-dehydratase (MBI-D) fungicides; (17) hydroxyanilide fungicides; (18) squalene-epoxidase inhibitor fungicides; (19) polyoxin fungicides; (20) phenylurea fungicides; (21) quinone inside inhibitor (Qil) fungicides; (22) benzamide fungicides; (23) enopyranuronic acid antibiotic fungicides; (24) hexopyranosyl antibiotic fungicides; (25) glucopyranosyl antibiotic: protein synthesis fungicides; (26) glucopyranosyl antibiotic: trehalase and inositol biosynthesis fungicides; (27) cyanoacetamideoxime fungicides; (28) carbamate fungicides; (29) oxidative phosphorylation uncoupling fungicides; (30) organo tin fungicides; (31) carboxylic acid fungicides; (32) heteroaromatic fungicides; (33) phosphonate fungicides; (34) phthalamic acid fungicides; (35) benzotriazine fungicides; (36) benzene-sulfonamide fungicides; (37) pyridazinone fungicides; (38) thiophene-carboxamide fungicides; (39) pyrimidinamide fungicides; (40) carboxylic acid amide (CAA) fungicides; (41) tetracycline antibiotic fungicides; (42) thiocarbamate fungicides; (43) benzamide fungicides; (44) host plant defense induction fungicides; (45) multi-site contact activity fungicides; (46) fungicides other than classes (1) through (45); and salts of compounds of classes (1) through (46).
Further descriptions of these classes of fungicidal compounds are provided below. (1) "Methyl benzimidazole carbamate (MBC) fungicides" (Fungicide Resistance
Action Committee (FRAC) code 1) inhibit mitosis by binding to β-tubulin during microtubule assembly. Inhibition of microtubule assembly can disrupt cell division, transport within the cell and cell structure. Methyl benzimidazole carbamate fungicides include benzimidazoles and thiophanates. The benzimidazoles include benomyl, carbendazim, fuberidazole and thiabendazole. The thiophanates include thiophanate and thiophanate-methy 1.
(2) "Dicarboximide fungicides" (Fungicide Resistance Action Committee (FRAC) code 2) are proposed to inhibit a lipid peroxidation in fungi through interference with NADH cytochrome c reductase. Examples include chlozolinate, iprodione, procymidone and vinclozolin.
(3) "Demethylation inhibitor (DMI) fungicides" (Fungicide Resistance Action Committee (FRAC) code 3) inhibit C14-demethylase, which plays a role in sterol production. Sterols, such as ergosterol, are needed for membrane structure and function, making them essential for the development of functional cell walls. Therefore, exposure to these fungicides results in abnormal growth and eventually death of sensitive fungi. Demethylation fungicides include piperazines, pyridines, pyrimidines, imidazoles and triazoles. The piperazines include triforine. The pyridines include buthiobate and pyrifenox. The pyrimidines include fenarimol, nuarimol and triarimol. The imidazoles include clotrimazole, imazalil, oxpoconazole, prochloraz, pefurazoate and triflumizole. The triazoles include azaconazole, bitertanol, bromuconazole, cyproconazole, difenoconazole, diniconazole (including diniconazole-M), epoxiconazole, etaconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, imibenconazole, ipconazole, metconazole, myclobutanil, penconazole, propiconazole, prothioconazole, quinconazole, simeconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole, uniconazole, 1 -[[(25',3i?)-3-(2-chlorophenyl)-2-(2,4-difluorophenyl)-2-oxiranyl]methyl]- 1H- 1,2,4-triazole, 2-[[(25',3i?)-3-(2-chlorophenyl)-2-(2,4-difluorophenyl)-2-oxiranyl]methyl]- l,2-dihydro-3H-l,2,4-triazole-3-thione and l-[[(2S,3R)-3-(2-chlorophenyl)-2-(2,4- difluorophenyl)-2-oxiranyl]methyl]-5-(2-propen-l-ylthio)-lH-l,2,4-triazole. The imidazoles include clotrimazole, imazalil, oxpoconazole, prochloraz, pefurazoate and trifiumizole. Biochemical investigations have shown that all of the above mentioned fungicides are DMI fungicides as described by K. H. Kuck et al. in Modern Selective Fungicides - Properties, Applications and Mechanisms of Action, H. Lyr (Ed.), Gustav Fischer Verlag: New York, 1995, 205-258.
(4) "Phenylamide fungicides" (Fungicide Resistance Action Committee (FRAC) code 4) are specific inhibitors of RNA polymerase in Oomycete fungi. Sensitive fungi exposed to these fungicides show a reduced capacity to incorporate uridine into rRNA. Growth and development in sensitive fungi is prevented by exposure to this class of fungicide. Phenylamide fungicides include acylalanines, oxazolidinones and butyrolactones. The acylalanines include benalaxyl, benalaxyl-M, furalaxyl, metalaxyl and metalaxyl- M/mefenoxam. The oxazolidinones include oxadixyl. The butyrolactones include ofurace.
(5) "Amine/morpholine fungicides" (Fungicide Resistance Action Committee (FRAC) code 5) inhibit two target sites within the sterol biosynthetic pathway, Δ8→ Δ7 isomerase and Δ14 reductase. Sterols, such as ergosterol, are needed for membrane structure and function, making them essential for the development of functional cell walls. Therefore, exposure to these fungicides results in abnormal growth and eventually death of sensitive fungi. Amine/morpholine fungicides (also known as non-DMI sterol biosynthesis inhibitors) include morpholines, piperidines and spiroketal-amines. The morpholines include aldimorph, dodemorph, fenpropimorph, tridemorph and trimorphamide. The piperidines include fenpropidin and piperalin. The spiroketal-amines include spiroxamine.
(6) "Phospholipid biosynthesis inhibitor fungicides" (Fungicide Resistance Action Committee (FRAC) code 6) inhibit growth of fungi by affecting phospholipid biosynthesis. Phospholipid biosynthesis fungicides include phophorothiolates and dithiolanes. The phosphorothiolates include edifenphos, iprobenfos and pyrazophos. The dithiolanes include isoprothiolane.
(7) "Carboxamide fungicides" (Fungicide Resistance Action Committee (FRAC) code 7) inhibit Complex II (succinate dehydrogenase) fungal respiration by disrupting a key enzyme in the Krebs Cycle (TCA cycle) named succinate dehydrogenase. Inhibiting respiration prevents the fungus from making ATP, and thus inhibits growth and reproduction. Carboxamide fungicides include phenyl benzamides, pyridinyl ethyl benzamides, furan carboxamides, oxathiin carboxamides, thiazole carboxamides, pyrazole carboxamides and pyridine carboxamides. The phenyl benzamides include benodanil, flutolanil and mepronil. The pyridinyl ethyl benzamides include fluopyram. The furan carboxamides include fenfuram. The oxathiin carboxamides include carboxin and oxycarboxin. The thiazole carboxamides include thifluzamide. The pyrazole carboxamides include furametpyr, penthiopyrad, bixafen, isopyrazam, benzovindiflupyr, N-[2-(lS,2R)- [1,1 '-bicyclopropyl]-2-ylphenyl]-3-(difluoromethyl)- 1 -methyl- lH-pyrazole-4-carboxamide, penflufen, (N-[2-(l ,3-dimethylbutyl)phenyl]-5-fluoro- 1 ,3-dimethyl- lH-pyrazole-4- carboxamide), N-[2-(2,4-dichlorophenyl)-2-methoxy-l-methylethyl]-3-(difluoromethyl)-l- methyl- lH-pyrazole-4-carboxamide and N-cyclopropyl-3 -(difluoromethyl)-5 -fluoro- 1 - methyl-N-[[2-(l-methylethyl)phenyl]methyl]-lH-pyrazole-4-carboxamide. The pyridine carboxamides include boscalid.
(8) "Hydroxy(2-amino-)pyrimidine fungicides" (Fungicide Resistance Action Committee (FRAC) code 8) inhibit nucleic acid synthesis by interfering with adenosine deaminase. Examples include bupirimate, dimethirimol and ethirimol.
(9) 'Anilinopyrimidine fungicides" (Fungicide Resistance Action Committee (FRAC) code 9) are proposed to inhibit biosynthesis of the amino acid methionine and to disrupt the secretion of hydrolytic enzymes that lyse plant cells during infection. Examples include cyprodinil, mepanipyrim and pyrimethanil.
(10) "N-Phenyl carbamate fungicides" (Fungicide Resistance Action Committee (FRAC) code 10) inhibit mitosis by binding to β-tubulin and disrupting microtubule assembly. Inhibition of microtubule assembly can disrupt cell division, transport within the cell and cell structure. Examples include diethofencarb.
