WO2011051958A1 - Fungicidal pyrazolones - Google Patents

Fungicidal pyrazolones Download PDF

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Publication number
WO2011051958A1
WO2011051958A1 PCT/IN2009/000616 IN2009000616W WO2011051958A1 WO 2011051958 A1 WO2011051958 A1 WO 2011051958A1 IN 2009000616 W IN2009000616 W IN 2009000616W WO 2011051958 A1 WO2011051958 A1 WO 2011051958A1
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Prior art keywords
ring
independently selected
compound
ring members
alkyl
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PCT/IN2009/000616
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French (fr)
Inventor
Vijayagopal Gopalsamuthiram
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E.I. Du Pont De Nemours And Company
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Priority to PCT/IN2009/000616 priority Critical patent/WO2011051958A1/en
Publication of WO2011051958A1 publication Critical patent/WO2011051958A1/en

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    • 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
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
    • 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
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to certain pyrazolones, their JV-oxides, salts and compositions, and methods of their use as fungicides.
  • EP-987253-A1 discloses certain pyrazolone derivatives of Formula i
  • PCT Patent Publication WO 99/31070 discloses certain substituted phenylpyrazolone derivatives of Formula ii
  • 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:
  • Y is O or S
  • W 1 is a phenyl ring optionally substituted with up to 5 substituents independently
  • Q 2 is a phenyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 5 substituents independently selected from R 3c ; or a 5- to
  • W 2 is a phenyl ring optionally substituted with up to 5.
  • R 1 is H, halogen, cyano, amino, nitro, -CHO, -SCN, C r C 7 alkyl, C2-C7 alkenyl, C 2 -C 7 alkynyl, C ] -C 7 haloalkyl, C 2 -C 7 haloalkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 halocycloalkyl, C 4 -C)o alkylcycloalkyl, C4-C 10 cycloalkylalkyl, C 6 -C ]4 cycloalkylcycloalkyl, C2-C alkoxyalkyl, C j -C 7 alkoxy, C 1 -C 7 haloalkoxy, C r C 7 alkylthio, C,-C 7 haloalkylthio, C 2 -C 7 alkylthioalkyl, C r C 7 alkylsulfinyl, C
  • R 2 is cyano, C r C 7 alkyl, C 3 -C 7 alkenyl, C 3 -C 7 alkynyl, C r C 7 haloalkyl, C 3 -C 7
  • haloalkenyl C 3 -C 7 cycloalkyl, C 3 -C 7 halocycloalkyl, C4-C10 alkylcycloalkyl, C4-C10 cycloalkylalkyl, Cg-C j4 cycloalkylcycloalkyl, C 2 -C 7 alkoxyalkyl, C 2 -C 7 alkylthioalkyl, C r C 7 alkylsulfinyl, C,-C 7 alkylsulfonyl, C,-C 7
  • each R 3a and R 3c is independently halogen, cyano, hydroxy, nitro, CJ-C7 alkyl, C2-C7 alkenyl, C 2 -C 7 alkynyl, C 1-C7 haloalkyl, C 2 -C 7 haloalkenyl, C3-C7 cycloalkyl, C3-C7 halocycloalkyl, C4-C10 alkylcycloalkyl, C 4 -C JO cycloalkylalkyl, C 6 -Ci4 cycloalkylcycloalkyl, C1-C7 alkoxy, C ] -C 7 haloalkoxy, C3-C7 cycloalkoxy, C3-C7 halocycloalkoxy, C ] -C 7 halocycloalkoxy, C ] -C 7 haloalkoxy, C3-C7 cycloalkoxy, C3-C7 halo
  • alkylsulfinyl C j -C 7 alkylsulfonyl, C j -C 7 haloalkylsulfinyl, C j -C 7
  • each R 3b and R 3d is independently cyano, C j -C 6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C j -C6 alkoxy, C 2 -C 6 alkoxyalkyl, C2-Cg alkylcarbonyl,
  • each R 4 is independently H, cyano, C1-C3 alkyl, C ] -C3 alkoxy or C ⁇ -C3 haloalkyl; each R 5a and R 5c is independently H, cyano or C C 4 alkyl;
  • each R 5b is independently H or C j -C4 alkyl
  • each R 6 is independently H, C j -C ⁇ alkyl, C Cg haloalkyl, -C ⁇ alkylcarbonyl, C2-Cg alkoxycarbonyl, C 2 -C6 (alkylthio)carbonyl, C 2 -C 6 alkoxy(thiocarbonyl), C4-C cycloalkylcarbonyl, C4-Cg cycloalkoxycarbonyl, C 4 -Cg (cycloalkylthio)carbonyl or C4-C cycloalkoxy(thiocarbonyl);
  • each R 7a and R 7b is independently H, C r C 6 alkyl, C r C 6 haloalkyl, C 2 -C 6 alkenyl, C3-C6 alkynyl, C3-C 6 cycloalkyl, C3-C6 halocycloalkyl, C 2 -C6 alkylcarbonyl, C 2 -C6 alkoxycarbonyl, C 2 -C 6 (alkylthio)carbonyl, C 2 -C 6 alkoxy(thiocarbonyl), C4-Cg cycloalkylcarbonyl, C 4 -Cg cycloalkoxycarbonyl, C 4 -C " g .
  • each R 8 is independently H, C j -C 6 alkyl, C j -Cg haloalkyl, C 2 -C 6 alkenyl, C3-C6
  • alkynyl C3 ⁇ C 6 cycloalkyl, C3-C6 halocycloalkyl, C 2 -C 6 alkylcarbonyl, C2-C 6 alkoxycarbonyl, C2-C ⁇ (alkylthio)carbonyl, C2-Cg alkoxy(thiocarbonyl), C 4 -Cg cycloalkylcarbonyl, C 4 -Cg cycloalkoxycarbonyl, C4-Cg (cycloalkylthio)carbonyl or C 4 -Cg cycloalkoxy(thiocarbonyl);
  • each R 9 is independently halogen, C j -Cg alkyl, C j -C 6 haloalkyl or C j -C ⁇ alkoxy;
  • each n is independently 0, 1 or 2;
  • the compound is other than 1 ,2-dihydro-2-methyl- 1 -(3-nitrophenyl)-5- phenyl-3H-pyrazol-3-one, l,2-dihydro-2-methyl-l,5-diphenyl-3H-pyrazol-3-one or 2-(3 ⁇ chloropropyl)-l,2-dihydro-l,5-diphenyl-3H-pyrazol-3-one.
  • this invention pertains to a compound of Formula 1 (including all stereoisomers), an N-oxide, or a salt 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); arid (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).
  • 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 or method 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 or method.
  • transitional phrase consisting essentially of is used to define a composition or method 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.
  • alkylating agent refers to a chemical compound in which a carbon-containing radical is bound through a carbon atom to a leaving group such as halide or sulfonate, which is displaceable by bonding of a nucleophile to said carbon atom. Unless otherwise indicated, the term “alkylating” does not limit the carbon ⁇ containing radical to alkyl; the carbon-containing radicals in alkylating agents include the variety of carbon-bound substituent radicals specified, for example, for R 1 and R 2 .
  • alkyl used either alone or in compound words such as “alkylthio” or “haloalkyl” includes straight-chain or branched alkyl, such as, methyl, ethyl, w-propyl, / ' -propyl, and the different butyl, pentyl, hexyl or heptyl isomers.
  • Alkenyl includes straight-chain or branched alkenes such as ethenyl, 1 -propenyl, 2-propenyl, and the different butenyl, pentenyl, hexenyl or heptenyl isomers.
  • Alkenyl also includes polyenes such as 1 ,2-propadienyl and 2,4-hexadienyl.
  • Alkynyl includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl, and the different butynyl, pentynyl, hexynyl or heptynyl 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, pentylene or hexylene .isomers.
  • Alkynylene denotes a straight-chain or branched alkynediyl containing one triple bond. Examples of “alkynylene” include CH 2 C ⁇ C, C ⁇ CCH 2 , and the different butynylene, pentynylene or hexynylene isomers.
  • Alkoxy includes, for example, methoxy, ethoxy, «-propyloxy, /-propyloxy, and the different butoxy, pentoxy, hexyloxy or heptyloxy isomers.
  • Alkylthio includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio, hexylthio or heptylthio isomers.
  • Alkylsulfinyl includes both enantiomers of an alkylsulfinyl group.
  • Alkylamino includes an NH radical substituted with straight-chain or branched alkyl. Examples of “alkylamino” include CH 3 CH 2 NH, CH 3 CH 2 CH 2 NH and (CH ⁇ CHC ⁇ NH. Examples of “dialkylamino” include (CH 3 ) 2 N, (CH 3 CH 2 GH 2 ) 2 N and CH 3 CH 2 (CH 3 )N.
  • Alkoxyalkyl denotes alkoxy substitution on alkyl.
  • alkoxyalkyl examples 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 .
  • Alkylthioalkyl denotes alkylthio substitution on alkyl.
  • alkylthioalkyl examples 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 .
  • Alkylaminoalkyl denotes alkylamino substitution on alkyl.
  • alkylaminoalkyl examples 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 examples include (CH ⁇ CH ⁇ NCfT,, (CH 3 CH 2 CH 2 )2NCH 2 and CH 3 CH 2 (CH 3 )NCH 2 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 .
  • Cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • alkylcycloalkyl denotes alkyl substitution on a cycloalkyl moiety and includes, for example, ethylcyclopropyl, / ' -propylcyclobutyl, methylcyclopentyl and methylcyclohexyl.
  • cycloalkylalkyl denotes cycloalkyl substitution on an alkyl moiety.
  • cycloalkylalkyl examples include cyclopropylmethyl, cyclopentylethyl, and other cycloalkyl moieties bonded to straight-chain or branched alkyl groups.
  • cycloalkylcycloalkyl denotes cycloalkyl substitution on another cycloalkyl ring, wherein each cycloalkyl ring independently has from 3 to 7 carbon atom ring members.
  • cycloalkylcycloalkyl examples include cyclopropylcyclopropyl (such as ⁇ , -bicyclopropyl-l-yl, ⁇ , - 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 (U?,2S)-l,l'-bicyclopropyl-2-yl and ( ⁇ R,2R)- ⁇ ,V- bicyclopropyl-2-yl).
  • cyclopropylcyclopropyl such as ⁇ , -bicyclopropyl-l-yl, ⁇ , - bicyclopropyl-2-yl
  • cycloalkoxy denotes cycloalkyl attached to and linked through an oxygen atom including, for example, cyclopentyloxy and cyclohexyloxy.
  • cycloalkenylene denotes a cycloalkenediyl ring containing one olefinic bond.
  • examples of “cycloalkenylene” include cyclopropenylene and cyclopentenylene.
  • Trialkylsilyl includes 3 branched and/or straight-chain alkyl radicals attached to and linked through a silicon atom, such as trimethylsilyl, triethylsilyl and ter/-butyldimethylsilyl.
  • halogen either alone or in compound words such as “haloalkyl”, or when used in descriptions such as “alkyl substituted with halogen” includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as “haloalkyl”, or when used in descriptions such as “alkyl substituted with halogen” said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of “haloalkyl” or “alkyl substituted with halogen” include F 3 C, C1CH 2 , CF 3 CH 2 and CF 3 CC1 2 .
  • haloalkoxy examples include CF 3 0, CC1 3 CH 2 0, 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.
  • halocycloalkyl examples include chlorocyclopropyl, fluorocyclobutyl and chlorocyclohexyl.
  • C j -Cj The total number of carbon atoms in a substituent group is indicated by the "C j -Cj" prefix where i and j are numbers from 1 to 14.
  • CJ-C4 alkylsulfonyl designates methylsulfonyl through butylsulfonyl
  • 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
  • C 4 alkoxyalkyl designates the various isomers of an alkyl group substituted with an alkoxy group containing a total of four carbon atoms, examples including CH 3 CH 2 CH 2 OCH 2 and CH 3 CH 2 OCH 2 CH 2 .
  • 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 3a on carbon atom ring members” means that 0, 1, 2 or 3 substituents can be present (if the number of potential connection points allows).
  • the phrase “optionally substituted with up to 5 substituents independently selected from R 3a on carbon atom ring members” means that 0, 1, 2, 3, 4 or 5 substituents can be present if the number of available connection points allows.
  • said substituents are independently selected from the group of defined substituents (e.g., (R v ) r wherein r is 1, 2, 3, 4 or 5 in Exhibit 1).
  • substituents e.g., (R v ) r wherein r is 1, 2, 3, 4 or 5 in Exhibit 1).
  • ring system denotes two fused rings (e.g., two phenyl rings fused to form a naphthalenyl ring system or two rings fused to form a heteroaromatic bicyclic ring system).
  • nonaromatic includes rings that are fully saturated as well as partially or fully unsaturated, provided that none of the rings are aromatic.
  • aromatic indicates that each of the ring atoms of a fully unsaturated ring 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.
  • the term "fully unsaturated heterocyclic ring” includes both aromatic and nonaromatic heterocycles.
  • carbocyclic ring denotes a ring or ring system wherein the atoms forming the ring backbone are selected only from carbon.
  • a carbocyclic ring can be a saturated, partially unsaturated or fully unsaturated ring.
  • saturated carbocyclic ring 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.
  • heterocyclic ring or “heterocycle” denote rings in which at least one atom forming the ring backbone is not carbon (e.g., N, O or S).
  • a heterocyclic ring contains no more than 4 N atoms, no more than 2 O atoms and no more than 2 S atoms.
  • 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”.
  • heterocyclic ring system or “heteroaromatic bicyclic ring system” denote a ring system in which at least one atom forming the ring backbone is not carbon (e.g., N, O or S) 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.
  • an instance of Q 1 and Q 2 comprises a phenyl ring or a 6-membered fully unsaturated heterocyclic ring
  • the ortho, meta and para positions of each ring is relative to the connection of the ring to the remainder of Formula 1.
  • an instance of Q 1 and Q 2 comprises a phenyl ring or a 6-membered fully unsaturated heterocyclic ring attached through a linker (e.g., C(R 5a R 5b ) >.
  • the Q 1 -heterocyclic ring or heteroaromatic ring system is optionally substituted with R 3a on carbon atom ring members and R 3b on nitrogen atom ring members; and the Q 2 heterocyclic ring or heteroaromatic ring system is optionally substituted with R 3c on carbon atom ring members and R 3d on nitrogen atom ring members).
  • substituents are optional, 0 to 5 substituents may be present, limited only by the number of available points of attachment.
  • the ring members selected from up to 2 O, up to 2 S and up to 4 N atoms are optional, provided at least one ring member is not carbon (e.g., N, O or S).
  • the nitrogen atom ring members may be oxidized as N-oxides, because compounds relating to Formula 1 also include N-oxide derivatives.
  • Examples of a 5- to 6-membered fully unsaturated heterocyclic ring include the rings A-1 through A-31 illustrated in Exhibit 1, and examples of an 8- to 10-membered heteroaromatic bicyclic ring system include the ring systems A-32 through A-72 illustrated in Exhibit 2.
  • the variable R v is any substituent as defined in the Summary of the Invention for Q 1 and Q 2 (i.e.
  • the Q> heterocyclic ring or heteroaromatic ring system is optionally substituted with R 3a on carbon atom ring members and R 3b on nitrogen atom ring members; and the Q 2 heterocyclic ring or heteroaromatic ring system is optionally substituted with R 3c on carbon atom ring members and R 3d on nitrogen atom ring members) and r is an integer from 0 to 5, limited by the number of available positions on each depicted ring or ring system.
  • the W 1 heterocyclic ring is optionally substituted with R 3a on carbon atom ring members and R 3b on nitrogen atom ring members; and the W 2 heterocyclic ring optionally substituted with R 3c on carbon atom ring members and R 3d on nitrogen atom ring members).
  • substituents are optional, 0 to 5 substituents may be present, limited only by the number of available points of attachment.
  • the ring members selected from up to 2 O, up to 2 S and up to 4 N atoms are optional, provided at least one ring member is not carbon (e.g., N, O or S).
  • the nitrogen atom ring members may be oxidized as N-oxides, because compounds relating to Formula 1 also include N-oxide derivatives.
  • Examples of a 5- to 6-membered fully unsaturated heterocyclic ring include the rings A-1 through A-31 illustrated in Exhibit 1 wherein R v is any substituent as defined in the Summary of the Invention for W 1 or W 2 (i.e. the W 1 heterocyclic ring is optionally substituted with R 3a on carbon atom ring members and R 3b on nitrogen atom ring members; and the W 2 heterocyclic ring is optionally substituted with R 3c on carbon atom ring members and R 3d on nitrogen atom ring members) and r is an integer from 0 to 5, limited by the number of available positions on each depicted ring.
  • R v groups are shown in the structures A-1 through A-72, it is noted that they do not need to be present since they are optional substituents.
  • the nitrogen atoms that require substitution to fill their valence are substituted with H or R v .
  • (R v ) r can be attached to any available carbon or nitrogen atom of the depicted ring or ring system.
  • the depicted ring or ring system can be attached to the remainder of Formula 1 through any available carbon or nitrogen of the depicted ring or ring system by replacement of a hydrogen atom.
  • A-17 A-18 A-19 A-20 A wide variety of synthetic methods are known in the art to enable preparation of aromatic heterocyclic rings and ring systems; for extensive reviews see the eight volume set of Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees editors-in-chief, Pergamon Press, Oxford, 1984 and the twelve volume set of Comprehensive Heterocyclic Chemistry II, A. R. Katritzky, C. W. Rees and E. F. V. Scriven editors-in-chief, Pergamon Press, Oxford, 1996.
  • Stereoisomers of this invention can exist as one or more stereoisomers.
  • the various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers.
  • one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers.
  • the compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers or as an optically active form.
  • nitrogen-containing heterocycles can form N-oxides since the nitrogen requires an available lone pair for oxidation to the oxide; one skilled in the art will recognize those nitrogen-containing heterocycles which can form N-oxides.
  • nitrogen-containing heterocycles which can form N-oxides.
  • tertiary amines can form N-oxides.
  • N-oxides of heterocycles and tertiary amines are very well known by one skilled in the art including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as /-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane.
  • MCPBA peroxy acids
  • alkyl hydroperoxides such as /-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.
  • the present invention comprises compounds selected from Formula 1, N-oxides and agriculturally suitable salts thereof.
  • Non-crystalline forms include embodiments which are solids such as waxes and gums as well as embodiments which are liquids such as solutions and melts.