(11) "Quinone outside inhibitor (Qol) fungicides" (Fungicide Resistance Action Committee (FRAC) code 11) inhibit Complex III mitochondrial respiration in fungi by affecting ubiquinol oxidase. Oxidation of ubiquinol is blocked at the "quinone outside" (Q0) site of the cytochrome bc\ complex, which is located in the inner mitochondrial membrane of fungi. Inhibiting mitochondrial respiration prevents normal fungal growth and development. Quinone outside inhibitor fungicides (also known as strobilurin fungicides) include methoxyacrylates, methoxycarbamates, oximinoacetates, oximinoacetamides, oxazolidinediones, dihydrodioxazines, imidazolinones and benzylcarbamates. The methoxyacrylates include azoxystrobin, coumoxystrobin, enestroburin, flufenoxystrobin, picoxystrobin and pyraoxystrobin. The methoxycarbamates include pyraclostrobin, pyrametostrobin and triclopyricarb. The oximinoacetates include kresoxim-methyl and trifloxystrobin. The oximinoacetamides include dimoxystrobin, metominostrobin, orysastrobin, a-[methoxyimino]-N-methyl-2-[[[ 1 -[3-(trifluoromethyl)phenyl]ethoxy]imino]- methyljbenzeneacetamide and 2-[[[3-(2,6-dichlorophenyl)-l-methyl-2-propen-l-ylidene]- amino]oxy]methyl]-a-(methoxyimino)-N-methylbenzeneacetamide. The oxazolidinediones include famoxadone. The dihydrodioxazines include fluoxastrobin. The imidazolinones include fenamidone. The benzylcarbamates include pyribencarb. Class (11) also includes 2- [(2,5-dimethylphenoxy)methyl]-a-methoxy-N-benzeneacetamide.
(12) "Phenylpyrrole fungicides" (Fungicide Resistance Action Committee (FRAC) code 12) inhibit a MAP protein kinase associated with osmotic signal transduction in fungi. Fenpiclonil and fludioxonil are examples of this fungicide class. (13) "Azanaphthalene fungicides" (Fungicide Resistance Action Committee (FRAC) code 13) are proposed to inhibit signal transduction by affecting G-proteins in early cell signaling. They have been shown to interfere with germination and/or appressorium formation in fungi that cause powder mildew diseases. Azanaphthalene fungicides include aryloxyquinolines and quinazolinone. The aryloxyquinolines include quinoxyfen and tebufloquin. The quinazolinones include proquinazid.
(14) "Lipid peroxidation inhibitor fungicides" (Fungicide Resistance Action Committee (FRAC) code 14) are proposed to inhibit lipid peroxidation which affects membrane synthesis in fungi. Members of this class, such as etridiazole, may also affect other biological processes such as respiration and melanin biosynthesis. Lipid peroxidation fungicides include aromatic carbons and 1,2,4-thiadiazoles. The aromatic carbon fungicides include biphenyl, chloroneb, dicloran, quintozene, tecnazene and tolclofos-methyl. The 1,2,4-thiadiazole fungicides include etridiazole.
(15) "Melanin biosynthesis inhibitors-reductase (MBI-R) fungicides" (Fungicide Resistance Action Committee (FRAC) code 16.1) inhibit the naphthal reduction step in melanin biosynthesis. Melanin is required for host plant infection by some fungi. Melanin biosynthesis inhibitors-reductase fungicides include isobenzofuranones, pyrroloquinolinones and triazolobenzothiazoles. The isobenzofuranones include fthalide. The pyrroloquinolinones include pyroquilon. The triazolobenzothiazoles include tricyclazole.
(16) "Melanin biosynthesis inhibitors-dehydratase (MBI-D) fungicides" (Fungicide
Resistance Action Committee (FRAC) code 16.2) inhibit scytalone dehydratase in melanin biosynthesis. Melanin in required for host plant infection by some fungi. Melanin biosynthesis inhibitors-dehydratase fungicides include cyclopropanecarboxamides, carboxamides and propionamides. The cyclopropanecarboxamides include carpropamid. The carboxamides include diclocymet. The propionamides include fenoxanil.
(17) "Hydroxy anilide fungicides (Fungicide Resistance Action Committee (FRAC) code 17) inhibit C4-demethylase which plays a role in sterol production. Examples include fenhexamid.
(18) "Squalene-epoxidase inhibitor fungicides" (Fungicide Resistance Action Committee (FRAC) code 18) inhibit squalene-epoxidase in ergosterol biosynthesis pathway.
Sterols such as ergosterol are needed for membrane structure and function, making them essential for the development of functional cell walls. Therefore exposure to these fungicides results in abnormal growth and eventually death of sensitive fungi. Squalene- epoxidase inhibitor fungicides include thiocarbamates and allylaminess. The thiocarbamates include pyributicarb. The allylamines include naftifine and terbinafme.
(19) "Polyoxin fungicides" (Fungicide Resistance Action Committee (FRAC) code 19) inhibit chitin synthase. Examples include polyoxin. (20) "Phenylurea fungicides" (Fungicide Resistance Action Committee (FRAC) code 20) are proposed to affect cell division. Examples include pencycuron.
(21) "Quinone inside inhibitor (Qil) fungicides" (Fungicide Resistance Action Committee (FRAC) code 21) inhibit Complex III mitochondrial respiration in fungi by affecting ubiquinol reductase. Reduction of ubiquinol is blocked at the "quinone inside" (Qi) site of the cytochrome bc\ complex, which is located in the inner mitochondrial membrane of fungi. Inhibiting mitochondrial respiration prevents normal fungal growth and development. Quinone inside inhibitor fungicides include cyanoimidazoles and sulfamoyltriazoles. The cyanoimidazoles include cyazofamid. The sulfamoyltriazoles include amisulbrom.
(22) "Benzamide fungicides" (Fungicide Resistance Action Committee (FRAC) code 22) inhibit mitosis by binding to β-tubulin and disrupting microtubule assembly. Inhibition of microtubule assembly can disrupt cell division, transport within the cell and cell structure. Examples include zoxamide.
(23) "Enopyranuronic acid antibiotic fungicides" (Fungicide Resistance Action
Committee (FRAC) code 23) inhibit growth of fungi by affecting protein biosynthesis. Examples include blasticidin-S.
(24) "Hexopyranosyl antibiotic fungicides" (Fungicide Resistance Action Committee (FRAC) code 24) inhibit growth of fungi by affecting protein biosynthesis. Examples include kasugamycin.
(25) "Glucopyranosyl antibiotic: protein synthesis fungicides" (Fungicide Resistance Action Committee (FRAC) code 25) inhibit growth of fungi by affecting protein biosynthesis. Examples include streptomycin.
(26) "Glucopyranosyl antibiotic: trehalase and inositol biosynthesis fungicides" (Fungicide Resistance Action Committee (FRAC) code 26) inhibit trehalase in inositol biosynthesis pathway. Examples include validamycin.
(27) "Cyanoacetamideoxime fungicides (Fungicide Resistance Action Committee (FRAC) code 27) include cymoxanil.
(28) "Carbamate fungicides" (Fungicide Resistance Action Committee (FRAC) code 28) are considered multi-site inhibitors of fungal growth. They are proposed to interfere with the synthesis of fatty acids in cell membranes, which then disrupts cell membrane permeability. Propamacarb, propamacarb-hydrochloride, iodocarb, and prothiocarb are examples of this fungicide class.
(29) "Oxidative phosphorylation uncoupling fungicides" (Fungicide Resistance Action Committee (FRAC) code 29) inhibit fungal respiration by uncoupling oxidative phosphorylation. Inhibiting respiration prevents normal fungal growth and development. This class includes 2,6-dinitroanilines such as fluazinam, pyrimidonehydrazones such as ferimzone and dinitrophenyl crotonates such as dinocap, meptyldinocap and binapacryl. (30) "Organo tin fungicides" (Fungicide Resistance Action Committee (FRAC) code 30) inhibit adenosine triphosphate (ATP) synthase in oxidative phosphorylation pathway. Examples include fentin acetate, fentin chloride and fentin hydroxide.
(31) "Carboxylic acid fungicides" (Fungicide Resistance Action Committee (FRAC) code 31) inhibit growth of fungi by affecting deoxyribonucleic acid (DNA) topoisomerase type II (gyrase). Examples include oxolinic acid.
(32) "Heteroaromatic fungicides" (Fungicide Resistance Action Committee (FRAC) code 32) are proposed to affect DNA/ribonucleic acid (RNA) synthesis. Heteroaromatic fungicides include isoxazoles and isothiazolones. The isoxazoles include hymexazole and the isothiazolones include octhilinone.
(33) "Phosphonate fungicides" (Fungicide Resistance Action Committee (FRAC) code 33) include phosphorous acid and its various salts, including fosetyl-aluminum.
(34) "Phthalamic acid fungicides" (Fungicide Resistance Action Committee (FRAC) code 34) include teclofthalam.
(35) "Benzotriazine fungicides" (Fungicide Resistance Action Committee (FRAC) code 35) include triazoxide.
(36) "Benzene-sulfonamide fungicides" (Fungicide Resistance Action Committee (FRAC) code 36) include flusulfamide.
(37) "Pyridazinone fungicides" (Fungicide Resistance Action Committee (FRAC) code 37) include diclomezine.
(38) "Thiophene-carboxamide fungicides" (Fungicide Resistance Action Committee (FRAC) code 38) are proposed to affect ATP production. Examples include silthiofam.
(39) "Pyrimidinamide fungicides" (Fungicide Resistance Action Committee (FRAC) code 39) inhibit growth of fungi by affecting phospholipid biosynthesis and include diflumetorim.
(40) "Carboxylic acid amide (CAA) fungicides" (Fungicide Resistance Action Committee (FRAC) code 40) are proposed to inhibit phospholipid biosynthesis and cell wall deposition. Inhibition of these processes prevents growth and leads to death of the target fungus. Carboxylic acid amide fungicides include cinnamic acid amides, valinamide carbamates, carbamates and mandelic acid amides. The cinnamic acid amides include dimethomorph and flumorph. The valinamide carbamates include benthiavalicarb, benthiavalicarb-isopropyl, iprovalicarb, valifenalate and valiphenal. The carbamates include tolprocarb. The mandelic acid amides include mandipropamid, N-[2-[4-[[3-(4- chlorophenyl)-2-propyn-l-yl]oxy]-3-methoxyphenyl]ethyl]-3-methyl-2-[(methylsulfonyl)- amino Jbutanamide and N-[2-[4-[[3-(4-chlorophenyl)-2-propyn-l-yl]oxy]-3-methoxyphenyl]- ethyl] -3 -methyl-2- [(ethylsulfonyl)amino]butanamide. (41) "Tetracycline antibiotic fungicides" (Fungicide Resistance Action Committee (FRAC) code 41) inhibit growth of fungi by affecting complex 1 nicotinamide adenine dinucleotide (NADH) oxidoreductase. Examples include oxytetracycline.
(42) "Thiocarbamate fungicides" (Fungicide Resistance Action Committee (FRAC) code 42) include methasulfocarb.
(43) "Benzamide fungicides" (Fungicide Resistance Action Committee (FRAC) code 43) inhibit growth of fungi by derealization of spectrin-like proteins. Examples include acylpicolide fungicides such as fluopicolide.
(44) "Host plant defense induction fungicides" (Fungicide Resistance Action Committee (FRAC) code P) induce host plant defense mechanisms. Host plant defense induction fungicides include benzothiadiazoles, benzisothiazoles and thiadiazolecarboxamides. The benzothiadiazoles include acibenzolar-S-methyl. The benzisothiazoles include probenazole. The thiadiazolecarboxamides include tiadinil and isotianil.
(45) "Multi-site contact fungicides" inhibit fungal growth through multiple sites of action and have contact/preventive activity. This class of fungicides includes: (45.1) "copper fungicides" (Fungicide Resistance Action Committee (FRAC) code Ml)", (45.2) "sulfur fungicides" (Fungicide Resistance Action Committee (FRAC) code M2), (45.3) "dithiocarbamate fungicides" (Fungicide Resistance Action Committee (FRAC) code M3), (45.4) "phthalimide fungicides" (Fungicide Resistance Action Committee (FRAC) code M4), (45.5) "chloronitrile fungicides" (Fungicide Resistance Action Committee (FRAC) code M5), (45.6) "sulfamide fungicides" (Fungicide Resistance Action Committee (FRAC) code M6), (45.7) "guanidine fungicides" (Fungicide Resistance Action Committee (FRAC) code M7), (45.8) "triazine fungicides" (Fungicide Resistance Action Committee (FRAC) code M8) and (45.9) "quinone fungicides" (Fungicide Resistance Action Committee (FRAC) code M9). "Copper fungicides" are inorganic compounds containing copper, typically in the copper(II) oxidation state; examples include copper oxychloride, copper sulfate and copper hydroxide, including compositions such as Bordeaux mixture (tribasic copper sulfate). "Sulfur fungicides" are inorganic chemicals containing rings or chains of sulfur atoms; examples include elemental sulfur. "Dithiocarbamate fungicides" contain a dithiocarbamate molecular moiety; examples include mancozeb, metiram, propineb, ferbam, maneb, thiram, zineb and ziram. "Phthalimide fungicides" contain a phthalimide molecular moiety; examples include folpet, captan and captafol. "Chloronitrile fungicides" contain an aromatic ring substituted with chloro and cyano; examples include chlorothalonil. "Sulfamide fungicides" include dichlofluanid and tolyfluanid. "Guanidine fungicides" include dodine, guazatine, iminoctadine albesilate and iminoctadine triacetate. "Triazine fungicides" include anilazine. "Quinone fungicides" include dithianon. (46) "Fungicides other than fungicides of classes (1) through (45)" include certain fungicides whose mode of action may be unknown. These include: (46.1) "thiazole carboxamide fungicides" (Fungicide Resistance Action Committee (FRAC) code U5), (46.2) "phenylacetamide fungicides" (Fungicide Resistance Action Committee (FRAC) code U6), (46.3) "arylphenylketone fungicides" (Fungicide Resistance Action Committee (FRAC) code U8) and (46.4) "triazolopyrimidine fungicides". The thiazole carboxamides include ethaboxam. The phenylacetamides include cyflufenamid and N-[[(cyclopropylmethoxy)- amino][6-(difluoromethoxy)-2,3-difluorophenyl]-methylene]benzeneacetamide. The arylphenylketones include benzophenones such as metrafenone and benzoylpyridines such as pyriofenone. The triazolopyrimidines include ametoctradin. Class (46) (i.e. "Fungicides other than classes (1) through (45)") also includes bethoxazin, fluxapyroxad, neo-asozin (ferric methanearsonate), pyrrolnitrin, quinomethionate, tebufloquin, isofetamid, N-[2-[4-[[3- (4-chlorophenyl)-2-propyn- 1 -yl]oxy] -3 -methoxyphenyl] ethyl] -3 -methyl-2- [(methylsulfonyl)amino]butanamide, N-[2-[4-[[3-(4-chlorophenyl)-2-propyn-l-yl]oxy]-3- methoxyphenyl] ethyl]-3 -methyl-2- [(ethylsulfonyl)amino]butanamide, 2- [ [2-fluoro-5 -
(trifluoromethyl)phenyl]thio]-2-[3-(2-methoxyphenyl)-2-thiazolidinylidene]acetonitrile, 3- [5-(4-chlorophenyl)-2,3-dimethyl-3-isoxazolidinyl]pyridine, 4-fluorophenyl N-[ 1 -[[[1 -(4- cyanophenyl)ethyl]sulfonyl]methyl]propyl] carbamate, 5-chloro-6-(2,4,6-trifluorophenyl)-7- (4-methylpiperidin- 1 -yl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyrimidine, N-(4-chloro-2-nitrophenyl)-N- ethyl-4-methylbenzenesulfonamide, N-[[(cyclopropylmethoxy)amino][6-(difluoromethoxy)- 2,3-difluorophenyl]methylene]benzeneacetamide, N'-[4-[4-chloro-3-(trifluoromethyl)- phenoxy]-2,5-dimethylphenyl]-N-ethyl-N-methylmethanimidamide, l-[(2-propenylthio)- carbonyl]-2-(l-methylethyl)-4-(2-methylphenyl)-5-amino-lH-pyrazol-3-one, N"-[4-[[3-[(4- chlorophenyl)methyl]-l,2,4-thiadiazol-5-yl]oxy]-2,5-dimethylphenyl]-N-ethyl-N-methyl- methanimidamide, 1 , 1 -dimethylethyl N-[6-[[[[(l -methyl- lH-tetrazol-5-yl)phenylmethylene]- amino]oxy]methyl]-2-pyridinyl]carbamate, 3-butyn- 1 -yl N-[6-[[[[(l -methyl- lH-tetrazol-5- yl)phenylmethylene]amino]oxy]methyl]-2-pyridinyl]carbamate, 2,6-dimethyl-lH,5H- [l,4]dithiino[2,3-c:5,6-c']dipyrrole-l,3,5,7(2H,6H)-tetrone, 5-fluoro-2-[(4-methylphenyl)- methoxy]-4-pyrimidinamine, 5-fluoro-2-[(4-fluorophenyl)methoxy]-4-pyrimidinamine, a-[3- (4-chloro-2-fluorophenyl)-5-(2,4-difluorophenyl)isoxazol-4-yl]pyrid-3-ylmethanol, (aS)-[3- (4-chloro-2-fluorophenyl)-5-(2,4-difluorophenyl)isoxazol-4-yl]pyrid-3-ylmethanol and ( R)- [3-(4-chloro-2-fluorophenyl)-5-(2,4-difluorophenyl)isoxazol-4-yl]pyrid-3-ylmethanol.