  • Crystalline forms include embodiments which represent essentially a single crystal type and embodiments which represent a mixture of polymorphs (i.e. different crystalline types).
  • polymorph refers to a particular crystalline form of a chemical compound that can crystallize in different crystalline forms, these forms having different arrangements and/or conformations of the molecules in the crystal lattice.
  • polymorphs can have the same chemical composition, they can also differ in composition due the presence or absence of co-crystallized water or other molecules, which can be weakly or strongly bound in the lattice. Polymorphs can differ in such chemical, physical and biological properties as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspensibility, dissolution rate and biological availability.
  • a polymorph of a compound represented by Formula 1 can exhibit beneficial effects (e.g., suitability for preparation of useful formulations, improved biological performance) relative to another polymorph or a mixture of polymorphs of the same compound represented by Formula 1.
  • Preparation and isolation of a particular polymorph of a compound represented by Formula 1 can be achieved by methods known to those skilled in the art including, for example, crystallization using selected solvents and temperatures.
  • Embodiments of the present invention as described in the Summary of the Invention include those described below.
  • Formula 1 includes N-oxides and salts thereof, and reference to "a compound of Formula 1" includes the definitions of substituents specified in the Summary of the Invention unless further defined in the Embodiments.
  • Embodiment 1 A compound of Formula 1 wherein Y is O.
  • Embodiment 3 A compound of Embodiment 2 wherein Q 1 is a phenyl, thienyl,
  • pyridinyl pyridazinyl, pyrimidinyl or pyrazolyl ring or a naphfhalenyl ring system, each ring or ring system optionally substituted with up to 3 substituents independently selected from R 3a on carbon atom ring members and R 3b on nitrogen atom ring members; or C(R 5a R 5b )W 1 .
  • Embodiment 4 A compound of Embodiment 3 wherein Q 1 is a phenyl or pyridinyl ring optionally substituted with up to 3 substituents independently selected from R 3a .
  • Embodiment 5 A compound of Embodiment 4 wherein Q 1 is a phenyl ring optionally substituted with up to 3 substituents independently selected from R 3a .
  • Embodiment 6 A compound of Formula 1 or any one of Embodiments 1 through 3 .
  • W 1 is a phenyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazolyl ring optionally substituted with up to 3 substituents independently selected from R 3a on carbon atom ring members and R 3b on nitrogen atom ring members.
  • Embodiment 7 A compound of Embodiment 6 wherein W 1 is a phenyl or pyridinyl ring optionally substituted with up to 3 substituents independently selected from R 3 .
  • Embodiment 8 A compound of Embodiment 7 wherein W 1 is a phenyl ring optionally substituted with up to 3 substituents independently selected from R 3a .
  • Embodiment 10 A compound of Embodiment 9 wherein Q 2 is a phenyl, thienyl,
  • pyridinyl pyridazinyl, pyrimidinyl or pyrazolyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 3 substituents independently selected from R 3c on carbon atom ring members and R 3d on nitrogen atom ring members; or C(R 5a R 5b )W 2 .
  • Embodiment 11 A compound of Embodiment 10 wherein Q 2 is a phenyl or pyridinyl ring optionally substituted with up to 3 substituents independently selected from R 3c .
  • Embodiment 12 A compound of Embodiment 11 wherein Q 2 is a phenyl ring
  • Embodiment 13 A compound of Formula 1 or any one of Embodiments 1 through 10 wherein W 2 is a phenyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazolyl ring optionally substituted with up to 3 substituents independently selected from R 3c on carbon atom ring members and R 3d on nitrogen atom ring members.
  • Embodiment 14 A compound of Embodiment 13 wherein W 2 is a phenyl or pyridinyl ring optionally substituted with up to 3 substituents independently selected from R 3c .
  • Embodiment 15 A compound of Embodiment 14 wherein W 2 is a phenyl ring
  • Embodiment 16 A compound of Formula 1 or any one of Embodiments 1 through 15 wherein when each Q 1 and Q 2 is independently an optionally substituted phenyl or pyridinyl ring, then one of Q 5 and Q 2 is substituted with 2 or 3 substituents and the other of Q 1 and Q 2 is substituted with 0 to 3 substituents.
  • Embodiment 17 A compound of Embodiment 16 wherein when each Q 1 and Q 2 is independently an optionally substituted phenyl or pyridinyl ring, then one of Q 1 arid Q 2 is substituted with 2 or 3 substituents and the other of Q 1 and Q 2 is substituted with 1 or 2 substituents.
  • Embodiment 18 A compound of Embodiment 17 wherein when each Q 1 and Q 2 is independently an optionally substituted phenyl or pyridinyl ring, then one of Q 1 and Q 2 is substituted with 2 or 3 substituents and the other of Q 1 and Q 2 is substituted with 1 substituent.
  • Embodiment 19 A compound of Formula 1 or any one of Embodiments 1 through 18 wherein when each Q 1 and Q 2 is independently an optionally substituted phenyl or pyridinyl ring, then one of Q 1 and Q 2 is substituted with at least one substituent at an ortho position and the other of Q 1 and Q 2 is substituted with at least one substituent at a meta or para position.
  • Embodiment 20 A compound of Formula 1 or any one of Embodiments 1 through 19 wherein R 1 is H, halogen, Cj-C 3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C2-C3 haloalkyl, C 2 -C 3 haloalkenyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C j -C 3 alkylthio,
  • Embodiment 21 A compound of Embodiment 20 wherein R 1 is H, halogen, cyano or
  • Embodiment 22 A compound of Embodiment 21 wherein R 1 is CI, Br, I or C1-C2
  • Embodiment 23 A compound of Embodiment 22 wherein R 1 is CI, Br or methyl.
  • Embodiment 24 A compound of Formula 1 or any one of Embodiments 1 through 23 wherein R 2 is cyano, C ⁇ -C 3 alkyl, C3 alkenyl, cyclopropyl or C j -C3
  • Embodiment 25 A compound of Embodiment 24 wherein R 2 is C j -C 3 alkyl.
  • Embodiment 26 A compound of Embodiment 25 wherein R 2 is methyl.
  • Embodiment 27 A compound of Formula I or any one of Embodiments 1 through 26 wherein each R 3a and R 3c is independently halogen, cyano, C j -C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C]-C 3 haloalkyl, cyclopropyl, C 1 -C3 alkoxy, C 1-C3 haloalkoxy, C] -C 3 alkylthio, C j -C 3 alkylamino, C2-C4 dialkylamino, C2-C4 alkylcarbonyl, C2-C alkoxycarbonyl, C2-C4 alkylcarbonylamino or -X-U-Z.
  • Embodiment 28 A compound of Embodiment 27 wherein each R 3a and R 3c is independently halogen, cyano, C j -C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C
  • Embodiment 29 A compound of Embodiment 28 wherein each R 3a and R 3c is
  • Embodiment 30 A compound of Embodiment 29 wherein each R 3a and R 3c is
  • Embodiment 30a A compound of Embodiment 30 wherein each R 3a and R 3c is
  • Embodiment 31 A compound of Formula 1 or any one of Embodiments 1 through 30a wherein each R 3b and R 3d is independently cyano, C ] -C3 alkyl, C3 alkenyl, cyclopropyl or C 2 -C 3 alkoxyalkyl.
  • Embodiment 31a A compound of Embodiment 31 wherein each R b and R 3a is methyl.
  • Embodiment 32. A compound of Formula 1 or any one of Embodiments 1 through 31a wherein each X is independently O or NR. 6 .
  • Embodiment 33 A compound of Embodiment 32 wherein eaeh X is independently O or
  • Embodiment 34 A compound of Formula 1 or any one of Embodiments 1 through 33 wherein each U is C2-C alkylene.
  • Embodiment 35 A compound of Formula 1 or any one of Embodiments 1 through 34 wherein each Z is independently NR 7a R 7b or OR 8 .
  • Embodiment 36 A compound of Formula 1 or any one of Embodiments 1 through 35 wherein each R 7a and R 7b is independently H, C j -C 6 alkyl or C ] -Cg haloalkyl.
  • Embodiment 37 A compound of Formula 1 or any one of Embodiments 1 through 36 wherein each R 8 is independently H, C1-C6 alkyl or C j -C 6 haloalkyl.
  • Embodiment 38 A compound of Formula 1 or any one of Embodiments 1 through 37 wherein independently when an instance of R 5a is not taken together with the carbon atom to which the instance of R 5a is attached and a geminal instance of
  • R 5b to form a carbocyclic ring i.e. R 5a is taken alone
  • the instance of R 5a is independently H, cyano or methyl.
  • Embodiment 39 A compound of Embodiment 38 wherein the instance of R 5a is
  • Embodiment 40 A compound of Embodiment 39 wherein the instance of R 5a is H.
  • Embodiment 41 A compound of Formula 1 or any one of Embodiments 1 through 40 wherein independently when an instance of R 5b is not taken together with the carbon atom to which the instance of R 5b is attached and a geminal instance of
  • R 5a to form a carbocyclic ring i.e. R 5b is taken alone
  • the instance of R 5b is independently H or methyl
  • Embodiment 42 A compound of Embodiment 41 wherein the instance of R 5b is H.
  • Embodiment 43 A compound of Formula 1 or any one of Embodiments 1 through 42 wherein when a pair of R 5a and R 5b attached to the same carbon atom are taken together with the carbon atom to form a carbocyclic ring, the ring is a
  • Embodiment 44 A compound of Formula 1 or any one of Embodiments 1 through 42 wherein each pair of R 5a and R 5b attached to the same carbon atom are not taken together to form a carbocyclic ring (i.e. R 5a and R 5b are taken alone).
  • Embodiment 45 A compound of Formula 1 or any one of Embodiments 1 through 44 wherein R 5c is H or methyl.
  • Embodiment 46 A compound of Embodiment 45 wherein R 5c is H.
  • Embodiments of this invention including Embodiments 1-46 above as well as any other embodiments described herein, can be combined in any manner, and the descriptions of variables in the embodiments pertain not only to the compounds of Formula 1 but also to the starting compounds and intermediate compounds useful for preparing the compounds of Formula 1.
  • embodiments of this invention including Embodiments 1-46 above as well as any other embodiments described herein, and any combination thereof, pertain to the compositions and methods of the present invention.
  • Embodiment AL A compound of Formula 1 wherein
  • Y is O
  • Q 1 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 3a ; or a 5- to 6-membered fully unsaturated heterocyclic ring containing ring members selected from carbon atoms and 1 to .3 heteroatoms independently selected from up to 2 O, up to 2 S and up to
  • W 1 is a phenyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazolyl ring optionally substituted with up to 3 substituents independently selected from R 3a on carbon atom ring members and R 3b on nitrogen atom ring members;
  • Q 2 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 3c ; or a 5- to 6-membered fully unsaturated heterocyclic ring containing ring members selected from carbon atoms and 1 to 3 heteroatoms independently selected from up to 2 O, up to 2 S and up to
  • W 2 is a phenyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazolyl ring optionally substituted with up to 3 substituents independently selected from R 3c on carbon atom ring members and R 3d on nitrogen atom ring members;
  • R 1 is H, halogen, C r C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C r C 3
  • haloalkyl C2-C3 haloalkenyl, C 3 -C 6 cycloalkyl, C j -C 3 alkoxy, C j -C 3 alkylthio, C C 3 alkylamino, C 2 -C 4 dialkylamino or C j -C 3 hydroxy alkyl;
  • R 2 is cyano, C j -C 3 alkyl, C 3 alkenyl, cyclopropyl or C j -C 3 hydroxyalkyl; each R 3b and R 3d is methyl;
  • each R 5a is independently H, cyano or methyl
  • each R 5b is independently H or methyl
  • R 5c is H or methyl.
  • Embodiment A2 A compound of Embodiment Al wherein
  • Q 1 is a phenyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazolyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 3 substituents independently selected from R 3a on carbon atom ring members and R 3b on nitrogen atom ring members; or C(R 5a R 5b )W>;
  • W 1 is a phenyl or pyridinyl ring optionally substituted with up to 3 substituents independently selected from R 3a ;
  • Q 2 is a phenyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazolyl ring or a naphthalenyl ring system, each ring or ring system optionally. substituted with up to 3 substituents independently selected from R 3c on carbon atom ring members and R 3d on nitrogen atom ring members; or C(R5a R 5b) W 2 ;
  • W 2 is a phenyl or pyridinyl ring optionally substituted with up to 3 substituents independently selected from R 3c ;
  • each R 3a and R 3c is independently halogen, cyano, C j -C 3 alkyl, C 2 -C 3
  • dialkylamino C 2 -C 4 alkylcarbonyl, C2-C4 alkoxycarbonyl, C 2 -C 4 alkylcarbonylamino or -X-U-Z;
  • X is O or NH;
  • U is C2-C4 alkylene;
  • Z is NR 7a R 7b or OR 8 ;
  • each R 5a is independently H or methyl
  • each R 7a and R 7b is independently H, C ⁇ -C 6 alkyl or C Cg haloalkyl; and each R 8 is independently H, C Cg alkyl or C j -C 6 haloalkyl.
  • Embodiment A3 A compound of Embodiment A2 wherein
  • Q' is a phenyl or pyridinyl ring optionally substituted with up to 3
  • Q 2 is a phenyl or pyridinyl ring optionally substituted with up to 3
  • R 1 is H, halogen, cyano or C j -C 3 alkyl
  • R 2 is C r C 3 alkyl.
  • Embodiment A4 A compound of Embodiment A3 wherein
  • each R 3a and R 3c is independently halogen, cyano, C1-C3 * alkyl, C1-C3
  • haloalkyl C1-C3 alkoxy or C 1 -C3 haloalkoxy.
  • Embodiment A5 A compound of Embodiment A4 wherein
  • R 1 is independently CI, Br, I or C j -C 2 alkyl
  • R 2 is methyl
  • each R 3a and R 3c is independently Br, CI, F. cyano, C j -C 2 alkyl, C C2
  • Specific embodiments include compounds of Formula 1 selected from the group consisting of:
  • 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.
  • compositions comprising a compound corresponding to any of the compound embodiments described above.
  • This invention provides a fungicidal composition
  • a compound of Formula 1 comprising a compound of Formula 1
  • 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).
  • a compound of Formula 1 including all stereoisomers, N-oxides, and salts thereof.
  • 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.
  • halogenating reagents known in the art are suitable for this method including, for example, N-halosuccinimides (e.g., NBS, NCS, NIS), elemental halogen (e.g., CI2, Br 2 , 1 ⁇ 2), phosphorus oxyhalides, phosphorus trihalides, phosphorus pentahalides, thionyl chloride, sulfuryl chloride, bis(pyridine)iodonium(I) tetrafluoroborate, tetramethylammonium iodide chloride, tetrafluoroborate and sulfur tetrafluoride.
  • N-halosuccinimides e.g., NBS, NCS, NIS
  • elemental halogen e.g., CI2, Br 2 , 1 ⁇ 2
  • phosphorus oxyhalides e.g., phosphorus trihalides
  • phosphorus pentahalides e.g., thionyl chloride, sulfury
  • reaction is carried out in a suitable solvent such as NN-dimethylformamide, carbon tetrachloride, acetonitrile, dichloromethane, acetic acid, chloroform, benzene, xylenes, chlorobenzene, tetrahydrofuran, /?-dioxane, or the like.
  • a suitable solvent such as NN-dimethylformamide, carbon tetrachloride, acetonitrile, dichloromethane, acetic acid, chloroform, benzene, xylenes, chlorobenzene, tetrahydrofuran, /?-dioxane, or the like.
  • a suitable solvent such as NN-dimethylformamide, carbon tetrachloride, acetonitrile, dichloromethane, acetic acid, chloroform, benzene, xylenes, chlorobenzene, tetrahydrofuran
  • compounds of Formula la wherein R 1 is nitro (-NO2) can be prepared from compounds of Formula lb by nitration.
  • Compounds of Formula la wherein R 1 is nitro (-NO2) can be converted into the amino (-NH2) analog by catalytic reduction.
  • Nitration can be accomplished according to well-known methods such as treating a compound of Formula lb with nitric acid, a mixture of nitric acid and sulfuric acid or a mixture of nitric acid and trifluoroacetic anhydride.
  • Reduction of the nitro group can be done via hydrogenation in the presence of a metal catalyst such as palladium supported on an inert carrier such as activated carbon.
  • R' is alkyl
  • alkenyl alkynyl, or the like
  • R 1 is halogen
  • Scheme 2 a compound of Formula la wherein R 1 is halogen can be reacted with a compound of formula R'M 1 in the presence of a palladium, copper or nickel catalyst to provide a compound of Formula la wherein R 1 is alkyl, alkenyl, alkynyl, or the like.
  • compounds of formula R'Ml are organoboronic acids (e.g., M 1 is B(OH)2), organoboronic esters (e.g., M' is Bi-OQCF ⁇ QCF ⁇ O-)), organotrifluoroborates (e.g., M 1 is BF3 ), organotin reagents (e.g., M 1 is Sn(n-Bu) 3 , Sn(Me) 3 ), Grignard reagents (e.g., M 1 is gX 1 ) or organozinc reagents (e.g., M 1 is ZnX 1 ) wherein X 1 is Br or CI.
  • organoboronic acids e.g., M 1 is B(OH)2
  • organoboronic esters e.g., M' is Bi-OQCF ⁇ QCF ⁇ O-
  • organotrifluoroborates e.g., M 1 is BF3
  • organotin reagents e
  • Suitable transition metal catalysts include, but are not limited to: palladium(II) acetate, palladium(II) chloride, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, dichloro[l,r-bis(diphenylphosphino)ferrocene]palladium(H), bis(triphenyl- phosphine)dichloronickel(II) and copper(i) salts (e.g., copper(I) iodide, copper(I) bromide, copper(I) chloride, copper(I) cyanide or copper(I) triflate).
  • palladium(II) acetate palladium(II) chloride
  • tetrakis(triphenylphosphine)palladium(0) bis(triphenylphosphine)palladium(II) dichloride, dichloro[l
  • Example 4 illustrates the synthesis of a compound of Formula la wherein R 1 is methyl from the corresponding compound wherein R 1 is bromo.
  • transition metal-catalyzed cross coupling reactions are also useful for preparing compounds of Formula la wherein R 1 is alkyl, alkenyl, alkynyl, or the like including, for example, reaction of a terminal alkyne with Formula la wherein R 1 is halogen using Sonogashira reaction conditions as shown in Scheme 2.
  • the reaction typically involves the use of two catalysts, a zero-valent palladium complex (or one that can be reduced to Pd(0) in situ) and a halide salt of copper(I).
  • Useful catalysts for this type of transformation include tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)- palladium(II) chloride, dichlorobis(tri-o-tolylphosphine)palladium, copper(I) iodide, copper(I) bromide and copper(I) chloride.
  • Suitable solvents include amines (e.g., triethylamine or diethylamine), or solvents such as tetrahydrofuran, acetonitriie, ethyl acetate and N.N-dimethylformamide used in combination with a large excess of a base including, for example, triethylamine, diethylamine, potassium carbonate or cesium carbonate.
  • amines e.g., triethylamine or diethylamine
  • solvents such as tetrahydrofuran, acetonitriie, ethyl acetate and N.N-dimethylformamide used in combination with a large excess of a base including, for example, triethylamine, diethylamine, potassium carbonate or cesium carbonate.
  • R 1 ⁇ is portion of R 1 other wherein R 1 is alkyl, alkenyl, wherein R is halogen
  • compounds of Formula lb can be lithiated by treatment with «-butyllithium (M-BuLi) followed by treatment of the anion with an organotin reagent (e.g., «-Bu3SnCl, Me 3 SnCl), a boronic acid (or ester) or an organozinc reagent (e.g., ZnC1 ⁇ 2) to provide compounds of Formula 2 as illustrated in Scheme 3.
  • organotin reagent e.g., «-Bu3SnCl, Me 3 SnCl
  • a boronic acid or ester
  • an organozinc reagent e.g., ZnC1 ⁇ 2
  • catalysts for this method include bis(triphenylphosphine)palladium (II) dichloride, tetrakis(triphenyl- phosphine)palladium(O) and tris(dibenzylideneacetone)dipalladium(0).
  • M 2 is (alkyl) 3 Sn, wherein R 1 is alkyl, alkenyl,
  • preparation of the lithium derivative of Formula 2 precludes the presence of other functionalities (e.g., esters and cyano groups).
  • a magnesium derivative of Formula 2 which can be generated from Formula la wherein R 1 is halogen (preferably iodo) and a Grignard reagent such as i-propylmagnesium bromide according to the procedure given by Knochel et al., Synlett 2000, (3), 345-346; Knochel et al., Synthesis 2005, (75), 2625-2629 and Knochel et al., Journal of Organic Chemistry 2000 65(15), 4618-4634.
  • a suitable base e.g., sodium hydride, potassium t-butoxide, potassium carbonate or triethylamine
  • a palladium, nickel or copper catalyst e.g., tris(dibenzylideneacetone)dipalladium, palladium(II) acetate, bis(l ,5-cyclooctadiene)nickel or copper(I) iodide
  • a ligand e.g., l,l'-bis(diphenylphosphino)ferrocene, l,3-bis(diphenylphosphino)propane, 2,2'- bis(diphenylphosphirio)-l,l'-binaphthalene, l ,l'-binaphthalene-2,2'-diol or 1,1,1-tris- (hydroxymethyl)ethane) in a solvent such as methanol, acetonit
  • a solvent such as methanol
  • R 1 is halogen wherein R* is alkoxy, alkylthio, aikylamino, or the like
  • compounds of Formula la wherein R 1 is alkoxy can be prepared as outlined in Scheme 5.
  • a compound of Formula la wherein R 1 is halogen is first hydrolyzed with potassium hydroxide in an appropriate solvent such as toluene or methanol and in the presence of a phase transfer catalyst (e.g., benzyltrimethylammonium hydroxide) to provide the hydroxide compound of Formula 3.
  • a phase transfer catalyst e.g., benzyltrimethylammonium hydroxide
  • a suitable copper source e.g., copper(I) iodide
  • an amine ligand e.g., N ⁇ V-dimethylethylenediamine
  • an iodide salt e.g., copper(I) iodide, sodium iodide, potassium iodide or zinc iodide.
  • compounds of Formula la wherein R' is halogen can be used to prepare the corresponding compounds of Formula la wherein R' is thiocyanate (-SCN).
  • Typical conditions involve. contacting the halide of Formula la with a thiocyanating agent such as ammonium thiocyanate or K[Cu(SCN)2] (generated in situ from equimolar amounts of copper(I) thiocyanate and potassium thiocyanate).
  • the reaction can be carried out in a solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, 1 ,4-dioxane, ethanol or dimethylsulfoxide at a temperature between about room temperature (e.g., 20 °C) and the reflux temperature of the solvent.
  • a solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, 1 ,4-dioxane, ethanol or dimethylsulfoxide
  • room temperature e.g. 20 °C
  • the reaction can also be carried put at higher temperatures using a microwave reactor.
  • Suzuki et al. Synthetic Communications 1996, 2(5(18), 3413-3419
  • Yamamoto et al. Chemical & Pharmaceutical Bulletin 1964, 12(4), 433-440
  • Gakhar et al. Journal of Indian Chemical Society 1 74, 57(1 1), 941-943.
  • compounds of Formula l b can be prepared via a sequential condensation-ring closure reaction of a ⁇ -ketoester of Formula 4 and a hydrazine of formula R'NHNHQ 2 .
  • the reaction is typically conducted in an appropriate solvent (e.g., acetonitrile, methanol, ethanol, toluene, pyridine) at a temperature between about room temperature (e.g., 20 °C) and 200 °C, optionally in the presence of an acid such as /7-toluenesulfonic acid, acetic acid or formic acid.
  • an appropriate solvent e.g., acetonitrile, methanol, ethanol, toluene, pyridine
  • the reaction can also be conducted using a microwave reactor, which in some cases may reduce reaction time.
  • R is Me or Et lb
  • Example 1 illustrate a method for preparing a ⁇ -ketoester of Formula 4; and Example 1 , Steps C-D illustrate a method for preparing a hydrazine of formula R'NHNHQ 2 .
  • compounds of Formula lb can be prepared via the two step synthesis shown in Scheme 7. Using conditions analogous to those described for Scheme 6, ⁇ -ketoesters of Formula 4 are reacted with hydrazines of formula R'NHNH 2 to form intermediates of Formula 5.
  • ⁇ -ketoesters of Formula 4 are reacted with hydrazines of formula R'NHNH 2 to form intermediates of Formula 5.
  • hydrazines of formula R'NHNH 2 for relevant references see Katrizky et al., J. Chem. Soc. Perkin Trans. II 1987, 969-975; Muller et al., Monatshefte fuer Chemie 1958, 89, 23-35; PCT Patent Application Publication WO 2006/116713 and U.S. Patent Application Publication US 2007/0049574.
  • compounds of Formula lb are prepared via the two-step synthesis shown in Scheme 8.
  • alkynoic esters of Formula 6 are reacted with hydrazines of formula Q'NHNF ⁇ in the presence of a base (e.g., sodium hydroxide or potassium hydroxide) in a solvent such as methanol, ethanol or r/-butanol to provide intermediates of Formula 7 according to the procedure disclosed in PCT Patent Application Publication WO 2008/144463 and U.S. Patent Application Publication US 2007/0049574.
  • a base e.g., sodium hydroxide or potassium hydroxide
  • Intermediates of Formula 7 can then be reacted with halides of formula R 2 X 2 to provide compounds of Formula lb wherein R 2 is alkyl, alkenyl, alkynyl, or the like.
  • Typical reactions conditions involve combining a compound of Formula 7 with R 2 X 2 in a solvent (e.g., N ⁇ V-dimethylformamide, methyl sulfoxide or acetone), in the presence of a base (e.g., potassium carbonate, sodium carbonate, /er/-butoxide, sodium hydroxide or potassium hydroxide) and optionally in the presence of a phase transfer catalyst.
  • a solvent e.g., N ⁇ V-dimethylformamide, methyl sulfoxide or acetone
  • a base e.g., potassium carbonate, sodium carbonate, /er/-butoxide, sodium hydroxide or potassium hydroxide
  • phase transfer catalyst e.g., potassium carbonate, sodium carbonate, /er/-but
  • intermediates of Formulae 5 and 7 are also useful for preparing intermediates of Formulae 8 and 9, which can then be converted to compounds of Formula la.
  • compounds of Formulae 8 and 9 can be obtained from Formulae 5 and 1.
  • compounds of Formulae 8 and 9 can be converted to compounds of Formula la.
  • Compounds of Formula 1 wherein Y is O can be converted to the corresponding thioamides wherein Y is S 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).
  • 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).
  • R 3a , R 3b , R 3c and/or R 3d substituents attached to the rings and ring systems of Q 1 and Q 2 may be more conveniently incorporated after forming the central pyrazolone ring with Qj and Q 2 attached.
  • R 3a , R 3b , R 3c and or R 3d is halogen or another suitable leaving group
  • the leaving group can be replaced using various electrophilic, nucleophilic and organometallic reactions known in the art to introduce other functional groups as R 3a , R 3b , R 3c and/or R 3d .
  • compounds of Formula 1 wherein a ring or ring system of Q J or Q 2 is substituted with an R 3a , R 3b , R 3c and/or R 3d substituent which is -X-U-Z can be prepared from the corresponding compounds of Formula 1 wherein R 3a , R 3b , R 3c and/or R 3d is a halogen or other suitable leaving group, such as by the general method described in PCT Patent Application Publication WO 07/149448 (see Scheme 15 therein).
  • This reference also describes other general methods for forming an R 3a , R 3b , R 3c and/or R 3d substituent as -X-U-Z (see Schemes 16—19 therein).
  • MS mass spectra
  • Step B Preparation of ethyl 2,6-difluoro-4-methoxy-P-oxobenzenepropanoate
  • reaction mixture was stirred for 5 h at room temperature and then cooled to 0 °C, and hydrochloric acid (1.5 N, 5 mL) was added.
  • the reaction mixture was diluted with water, the layers were separated, and the aqueous layer was extracted with ter/-butyl methyl ether.
  • the combined organic layers were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • the resulting material was purified by silica gel column chromatography (10% /er/-butyl methyl ether in petroleum ether as eluant) to provide the title compound as an oil (2.0 g).
  • Step D Preparation of 1 -(4-chlorophenyl)-2-methylhydrazine
  • Step E Preparation of l-(4-chlorophenyl)-5-(2,6-difluoro-4-methoxyphenyl)- 1 ,2- dihydro-2-methyl-3H-pyrazol-3-one
  • the reaction mixture was diluted with ethyl acetate, the layers were separated, and the organic layer was washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether as eluant) to provide the title compound, a compound of the present invention, as a brown solid (0.15 g).
  • Q 2 is 4-Cl-Ph and R 1 is CI.
  • Q 2 is 4-Cl-Ph and R 1 is CI;
  • the present disclosure also includes Tables 1A through 299 A, each of which is constructed the same as Table 1 above except that the row heading in Table 1 (i.e. "Q 2 is 4-Cl-Ph and R 1 is CI") is replaced with the respective row heading shown below.
  • Table 1A the row heading is "Q 2 is 4-Cl-Ph and R 1 is H”
  • (R 3a ) m is as defined in Table 1 above.
  • Table l A specifically discloses l-(4- chlorophenyl)-l,2-dihydro-5-[(2-trifluoromethyl)phenyl)]-2-methyl-3H-pyrazol-3-one.
  • Tables 2A through 299A are constructed similarly.
  • Q 2 s 2-CI, 4-F-Ph and R 1 is CH 2 F.
  • R 1 is H.
  • 81A Q 2 is 3-Cl, 4-F-Ph and R 1 is CI.
  • 82A Q 2 is 3-Cl, 4-F-Ph and R 1 is Br.
  • 83A Q 2 is 3-Cl, 4-F-Ph and R 1 is Me.
  • Q 2 is 6-MeO-3-pyridinyI and R' is H.
  • 87A Q 2 is 6-MeO-3-pyridinyl and R1 is Br.
  • 91A Q 2 is 6-Cl-3-pyridinyl and R 1 is CI.
  • 92A Q 2 is 6-Cl-3-pyridinyl and R 1 is Br.
  • Q 2 is 6-CF 3 -3-pyridinyl and R 1 is H.
  • 96A Q 2 is 6-CF 3 -3-pyridinyl and R 1 is CI.
  • 99A Q 2 is 6-CF 3 -3-pyridinyl and R 1 is CH 2 F.
  • 100A Q 2 is 6-Br-3-pyridinyl and R 1 is H.
  • Q 2 is 6-Br-3-pyridinyl and R 1 is CI.
  • Q 2 is 6-Br-3-pyridinyl and R' is Br.
  • 104A Q 2 is 6-Br-3-pyridinyl and R' is CH 2 F.
  • Q 2 is 6-Me-3-pyridinyl and R' is CI.
  • Q 2 is 6-Me-3-pyridiny) and R ⁇ is Br.
  • Q 2 is 6-Me-3-pyridinyl and R' is CH 2 F.
  • Q 2 is 6-F-3-pyridinyl and R' is Br.
  • Q 2 is 6-F-3-pyridinyl and R' is Me.
  • Q 2 is 6-F-3-pyridinyl and R 1 is CH 2 F.
  • 1 15A Q 2 is 2-Cl, 6-Me-4-pyridinyl and R 1 is H.
  • 1 16A Q 2 is 2-Cl, 6-Me-4-pyridinyl and R 1 is CI.
  • 1 17A Q 2 is 2-Cl, 6-Me-4-pyridinyl and R 1 is Br.
  • 1 18A Q 2 is 2-Cl, 6-Me-4-pyridinyl and R' is Me.
  • 1 19A Q 2 is 2-Cl, 6-Me-4-pyridinyl and R 1 is CH 2 F.
  • 120A Q 2 is 2-Cl, 6-MeO-3-pyridinyl and R 1 is H.
  • 121 A Q 2 is 2-Cl, 6-MeO-3-pyridinyI and R 1 is CI.
  • a Q 2 is 2-Cl, 6-MeO-3-pyridinyl and R 1 is Br. .
  • 123A Q 2 is 2-Cl, 6-MeO-3-pyridinyl and R 1 is Me.
  • Table Row Heading 124A Q 2 s 2-Cl, 6-MeO-3-pyridinyl and R 1 is CH 2 F.
  • 125A Q 2 s 2-Cl, 6-CF 3 -3-pyridinyt and R 1 is H.
  • 126A Q 2 s 2-Cl, 6-CF3-3-pyridinyl and R 1 is CI.
  • a Q 2 s 2-Cl, 6-CF 3 -3-pyridinyl and R 1 is Me.
  • 129A Q 2 s 2-Cl, 6-CF 3 -3-pyridinyl and R 1 is CH 2 F.
  • 130A Q 2 s 5-Cl-3-pyridinyl and R ⁇ is H.
  • 149A Q 2 s 5-MeO-3-pyridinyl and R 1 is CH 2 F.
  • 150A Q 2 s 6-CI, 5-MeO-3-pyridinyl and R 1 is H.
  • 151A Q 2 s 6-Cl, 5-MeO-3-pyridinyl and R 1 is CI.
  • 152 A Q 2 s 6-Cl, 5-MeO-3-pyridinyl and R 1 is Br.
  • 153A Q 2 s 6-Cl, 5-MeO-3-pyridinyl and R' is Me.
  • Q 2 s 6-Cl-3-pyridazinyl and R 1 is CH2F.
  • Q 2 is 6-MeO-3-pyridazinyI and R ⁇ is H.
  • Q 2 s 6-MeO-3-pyridazinyl and R ⁇ is CI.
  • Q 2 s 6-MeO-3-pyridazinyl and R* is Br.
  • Q 2 s 6-MeO-3-pyridazinyl and R ⁇ is Me.
  • Q 2 is 6-MeO-3-pyridazinyl and R 1 is CH2F.
  • Q 2 s 6-CF3-3-pyridazinyI and R' is H.
  • Q 2 s 6-CF3-3-pyridazinyl and R ⁇ is Me.
  • Q 2 is 6-CF3-3-pyridazinyl and R ⁇ is CH2F.
  • Q 2 s 5-Cl-3-pyridazinyl and R 1 is H.
  • Q 2 s 5-Cl-3-pyridazinyl and R 1 is CH 2 F.
  • Q 2 s 5-F-3-pyridazinyl and R ' is H.
  • Q 2 s 5-F-3-pyridazinyl and R ' is CH2F.
  • Q 2 s 5-MeO-3-pyridazinyl and R ⁇ is H.
  • Q 2 s 5-MeO-3-pyridazinyl and R' is CI.
  • Q 2 s 5-MeO-3-pyridazinyI and R ⁇ is Br.
  • Q 2 s 5-MeO-3-pyridazinyl and R' is Me.
  • Q 2 s 5-MeO-3-pyridazinyl and R ⁇ is CH2F.
  • Q 2 s 2-Cl-5-pyrimidinyl and R' is H.
  • Q 2 s 2-Cl-5-pyrimidinyl and ⁇ is CH2F.
  • Q 2 s 2-Me-5-pyrimidiny] and R ⁇ is H.
  • Q 2 is 2-Me-5-pyrimidinyl and R* is Me.
  • a Q 2 is 2-Me-5-pyrimidinyl and R* is CH2F.
  • 207A Q 2 is 5-Cl-2-pyrimidinyl and R ⁇ is Br.
  • Q 2 is 5-MeO-2-pyrimidinyl and R ' is Me.
  • Q 2 is 5-Me-3-thienyl and R 1 is Br.
  • Q 2 is 5-Cl-3-thienyl and R 1 is Br.
  • 256A Q 2 is 5-F-3-thienyl and R 1 is CI.
  • Q 2 is 4-F-Bn and R 1 is CH 2 F.
  • Q 1 is 4-Cl-Ph and
  • the present disclosure also includes Tables IB through 299B, each of which is constructed the same as Table 2 above except that the row heading in Table 2 (i.e. "Q 1 is 4-Cl-Ph and R 1 is CI") is replaced with the respective row heading shown below.
  • Table IB the row heading is "Q 1 is 4-Cl-Ph and R 1 is H”
  • (R 5b ) m is as defined in Table 2 above.
  • the first entry in Table IB specifically discloses 5-(4- chlorophenyl)-l,2-dihydro-l-[(2-trifluoromethyl)phenyl)]-2-methyl-3H-pyrazol-3-one.
  • Tables 2B through 299B are constructed similarly.
  • IB Q 1 is 4-Cl-Ph and R' is H.
  • Q 1 is 3-F-Ph and R 1 is Me.
  • 34B Q 1 is 3,4-di-F-Ph and R 1 is CH 2 F.
  • 35B Q 1 is 3,4-di-Cl-Ph and R 1 is H.