Therefore of note is a mixture (i.e. composition) comprising a compound of Formula 1 and at least one fungicidal compound selected from the group consisting of the aforedescribed classes (1) through (46). Also of note is a composition comprising said mixture (in fungicidally effective amount) and further comprising at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents. Of particular note is a mixture (i.e. composition) comprising a compound of Formula 1 and at least one fungicidal compound selected from the group of specific compounds listed above in connection with classes (1) through (46). Also of particular note is a composition comprising said mixture (in fungicidally effective amount) and further comprising at least one additional surfactant selected from the group consisting of surfactants, solid diluents and liquid diluents.
Examples of other biologically active compounds or agents with which compounds of this invention can be formulated are: insecticides such as abamectin, acephate, acetamiprid, acrinathrin, amidoflumet (S-1955), avermectin, azadirachtin, azinphos-methyl, bifenthrin, bifenazate, buprofezin, carbofuran, cartap, chlorantraniliprole, chlorfenapyr, chlorfluazuron, chlorpyrifos, chlorpyrifos-methyl, chromafenozide, clothianidin, cyantraniliprole (3-bromo- l-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-lH- pyrazole-5-carboxamide), cyflumetofen, cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda- cyhalothrin, cypermethrin, cyromazine, deltamethrin, diafenthiuron, diazinon, dieldrin, diflubenzuron, dimefluthrin, dimethoate, dinotefuran, diofenolan, emamectin, endosulfan, esfenvalerate, ethiprole, fenothiocarb, fenoxycarb, fenpropathrin, fenvalerate, fipronil, flonicamid, flubendiamide, flucythrinate, tau-fluvalinate, flufenerim (UR-50701), flufenoxuron, fonophos, halofenozide, hexaflumuron, hydramethylnon, imidacloprid, indoxacarb, isofenphos, lufenuron, malathion, meperfluthrin, metaflumizone, metaldehyde, methamidophos, methidathion, methomyl, methoprene, methoxychlor, methoxyfenozide, metofluthrin, milbemycin oxime, monocrotophos, nicotine, nitenpyram, nithiazine, novaluron, noviflumuron (XDE-007), oxamyl, parathion, parathion-methyl, permethrin, phorate, phosalone, phosmet, phosphamidon, pirimicarb, profenofos, profluthrin, pymetrozine, pyrafluprole, pyrethrin, pyridalyl, pyrifluquinazon, pyriprole, pyriproxyfen, rotenone, ryanodine, spinetoram, spinosad, spirodiclofen, spiromesifen (BSN 2060), spirotetramat, sulfoxaflor, sulprofos, tebufenozide, teflubenzuron, tefluthrin, terbufos, tetrachlorvinphos, tetramethylfluthrin, thiacloprid, thiamethoxam, thiodicarb, thiosultap- sodium, tolfenpyrad, tralomethrin, triazamate, trichlorfon and triflumuron; and biological agents including entomopathogenic bacteria, such as Bacillus thuringiensis subsp. aizawai, Bacillus thuringiensis subsp. kurstaki, and the encapsulated delta-endotoxins of Bacillus thuringiensis (e.g., Cellcap, MPV, MPVII); entomopathogenic fungi, such as green muscardine fungus; and entomopathogenic virus including baculovirus, nucleopolyhedro virus (NPV) such as HzNPV, AfNPV; and granulosis virus (GV) such as CpGV.
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). The effect of the exogenously applied fungicidal compounds of this invention may be synergistic with the expressed toxin proteins.
General references for 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 may expand the spectrum of diseases controlled beyond the spectrum controlled by the compound of Formula 1 alone.
In certain instances, combinations of a compound of this invention with other biologically active (particularly fungicidal) 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 fungicidal active ingredients occurs at application rates giving agronomically satisfactory levels of fungal control, such combinations can be advantageous for reducing crop production cost and decreasing environmental load.
Also in certain instances, combinations of a compound of the invention with other biologically active compounds or agents can result in a less-than-additive (i.e. safening) furthe invention may safen a herbicide on crop plants or protect a beneficial insect species (e.g., insect predators, pollinators such as bees) from an insecticide.
Of note is a combination of a compound of Formula 1 with at least one other fungicidal active ingredient. Of particular note is such a combination where the other fungicidal active ingredient has different site of action from the compound of Formula 1. In certain instances, a combination with at least one other fungicidal 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 fungicidal active ingredient having a similar spectrum of control but a different site of action.
Of particular note are compositions which in addition to compound of Formula 1 include at least one compound selected from the group consisting of (1) alkylenebis(dithiocarbamate) fungicides; (2) cymoxanil; (3) phenylamide fungicides; (4) proquinazid (6-iodo-3-propyl-2-propyloxy-4(3H)-quinazolinone); (5) chlorothalonil; (6) carboxamides acting at complex II of the fungal mitochondrial respiratory electron transfer site; (7) quinoxyfen; (8) metrafenone; (9) cyflufenamid; (10) cyprodinil; (11) copper compounds; (12) phthalimide fungicides; (13) fosetyl-aluminum; (14) benzimidazole fungicides; (15) cyazofamid; (16) fluazinam; (17) iprovalicarb; (18) propamocarb; (19) validomycin; (20) dichlorophenyl dicarboximide fungicides; (21) zoxamide; (22) fluopicolide; (23) mandipropamid; (24) carboxylic acid amides acting on phospholipid biosynthesis and cell wall deposition; (25) dimethomorph; (26) non-DMI sterol biosynthesis inhibitors; (27) inhibitors of demethylase in sterol biosynthesis; (28) bc\ complex fungicides; and salts of compounds of (1) through (28).
Further descriptions of classes of fungicidal compounds are provided below.
Sterol biosynthesis inhibitors (group (27)) control fungi by inhibiting enzymes in the sterol biosynthesis pathway. Demethylase-inhibiting fungicides have a common site of action within the fungal sterol biosynthesis pathway, involving inhibition of demethylation at position 14 of lanosterol or 24-methylene dihydrolanosterol, which are precursors to sterols in fungi. Compounds acting at this site are often referred to as demethylase inhibitors, DMI fungicides, or DMIs. The demethylase enzyme is sometimes referred to by other names in the biochemical literature, including cytochrome P-450 (14DM). The demethylase enzyme is described in, for example, J. Biol. Chem. 1992, 267, 13175-79 and references cited therein. DMI fungicides are divided between several chemical classes: azoles (including triazoles and imidazoles), pyrimidines, piperazines and pyridines. The triazoles include azaconazole, bromuconazole, cyproconazole, difenoconazole, diniconazole (including diniconazole-M), epoxiconazole, etaconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, imibenconazole, ipconazole, metconazole, myclobutanil, penconazole, propiconazole, prothioconazole, quinconazole, simeconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole and uniconazole. The imidazoles include clotrimazole, econazole, imazalil, isoconazole, miconazole, oxpoconazole, prochloraz and triflumizole. The pyrimidines include fenarimol, nuarimol and triarimol. The piperazines include triforine. The pyridines include buthiobate and pyrifenox. Biochemical investigations have shown that all of the above mentioned fungicides are DMI fungicides as described by K. H. Kuck et al. in Modern Selective Fungicides - Properties, Applications and Mechanisms of Action, H. Lyr (Ed.), Gustav Fischer Verlag: New York, 1995, 205-258.
bc\ Complex Fungicides (group 28) have a fungicidal mode of action which inhibits the be i complex in the mitochondrial respiration chain. The bc\ complex is sometimes referred to by other names in the biochemical literature, including complex III of the electron transfer chain, and ubihydroquinone: cytochrome c oxidoreductase. This complex is uniquely identified by Enzyme Commission number EC 1.10.2.2. The bc\ complex is described in, for example, J. Biol. Chem. 1989, 264, 14543-48; Methods Enzymol. 1986, 126, 253-71; and references cited therein. Strobilurin fungicides such as azoxystrobin, dimoxystrobin, enestroburin (SYP-Z071), fluoxastrobin, kresoxim-methyl, metominostrobin, orysastrobin, picoxystrobin, pyraclostrobin, pyrametostrobin, pyraoxystrobin and trifloxystrobin are known to have this mode of action (H. Sauter et al., Angew. Chem. Int. Ed. 1999, 38, 1328-1349). Other fungicidal compounds that inhibit the bc\ complex in the mitochondrial respiration chain include famoxadone and fenamidone.
Alkylenebis(dithiocarbamate)s (group (1)) include compounds such as mancozeb, maneb, propineb and zineb. Phenylamides (group (3)) include compounds such as metalaxyl, benalaxyl, furalaxyl and oxadixyl. Carboxamides (group (6)) include compounds such as boscalid, carboxin, fenfuram, flutolanil, furametpyr, mepronil, oxycarboxin, thifluzamide, penthiopyrad and N-[2-(l,3-dimethylbutyl)phenyl]-5-fluoro-l,3-dimethyl-lH- pyrazole-4-carboxamide (PCT Patent Publication WO 2003/010149), and are known to inhibit mitochondrial function by disrupting complex II (succinate dehydrogenase) in the respiratory electron transport chain. Copper compounds (group (11)) include compounds such as copper oxychloride, copper sulfate and copper hydroxide, including compositions such as Bordeaux mixture (tribasic copper sulfate). Phthalimides (group (12)) include compounds such as folpet and captan. Benzimidazole fungicides (group (14)) include benomyl and carbendazim. Dichlorophenyl dicarboximide fungicides (group (20)) include chlozolinate, dichlozoline, iprodione, isovaledione, myclozolin, procymidone and vinclozolin.
Non-DMI sterol biosynthesis inhibitors (group (26)) include morpholine and piperidine fungicides. The morpho lines and piperidines are sterol biosynthesis inhibitors that have been shown to inhibit steps in the sterol biosynthesis pathway at a point later than the inhibitions achieved by the DMI sterol biosynthesis (group (27)). The morpholines include aldimorph, dodemorph, fenpropimorph, tridemorph and trimorphamide. The piperidines include fenpropidin.
The following TESTS demonstrate the control efficacy of compounds of this invention on specific pathogens. The pathogen control protection afforded by the compounds is not limited, however, to these species. See Index Table A for compounds. In the Index Table A the abbreviation "Cmpd." stands for "Compound", and the abbreviation "Ex." stands for "Example" and is followed by a number indicating in which example the compound is prepared. The numerical value reported in the column "AP+ (M+l)", is the molecular weight of the observed molecular ion formed by addition of H+ (molecular weight of 1) to the molecule having the greatest isotopic abundance (i.e. M). The presence of molecular ions containing one or more higher atomic weight isotopes of lower abundance (e.g., 37C1, 81 Br) is not reported. The reported M+l peaks were observed by mass spectrometry using atmospheric pressure chemical ionization (AP+).
INDEX TABLE A
F c\ ' 71 \ / 72 \
X G Q
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
AP+
)
Figure imgf000134_0001
BIOLOGICAL EXAMPLES OF THE INVENTION
General protocol for preparing test suspensions for Tests A-B2: The test compounds were first dissolved in acetone in an amount equal to 3% of the final volume and then suspended at the desired concentration (in ppm) in acetone and purified water (50/50 mix by volume) containing 250 ppm of the surfactant Trem® 014 (polyhydric alcohol esters). The resulting test suspensions were then used in Tests A-B2. Spraying a 40 ppm or 200ppm (*) test suspension to the point of run-off on the test plants was equivalent to a rate of 160 g/ha respectively. TEST A
Grape seedlings were inoculated with a spore suspension of Plasmopara viticola (the causal agent of grape downy mildew) and incubated in a saturated atmosphere at 20 °C for 24 h. After a short drying period, the grape seedlings were sprayed with the test suspension to the point of run-off, then moved to a growth chamber at 20 °C for 6 days, and then back into a saturated atmosphere at 20 °C for 24 h. Upon removal, visual disease ratings were made.
TEST Bl
The test suspension was sprayed to the point of run-off on tomato seedlings. The following day the seedlings were inoculated with a spore suspension of Phytophthora infestans (the causal agent of tomato late blight) and incubated in a saturated atmosphere at 20 °C for 24 h, and then moved to a growth chamber at 20 °C for 5 days, after which time visual disease ratings were made.
TEST B2
Tomato seedlings were inoculated with a spore suspension of Phytophthora infestans
(the causal agent of tomato late blight) and incubated in a saturated atmosphere at 20 °C for 17 h. After a short drying period, the tomato seedlings were sprayed with test suspension to the point of run-off, and then moved to a growth chamber at 20 °C for 4 days, after which time visual disease ratings were made.
Results for Tests A-B2 are given in Table A. In the Table, a rating of 100 indicates
100% disease control and a rating of 0 indicates no disease control (relative to the controls). All results are for compounds tested at 40 ppm except where the compound number is followed by "*" which indicates the compound was tested at 200 ppm.
Table A
Cmpd. No. Test A Test Bl Test B2
1 0 0 16
3 0 9 0
4 0 31 0
5 0 0 -
6 55 0 -
6* 71 90 -
7 0 0 -
8 9 0 -
9 0 0 -
10* 0 0 -
11 19 46 0 20 0 0
100 100 98
10 100 99
64 100 99
100 100 97
100 100 99
90 57 0
21 100 97
0 0 0
24 24 0
99 47 47
99 47 17
27 100 99
7 17 0
7 26 0
17 71 53
60 9 0* 82 47 0
99 100 58
83 0 0
98 100 95
24 8 0
99 88 67
7 0 16
46 68 93
31 95 99
24 83 66
17 33 0* 40 90 0
23 17 0

Claims

What is claimed is:
1. A compound selected from Formula 1, N-oxides and salts thereof,
1
wherein
E is a radical selected from the group consistin of
Figure imgf000137_0001
E2
X i a radical selected from the group consisting of
Figure imgf000137_0002
X1 X2 X3
wherein the bond projecting to the left is connected to E, and the bond projecting to the right is connected to Z1;
Z1 is a saturated, partially unsaturated or fully unsaturated chain containing 1- to
3-atoms selected from up to 3 carbon, up to 1 O, up to 1 S and up to 2 N, wherein up to 1 carbon atom is selected from C(=0) and C(=NOH), the chain optionally substituted with up to 2 substituents independently selected from R7a on carbon atoms and R7^ on nitrogen atoms;
G is a phenyl ring, a 5- to 6-membered heteroaromatic ring, a 3- to 6-membered
nonaromatic heterocyclic ring or a 3- to 6-membered nonaromatic carbocyclic ring, each ring optionally substituted with up to 3 substituents independently selected from R8a on carbon atom ring members and R8^ on nitrogen atom ring members;
Z2 is a direct bond or a saturated, partially unsaturated or fully unsaturated chain
containing 1- to 3-atoms selected from up to 3 carbon, up to 1 O, up to 1 S and up to 2 N, wherein up to 2 carbon atoms are independently selected from C(=0) and C(=NOH), the chain optionally substituted with up to 2 substituents independently selected from R7c on carbon atoms and R7^ on nitrogen atoms;