  • 40B Q 1 is 3,5-di-MeO-Ph and R 1 is H.
  • Q 1 is 2-Cl, 3,5-di-MeO-Ph and R 1 is H.
  • Q 1 is 2-Cl, 3,5-di-MeO-Ph and R 1 is CI.
  • Q 1 is 2-Cl, 3,5-di-MeO-Ph and R 1 is Me.
  • Q 1 is 2-Cl, 3,5-di-MeO-Ph and R 1 is CH 2 F.
  • 50B Q 1 is 4-Cl, 3,5-di-MeO-Ph and R 1 is H.
  • Q 1 is 4-Cl, 3,5-di-MeO-Ph and R 1 is CI.
  • Q 1 is 4-Cl, 3,5-di-MeO-Ph and R 1 is Me.
  • Q* is 4-Cl, 3,5-di-MeO-Ph and R 1 is CH 2 F.
  • Q 5 is 4-CHF 2 0-Ph and R 1 is H.
  • Q 1 is 4-CHF 2 0-Ph and R 1 is CI.
  • 57B Q 1 is 4-CHF 2 0-Ph and R 1 is Br.
  • 58B Q' is 4-CHF 2 0-Ph and R 1 is Me.
  • 59B Q 1 is 4-CHF 2 0-Ph and R 1 is CH 2 F.
  • 60B Q 1 is 3-CHF 2 0-Ph and R 1 is H.
  • 61B Q 1 is 3-CHF 2 0-Ph and R 1 is CI.
  • 62B Q 1 is 3-CHF 2 0-Ph and R 1 is Br.
  • 63B Q 1 is 3-CHF 2 0-Ph and R 1 is Me.
  • 64B Q 1 is 3-CHF 2 0-Ph and R 1 is CH 2 F.
  • 65B Q 1 is 4-F-Ph and R 1 is H.
  • 66B Q 1 is 4-F-Ph and R 1 is CI.
  • 67B Q 1 is 4-F-Ph and R 1 is Br.
  • 70B Q 1 is 4-Me-Ph and R 1 is H.
  • 74B Q 1 is 4-Me-Ph and R 1 is CH 2 F.
  • 76B Q 1 is 4-Cl, 3-F-Ph and R 1 is CI.
  • 77B Q 1 is 4-Cl, 3-F-Ph and R 1 is Br.
  • 78B Q 1 is 4-Cl, 3-F-Ph and R 1 is Me.
  • 79B Q 1 is 4-Cl, 3-F-Ph and R 1 is CH 2 F.
  • 80B Q 1 is 3-Cl, 4-F-Ph and R 1 is H.
  • 82B Q 1 is 3-Cl, 4-F-Ph and R 1 is Br.
  • 83B Q 1 is 3-Cl, 4-F-Ph and R 1 is Me.
  • Q 1 is 6-MeO-3-pyridinyl and R' is H.
  • 87B Q 1 is 6-MeO-3-pyridinyl and R' is Br.
  • 88B Q 1 is 6-MeO-3-pyridinyl and R' is Me.
  • 89B Q 1 is 6-MeO-3-pyridinyl and R 1 is CH 2 F.
  • 90B Q 1 is 6-Cl-3-pyridinyl and R' is H.
  • 91B Q 1 is 6-Cl-3-pyridinyl and R' is CI.
  • 92B Q 1 is 6-Cl-3-pyridinyl and R' is Br.
  • Q 1 is 6-CF3-3-pyridinyl and R' is H.
  • 96B Q 1 is 6-CF3-3-pyridinyl and R' is CI.
  • 97B Q 1 is 6-CF3-3-pyridinyl and R' is Br.
  • 98B Q 1 is 6-CF3-3-pyridinyl and R' is Me.
  • 99B Q' is 6-CF 3 -3-pyridinyl and R 1 is CH 2 F.
  • 100B Q 1 is 6-Br-3-pyridinyl and R* is H.
  • 101B Q 1 is 6-Br-3-pyridinyl and R' is CI.
  • 102B Q 1 is 6-Br-3-pyridinyl and R' is Br.
  • 103B Q 1 is 6-Br-3-pyridinyl and R' is Me.
  • 104B Q 1 is 6-Br-3-pyridiny! and R 1 is CH 2 F,
  • 105B Q 1 is 6-Me-3-pyridihyl and R' is H.
  • 106B Q 1 is 6-Me-3-pyridinyl and R ' is CI.
  • 107B Q 1 is 6-Me-3-pyridinyl and R ' is Br.
  • HOB Q is 6-F-3-pyridinyl and Rl is H.
  • 1 15B Q is 2-Cl, 6-Me-4-pyridinyl and R 1 is H.
  • 1 16B Q is 2-CI, 6-Me-4-pyridinyl and R 1 is CI.
  • 1 17B Q is 2-Cl, 6-Me-4-pyridiny] and R* is Br.
  • 1 18B Q is 2-C), 6-Me-4-pyridinyl and R' is Me.
  • 119B Q is 2-Cl, 6-Me-4-pyridinyl and R 1 is CH 2 F.
  • 120B Q is 2-Cl, 6-MeO-3-pyridinyl and R 1 is H.
  • 121 B Q is 2-Cl, 6-MeO-3-pyridinyl and R 1 is CI.
  • 122B Q is 2-Cl, 6-MeO-3-pyridinyl and R 1 is Br.
  • 123B Q is 2-Cl, 6-MeO-3-pyridin I and R' is Me.
  • 124B Q is 2-Cl, 6-MeO-3-pyridinyl and R 1 is CH 2 F.
  • 125B Q s 2-Cl, 6-CF 3 -3-pyridinyI and R 1 is H.
  • 126B Q s 2-Ci, 6-CF 3 -3-pyridinyl and R 1 is CI.
  • 129B Q s 2-Cl, 6-CF 3 -3-pyridinyl and R 1 is CH 2 F.
  • 130B Q is 5-Cl-3-pyridinyl and R' is H.
  • 134B Q is 5-Cl-3-pyridinyl and R 1 is CH 2 F.
  • 142B Q is 5-Me-3-pyridinyl and R' is Br.
  • 144B is 5-Me-3-pyridinyl and R 1 is CH2F.
  • 145B is 5-MeO-3-pyridinyI and R 1 is H.
  • 146B is 5-MeO-3-pyridinyl and R 1 is CI.
  • 147B is 5-MeO-3-pyridinyl and R ⁇ is Br.
  • 148B is 5-MeO-3-pyridinyl and R' is Me.
  • 149B is 5-MeO-3-pyridinyl and R 1 is CH 2 F.
  • 150B is 6-CJ, 5-MeO-3-pyridinyl and R 1 is H.
  • 151B is 6-CI, 5-MeO-3-pyridinyl and R 1 is CI.
  • 152B is 6-Cl, 5-MeO-3-pyridinyl and R 1 is Br.
  • 153B is 6-Cl, 5-MeO-3-pyridinyl and R ⁇ is Me.
  • 154B is 6-Cl, 5-MeO-3-pyridinyl and R 1 is CH2F.
  • 155B is 6-Cl-3-pyridazinyI and R' is H.
  • 156B is 6-CI-3-pyridazinyl and R ⁇ is CI.
  • 158B is 6-Cl-3-pyridazinyI and R ⁇ is Me.
  • 159B is 6-Cl-3-pyridazinyI and R ! is CH 2 F.
  • 160B s 6-MeO-3-pyridazinyI and R ⁇ is H.
  • 162B s 6-MeO-3-pyridazinyl and R' is Br.
  • 163B s 6-MeO-3-pyridazinyl and Rl is Me.
  • 164B is 6-MeO-3-pyridazinyl and R ⁇ is CH2F.
  • 165B s 6-CF3-3-pyridazinyI and R' is H.
  • 166B is 6-CF3-3-pyridazinyl and R' is CI.
  • 167B is 6-CF3-3-pyridazinyl and R' is Br.
  • 168B is 6-CF3-3-pyridazinyl and R ⁇ is Me.
  • I69B is 6-CF3-3-pyridazinyl and R ⁇ is CH2F.
  • 170B is 5-Cl-3-pyridazinyl and R' is H.
  • 171B is 5-Cl-3-pyridazinyl and R' is CI.
  • 172B is 5-Cl-3-pyridazinyl and R' is Br.
  • 173B is 5-CI-3-pyridazinyl and R ⁇ is Me.
  • 174B is 5-C)-3-pyridazinyl and R' is CH2F.
  • 175B is 5-F-3-pyridazinyI and R' is H.
  • 176B is 5-F-3-pyridazinyl and ' is CI.
  • 177B is 5-F-3-pytidazinyI and R ' is Br.
  • 178B is 5-F-3-pyridazinyl and R' is Me.
  • Table Row Heading 179B Q 1 is 5-F-3-pyridazinyl and R 1 is CH2F.
  • 180B Q 1 is 5-MeO-3-pyridazinyl and R is H.
  • 181B Q 1 s 5-MeO-3-pyridazinyl and R ⁇ is Cl.
  • 182B Q 1 s 5-MeO-3-pyridazinyl and R ⁇ is Br.
  • 183B Q 1 is 5-MeO-3-pyridazinyJ and is Me.
  • 184B Q 1 s 5-MeO-3-pyridazinyl and R* is CH2F.
  • 185B Q 1 s 2-CJ-5-pyrimidinyl and R 1 is H.
  • 189B Q 1 is 2-CJ-5-pyrimidinyi and R 1 is CH 2 F.
  • 190B Q 1 s 2-Me-5-pyrimidinyl and R' is H.
  • 193B Q l s'2-Me-5-pyrimidinyl and R' is Me.
  • 194B Q 1 s 2-Me-5-pyrimidinyl and R' is CH2F.
  • J95B Q 1 s 2-MeO-5-pyrimidinyl and R' is H.
  • 196B Q 1 is 2-MeO-5-pyrimidinyl and R' is Cl.
  • 197B Q 1 s 2-MeO-5-pyrimidinyl and R' is Br.
  • 198B Q 1 s 2-MeO-5-pyrimidinyl and R* is Me.
  • 199B Q 1 s 2-MeO-5-pyrimidinyI and R 5 is CH 2 F.
  • 200B Q' s 2-CF3-5-pyrimidinyl and R' is H.
  • 201B Q 1 s 2-CF3-5-pyrimidinyl and R ⁇ is Cl.
  • 202B Q 1 s 2-CF3-5-pyrimidinyl and R ⁇ is Br.
  • 203B Q 1 s 2-CF3-5-pyrimidinyl and R' is Me.
  • 204B Q 1 s 2-CF3-5-pyrimidinyl and R 1 is CH2F.
  • 205B Q 1 is 5-Cl-2-pyrimidinyl and R' is H.
  • 211B Q 1 is 5-Me-2-pyrimidinyl and R' is Cl.
  • 258B Q1 is 5-F-3-thienyl and R* is Me.
  • Q 1 is 2-Cl-5-thiazoIyl and R 1 is Br.
  • 289B Q 1 is 5-Cl-3-isothiazolyl and R 1 is CH 2 F.
  • 290B Q 1 s 4-Cl-Bn and R 1 is H.
  • R 1 is CI.
  • R 1 is Br.
  • R 1 is CI.
  • R l is Br.
  • a compound of Formula 1 of this invention (including N-oxides and salts thereof) 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.
  • a composition i.e. formulation
  • 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.
  • Liquid compositions include solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions and/or suspoemulsions) and the like, which optionally can be thickened into gels.
  • aqueous liquid compositions are soluble concentrate, suspension concentrate, capsule suspension, concentrated emulsion, microemulsion and suspo-emulsion.
  • nonaqueous liquid compositions are emulsifiable concentrate, microemulsifiable concentrate, dispersible concentrate and oil dispersion.
  • 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.
  • 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 ⁇ -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
  • Liquid diluents also include glycerol esters of saturated and unsaturated fatty acids (typically Cg-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.
  • plant seed and fruit oils e.g., oils of olive, castor, linseed, sesame, corn (maize), peanut, sunflower, grapeseed, safflower, cottonseed, soybean, rapeseed, coconut and palm kernel
  • animal-sourced fats e.g., beef tallow, pork tallow, lard, cod liver oil, fish oil
  • Liquid diluents also include alkylated fatty acids (e.g., methylated, ethylated, butylated) wherein the fatty acids may be obtained by hydrolysis of glycerol esters from plant and animal sources, and can be purified by distillation.
  • alkylated fatty acids e.g., methylated, ethylated, butylated
  • Typical liquid diluents are described in Marsden, Solvents Guide, 2nd Ed., Interscience, New York, 1950.
  • the solid and liquid compositions of the present invention often include one or more surfactants.
  • surfactants also known as “surface-active agents”
  • surface-active agents generally modify, most often reduce, the surface tension of the liquid.
  • surfactants can be useful as wetting agents, dispersants, emulsifiers or defoaming agents.
  • Nonionic surfactants useful for the present compositions include, but are not limited to: alcohol alkoxylates such as alcohol alkoxylates based on natural and synthetic alcohols (which may be branched or linear) and prepared from the alcohols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof; amine ethoxylates, alkanolamides and ethoxylated alkanolamides; alkoxylated triglycerides such as ethoxylated soybean, castor and rapeseed oils; alkylphenol alkoxylates such as octylphenol ethoxylates, nonylphenol ethoxylates, dinonyl phenol ethoxylates and dodecyl phenol ethoxylates (prepared from the phenols and ethylene oxide, propylene - oxide, butylene oxide or mixtures thereof); block polymers prepared from ethylene oxide or propylene - oxide, butylene oxide or mixtures thereof); block poly
  • Useful anionic surfactants include, but are not limited to: alkylaryl sulfonic acids and their salts; carboxylated alcohol or alkylphenol ethoxylates; diphenyl sulfonate derivatives; lignin and lignin derivatives such as lignosulfonates; maleic or succinic acids or their anhydrides; olefin sulfonates; phosphate esters such as phosphate esters of alcohol alkoxylates, phosphate esters of alkylphenol alkoxylates and phosphate esters of styryl phenol ethoxylates; protein-based surfactants; sarcosine derivatives; styryl phenol ether sulfate; sulfates and sulfonates of oils and fatty acids; sulfates and sulfonates of ethoxylated alkylphenols; sulfates of alcohols; sulfates of e
  • Useful cationic surfactants include, but are not limited to: amides and ethoxylated amides; amines such as N-alkyl propanediamines, tripropylenetriamines and dipropylenetetramines, and ethoxylated amines, ethoxylated diamines and propoxylated amines (prepared from the amines and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); amine salts such _as amine acetates and diamine salts; quaternary ammonium salts such as quaternary salts, ethoxylated quaternary salts and diquatemary salts; and amine oxides such as alkyldimethylamine oxides and bis-(2-hydroxyethyl)-alkylamine oxides.
  • amines such as N-alkyl propanediamines, tripropylenetriamines and dipropylenetetramines, and ethoxyl
  • 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 ai formulation aids (some of which may be considered to also function as solid diluents, liquid diluents or surfactants).
  • formulation auxiliaries and additives may control: pH (buffers), foaming during processing (antifoams such polyorganosiloxanes), sedimentation of active ingredients (suspending agents), viscosity (thixotropic thickeners), in-container microbial growth (antimicrobials), product freezing (antifreezes), color (dyes pigment dispersions), wash-off (film formers or stickers), evaporation (evaporation retardants), and other formulation attributes.
  • Film formers include, for example, polyvinyl acetates, polyvinyl acetate copolymers, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohols, polyvinyl alcohol copolymers and waxes.
  • formulation auxiliaries and additives include those listed in McCutcheon 's Volume 2: Functional Materials, annual International and North American editions published by McCutcheon's Division, The Manufacturing Confectioner Publishing Co.; and PCT Publication WO 03/024222.
  • the compound of Formula 1 and any other active ingredients are typically incorporated into the present compositions by dissolving the active ingredient in a solvent or by grinding in a liquid or dry diluent.
  • Solutions, including emulsifiable concentrates,. can be prepared by simply mixing the ingredients. If the solvent of a liquid composition intended for use as an emulsifiable concentrate is water-immiscible, an emulsifier is typically added to emulsify the active-containing solvent upon dilution with water.
  • Active ingredient slurries, with particle diameters of up to 2,000 ⁇ can be wet milled using media mills to obtain particles with average diameters below 3 ⁇ .
  • Aqueous slurries can be made into finished suspension concentrates (see, for example, U.S. 3,060,084) or further processed by spray drying to form water-dispersible granules. Dry formulations usually require dry milling processes, which produce average particle diameters in the 2 to 10 urn range. Dusts and powders can be prepared by blending and usually grinding (such as with a hammer mill or fluids-energy mill). Granules and pellets can be prepared by spraying the active material upon preformed granular carriers or by agglomeration techniques.
  • Pellets can be prepared as described in U.S. 4,172,714.
  • Water-dispersible and water-soluble granules can be prepared as taught in U.S. 4,144 ⁇ 050, U.S. 3,920,442 and DE 3,246,493.
  • Tablets can be prepared as taught in U.S. 5,180,587, U.S. 5,232,701 and U.S. 5,208,030.
  • Films can be prepared as taught in GB 2,095,558 and U.S.
  • Compound 3 65.0% dodecylphenol polyethylene glycol ether 2.0% sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0% montmorillonite (calcined) 23.0%
  • Compound 4 10.0% attapulgite granules (low volatile matter, 0.71/0.30 mm; 90.0% U.S.S. No..25-50 sieves)
  • Compound 12 25.0% anhydrous sodium sulfate 10.0% crude calcium ligninsulfonate 5.0% sodium alkylnaphthalenesulfonate 1.0% calcium/magnesium bentonite 59.0%
  • Compound 2 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 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.
  • This aspect of the present invention can also be described as a method for protecting a plant or plant seed from diseases caused by fungal pathogens comprising applying a fungicidally effective amount of a compound of the invention (e.g., as a composition described herein) to the plant (or portion thereof) or plant seed (directly or through the environment (e.g., growing medium) of the plant or plant seed).
  • 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.
  • 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.
  • Phytophthora diseases such as Phytophthora infestans, Phytophthora megasperma, Phytophthora parasitica, Phytophthora cinnamomi and Phytophthora capsici
  • Pythium diseases such as Pythium aphanidermatum
  • diseases in the Peronosporaceae family such as
  • Botrytis diseases such as Botrytis cinerea, Monilinia fructicola, Sclerotinia diseases such as Sclerotinia sclerotiorum, Magnaporthe grisea, Phomopsis viticola, Helminthosporium diseases such as Helminthosporium tritici repentis, Pyrenophora teres, anthracnose diseases such as Glomerella or Colletotrichum spp.