Q is a phenyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 3 substituents independently selected from R9a; or Q is a 5- to 6-membered heteroaromatic ring or an 8- to 11-membered heteroaromatic bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and 1 to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, each ring or ring system optionally substituted with up to 3 substituents independently selected from R9a on carbon atom ring members and R9^ on nitrogen atom ring members; or
Q is a 3- to 7-membered nonaromatic carbocyclic ring, a 5- to 7-membered
nonaromatic heterocyclic ring or an 8- to 11-membered nonaromatic bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, wherein up to 3 carbon atom ring members are independently selected from C(=0) and C(=S), and the sulfur atom ring members are independently selected from S(=O)s(=NR20)f, each ring or ring system optionally substituted with up to 3 substituents independently selected from R9a on carbon atom ring members and R9^ on nitrogen atom ring members;
A is CH(R10), N(Rn) or C(=0);
A1 is O, S, C(R12)2, N(R13), -OC(R12)2-, -SC(R12)2- or -N(R13)C(R12)2-, wherein the bond projecting to the left is connected to the nitrogen atom, and the bond projecting to the right is connected to the carbon atom in Formula 1;
W is O or S;
R1 is an optionally substituted phenyl ring, an optionally substituted naphthalenyl ring system or an optionally substituted 5- to 6-membered heteroaromatic ring; or cyano, Cj-Cg alkyl, Cj-Cg haloalkyl, C2-Cg alkenyl, C2-Cg haloalkenyl, C2-Cg alkynyl, C2-Cg haloalkynyl, C3-Cg cycloalkyl, C3-Cg halocycloalkyl, C4-C10 alkylcycloalkyl, C4-C10 cycloalkylalkyl, C4-C10 halocycloalkylalkyl, C5-C10 alkylcycloalkylalkyl, C2-Cg alkoxyalkyl, C2-Cg haloalkoxyalkyl, C4-C10 cycloalkoxyalkyl, C3-C10 alkoxyalkoxyalkyl, C2-Cg alkylthioalkyl, C2-Cg haloalkylthioalkyl, C2-Cg alkylsulfinylalkyl, C2-Cg alkylsulfonylalkyl, C2-Cg alkylaminoalkyl, C2-Cg haloalkylaminoalkyl, C3-C10 dialkylaminoalkyl, C4-C10 cycloalkylaminoalkyl, C3-Cg alkoxycarbonylalkyl, C3-Cg
haloalkoxycarbonylalkyl, C^-Cg alkoxy, C^-Cg haloalkoxy, C2-Cg alkenyloxy, C2-Cg haloalkenyloxy, C2-Cg alkynyloxy, C3-Cg haloalkynyloxy, C3-Cg cycloalkoxy, C3-Cg halocycloalkoxy, C4-C10 cycloalkylalkoxy, C2-Cg alkoxyalkoxy, C2-Cg alkylcarbonyloxy, C2-Cg haloalkylcarbonyloxy, C^-Cg alkylthio, C^-Cg haloalkylthio, C3-Cg cycloalkylthio, C^-Cg alkylamino, C^-Cg haloalkylamino, C2-Cg dialkylamino, C2-Cg halodialkylamino, C3-Cg cycloalkylamino, C2-Cg alkylcarbonylamino, C2-Cg haloalkylcarbonylamino, Ci -Cg alkylsulfonylamino, Ci -Cg haloalkylsulfonylamino, C3-C10 trialkylsilyl, pyrrolidinyl, piperidinyl or morpholinyl;
R2 is H, amino, cyano, halogen, -CH(=0), -C(=0)OH, -C(=0)NH2, CrC6 alkyl, Cj-Cg haloalkyl, C2-Cg alkenyl, C2-Cg haloalkenyl, C2-Cg alkynyl, C2-Cg haloalkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C4-C6 alkylcycloalkyl, C4-C6 cycloalkylalkyl, C4-C6 halocycloalkylalkyl, C3-C6 cycloalkenyl, C3-C6 halocycloalkenyl, C2-C6 alkoxyalkyl, C2-C6 alkylthioalkyl, C2-C6
alkylsulfinylalkyl, C2-C6 alkylsulfonylalkyl, C2-C6 alkylaminoalkyl, C2-C6 haloalkylaminoalkyl, C3-C6 dialkylaminoalkyl, C^-C^ alkoxy, C^-C^
haloalkoxy, C2-Cg alkenyloxy, C2-Cg haloalkenyloxy, C2-Cg alkynyloxy, C3-C6 haloalkynyloxy, C3-C6 cycloalkoxy, C3-C6 halocycloalkoxy, C2-Cg
alkoxyalkoxy, C2-C6 alkylcarbonyloxy, C2-C6 haloalkylcarbonyloxy, C^-C^ alkylthio, C^-C^ haloalkylthio, C3-C6 cycloalkylthio, C^-C^ alkylamino, C^-C^ haloalkylamino, C2-C6 dialkylamino, C2-C6 halodialkylamino, C3-C6 cycloalkylamino, C^-C^ alkylsulfonylamino, C^-C^ haloalkylsulfonylamino, C2-C6 alkylcarbonylamino, C2-C6 haloalkylcarbonylamino, C2-C6
alkylcarbonyl, C2-C6 haloalkylcarbonyl, C4-C6 cycloalkylcarbonyl, C2-C6 alkoxycarbonyl, C4-C6 cycloalkoxycarbonyl, C5-C6 cycloalkylalkoxycarbonyl, C2-C6 alkylaminocarbonyl or C3-C6 dialkylaminocarbonyl;
R3 is H, cyano, halogen, hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1 -C3 haloalkoxy; or
R2 and R3 are taken together with the carbon atom to which they are attached to form a 3- to 7-membered ring containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 2 N atoms, wherein up to 3 carbon atom ring members are independently selected from C(=0) and C(=S), and the sulfur atom ring members are independently selected from S(=O)s(=NR20)f, the ring optionally substituted with up to 4 substituents independently selected from cyano, halogen, C 1 -C2 alkyl, C1 -C2 haloalkyl, Ci -C2 alkoxy and Ci -C2 haloalkoxy on carbon atom ring members and cyano, Ci -C2 alkyl and Ci -C2 alkoxy on nitrogen atom ring members;
R4 is an optionally substituted phenyl ring, an optionally substituted naphthalenyl ring system or an optionally substituted 5- to 6-membered heteroaromatic ring; or H, cyano, halogen, hydroxy, -CH(=0), C1 -C4 alkyl, C 1 -C4 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, C2-C4 alkoxyalkyl, C2-C4 alkylthioalkyl, C2-C4 alkylsulfinylalkyl, C2-C4
alkylsulfonylalkyl, Ci -C4 alkoxy, Ci -C4 haloalkoxy, C2-C4 alkylcarbonyloxy, C2-C4 haloalkylcarbonyloxy, C2-C5 alkoxycarbonyloxy, C2-C5
alkylaminocarbonyloxy, C3-C5 dialkylaminocarbonyloxy, C 1 -C4 alkylthio, C1 -C4 haloalkylthio, C1 -C4 alkylsulfinyl, C1 -C4 haloalkylsulfinyl, C 1 -C4 alkylsulfonyl, C1 -C4 haloalkylsulfonyl, C2-C4 alkylcarbonyl, C2-C4
haloalkylcarbonyl, C2-C5 alkoxycarbonyl, C2-C5 alkylaminocarbonyl or C3-C5 dialkylaminocarbonyl;
R5 is H, CrC3 alkyl or CrC3 haloalkyl;
each R6 is independently cyano, halogen, hydroxy, Ci -C4 alkyl, Ci -C4 haloalkyl,
C2-C4 alkenyl or Ci -C4 alkoxy; or
two R6 are taken together as Ci -C4 alkylene or C2-C4 alkenylene to form a bridged or fused ring system;
each R7a and R7c is independently cyano, halogen, hydroxy, Ci -C4 alkyl, Ci -C4
haloalkyl, Ci -C4 alkoxy or Ci -C4 haloalkoxy;
each R7b and R7d is independently cyano, Ci -C4 alkyl, Ci -C4 haloalkyl, Ci -C4 alkoxy,
C2-C4 alkylcarbonyl or C2-C4 alkoxycarbonyl;
each R8a is independently cyano, halogen, hydroxy, Ci -C3 alkyl, Ci -C3 haloalkyl or
C1 -C3 alkoxy;
each R8b is independently Ci -C3 alkyl, Ci -C3 haloalkyl, C2-C4 alkylcarbonyl, C2-C4 alkoxycarbonyl;
each R9a is independently amino, cyano, halogen, hydroxy, nitro, SF5, Ci -Cg alkyl, Ci -Cg haloalkyl, C2-Cg alkenyl, C2-Cg haloalkenyl, C2-Cg alkynyl, C2-Cg haloalkynyl, C2-Cg cyanoalkyl, Ci -Cg hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C4-C10 cycloalkylalkyl, C4-C10 alkylcycloalkyl, C5-C10 alkylcycloalkylalkyl, Cg-C^ cycloalkylcycloalkyl, C4-C8 halocycloalkoxyalkyl, C4-C8 cycloalkenyloxyalkyl, C4-C8 halocycloalkenyloxyalkyl, C5-C8
cycloalkylalkylaminoalkyl, C2-C6 alkoxyalkyl, C2-C6 alkoxyhaloalkyl, C2-C6 haloalkoxyhaloalkyl, C3-C6 dialkoxyalkyl, C3-C6 alkoxyalkenyl, C3-C6 alkoxyalkynyl, C3-C6 alkoxycarbonylalkyl, C3-C6 halodialkylaminoalkyl, C^-C^ alkoxy, C^-Cg haloalkoxy, C3-C6 alkenyloxy, C3-C6 haloalkenyloxy, C3-C6 alkynyloxy, C2-Cg haloalkynyloxy, C2-C6 alkoxyhaloalkoxy, C2-C6