  • Puccinia spp. such as Puccinia recondita, Puccinia striiformis, Puccinia hordei, Puccinia graminis and Puccinia arachidis
  • Rutstroemia floccosum also known as Sclerontina homoeocarpa
  • compositions or combinations also have activity against bacteria such as Erwinia amylovora, Xanthomonas campestris, Pseudomonas syringae, and other related species.
  • 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, fruity 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.
  • Rates of application for these compounds 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.
  • 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.
  • 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
  • the present invention also pertains to a composition
  • 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.
  • 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.
  • compositions 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 (DM1) 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) fungicide
  • Methyl benzimidazole carbamate (MBC) fungicides (Fungicide Resistance Action Committee (FRAC) code 1) inhibit mitosis by binding to ⁇ -tubulin during microtubule assembly. Inhibition of microtubule assembly can disrupt cell division, transport within the cell and cell structure.
  • Methyl benzimidazole carbamate fungicides include benzimidazole and thiophanate fungicides.
  • the benzimidazoles include benomyl, carbendazim, fuberidazole and thiabendazole.
  • the thiophanates include thiophanate and thiophanate-methyl .
  • DMI Demethylation inhibitor
  • the triazoles include azaconazole, bitertanol, bromuconazole, cyproconazole, difenoconazole, diniconazole (including diniconazole-M), epoxiconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, imibenconazole, ipconazole, metconazole, myclobutanil, penconazole, propiconazole, prothioconazole, simeconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole and uniconazole.
  • the imidazoles include clotrimazole, imazalil, oxpoconazole, prochloraz, pefurazoate and triflumizole.
  • the pyrimidines include fenarimol and nuarimol.
  • the piperazines include triforine.
  • the pyridines include 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.
  • Phenylamide fungicides include acylalanine, oxazolidinone and butyrolactone fungicides.
  • the acylalanines include benalaxyl, benalaxyl-M, furalaxyl, metalaxyl and metalaxyl- M/mefenoxam.
  • the oxazolidinones include oxadixyl.
  • the butyrolactones include ofurace.
  • Arnine/morpholine fungicides include morpholine, piperidine and spiroketal-amine fungicides.
  • the morpholines include aldimorph, dodemorph, fenpropimorph, tridemorph and trimorphamide.
  • the piperidines include fenpropidin and piperalin.
  • the spiroketal -amines include spiroxamine.
  • Phospholipid biosynthesis fungicides include phophorothiolate and dithiolane fungicides.
  • the phosphorothiolates include edifenphos, iprobenfos and pyrazophos.
  • the dithiolanes include isoprothiolane.
  • Carboxamide fungicides include benzamides, furan carboxamides, oxathiin carboxamides, thiazole carboxamides, pyrazole carboxamides and pyridine carboxamides.
  • the benzamides include benodanil, flutolanil and mepronil.
  • 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, N-[2-(lS,2i?)-[l,r-bicyclopropyl]-2-ylphenyl]-3- (difluoromethyl)-l -methyl- lH-pyrazole-4-carboxamide and penflufen (N-[2-(l,3-dimethyl- butyl)phenyl]-5-fluoro-l,3-dimethyl-lH-pyrazole-4-carboxamide).
  • the pyridine carboxamides include boscalid.
  • 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.
  • Qol Quality of disease 2019
  • FRAC Federal Action Committee
  • Quinone outside inhibitor fungicides include methoxyacrylate, methoxycarbamate, oximinoacetate, oximinoacetamide, oxazolidinedione, dihydrodioxazine, imidazolinone and benzylcarbamate fungicides.
  • the methoxyacrylates include azoxystrobin, enestroburin (SYP-Z071), picoxystrobin and pyraoxystrobin (SYP-3343).
  • the methoxycarbamates include pyraclostrobin and pyrametostrobin (SYP-4155).
  • the oximinoacetates include kresoxim-methyl and trifloxystrobin.
  • the oximinoacetamides include dimoxystrobin, metominostrobin, orysastrobin, a-[methoxyimino]-N-methyl-2-[[[l -[3-(trifluoromethyl)phenyl]ethoxy]imino]- methyljbenzeneacetarnide and 2-[[[3-(2,6-dichlorophenyl)-l-methyl-2-propen-l-ylidene]- ammo]oxy]methyl]-a-(methoxyi ⁇
  • the oxazolidinediones include famoxadone.
  • the dihydrodioxazines include fluoxastrobin.
  • the imidazolinones include fenamidone.
  • the benzylcarbamates include pyribencarb.
  • Fenpiclonil and fludioxonil are examples of this fungicide class.
  • Quinoline 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. Quinoxyfen and tebufloquin are examples of this class of fungicide.
  • Lipid peroxidation inhibitor fungicides 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 carbon and 1,2,4-thiadiazole fungicides.
  • the aromatic carbon fungicides include biphenyl, chloroneb, dicloran, quintozene, tecnazene and tolclofos- methyl.
  • the 1 ,2,4-thiadiazole ungicides include etridiazole.
  • MMI-R Melanin biosynthesis inhibitors-reductase fungicides
  • FRAC Field Action Committee
  • MBI-D Mellanin biosynthesis inhibitors-dehydratase
  • Melanin biosynthesis inhibitors-dehydratase fungicides include cyclopropanecarboxamide, carboxamide and propionamide fungicides.
  • the cyclopropanecarboxamides include carpropamid.
  • the carboxamides include diclocymet.
  • the propionamides include fenoxanil.
  • Squalene- epoxidase inhibitor fungicides include thiocarbamate and allylamine fungicides.
  • the thiocarbamates include pyributicarb.
  • the allylamines include naftifine and terbinafine.
  • Polyoxin fungicides (Fungicide Resistance Action Committee (FRAC) code 19) inhibit chitin synthase. Examples include polyoxin.
  • 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" (Q j ) 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 cyanoimidazole and sulfamoyltriazole fungicides.
  • the cyanoimidazoles include cyazofamid.
  • the sulfamoyltriazoles include amisulbrom.
  • Benzamide fungicides (Fungicide Resistance Action Committee (FRAC) code 22) inhibit mitosis by binding to ⁇ -tubulin and disrupting microtubule assembly. Inhibition of microtubule assembly can disrupt cell division, transport within the cell and cell structure. Examples include zoxamide.
  • Halopyranosyl antibiotic fungicides (Fungicide Resistance Action Committee - (FRAC) code 24) inhibit growth of fungi by affecting protein biosynthesis. Examples include kasugamycin.
  • Glucopyranosyl antibiotic protein synthesis fungicides
  • FRAC Field Resistance Action Committee
  • FRAC Food Resistance Action Committee
  • Oxidative phosphorylation uncoupling fungicides 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.
  • Examples include fentin acetate, fentin chloride and fentin hydroxide.
  • 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.
  • Heteroaromatic fungicides include isoxazole and isothiazolone fungicides.
  • the isoxazoles include hymexazole and the isothiazolones include octhilinone.
  • Phosphonate fungicides include phosphorous acid and its various salts, including fosetyl-aluminum.
  • Phthalamic acid fungicides include teclofthalam.
  • Thiophene-carboxamide fungicides (Fungicide Resistance Action Committee (FRAC) code 38) are proposed to affect ATP production. Examples include silthiofam.
  • Carboxylic acid amide (CAA) fungicides 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 amide, valinamide carbamate and mandelic acid amide fungicides.
  • the cinnamic acid amides include dimethomorph and flumorpb.
  • the valinamide carbamates include benthiavalicarb, benthiavalicarb-isopropyl, iprovalicarb, valifenalate and valiphenal.
  • 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]butanamide and N-[2-[4-[[3-(4- chlorophenyl)-2-propyn- 1 -yl]oxy]-3-methoxyphenyl]ethyl]-3-methyl-2- [(ethylsulfonyl)amino]butanamide.
  • 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.
  • Thiocarbamate fungicides (b42) include methasulfocarb.
  • Benzamide fungicides (Fungicide Resistance Action Committee (FRAC) cod( 43) inhibit growth of fungi by derealization of spectrin-like proteins. Examples includedt acylpicolide fungicides such as fluopicolide and fluopyram.
  • Host plant defens induction fungicides include benzo-thiadiazole, benzisothiazole and thiadiazole-carboxamid fungicides.
  • the benzo-thiadiazoles include acibenzolar-S-methyl.
  • the benzisothiazole include probenazole.
  • the thiadiazole-carboxamides include tiadinil and isotianil.
  • (45) Multi-site contact fungicides inhibit fungal growth through multiple sites ( action and have contact/preventive activity.
  • This class of fungicides includes: (45.' “copper fungicides” (Fungicide Resistance Action Committee (FRAC) code Ml)", (45.- “sulfur fungicides” (Fungicide Resistance Action Committee (FRAC) code M2), (45..
  • Copper fungicides are inorganic compounds containing copper, typically in 1 copper(II) oxidation state; examples include copper oxychloride, copper sulfate and copj hydroxide, including compositions such as Bordeaux mixture (tribasic copper sulfal "Sulfur fungicides” are inorganic chemicals containing rings or chains of sulfur ator examples include elemental sulfur.
  • Dithiocarbamate fungicides contain a dithiocarbamate molecular moiety; examples include mancozeb, metiram, propineb, ferbam, manebj 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.
  • 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) “phenyl-acetarnide fungicides” (Fungicide Resistance Action Committee (FRAC) code U6), (46.3) “quinazolinone fungicides” (Fungicide Resistance Action Committee (FRAC) code U7), (46.4) "benzophenone fungicides” (Fungicide Resistance Action Committee (FRAC) code U8) and (46.5) "triazolopyrimidine fungicides”.
  • the thiazole carboxamides include ethaboxam.
  • the phenyl-acetamides include cyflufenamid and N-[[(cyclopropylmethoxy)- amino] [6-(difluoromethoxy)-2,3-difluorophenyl]-methylene]benzeneacetamide.
  • the quinazolinones include proquinazid and 2-butoxy-6-iodo-3-propyI-4H-l-benzopyran-4-one.
  • the benzophenones include metrafenone.
  • the triazolopyrimidines include ametoctradin.
  • the (b46) class also includes bethoxazin, neo-asozin (ferric methanearsonate), pyrrolnitrin, quinomethionate, N-[2-[4-[[3-(4-chlorophenyl)-2-propyn-l-yl]oxy]-3-methoxyphenyl]ethyl]- 3-methyl-2-[(methylsulfonyl)amino]butanamide, N-[2-[4-[[3-(4-chlorophenyl)-2-propyn- 1 - 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
  • a mixture comprising a compound of Formula 1 and at least one fungicidal compound selected from the group consisting of the aforedescribed classes (1) through (46).
  • 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.
  • a mixture 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).
  • 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.
  • 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,
  • Bacillus thuringiensis e.g., Cellcap, MPV, MPVII
  • entomopathogenic fungi such as green muscardine fungus
  • entomopathogenic virus including baculovirus, nucleopolyhedro virus (NPV) such as HzNPV, AfNPV
  • GV granulosis virus
  • 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.
  • the weight ratio of these various mixing partners (in total) to the compound of Formula 1 is typically between about 1 :3000 and about 3000:1. Of note are weight ratios between about 1 :300 and about 300:1 (for example ratios between about 1 :30 and about 30: 1).
  • weight ratios between about 1 :300 and about 300:1 for example ratios between about 1 :30 and about 30: 1).
  • One skilled in the art can easily determine through simple experimentation the biologically effective amounts of active ingredients necessary for the desired spectrum of biological activity. It will be evident that including these additional components may expand the spectrum of diseases controlled beyond the spectrum controlled by the compound of Formula 1 alone.
  • combinations of a compound of this invention with other biologically active (particularly fungicidal) compounds or agents can result in a greater-than-additive (i.e. synergistic) effect. Reducing the quantity of active ingredients released in the environment while ensuring effective pest control is always desirable.
  • synergism of 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.
  • a combination of a compound of Formula 1 with at least one other fungicidal active ingredient is such a combination where the other fungicidal active ingredient has different site of action from the compound of Formula 1.
  • 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.
  • 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.
  • 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) pyrimidinone fungicides; (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) fluopi
  • Pyrimidinone fungicides include compounds of Formula Al
  • M forms a fused phenyl, thiophene or pyridine ring;
  • R 1 1 is C j -C 6 alkyl;
  • R 12 is C j -Cg alkyl or C j -C ⁇ alkoxy;
  • R 13 is halogen; and
  • R 1 is hydrogen or halogen.
  • Pyrimidinone fungicides are described in PCT Patent Application Publication WO 94/26722 and U.S. Patents 6,066,638, 6,245,770, 6,262,058 and 6,277,858.
  • pyrimidinone fungicides selected from the group: 6-bromo-3-propyl-2-propyloxy- 4(3H)-quinazolinone, 6,8-diiodo-3-propyl-2-propyloxy-4(3H)-quinazolinone, 6-iodo- 3-propyl-2-propyloxy-4(3H)-quinazolinone (proquinazid), 6-chloro-2-propoxy-3-propyI- thieno[2,3- ⁇
  • 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.
  • 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 unicon
  • 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.
  • 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 ytochrome c oxidoreductase. This complex is uniquely identified by Enzyme Commission number ECl.10.2.2.
  • the bc ⁇ complex is described in, for example, J. Biol. Chem. 1989, 264, 14543 ⁇ 8; Methods Enzymol. 1986, 726, 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 include compounds such as mancozeb, maneb, propineb and zineb.
  • Phenylamides (group (3)) include compounds such as metalaxyl, benalaxyl, furalaxyl and oxadixyl.
  • Carboxamides include compounds such as boscalid, carboxin, fenfuram, flutolanil, furametpyr, mepronil, oxycarboxin, thifluzamide, penthiopyrad and 7V-[2-(l,3-dimethylbutyl)phenyl]-5-fluoro-l,3-dimethyl-lH- pyrazole-4-carboxamide (PCT Patent Publication WG 2003/010149), and are known to inhibit mitochondrial function by disrupting complex II (succinate dehydrogenase) in the respiratory electron transport chain.
  • complex II succinate dehydrogenase
  • Copper compounds include compounds such as copper oxychloride, copper sulfate and copper hydroxide, including compositions such as Bordeaux mixture (tribasic copper sulfate).
  • Phthalimides include compounds such as folpet and captan.
  • Benzimidazole fungicides include benomyl and carbendazim.
  • Dichlorophenyl dicarboximide fungicides include chlozolinate, dichlozoline, iprodione, isovaledione, myclozolin, procymidone and vinclozolin.
  • Non-DMI sterol biosynthesis inhibitors include morpholine and piperidine fungicides.
  • the morpholines 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.
  • Preferred for better control of plant diseases caused by fungal plant pathogens are mixtures of a compound of this invention with a fungicide selected from the group: azoxystrobin, kresoxim-methyl, trifloxystrobin, pyraclostrobin, picoxystrobin, dimoxystrobin, metominostrobin/fenominostrobin, quinoxyfen, metrafenone, cyflufenamid, fenpropidine, fenpropimorph, cyproconazole, epoxiconazole, flusilazole, metconazole, propiconazole, proquinazid, prothioconazole, tebuconazole, triticonazole, famoxadone and penthiopyrad.
  • azoxystrobin kresoxim-methyl
  • trifloxystrobin e.g., pyraclostrobin
  • picoxystrobin dimoxystrobin
  • Specifically preferred mixtures are selected from the group: combinations of Compound 1 , Compound 2, Compound 4, Compound 12, Compound 14 or Compound 15 with azoxystrobin, combinations of Compound 1, Compound 2, Compound 4, Compound 12, Compound 14 or Compound 15 with kresoxim-methyl, combinations of Compound 1, Compound 2, Compound 4, Compound 12, Compound 14 or Compound 15 with trifloxystrobin, combinations of Compound 1, Compound 2, Compound 4, Compound 12, Compound 14 or Compound 15 with picoxystrobin, combinations of Compound 1, Compound 2, Compound 4, Compound 12, Compound 14 or Compound 15 with metominostrobin/fenominostrobin, combinations of Compound 1, Compound 2, Compound 4, Compound 12, Compound 14 or Compound 15 with quinoxyfen, combinations of Compound 1, Compound 2, Compound 4, Compound 12, Compound 14 or Compound 15 with metrafenone, combinations of Compound 1 , Compounds, Compound 4, Compound 12, Compound 14 or Compound 15 with metrafenone, combinations of Com

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Abstract

Compounds of Formula (1), including all stereoisomers, N-oxides, and salts thereof, Formula (1): wherein R1, R2, Q1, Q2 and Y 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

FUNGICIDAL PYRAZOLONES
FIELD OF THE INVENTION
This invention relates to certain pyrazolones, their JV-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.
European Patent Application Publication EP-987253-A1 discloses certain pyrazolone derivatives of Formula i
Figure imgf000002_0001
and their use as pharmaceuticals.
PCT Patent Publication WO 99/31070 discloses certain substituted phenylpyrazolone derivatives of Formula ii
Figure imgf000002_0002
II
and their use in combating parasitic fungi and animal parasites.
U.S. Patent Application Publication US 2007/0049574 discloses certain pyrazolone derivatives of Formula in
Figure imgf000003_0001
111
and their use as pharmaceuticals.