haloalkoxyalkoxy, C2-C6 haloalkoxyhaloalkoxy, C^-C^ alkylsulfonyloxy, C^-C^ haloalkylsulfonyloxy, C2-C6 alkylcarbonyloxy, C3-C6 alkenylcarbonyloxy, C3-C6 haloalkenylcarbonyloxy, C4-C8 halocycloalkylcarbonyloxy, C3-C6 alkoxycarbonylalkoxy, C2-C6 alkylthiocarbonyloxy, C3-C6 trialkylsilyloxy, C5-C10 trialkylsilylalkynyloxy, C^-Cg alkylthio, C^-Cg haloalkylthio, C2-Cg alkenylthio, C2-C6 alkynylthio, C2-C6 alkoxy alkylthio, C2-C6 alkylcarbonylthio, C^-Cg alkylsulfinyl, C^-Cg haloalkylsulfinyl, C^-Cg alkylsulfonyl, C^-Cg haloalkylsulfonyl, C^-C^ alkylamino, C^-C^ haloalkylamino, C2-C6
dialkylamino, C2-C6 halodialkylamino, C2-C6 alkenylamino, C2-C6
alkynylamino, C3-C6 cycloalkylamino, C4-C8 cycloalkylalkylamino, C^-C^ alkoxyamino, C^-C^ haloalkoxyamino, C2-Cg alkylcarbonylamino, C2-C6 haloalkylcarbonylamino, C2-C6 alkoxy carbonylamino, C2-C6
haloalkoxycarbonylamino, C3-C6 alkylcarbonyl(alkyl)amino, C3-C6
haloalkylcarbonyl(alkyl)amino, C3-C6 alkoxy carbonyl(alkyl)amino, C2-C6 alkylaminocarbonylamino, C3-C6 dialkylamino carbonylamino, C3-C6 alkylaminocarbonylalkylamino C2-C6 alkylamino(thiocarbonyl)amino, C3-C6 dialkylamino(thiocarbonyl)amino, C2-C6 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 haloalkoxycarbonyl, C2-C6 alkylaminocarbonyl, C3-C6
dialkylaminocarbonyl, C3-C6 alkoxy(alkyl)aminocarbonyl, C3-C6
alkoxyalkylcarbonyl, C3-C6 alkoxyalkoxycarbonyl, C2-C6 alkylthiocarbonyl, C2-
C^ alkylsulfonylaminocarbonyl, C2-C6 haloalkylsulfonylaminocarbonyl, C3-C6 trialkylsilyl, -S(=0)ONR14R15, -S(=0)ONHC≡N, -NHC≡N, -NHC(=0)H, -N=C(R16)2, -N(R14)S(=0)OR17, -CH(=0), -C(=0)OH, -C(=0)NH2,
-C(=0)NHC≡N, -C(=S)NR14R15, -OS(=0)OR17, -OC(=S)NR14R15,
-OC(=S)SR16 or -C(=NOR18)R19; or
each R9a is independently a phenyl ring or a naphthalenyl ring system, each optionally substituted with up to 3 substituents independently selected from cyano, halogen, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy and C1-C2 haloalkoxy; or each R9a is independently a 5- to 6-membered heteroaromatic ring containing ring members selected from carbon atoms and 1 to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, the ring optionally substituted with up to 3 substituents independently selected from cyano, halogen, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy and C1-C2 haloalkoxy on carbon atom ring members and cyano, C1-C2 alkyl and C1-C2 alkoxy on nitrogen atom ring members; or
each R9a is independently a 3- to 7-membered nonaromatic ring containing ring
members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, wherein up to 3 carbon atom ring members are independently selected from C(=0) and C(=S), the ring optionally substituted with up to 3 substituents independently selected from cyano, halogen, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy and C1-C2 haloalkoxy on carbon atom ring members and cyano, C1-C2 alkyl and C1-C2 alkoxy on nitrogen atom ring members;
each R9b is independently cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C2-C3 alkylcarbonyl, C2-C3 alkoxycarbonyl or C3-C6 cycloalkyl;
R10 is H, cyano, halogen, hydroxy, -CH(=0), C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, C2-C4 alkoxyalkyl, C2-C4 alkylthioalkyl, C2-C4 alkylsulfinylalkyl, C2-C4 alkylsulfonylalkyl, C3-C5 alkoxycarbonylalkyl, C1 -C4 alkoxy, C1 -C4 haloalkoxy, C 1 -C4 alkylthio, C1 -C4 haloalkylthio, C1 -C4 alkylsulfinyl, C 1 -C4 haloalkylsulfinyl, Ci -C4 alkylsulfonyl, Ci -C4 haloalkylsulfonyl, C2-C4 alkylcarbonyl, C2-C4 haloalkylcarbonyl, C2-C5 alkoxycarbonyl, C2-C5 alkylaminocarbonyl or C3-C5 dialkylaminocarbonyl;
R1 1 is H, CrC4 alkyl, CrC4 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C3-C4 alkynyl, C2-C4 haloalkynyl, C2-C4 alkoxyalkyl, C2-C4 alkylthioalkyl, C2-C4 alkylsulfinylalkyl, C2-C4 alkylsulfonylalkyl, C3-C5 alkoxycarbonylalkyl, C1 -C4 alkylsulfonyl, C1 -C4 haloalkylsulfonyl, C2-C4 alkylcarbonyl, C2-C4
haloalkylcarbonyl, C2-C5 alkoxycarbonyl, C2-C5 alkylaminocarbonyl or C3-C5 dialkylaminocarbonyl;
each R12 is independently H, Ci -C3 alkyl or Ci -C3 haloalkyl;
R1 is H, cyano, Ci -C4 alkyl, Ci -C4 haloalkyl, C2-C4 alkoxyalkyl, C2-C4
alkylthioalkyl, C1 -C4 alkylsulfonyl, C1 -C4 haloalkylsulfonyl, C2-C4
alkylcarbonyl, C2-C4 haloalkylcarbonyl, C2-C4 alkoxycarbonyl, C2-C4 alkylaminocarbonyl or C3-C5 dialkylaminocarbonyl; or
R13 and R3 are taken together with the atoms to which they are attached to form a 5- to 7-membered partially saturated ring containing ring members selected from carbon atoms and up to 3 heteroatoms independently selected from up to 1 O, up to 1 S and up to 1 N atom, the ring optionally substituted with up to 3 substituents independently selected from cyano, halogen, nitro, Ci -C2 alkyl, Ci -C2 haloalkyl, Ci -C2 alkoxy and Ci -C2 haloalkoxy on carbon atom ring members and cyano, Ci -C2 alkyl and Ci -C2 alkoxy on nitrogen atom ring members;
each R14 and R15 is independently H, Ci -C3 alkyl, Ci -C3 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, benzyl or phenyl;
each R16 is independently Ci -C3 alkyl, Ci -C3 haloalkyl, C2-C4 alkenyl, C3-C6
cycloalkyl, benzyl or phenyl;
each R17 is a phenyl ring, a naphthalenyl ring system or a 5- to 6-membered
heteroaromatic ring, each ring or ring system optionally substituted with up to 3 substituents independently selected from halogen, cyano, nitro, Ci -C2 alkyl, Ci -C2 haloalkyl, Ci -C2 alkoxy and Ci -C2 haloalkoxy on carbon atom ring members and cyano, Ci -C2 alkyl and Ci -C2 alkoxy on nitrogen atom ring members;
each R18 is independently H, Ci -C3 alkyl, Ci -C3 haloalkyl or benzyl;
each R19 is independently H, Ci -C3 alkyl, Ci -C3 haloalkyl, C3-C6 cycloalkyl, C4-C6 cycloalkylalkyl, C4-C6 alkylcycloalkyl, C4-C6 haloalkylcycloalkyl, C2-C4 alkoxyalkyl, C2-C4 haloalkoxyalkyl, benzyl or phenyl; each R20 is independently H, cyano, C^-Cg alkyl, C^-Cg haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C^-Cg alkoxy, C^-Cg haloalkoxy, C^-Cg alkylamino, C^-Cg haloalkylamino, C2-Cg dialkylamino or phenyl; and
n is 0, 1 or 2;
provided that:
(a) that the sum of s and f is 0, 1 or 2 in each instance of S(=O)s(=NR20)f;
(b) when Z1 and Z2 are each independently a chain containing 1- to 3 -atoms, then the sum of atoms in Z1 and Z2 is 1, 2, 3 or 4;
(c) when A is C(=0) or CH(R10) and R10 is hydroxy, then R1 is linked through a carbon atom to A;
(d) when X is X2 or X3, then Z1 is linked to X through carbon, nitrogen or C(=NOH);
(e) when X is X1, E is E-l and A is NH, then R1 is other than an unsubstituted
heterocyclic ring, a monosubstituted 2-pyridinyl ring, a monosubstituted
3-pyridinyl ring, a monosubstituted pyrazinyl ring, an unsubstituted phenyl ring or a monosubstituted phenyl ring; and
(f) when X is X2, Z1 is CH, E is E-l and A is NH, then R1 is other than an
unsubstituted 3-pyridinyl ring, an unsubstituted pyrazinyl ring or monosubstituted pyrazinyl ring.