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 imgf000003_0002
1
wherein
Y is O or S;
Q1 is a phenyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 5 substituents independently selected from R3a; or a 5- to 6-membered fully unsaturated heterocyclic ring or an 8- to 10-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 Ν 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(=0)q(=NR4)p, each ring or ring system optionally substituted with up to 5 substituents independently selected from R3a on carbon atom ring members and R3b on nitrogen atom ring members; or C(R5aR5b)W, NCR^W1, OWl or S^^W1;
W1 is a phenyl ring optionally substituted with up to 5 substituents independently
selected from R3a; or a 5- to 6-membered fully unsaturated heterocyclic 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, wherein up to 2 carbon atom ring members are independently selected from C(=0) and
C(=S), and the sulfur atom ring members are independently selected from S(=0)q(=NR4)p, the ring optionally substituted with up to 5 substituents independently selected from R3a on carbon atom ring members and R3b on nitrogen atom ring members;
Q2 is a phenyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 5 substituents independently selected from R3c; or a 5- to
6-membered fully unsaturated heterocyclic ring or an 8- to 10-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, 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(=0)q(=NR4)p, each ring or ring system optionally substituted with up to 5 substituents independently selected from R3c on carbon atom ring members and R3d on nitrogen atom ring members; or C(R5aR5b)W2;
W2 is a phenyl ring optionally substituted with up to 5. substituents independently selected from R3c; or a 5- to 6-membered fully unsaturated heterocyclic 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 2 carbon atom ring members are independently selected from C(=0) and C(=S), and the sulfur atom ring members are independently selected from
S(=0)q(=NR )p, the ring optionally substituted with up to 5 substituents independently selected from R3c on carbon atom ring members and R3d on nitrogen atom ring members;
R1 is H, halogen, cyano, amino, nitro, -CHO, -SCN, CrC7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C] -C7 haloalkyl, C2-C7 haloalkenyl, C3-C7 cycloalkyl, C3-C7 halocycloalkyl, C4-C)o alkylcycloalkyl, C4-C10 cycloalkylalkyl, C6-C]4 cycloalkylcycloalkyl, C2-C alkoxyalkyl, C j -C7 alkoxy, C 1 -C7 haloalkoxy, CrC7 alkylthio, C,-C7 haloalkylthio, C2-C7 alkylthioalkyl, CrC7 alkylsulfinyl, Cj-C7 alkylsulfonyl, Cj-C7 haloalkylsulfinyl, Cj-C7 haloalkylsulfonyl, C]-C7 alkylamino, C2-C7 dialkylamino or Cj-C7 hydroxyalkyl;
R2 is cyano, CrC7 alkyl, C3-C7 alkenyl, C3-C7 alkynyl, CrC7 haloalkyl, C3-C7
haloalkenyl, C3-C7 cycloalkyl, C3-C7 halocycloalkyl, C4-C10 alkylcycloalkyl, C4-C10 cycloalkylalkyl, Cg-C j4 cycloalkylcycloalkyl, C2-C7 alkoxyalkyl, C2-C7 alkylthioalkyl, CrC7 alkylsulfinyl, C,-C7 alkylsulfonyl, C,-C7
haloalkylsulfinyl, C j-C7 haloalkylsulfonyl or Cj-C7 hydroxyalkyl; each R3a and R3c is independently halogen, cyano, hydroxy, nitro, CJ-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C 1-C7 haloalkyl, C2-C7 haloalkenyl, C3-C7 cycloalkyl, C3-C7 halocycloalkyl, C4-C10 alkylcycloalkyl, C4-C JO cycloalkylalkyl, C6-Ci4 cycloalkylcycloalkyl, C1-C7 alkoxy, C]-C7 haloalkoxy, C3-C7 cycloalkoxy, C3-C7 halocycloalkoxy, C]-C7 alkylthio, C1-C7 haloalkylthio, C1-C7
alkylsulfinyl, Cj-C7 alkylsulfonyl, Cj-C7 haloalkylsulfinyl, Cj-C7
haloalkylsulfonyl, C1-C7 alkylamino, C2-C7 dialkylamino, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C2-C7 alkylcarbonylamino, C3-C] Q trialkylsilyl, SF5, -SCN, -C(=S)NH2, -C(=0)NHOH or -X-U-Z;
each R3b and R3d is independently cyano, Cj-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, Cj-C6 alkoxy, C2-C6 alkoxyalkyl, C2-Cg alkylcarbonyl,
2-Cg alkoxycarbonyl, C2-C6 alkylaminoalkyl or C3-C6 dialkylaminoalkyl; each X is independently O, S(=0)n, NR6 or a direct bond;
each U is independently Cj-C6 alkylene, Cj-C^ alkenylene, C3-Cg alkynylene, C3-C6 cycloalkylene or C3-C6 cycloalkenylene, wherein up to 3 carbon atoms are independently selected from C(=0), each optionally substituted with up to 5 substituents independently selected from halogen, cyano, nitro, hydroxy, Cj-Cg alkyl, C Cg haloalkyl, C]-Cg alkoxy and Cj-C^ haloalkoxy;
each Z is independently NR7aR7b, OR8 or S(=0)nR8;
each R4 is independently H, cyano, C1-C3 alkyl, C] -C3 alkoxy or C}-C3 haloalkyl; each R5a and R5c is independently H, cyano or C C4 alkyl;
each R5b is independently H or Cj-C4 alkyl; or
a pair of R5a and R5b attached to the same carbon atom are taken together with the carbon atom to form a 3- to 6-membered saturated carbocyclic ring;
each R6 is independently H, Cj-C^ alkyl, C Cg haloalkyl, -C^ alkylcarbonyl, C2-Cg alkoxycarbonyl, C2-C6 (alkylthio)carbonyl, C2-C6 alkoxy(thiocarbonyl), C4-C cycloalkylcarbonyl, C4-Cg cycloalkoxycarbonyl, C4-Cg (cycloalkylthio)carbonyl or C4-C cycloalkoxy(thiocarbonyl);
each R7a and R7b is independently H, CrC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C2-C6 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 (alkylthio)carbonyl, C2-C6 alkoxy(thiocarbonyl), C4-Cg cycloalkylcarbonyl, C4-Cg cycloalkoxycarbonyl, C4-C"g .
(cycloalkylthio)carbonyl or C4-Cg cycloalkoxy(thiocarbonyl); or
a pair of R7a and R7b attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3- to 6-membered heterocyclic ring, the ring optionally substituted with up to 5 substituents independently selected from R9; 2009/000616 each R8 is independently H, Cj-C6 alkyl, Cj-Cg haloalkyl, C2-C6 alkenyl, C3-C6
alkynyl, C3~C6 cycloalkyl, C3-C6 halocycloalkyl, C2-C6 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C§ (alkylthio)carbonyl, C2-Cg alkoxy(thiocarbonyl), C4-Cg cycloalkylcarbonyl, C4-Cg cycloalkoxycarbonyl, C4-Cg (cycloalkylthio)carbonyl or C4-Cg cycloalkoxy(thiocarbonyl);
each R9 is independently halogen, Cj-Cg alkyl, Cj-C6 haloalkyl or Cj-C^ alkoxy;
each n is independently 0, 1 or 2; and
each q and p are independently 0, 1 or 2 in each instance of S(=0)q(:=NR )p, provided that the sum of q and p is 0, 1 or 2;
provided that the compound is other than 1 ,2-dihydro-2-methyl- 1 -(3-nitrophenyl)-5- phenyl-3H-pyrazol-3-one, l,2-dihydro-2-methyl-l,5-diphenyl-3H-pyrazol-3-one or 2-(3^chloropropyl)-l,2-dihydro-l,5-diphenyl-3H-pyrazol-3-one.
More particularly, this invention pertains to a compound of Formula 1 (including all stereoisomers), an N-oxide, or a salt thereof.
This invention also relates to a fungicidal composition comprising (a) a compound of the invention (i.e. in a fungicidally effective amount); arid (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).
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 or method 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 or method.
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 or method 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.
As used herein, the term "alkylating agent" refers to a chemical compound in which a carbon-containing radical is bound through a carbon atom to a leaving group such as halide or sulfonate, which is displaceable by bonding of a nucleophile to said carbon atom. Unless otherwise indicated, the term "alkylating" does not limit the carbon^containing radical to alkyl; the carbon-containing radicals in alkylating agents include the variety of carbon-bound substituent radicals specified, for example, for R1 and R2.
In the above recitations, the term "alkyl", used either alone or in compound words such as "alkylthio" or "haloalkyl" includes straight-chain or branched alkyl, such as, methyl, ethyl, w-propyl, /'-propyl, and the different butyl, pentyl, hexyl or heptyl isomers. "Alkenyl" includes straight-chain or branched alkenes such as ethenyl, 1 -propenyl, 2-propenyl, and the different butenyl, pentenyl, hexenyl or heptenyl isomers. "Alkenyl" also includes polyenes such as 1 ,2-propadienyl and 2,4-hexadienyl. "Alkynyl" includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl, and the different butynyl, pentynyl, hexynyl or heptynyl 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, pentylene or hexylene .isomers. "Alkenylene" denotes a straight-chain or branched alkenediyl containing one olefinic bond. Examples of "alkenylene" include CH=CH, CH2CH=CH and CH=C(CH3). "Alkynylene" denotes a straight-chain or branched alkynediyl containing one triple bond. Examples of "alkynylene" include CH2C≡C, C≡CCH2, and the different butynylene, pentynylene or hexynylene isomers.
"Alkoxy" includes, for example, methoxy, ethoxy, «-propyloxy, /-propyloxy, and the different butoxy, pentoxy, hexyloxy or heptyloxy isomers. "Alkylthio" includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio, hexylthio or heptylthio isomers. "Alkylsulfinyl" includes both enantiomers of an alkylsulfinyl group. Examples of "alkylsulfinyl" include CH3S(=0), CH3CH2S(=0), CH3CH2CH2S(=0), (CH3)2CHS(=0), and the different butylsulfinyl, pentylsulfinyl, hexylsulfinyl or heptyl sulfinyl isomers. Examples of "alkylsulfonyl" include CH3S(=0)2, CH3CH2S(=0)2, CH3CH2CH2S(=0)2, (CH3)2CHS(=0)2, and the different butylsulfonyl, pentylsulfonyl, hexylsulfonyl or heptylsulfonyl isomers. "Alkylamino" includes an NH radical substituted with straight-chain or branched alkyl. Examples of "alkylamino" include CH3CH2NH, CH3CH2CH2NH and (CH^CHC^NH. Examples of "dialkylamino" include (CH3)2N, (CH3CH2GH2)2N and CH3CH2(CH3)N.
"Alkoxyalkyl" denotes alkoxy substitution on alkyl. Examples of "alkoxyalkyl" include CH3OCH2, CH3OCH2CH2, CH3CH2OCH2, CH3CH2CH2CH2OCH2 and CH3CH2OCH2CH2. "Alkylthioalkyl" denotes alkylthio substitution on alkyl. Examples of "alkylthioalkyl" include CH3SCH2, CH3SCH2CH2, CH3CH2SCH2, CH3CH2CH2CH2SCH2 and CH3CH2SCH2CH2. "Alkylaminoalkyl" denotes alkylamino substitution on alkyl. Examples of "alkylaminoalkyl" include CH3NHCH2, CH3NHCH2CH2, CH3CH2NHCH2, CH3CH2CH2CH2NHCH2 and CH3CH2NHCH2CH2. Examples of "dialkylaminoalkyl" include (CH^CH^NCfT,, (CH3CH2CH2)2NCH2 and CH3CH2(CH3)NCH2CH2.
"Alkylcarbonyl" denotes a straight-chain or branched alkyl bonded to a C(=0) moiety. Examples of "alkylcarbonyl" include CH3C(=0), CH3CH2CH2C(=G) and (CH^CHC^O): Examples of "alkoxycarbonyl" include CH3OC(=0), CH3CH2OC(=0), CH3CH2CH2OC(=0), (CH3)2CHOC(=0), and the different butoxy-, pentoxy-, hexoxy- or heptoxycarbonyl isomers. "Alkoxy(thiocarbonyl)" denotes a straight-chain or branched alkoxy group bonded to a C(=S) moiety. Examples of "alkoxy(thiocarbonyl)" include CH3OC(=S), CH3CH2CH2OC(=S) and (CH3)2CHOC(=S). "(Alkylthio)carbonyl" denotes a straight-chain or branched alkylthio group bonded to a C(=0) moiety. Examples of "(alkylthio)carbonyl" include CH3SC(=0), CH3CH2CH2SC(=0) and (CH3)2CHSC(=0). The term "alkylcarbonylamino" denotes alkyl bonded to a C(=0)NH moiety. Examples of "alkylcarbonylamino" include CH3CH2C(=0)NH and CH3CH2CH2C(=0)NH.
"Hydroxyalkyl" denotes an alkyl group substituted with one hydroxy group. Examples of "hydroxyalkyl" include HOCH2CH2, CH3CH2(OH)CH and HOCH2CH2CH2CH2.
"Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term "alkylcycloalkyl" denotes alkyl substitution on a cycloalkyl moiety and includes, for example, ethylcyclopropyl, /'-propylcyclobutyl, methylcyclopentyl and methylcyclohexyl. The term "cycloalkylalkyl" denotes cycloalkyl substitution on an alkyl moiety. Examples of "cycloalkylalkyl" include cyclopropylmethyl, cyclopentylethyl, and other cycloalkyl moieties bonded to straight-chain or branched alkyl groups. The term "cycloalkylcycloalkyl" denotes cycloalkyl substitution on another cycloalkyl ring, wherein each cycloalkyl ring independently has from 3 to 7 carbon atom ring members. Examples of cycloalkylcycloalkyl include cyclopropylcyclopropyl (such as Ι , -bicyclopropyl-l-yl, Ι, - 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 (U?,2S)-l,l'-bicyclopropyl-2-yl and (\R,2R)-\,V- bicyclopropyl-2-yl). The term "cycloalkoxy" denotes cycloalkyl attached to and linked through an oxygen atom including, for example, cyclopentyloxy and cyclohexyloxy. "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. The term "cycloalkenylene" denotes a cycloalkenediyl ring containing one olefinic bond. Examples of "cycloalkenylene" include cyclopropenylene and cyclopentenylene. "Trialkylsilyl" includes 3 branched and/or straight-chain alkyl radicals attached to and linked through a silicon atom, such as trimethylsilyl, triethylsilyl and ter/-butyldimethylsilyl.
The term "halogen", either alone or in compound words such as "haloalkyl", or when used in descriptions such as "alkyl substituted with halogen" includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as "haloalkyl", or when used in descriptions such as "alkyl substituted with halogen" said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of "haloalkyl" or "alkyl substituted with halogen" include F3C, C1CH2, CF3CH2 and CF3CC12. The terms "haloalkenyl", "haloalkoxy", "haloalkylthio", "haloalkylsulfinyl", "haloalkylsulfonyl", "halocycloalkyl", and the like, are defined analogously to the term "haloalkyl". Examples of "haloalkenyl" include C12C=CHCH2 and CF3CH2CH=CHCH2. Examples of "haloalkoxy" include CF30, CC13CH20, F2CHCH2CH20 and CF3CH20. Examples of "haloalkylthio" include CC13S, CF3S, CC13CH2S and C1CH2CH2CH2S. Examples of "haloalkylsulfinyl" include CF3S(=Q), 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 chlorocyclopropyl, fluorocyclobutyl and chlorocyclohexyl.
The total number of carbon atoms in a substituent group is indicated by the "Cj-Cj" prefix where i and j are numbers from 1 to 14. For example, CJ-C4 alkylsulfonyl designates methylsulfonyl through butylsulfonyl; 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 hot 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) range 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 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 R3a on carbon atom ring members" means that 0, 1, 2 or 3 substituents can be present (if the number of potential connection points allows). Similarly, the phrase "optionally substituted with up to 5 substituents independently selected from R3a on carbon atom ring members" means that 0, 1, 2, 3, 4 or 5 substituents can be present if the number of available connection points allows. When a range specified for the number of substituents (e.g., r being an integer from 0 to 5 in Exhibit 1) exceeds the number of positions available for substituents on a ring (e.g., 2 positions available for (Rv)r on AA 1 in Exhibit 1), 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 exceed 1 , said substituents (when they exceed 1) are independently selected from the group of defined substituents (e.g., (Rv)r wherein r is 1, 2, 3, 4 or 5 in Exhibit 1). When a variable group is shown to be optionally attached to a position, for example (Rv)r wherein r may be 0, then hydrogen may be at the position even if not recited in the variable group definition. When one or more positions on a group are said to be "not substituted" or "unsubstituted", then hydrogen atoms are attached to take up any free valency.
Unless otherwise indicated, a "ring" or "ring system" as a component of Formula 1
(e.g., substituent Q1 and Q2) is carbocyclic or heterocyclic. In the context of the present invention the term "ring system" denotes two fused rings (e.g., two phenyl rings fused to form a naphthalenyl ring system or two rings fused to form a heteroaromatic bicyclic ring system). 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(=0)q(=NR4)p) forming the backbone of a ring or ring system.
The term "nonaromatic" includes rings that are fully saturated as well as partially or fully unsaturated, provided that none of the rings are aromatic. The term "aromatic" indicates that each of the ring atoms of a fully unsaturated ring 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 "fully unsaturated heterocyclic ring" includes both aromatic and nonaromatic heterocycles.
The terms "carbocyclic ring", "carbocycle" or "carbocyclic ring system" denote a ring or ring system wherein the atoms forming the ring backbone are selected only from carbon. Unless otherwise indicated, a carbocyclic ring can be a saturated, partially unsaturated or fully unsaturated ring. When a fully unsaturated carbocyclic ring satisfies Huckel's rule, then said ring is also called an "aromatic carbocyclic ring". The term "saturated carbocyclic ring" 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.
The terms "heterocyclic ring" or "heterocycle" denote rings in which at least one atom forming the ring backbone is not carbon (e.g., N, O or S). Typically a heterocyclic ring contains no more than 4 N atoms, no more than 2 O atoms and no more than 2 S atoms. 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". The terms "heteroaromatic ring system" or "heteroaromatic bicyclic ring system" denote a ring system in which at least one atom forming the ring backbone is not carbon (e.g., N, O or S) 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.
In the context of the present invention when an instance of Q1 and Q2 comprises a phenyl ring or a 6-membered fully unsaturated heterocyclic ring, the ortho, meta and para positions of each ring is relative to the connection of the ring to the remainder of Formula 1. Further, when an instance of Q1 and Q2 comprises a phenyl ring or a 6-membered fully unsaturated heterocyclic ring attached through a linker (e.g., C(R5aR5b)>. N(R5c), O or S^O)^) to the remainder of Formula 1, the orthp, meta and para positions of each ring is relative to the connection of the ring to the linker (e.g.,C(R5aR5b), N(R5c), O or S(=0)n).
As noted above, each Q' and Q2 is, inter alia, a 5- to 6-membered fully unsaturated heterocyclic ring or an 8- to 10-membered heteroaromatic 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(=0)q(=NR4)p, each ring or ring system optionally substituted with up to 5 substituents independently selected from any substituent as defined in the Summary of the Invention for Q1 and Q2 (i.e. the Q1 -heterocyclic ring or heteroaromatic ring system is optionally substituted with R3a on carbon atom ring members and R3b on nitrogen atom ring members; and the Q2 heterocyclic ring or heteroaromatic ring system is optionally substituted with R3c on carbon atom ring members and R3d on nitrogen atom ring members). As the substituents are optional, 0 to 5 substituents may be present, limited only by the number of available points of attachment. In this definition the ring members selected from up to 2 O, up to 2 S and up to 4 N atoms are optional, provided at least one ring member is not carbon (e.g., N, O or S). The definition of S(=0)q(=NR4)p allows the up to 2 sulfur ring members to be oxidized sulfur moieties (e.g., S(=0) or S(=0)2) or unoxidized sulfur atoms (i.e. when q and p 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. Examples of a 5- to 6-membered fully unsaturated heterocyclic ring include the rings A-1 through A-31 illustrated in Exhibit 1, and examples of an 8- to 10-membered heteroaromatic bicyclic ring system include the ring systems A-32 through A-72 illustrated in Exhibit 2. In Exhibits 1 and 2 the variable Rv is any substituent as defined in the Summary of the Invention for Q1 and Q2 (i.e. the Q> heterocyclic ring or heteroaromatic ring system is optionally substituted with R3a on carbon atom ring members and R3b on nitrogen atom ring members; and the Q2 heterocyclic ring or heteroaromatic ring system is optionally substituted with R3c on carbon atom ring members and R3d on nitrogen atom ring members) and r is an integer from 0 to 5, limited by the number of available positions on each depicted ring or ring system.
As noted above, each W1 and.W2 is, inter alia, a 5- to 6-membered fully unsaturated heterocyclic 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 2 carbon atom ring members are independently selected from C(=0) and C(=S), and the sulfur atom ring members are independently selected from S(=0)q(=NR4)p, the ring optionally substituted with up to 5 substituents independently selected from any substituent as defined in the Summary of the Invention for W1 and W2 (i.e. the W1 heterocyclic ring is optionally substituted with R3a on carbon atom ring members and R3b on nitrogen atom ring members; and the W2 heterocyclic ring optionally substituted with R3c on carbon atom ring members and R3d on nitrogen atom ring members). As the substituents are optional, 0 to 5 substituents may be present, limited only by the number of available points of attachment. In this definition the ring members selected from up to 2 O, up to 2 S and up to 4 N atoms are optional, provided at least one ring member is not carbon (e.g., N, O or S). The definition of S(=0)q(=NR4)p allows the up to 2 sulfur ring members to be oxidized sulfur moieties (e.g., S(=0) or S(=0)2) or unoxidized sulfur atoms (i.e. when q and p 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 2 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. Examples of a 5- to 6-membered fully unsaturated heterocyclic ring include the rings A-1 through A-31 illustrated in Exhibit 1 wherein Rv is any substituent as defined in the Summary of the Invention for W1 or W2 (i.e. the W1 heterocyclic ring is optionally substituted with R3a on carbon atom ring members and R3b on nitrogen atom ring members; and the W2 heterocyclic ring is optionally substituted with R3c on carbon atom ring members and R3d on nitrogen atom ring members) and r is an integer from 0 to 5, limited by the number of available positions on each depicted ring. Although Rv groups are shown in the structures A-1 through A-72, it is noted that they do not need to be present since they are optional substituents. The nitrogen atoms that require substitution to fill their valence are substituted with H or Rv. Note that when the attachment point between (Rv)r and the depicted ring or ring system is illustrated as floating, (Rv)r can be attached to any available carbon or nitrogen atom of the depicted ring or ring system. Note that when the attachment point on the depicted ring or ring system is illustrated as floating, the depicted ring or ring system can be attached to the remainder of Formula 1 through any available carbon or nitrogen of the depicted ring or ring system by replacement of a hydrogen atom.
Exhibit 1
Figure imgf000014_0001
A-1 A-2 A-3 A-4
Figure imgf000014_0002
-5 A-6 A-7 -8
Figure imgf000014_0003
Figure imgf000014_0004
A-1 A-14 -15 A-16
Figure imgf000014_0005
A-17 A-18 A-19 A-20
Figure imgf000015_0001
Figure imgf000016_0001
A wide variety of synthetic methods are known in the art to enable preparation of aromatic heterocyclic rings and ring systems; for extensive reviews see the eight volume set of Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees editors-in-chief, Pergamon Press, Oxford, 1984 and the twelve volume set of Comprehensive Heterocyclic Chemistry II, A. R. Katritzky, C. W. Rees and E. F. V. Scriven editors-in-chief, Pergamon Press, Oxford, 1996.
Compounds of this invention can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. One skilled in the art will appreciate that one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers. The compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers or as an optically active form.
One skilled in the art will appreciate that not all nitrogen-containing heterocycles can form N-oxides since the nitrogen requires an available lone pair for oxidation to the oxide; one skilled in the art will recognize those nitrogen-containing heterocycles which can form N-oxides. One skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for the preparation of N-oxides of heterocycles and tertiary amines are very well known by one skilled in the art including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as /-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. Accordingly, the present invention comprises compounds selected from Formula 1, N-oxides and agriculturally suitable salts thereof.
Compounds selected from Formula 1, stereoisomers, N-oxides, and salts thereof, typically exist in more than one form, and Formula 1 thus 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 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 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 Y is O.
Embodiment 2. A compound of Formula 1 or Embodiment 1 wherein Q1 is a phenyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 3 substituents independently selected from R3a; or a 5- to 6-membered fully unsaturated heterocyclic ring containing ring members selected from carbon atoms and 1 to 3 heteroatoms independently selected from up to 2 O, up to 2 S and up to 3 N atoms, wherein up to 2 carbon atom ring members are independently selected from C(=0) and C(=S), and the sulfur atom ring members are independently selected from S(=0)q(=NR4)p, the ring optionally substituted with up to 3 substituents independently selected from R3a on carbon atom ring members and R3b on nitrogen atom ring members; or
Figure imgf000019_0001
Embodiment 3. A compound of Embodiment 2 wherein Q1 is a phenyl, thienyl,
pyridinyl, pyridazinyl, pyrimidinyl or pyrazolyl ring or a naphfhalenyl ring system, each ring or ring system optionally substituted with up to 3 substituents independently selected from R3a on carbon atom ring members and R3b on nitrogen atom ring members; or C(R5aR5b)W1.
Embodiment 4. A compound of Embodiment 3 wherein Q1 is a phenyl or pyridinyl ring optionally substituted with up to 3 substituents independently selected from R3a.
Embodiment 5. A compound of Embodiment 4 wherein Q1 is a phenyl ring optionally substituted with up to 3 substituents independently selected from R3a.
Embodiment 6. A compound of Formula 1 or any one of Embodiments 1 through 3 . wherein W1 is a phenyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazolyl ring optionally substituted with up to 3 substituents independently selected from R3a on carbon atom ring members and R3b on nitrogen atom ring members.
Embodiment 7. A compound of Embodiment 6 wherein W1 is a phenyl or pyridinyl ring optionally substituted with up to 3 substituents independently selected from R3 .
Embodiment 8. A compound of Embodiment 7 wherein W1 is a phenyl ring optionally substituted with up to 3 substituents independently selected from R3a.
Embodiment 9. A compound of Formula 1 or any one of Embodiments 1 through 8 wherein Q2 is a phenyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 3 substituents independently selected from R3c; or a 5- to 6-membered fully unsaturated heterocyclic ring containing ring members selected from carbon atoms and 1 to 3 heteroatoms independently selected from up to 2 O, up to 2 S and up to 3 N atoms, wherein up to 2 carbon atom ring members are independently selected from C(=0) and C(=S), and the sulfur atom ring members are independently selected from S(=0)q(=NR4)p, the ring optionally substituted with up to 3 substituents independently selected from R3c on carbon atom ring members and R3d on nitrogen atom ring members; or
Figure imgf000020_0001
Embodiment 10. A compound of Embodiment 9 wherein Q2 is a phenyl, thienyl,
pyridinyl, pyridazinyl, pyrimidinyl or pyrazolyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 3 substituents independently selected from R3c on carbon atom ring members and R3d on nitrogen atom ring members; or C(R5aR5b)W2.
Embodiment 11. A compound of Embodiment 10 wherein Q2 is a phenyl or pyridinyl ring optionally substituted with up to 3 substituents independently selected from R3c.
Embodiment 12. A compound of Embodiment 11 wherein Q2 is a phenyl ring
optionally substituted with up to 3 substituents independently selected from R3c.
Embodiment 13. A compound of Formula 1 or any one of Embodiments 1 through 10 wherein W2 is a phenyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazolyl ring optionally substituted with up to 3 substituents independently selected from R3c on carbon atom ring members and R3d on nitrogen atom ring members.
Embodiment 14. A compound of Embodiment 13 wherein W2 is a phenyl or pyridinyl ring optionally substituted with up to 3 substituents independently selected from R3c.
Embodiment 15. A compound of Embodiment 14 wherein W2 is a phenyl ring
optionally substituted with up to 3 substituents independently selected from R3c.
Embodiment 16. A compound of Formula 1 or any one of Embodiments 1 through 15 wherein when each Q1 and Q2 is independently an optionally substituted phenyl or pyridinyl ring, then one of Q5 and Q2 is substituted with 2 or 3 substituents and the other of Q1 and Q2 is substituted with 0 to 3 substituents.
Embodiment 17. A compound of Embodiment 16 wherein when each Q1 and Q2 is independently an optionally substituted phenyl or pyridinyl ring, then one of Q1 arid Q2 is substituted with 2 or 3 substituents and the other of Q1 and Q2 is substituted with 1 or 2 substituents.
Embodiment 18. A compound of Embodiment 17 wherein when each Q1 and Q2 is independently an optionally substituted phenyl or pyridinyl ring, then one of Q1 and Q2 is substituted with 2 or 3 substituents and the other of Q1 and Q2 is substituted with 1 substituent.
Embodiment 19. A compound of Formula 1 or any one of Embodiments 1 through 18 wherein when each Q1 and Q2 is independently an optionally substituted phenyl or pyridinyl ring, then one of Q1 and Q2 is substituted with at least one substituent at an ortho position and the other of Q1 and Q2 is substituted with at least one substituent at a meta or para position.
Embodiment 20. A compound of Formula 1 or any one of Embodiments 1 through 19 wherein R1 is H, halogen, Cj-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C2-C3 haloalkyl, C2-C3 haloalkenyl, C3-C6 cycloalkyl, C1-C3 alkoxy, Cj-C3 alkylthio,
C]-C3 alkylamino, C2-C4 dialkylamino or Cj-C3 hydroxyalkyl.
Embodiment 21. A compound of Embodiment 20 wherein R1 is H, halogen, cyano or
CrC3 alkyL
Embodiment 22. A compound of Embodiment 21 wherein R1 is CI, Br, I or C1-C2
alkyl.
Embodiment 23. A compound of Embodiment 22 wherein R1 is CI, Br or methyl.
Embodiment 24. A compound of Formula 1 or any one of Embodiments 1 through 23 wherein R2 is cyano, C}-C3 alkyl, C3 alkenyl, cyclopropyl or Cj -C3
hydroxyalkyl.
Embodiment 25. A compound of Embodiment 24 wherein R2 is Cj-C3 alkyl.
Embodiment 26. A compound of Embodiment 25 wherein R2 is methyl.
Embodiment 27. A compound of Formula I or any one of Embodiments 1 through 26 wherein each R3a and R3c is independently halogen, cyano, Cj-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C]-C3 haloalkyl, cyclopropyl, C 1 -C3 alkoxy, C 1-C3 haloalkoxy, C] -C3 alkylthio, Cj-C3 alkylamino, C2-C4 dialkylamino, C2-C4 alkylcarbonyl, C2-C alkoxycarbonyl, C2-C4 alkylcarbonylamino or -X-U-Z. Embodiment 28. A compound of Embodiment 27 wherein each R3a and R3c is
independently halogen, cyano, C]-C3 alkyl, C2-C3 alkenyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1 -C3 haloalkoxy, Cj -C3 alkylthio or Cj -C^ alkylamino.
Embodiment 29. A compound of Embodiment 28 wherein each R3a and R3c is
independently halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C C3 alkoxy or CJ-C3 haloalkoxy.
Embodiment 30. A compound of Embodiment 29 wherein each R3a and R3c is
independently Br, CI, F, cyano, Cj-C2 alkyl, Ci-C2 haloalkyl, C C2 alkoxy or C,-C2 haloalkoxy.
Embodiment 30a. A compound of Embodiment 30 wherein each R3a and R3c is
independently Br, CI, F, cyano, methyl, methoxy or Cj-C2 fluoroalkoxy.
Embodiment 31. A compound of Formula 1 or any one of Embodiments 1 through 30a wherein each R3b and R3d is independently cyano, C] -C3 alkyl, C3 alkenyl, cyclopropyl or C2-C3 alkoxyalkyl.
Embodiment 31a. A compound of Embodiment 31 wherein each R b and R3a is methyl. Embodiment 32. A compound of Formula 1 or any one of Embodiments 1 through 31a wherein each X is independently O or NR.6.
Embodiment 33. A compound of Embodiment 32 wherein eaeh X is independently O or
NH,
Embodiment 34. A compound of Formula 1 or any one of Embodiments 1 through 33 wherein each U is C2-C alkylene.
Embodiment 35. A compound of Formula 1 or any one of Embodiments 1 through 34 wherein each Z is independently NR7aR7b or OR8.
Embodiment 36. A compound of Formula 1 or any one of Embodiments 1 through 35 wherein each R7a and R7b is independently H, Cj-C6 alkyl or C]-Cg haloalkyl. Embodiment 37. A compound of Formula 1 or any one of Embodiments 1 through 36 wherein each R8 is independently H, C1-C6 alkyl or Cj-C6 haloalkyl.
Embodiment 38. A compound of Formula 1 or any one of Embodiments 1 through 37 wherein independently when an instance of R5a is not taken together with the carbon atom to which the instance of R5a is attached and a geminal instance of
R5b to form a carbocyclic ring (i.e. R5a is taken alone) then the instance of R5a is independently H, cyano or methyl.
Embodiment 39. A compound of Embodiment 38 wherein the instance of R5a is
independently H or methyl.
Embodiment 40. A compound of Embodiment 39 wherein the instance of R5a is H. Embodiment 41. A compound of Formula 1 or any one of Embodiments 1 through 40 wherein independently when an instance of R5b is not taken together with the carbon atom to which the instance of R5b is attached and a geminal instance of
R5a to form a carbocyclic ring (i.e. R5b is taken alone) then the instance of R5b is independently H or methyl.
Embodiment 42. A compound of Embodiment 41 wherein the instance of R5b is H. Embodiment 43. A compound of Formula 1 or any one of Embodiments 1 through 42 wherein when a pair of R5a and R5b attached to the same carbon atom are taken together with the carbon atom to form a carbocyclic ring, the ring is a
cyclopropyl ring.
Embodiment 44. A compound of Formula 1 or any one of Embodiments 1 through 42 wherein each pair of R5a and R5b attached to the same carbon atom are not taken together to form a carbocyclic ring (i.e. R5a and R5b are taken alone).
Embodiment 45. A compound of Formula 1 or any one of Embodiments 1 through 44 wherein R5c is H or methyl.
Embodiment 46. A compound of Embodiment 45 wherein R5c is H. Embodiments of this invention, including Embodiments 1-46 above as well as any other embodiments described herein, can be combined in any manner, and the descriptions of variables in the embodiments pertain not only to the compounds of Formula 1 but also to the starting compounds and intermediate compounds useful for preparing the compounds of Formula 1. In addition, embodiments of this invention, including Embodiments 1-46 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 1-46 are illustrated by:
Embodiment AL A compound of Formula 1 wherein
Y is O;
Q1 is a phenyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 3 substituents independently selected from R3a; or a 5- to 6-membered fully unsaturated heterocyclic ring containing ring members selected from carbon atoms and 1 to .3 heteroatoms independently selected from up to 2 O, up to 2 S and up to
3 N atoms, wherein up to 2 carbon atom ring members are
independently selected from C(=0) and C(=S), and the sulfur atom ring members are independently selected from S(=0)q(=NR )p, the ring optionally substituted with up to 3 substituents independently selected from R3a on carbon atom ring members and R3b on nitrogen atom ring members; or C(R5aR5b)W», N(R5c)W , OW1 or S(=0)nW! 1 ;
W1 is a phenyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazolyl ring optionally substituted with up to 3 substituents independently selected from R3a on carbon atom ring members and R3b on nitrogen atom ring members;
Q2 is a phenyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 3 substituents independently selected from R3c; or a 5- to 6-membered fully unsaturated heterocyclic ring containing ring members selected from carbon atoms and 1 to 3 heteroatoms independently selected from up to 2 O, up to 2 S and up to
3 N atoms, wherein up to 2 carbon atom ring members are
independently selected from C(=0) and C(=S), and the sulfur atom ring members are independently selected from S(=0)q(=NR )p, the ring optionally substituted with up to 3 substituents independently selected from R3c on carbon atom ring members and R3d on nitrogen atom ring members; or C(R5aR5b)W2; W2 is a phenyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazolyl ring optionally substituted with up to 3 substituents independently selected from R3c on carbon atom ring members and R3d on nitrogen atom ring members;
R1 is H, halogen, CrC3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, CrC3
haloalkyl, C2-C3 haloalkenyl, C3-C6 cycloalkyl, Cj-C3 alkoxy, Cj-C3 alkylthio, C C3 alkylamino, C2-C4 dialkylamino or Cj-C3 hydroxy alkyl;
R2 is cyano, Cj-C3 alkyl, C3 alkenyl, cyclopropyl or Cj-C3 hydroxyalkyl; each R3b and R3d is methyl;
each R5a is independently H, cyano or methyl;
each R5b.is independently H or methyl; or
a pair of R5a and R51* attached to the same carbon atom are taken together with the carbon atom to form a cyclopropyl ring; and
R5c is H or methyl.
Embodiment A2. A compound of Embodiment Al wherein
Q1 is a phenyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazolyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 3 substituents independently selected from R3a on carbon atom ring members and R3b on nitrogen atom ring members; or C(R5aR5b)W>;
W1 is a phenyl or pyridinyl ring optionally substituted with up to 3 substituents independently selected from R3a;
Q2 is a phenyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazolyl ring or a naphthalenyl ring system, each ring or ring system optionally. substituted with up to 3 substituents independently selected from R3c on carbon atom ring members and R3d on nitrogen atom ring members; or C(R5aR5b)W2;
W2 is a phenyl or pyridinyl ring optionally substituted with up to 3 substituents independently selected from R3c;
each R3a and R3c is independently halogen, cyano, C j-C3 alkyl, C2-C3
alkenyl, C2-C3 alkynyl, CrC3 haloalkyl, C3 cycloalkyl, C C3 alkoxy, C j-C3 haloalkoxy, C j-C3 alkylthio, C C3 alkylamino, C2-C4
dialkylamino C2-C4 alkylcarbonyl, C2-C4 alkoxycarbonyl, C2-C4 alkylcarbonylamino or -X-U-Z;
X is O or NH; U is C2-C4 alkylene;
Z is NR7aR7b or OR8;
each R5a is independently H or methyl;
each R7a and R7b is independently H, C\-C6 alkyl or C Cg haloalkyl; and each R8 is independently H, C Cg alkyl or C j-C6 haloalkyl.