2. A compound of Claim 1 wherein:
E is E-l;
X is X1 or X2;
Z1 is O, S, NH, CH2, CH2CH2, CH2CH2CH2, OCH2, CH20, OCH2CH2, CH2CH20, CH2OCH2, SCH2, CH2S, SCH2CH2, CH2CH2S,
CH2SCH2, NHCH2, CH2NH, NHCH2CH2, CH2CH2NH, CHCH2, CHCH2CH2, NNH, NNHCH2, NHN=CH, CH=NNH, ON=CH,
CH=NO, CH2NHO, C(=0), C(=0)CH2, CH2C(=0), C(=0)CH2CH2, CH2CH2C(=0), NHC(=0), C(=0)NH, C(=0)NHCH2 or
CH2NHC(=0), each optionally substituted with up to 1 substituent selected from R7a on a carbon atom and R b on a nitrogen atom;
G is selected from G-l, G-9, G-12, G-15, G-19, G-22, G-30, G-36, G-46 through G-48, G-55, G-56 and G-68 through G-71 wherein the bond projecting to the left is connected to Z1, and the bond projecting to the right is connected to Z2; each R8c is independently selected from H and R8a; and R8d is selected from H and R8b.
Z2 is a direct bond, O, S, NH, CH2, CH2CH2, CH2CH2CH2, OCH2, CH20,
OCH2CH2, CH2CH20, CH2OCH2, SCH2, CH2S, SCH2CH2,
CH2CH2S, NHCH2, CH2NH, NHCH2CH2, CH2CH2NH, CHCHCH2, NNH, NNHCH2, NO, ONCH, CHNO, C(=0), C(=0)CH2, CH2C(=0), C(=0)CH2CH2, CH2CH2C(=0), NHC(=0), C(=0)NH, C(=0)NHCH2, CH2NHC(=0), CH2C(=0)NH, S02NH, NHS02, S02NHCH2 or CH2NHS02, each optionally substituted with up to 1 substituent selected from R7c on a carbon atom and R d on a nitrogen atom;
Q is selected from Q-45, Q-63, Q-70, Q-71, Q-72 and Q-84 wherein the bond projecting to the left is connected to Z2; R9c is selected from H and R9^; and p is 0, 1, 2 or 3;
A is CH(R10) or N(Rn);
W is O;
R1 is selected from U-1, U-20 and U-50 wherein the bond projecting to the left is connected to A; and k is 0, 1, 2 or 3;
each R21a is independently halogen, C1-C3 alkyl, -C3 haloalkyl or C2-C3 alkoxyalkyl;
each R6 is independently cyano, hydroxy, methyl or methoxy;
each R7a and R7c is independently halogen, -C4 alkyl or C1-C4 alkoxy; each R7b and R7d is independently C1-C4 alkyl;
each R8a is independently halogen or C1-C3 alkyl;
each R9a is independently halogen, C^-Cg alkyl, C^-Cg haloalkyl, C^-Cg
alkoxy, C3-C4 alkenyloxy or C3-C4 alkynyloxy;
R9b is CrC3 alkyl, C3-C6 cycloalkyl, C2-C3 alkylcarbonyl or C2-C3
alkoxycarbonyl;
R10 is H, cyano, halogen, hydroxy, methyl or methoxy; and
R1 1 is H, methyl, CH3C(=0) or CH3OC(=0).
A compound of Claim 2 wherein
Z1 is O, NH, CH2, OCH2, CH20, NHCH2, CH2NH, NHC(=0) or C(=0)NH, each optionally substituted with up to 1 substituent selected from R7a on a carbon atom and R7b on a nitrogen atom;
G is selected from G-l, G-56, G-68, G-70 and G-71;
G is unsubstituted except for its attachments to Z1 and Z2;
Z2 is a direct bond, O, S, NH, OCH2, CH20, SCH2, CH2S, NHCH2 or
CH2NH, each optionally substituted with up to 1 substituent selected from R7c on a carbon atom and R7d on a nitrogen atom;
Q is Q-45;
p is 0, 1 or 2;
A is CH2 or NH;
R1 is U-1; each R21 a is independently halogen, methyl or Ci -C2 haloalkyl;
k is 0, 1 or 2;
n is 0;
each R7a and R7c is methyl;
each R7^ and R d [s methyl; and
each R9a is independently halogen, Ci -C2 alkyl, Ci -C2 haloalkyl, Ci -C2 alkoxy, H2C=CHCH20- or HC≡CCH20-.
4. A compound of Claim 3 wherein
X is X1;
Z1 is O, OCH2, CH20 or CH2;
G is selected from G-56, G-68 and G-70;
Z2 is O, S, NH, OCH2, CH20, NHCH2 or CH2NH;
A is CH2;
each R21 a is independently halogen, methyl, CF3 or CF2H; and each R9a is independently is independently CI, F, methyl or halomethyl.
5. A compound of Claim 1 selected from the group consisting of:
1 -[4-[[6-[(2,6-difluorophenyl)methoxy]-3-pyridazinyl]oxy]- 1 -piperidinyl]- 2-[5-methyl-3-(trifluoromethyl)- IH-pyrazol- 1 -yljethanone,
1 -[4-[[6-[[(2,6-difluorophenyl)methyl]amino]-3-pyridazinyl]oxy]- 1 - piperidinyl]-2-[5-methyl-3-(trifluoromethyl)- IH-pyrazol- 1 -yljethanone, 1 -[4-[[6-methyl[(lR)- 1 -phenylethyl]amino]-3-pyridazinyl]oxy]- 1 - piperidinyl]-2-[5-methyl-3-(trifluoromethyl)- IH-pyrazol- 1 -yljethanone, 1,1,1 -trifluoro-2-propanone 0-[2-[4-[[6-[(2,6-difluorophenyl)methoxy]-3- pyridazinyljoxy]- 1 -piperidinyl]-2-oxoethyl]oxime,
1 -[4-[[6-[(2,6-difluorophenoxy)methyl]-3-pyridazinyl]oxy]- 1 -piperidinyl]-
2-[5-methyl-3-(trifluoromethyl)- IH-pyrazol- 1 -yljethanone,
1 -[4-[[6-[(2,6-difluorophenyl)amino]-3-pyridazinyl]oxy]- 1 -piperidinyl]-2-
[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]ethanone,
2-[5-methyl-3-(trifiuoromethyl)- lH-pyrazol-1 -yl]- 1 -[4-[[6-[[(lR)- 1 - phenylethyl]amino]-3-pyridazinyl]oxy]- 1 -piperidinyljethanone, l-[4-[[6-[(2,6-difluorophenyl)thio]-3-pyridazinyl]oxy]-l-piperidinyl]-2-[5- methyl-3-(trifluoromethyl)- IH-pyrazol- 1 -yljethanone and
1 -[4-[[6-(2,6-difluorophenoxy)-3-pyridazinyl]oxy]- 1 -piperidinyl]-2-[5- methyl-3-(trifluoromethyl)- IH-pyrazol- 1 -yljethanone.
6. A fungicidal composition comprising (a) a compound of Claim 1; and (b) at least one other fungicide.
7. A fungicidal composition comprising (a) a compound of Claim 1; and (b) at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents.
8. A method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof, or to the plant seed, a fungicidally effective amount of a compound of Claim 1.
PCT/US2014/035245 2013-04-29 2014-04-24 Fungicidal heterocyclic compounds Ceased WO2014179144A1 (en)

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