Embodiment A3. A compound of Embodiment A2 wherein
Q' is a phenyl or pyridinyl ring optionally substituted with up to 3
substituents independently selected from R3a;
Q2 is a phenyl or pyridinyl ring optionally substituted with up to 3
substituents independently selected from R3c;
R1 is H, halogen, cyano or C j-C3 alkyl; and
R2 is CrC3 alkyl.
Embodiment A4. A compound of Embodiment A3 wherein
each R3a and R3c is independently halogen, cyano, C1-C3* alkyl, C1-C3
haloalkyl, C1-C3 alkoxy or C 1 -C3 haloalkoxy.
Embodiment A5. A compound of Embodiment A4 wherein
R1 is independently CI, Br, I or C j -C2 alkyl;
R2 is methyl;
each R3a and R3c is independently Br, CI, F. cyano, Cj-C2 alkyl, C C2
haloalkyl , C j -C2 alkoxy or C ] -C2 haloalkoxy; and one of Q1 and Q2 is substituted with 2 to 3 substituents and the other of Q1 and Q2 is substituted with 0 to 3 substituents.
Specific embodiments include compounds of Formula 1 selected from the group consisting of:
4-bromo-l-(4-chlorophenyl)-5-(2,6-difluoro-4-methoxyphenyl)-l ,2-dihydro-2- methyl-3H-pyrazol-3-one;
4-chloro- 1 -(4-chlorophenyl)-5-(2,6-difluoro-4-methoxyphenyl)- 1 ,2-dihydro-2- methyl-3H-pyrazol-3-one;
l -(4-chlorophenyl)-5-(2,6-difluoro-4-methoxyphenyl)-l ,2-dihydro-2,4-dimethyl- 3H-pyrazol-3-one;
4-chloro-l-(4-chlorophenyl)-5-(2,6-difluoro-3-methoxyphenyl)-l,2-dihydro-2- methyl-3H-pyrazol-3-one;
4-bromo-5-(2,6-difluoro-3-methoxyphenyl)-l-(3-fluorophenyl)-l,2-dihydro-2- methyl-3H-pyrazol-3-one; and
4-chloro-5-(2,6-difluoro-3-methoxyphenyl)- 1 -(3 -fluorophenyl)- 1 ,2-dihydro-2- methyl-3H-pyrazol-3-one. 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 an embodiment 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 1-9 can be used to prepare the compounds of Formula 1. The definitions of Q1, Q2, R1 and R2 in the compounds of Formulae 1-9 below are as defined above in the Summary of the Invention unless otherwise noted. Compounds of Formulae la and lb are various subsets of Formula 1, and all substituents for Formulae la and lb are as defined above for Formula 1 unless otherwise noted.
Compounds of Formula la (i.e. Formula 1 wherein Y is O) wherein R1 is halogen can be prepared from compounds of Formula lb (i.e. Formula 1 wherein Y is O and R1 is H) by treatment with a halogenating reagent as shown in Scheme 1 for method A. A variety of halogenating reagents known in the art are suitable for this method including, for example, N-halosuccinimides (e.g., NBS, NCS, NIS), elemental halogen (e.g., CI2, Br2, ½), phosphorus oxyhalides, phosphorus trihalides, phosphorus pentahalides, thionyl chloride, sulfuryl chloride, bis(pyridine)iodonium(I) tetrafluoroborate, tetramethylammonium iodide chloride, tetrafluoroborate and sulfur tetrafluoride. Particularly useful as halogenating reagents are N-halosuccinimides. Typically the reaction is carried out in a suitable solvent such as NN-dimethylformamide, carbon tetrachloride, acetonitrile, dichloromethane, acetic acid, chloroform, benzene, xylenes, chlorobenzene, tetrahydrofuran, /?-dioxane, or the like. In some cases the reaction can be conducted without solvent other than the compound of Formula lb and the halogenating reagent. Optionally, an organic base such as triethylamine, pyridine, Ν,ΛΓ-dimethylaniline, or the like can be added. Addition of a catalyst such as N^-dimethylforrnamide or 2,2'-azobis(2-methylpropionitrile) (AIBN) is also an option. Typical reaction temperatures range from about room temperature (e.g., 20 °C) to 150 °C. For representative procedures see U.S. Patent Application Publication US 2007/0049574; PCT Patent Application Publication WO 2006/071730; Campos et al., Tetrahedron Letters 1997, JS(48), 8397-8400 and Gibert et al., Pharmaceutical Chemistry Journal 2007, 41(3), 154-156. Also, the method of Scheme 1 is illustrated in Examples 2 and 3.
As shown in Scheme 1 for Method B, compounds of Formula la wherein R1 is nitro (-NO2) can be prepared from compounds of Formula lb by nitration. Compounds of Formula la wherein R1 is nitro (-NO2) can be converted into the amino (-NH2) analog by catalytic reduction. Nitration can be accomplished according to well-known methods such as treating a compound of Formula lb with nitric acid, a mixture of nitric acid and sulfuric acid or a mixture of nitric acid and trifluoroacetic anhydride. Reduction of the nitro group can be done via hydrogenation in the presence of a metal catalyst such as palladium supported on an inert carrier such as activated carbon. One skilled in the art will recognize that certain functionalities that may be present in compounds of Formula lb can also be reduced under catalytic hydrogenation conditions, thus requiring a suitable choice of catalyst and conditions. The synthetic literature includes many general methods for nitrations and reduction of nitro groups; see, for example, Katritzky et a\., ARK1VOC 2005, (3), 179-191 ; Varvounis et al., Journal of Heterocyclic Chemistry 2001, 55(5), 1065-1069; Xu et al., Bioorganic & Medicinal Chemistry Letters 2006, 16(14), 3713-3718 and Lattmann et al., Journal of Pharmacy and Pharmacology 2006, 58(3), 393-401.
As shown in Scheme 1 for Method C, compounds of Formula la wherein R1 is alkyl, alkenyl, alkynyl, or the like can be obtained from compounds of Formula lb wherein R1 is halogen using Friedel-Crafts alkylation conditions. In particular a compound of Formula lb can be reacted with an alcohol of formula R!-OH in the presence of a Lewis acid (such as boron trifluoride diethyl etherate or tin tetrachloride) according to the conditions disclosed in U.S. Patent Application Publication US 2007/0049574. Also see Lui et al., Advanced Synthesis & Catalysis 2006, 348, 456-462, which describes a method using propargyl alcohol. Scheme 1
Figure imgf000028_0001
la
wherein R' is alkyl,
alkenyl, alkynyl, or the like
Alternatively, compounds of Formula la wherein Rl is alkyl, alkenyl, alkynyl, or the like can be prepared from compounds of Formula la wherein R1 is halogen (e.g., Br, CI or I) using well-known transition metal-catalyzed cross coupling reactions. As illustrated in Scheme 2, a compound of Formula la wherein R1 is halogen can be reacted with a compound of formula R'M1 in the presence of a palladium, copper or nickel catalyst to provide a compound of Formula la wherein R1 is alkyl, alkenyl, alkynyl, or the like. In this method compounds of formula R'Ml are organoboronic acids (e.g., M1 is B(OH)2), organoboronic esters (e.g., M' is Bi-OQCF^QCF^O-)), organotrifluoroborates (e.g., M1 is BF3 ), organotin reagents (e.g., M1 is Sn(n-Bu)3, Sn(Me)3), Grignard reagents (e.g., M1 is gX1) or organozinc reagents (e.g., M1 is ZnX1) wherein X1 is Br or CI. Suitable transition metal catalysts include, but are not limited to: palladium(II) acetate, palladium(II) chloride, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, dichloro[l,r-bis(diphenylphosphino)ferrocene]palladium(H), bis(triphenyl- phosphine)dichloronickel(II) and copper(i) salts (e.g., copper(I) iodide, copper(I) bromide, copper(I) chloride, copper(I) cyanide or copper(I) triflate). As is understood by one skilled in the art, optimal conditions for each reaction will depend upon the catalyst used, the counterion attached to the coupling reagent (i.e. M1) and the halogen' attached to Formula la. In some cases the addition of a ligand such as a substituted phosphine or a substituted bisphosphinoalkane promotes reactivity. Also, the presence of a base (such as an alkali carbonate, tertiary amine or alkali fluoride) is typically necessary for reactions involving organoboron reagents of formula R'M1. For reviews of this type of reaction see: E. Negishi, Handbook of Organopalladium Chemistry for Organic Synthesis, John Wiley and Sons, Inc., New York, 2002; N. Miyaura, Cross-Coupling Reactions: A Practical Guide, Springer, New York, 2002; H. C. Brown et al., Organic Synthesis via Boranes, Vol. 3, Aldrich Chemical Co., Milwaukee, WI, 2002; Suzuki et al., Chemical Review 1995, 95(7), 2457-2483 and Molander et al., Accounts of Chemical Research 2007, 40, 275-286. For a reference relevant to pyrazolones see U.S. Patent Application Publication US 2007/0049574. Also, Example 4 illustrates the synthesis of a compound of Formula la wherein R1 is methyl from the corresponding compound wherein R1 is bromo.
Many variations of transition metal-catalyzed cross coupling reactions known in the art are also useful for preparing compounds of Formula la wherein R1 is alkyl, alkenyl, alkynyl, or the like including, for example, reaction of a terminal alkyne with Formula la wherein R1 is halogen using Sonogashira reaction conditions as shown in Scheme 2. The reaction typically involves the use of two catalysts, a zero-valent palladium complex (or one that can be reduced to Pd(0) in situ) and a halide salt of copper(I). Useful catalysts for this type of transformation include tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)- palladium(II) chloride, dichlorobis(tri-o-tolylphosphine)palladium, copper(I) iodide, copper(I) bromide and copper(I) chloride. Suitable solvents include amines (e.g., triethylamine or diethylamine), or solvents such as tetrahydrofuran, acetonitriie, ethyl acetate and N.N-dimethylformamide used in combination with a large excess of a base including, for example, triethylamine, diethylamine, potassium carbonate or cesium carbonate. The general method is taught by Campbell, Organocopper. Reagents 1994, 217-235; Sonogashira et al., Tetrahedron Letters 1975, 50, 4467-4470; Chinchilla et al., Chemical Review 2007, 107, 874-922 and Kosower et al., Journal of Organic Chemistry 1996, 67(17), 5871-5884. Scheme 2
Figure imgf000030_0001
R1^ is portion of R1 other wherein R1 is alkyl, alkenyl, wherein R is halogen
than terminal C≡C moiety) alkynyl, or the like
In a method analogous to Scheme 2, compounds of Formula lb can be lithiated by treatment with «-butyllithium (M-BuLi) followed by treatment of the anion with an organotin reagent (e.g., «-Bu3SnCl, Me3SnCl), a boronic acid (or ester) or an organozinc reagent (e.g., ZnC½) to provide compounds of Formula 2 as illustrated in Scheme 3. The chemical literature describes many related reactions, for references see, for example, Ragan et al., Organic Process Research & Development 2003, 7(5), 675-683; Buchwald et al:, Journal of the American Chemical Society 2004, 126, 13028-13032 and Gaare et al., Acta Chemica Scandinavica 1993, 47(1), 57-62. Treatment of the compound of Formula 2 with a halide of formula R'X2 using conditions analogous to those described for Scheme 2 provides Formula la wherein R1 is alkyl, alkenyl, alkynyl, or the like. Particularly useful catalysts for this method include bis(triphenylphosphine)palladium (II) dichloride, tetrakis(triphenyl- phosphine)palladium(O) and tris(dibenzylideneacetone)dipalladium(0).
Scheme 3
Figure imgf000030_0002
wherein M2 is (alkyl)3Sn, wherein R1 is alkyl, alkenyl,
BiOH^ or ZnX1 alkynyl, or the like
In some cases preparation of the lithium derivative of Formula 2 precludes the presence of other functionalities (e.g., esters and cyano groups). In such instances it may be more advantageous to use a magnesium derivative of Formula 2, which can be generated from Formula la wherein R1 is halogen (preferably iodo) and a Grignard reagent such as i-propylmagnesium bromide according to the procedure given by Knochel et al., Synlett 2000, (3), 345-346; Knochel et al., Synthesis 2005, (75), 2625-2629 and Knochel et al., Journal of Organic Chemistry 2000 65(15), 4618-4634.
Compounds of Formula la wherein R1 is halogen can also undergo nucleophilic displacement reactions to provide compounds of Formula la wherein R' is alkoxy, alkylthio, aikylamino, or the like (e.g., displacements with alkoxides, thiolates or alkylamides) as illustrated in Scheme 4. Typically these reactions are run in the presence of a suitable base (e.g., sodium hydride, potassium t-butoxide, potassium carbonate or triethylamine), a palladium, nickel or copper catalyst (e.g., tris(dibenzylideneacetone)dipalladium, palladium(II) acetate, bis(l ,5-cyclooctadiene)nickel or copper(I) iodide) and optionally a ligand (e.g., l,l'-bis(diphenylphosphino)ferrocene, l,3-bis(diphenylphosphino)propane, 2,2'- bis(diphenylphosphirio)-l,l'-binaphthalene, l ,l'-binaphthalene-2,2'-diol or 1,1,1-tris- (hydroxymethyl)ethane) in a solvent such as methanol, acetonitrile or NJV-dimethylformamide at a temperature between about room temperature (e.g.,-20 °C) and the reflux temperature of the solvent. For references describing the general method of Scheme 4 see Chen et al., Organic Letters 2006, 8, 5609-5612; Hartwig, Angew. Chem. Int. Ed. 1998, 37(15), 2046-2067 and Buchwald et al., Accounts of Chemical Research 1998, 37(12), 805-818.
heme 4
Figure imgf000031_0001
O, S or NH) la wherein R1 is halogen wherein R* is alkoxy, alkylthio, aikylamino, or the like
In alternate approach, compounds of Formula la wherein R1 is alkoxy can be prepared as outlined in Scheme 5. In this method, a compound of Formula la wherein R1 is halogen is first hydrolyzed with potassium hydroxide in an appropriate solvent such as toluene or methanol and in the presence of a phase transfer catalyst (e.g., benzyltrimethylammonium hydroxide) to provide the hydroxide compound of Formula 3. Subsequent treatment of the compound of Formula 3 with an electrophile of formula R'Lg (wherein Lg is a leaving group such as CI, Br, I or a sulfonate, for example, / oluenesulfonate, methanesulfonate or trifluoromethanesulfonate) provides compounds of- Formula la wherein R1 is alkoxy. For relevant references see Krohn et al., Archiv der Pharmazie 1989, 322(6), 351-354 and PCT Patent Application Publication WO 2006/071730.
Figure imgf000032_0001
la la wherein R is halogen wherein R is alkoxy In addition to the methods discussed in Schemes 2-5, compounds of Formula la wherein R1 is halogen are useful starting materials for other structural modifications providing additional compounds of Formula la. For example, reaction of a compound of Formula la wherein R1 is halogen with a cyanating reagent such as sodium cyanide, potassium cyanide, potassium hexacyanoferrate(II) or sodium hexacyanoferrate(II) provides compounds of Formula la wherein R1 is nitrile. There are a variety of conditions published in the chemistry literature which can be used for converting a halide to a nitrile, including copper-catalyzed conditions involving the use of a suitable copper source (e.g., copper(I) iodide), an amine ligand (e.g., N^V-dimethylethylenediamine) and an iodide salt (e.g., copper(I) iodide, sodium iodide, potassium iodide or zinc iodide). For references see, for example, Buchwald et al., Journal of the American Chemical Society 2003, J 25, 2890-2891 ; Schareina et al., Synlett 2007, 4, 555-558 and Schareina et al., Chem. Eur. J. 2007, 13, 6249- 6254.
Additionally, compounds of Formula la wherein R' is halogen can be used to prepare the corresponding compounds of Formula la wherein R' is thiocyanate (-SCN). Typical conditions involve. contacting the halide of Formula la with a thiocyanating agent such as ammonium thiocyanate or K[Cu(SCN)2] (generated in situ from equimolar amounts of copper(I) thiocyanate and potassium thiocyanate). The reaction can be carried out in a solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, 1 ,4-dioxane, ethanol or dimethylsulfoxide at a temperature between about room temperature (e.g., 20 °C) and the reflux temperature of the solvent. The reaction can also be carried put at higher temperatures using a microwave reactor. For references see, for example, Suzuki et al., Synthetic Communications 1996, 2(5(18), 3413-3419; Yamamoto et al., Chemical & Pharmaceutical Bulletin 1964, 12(4), 433-440 and Gakhar et al., Journal of Indian Chemical Society 1 74, 57(1 1), 941-943. As shown in Scheme 6, compounds of Formula l b can be prepared via a sequential condensation-ring closure reaction of a β-ketoester of Formula 4 and a hydrazine of formula R'NHNHQ2. The reaction is typically conducted in an appropriate solvent (e.g., acetonitrile, methanol, ethanol, toluene, pyridine) at a temperature between about room temperature (e.g., 20 °C) and 200 °C, optionally in the presence of an acid such as /7-toluenesulfonic acid, acetic acid or formic acid. The reaction can also be conducted using a microwave reactor, which in some cases may reduce reaction time. Depending on the reactants and reaction conditions, the method of Scheme 5 can result in mixtures of regioisomers. It is believed the reaction proceeds through nucleophilic attack of the less hindered hydrazine nitrogen on the β-ketoester to form a hydrazone intermediate (not shown), which cyclizes to the final product. For further discussion of the 'reaction mechanism and conditions see Katrizky et al., J. Chem. Soc. Perhn Trans. II 1987, 969-975 and Pal et al., Journal Brazilian Chemical Society 2008, 19(6), 1207-1214. Also, Example 1 , Step E illustrates the method of Scheme 5.
Scheme 6
Figure imgf000033_0001
wherein R is Me or Et lb
The starting β-ketoesters of Formula 4 and hydrazines of formula R!NHNHQ2 are commercially available and can be prepared methods well-known in the art. Example 1, Steps A-B illustrate a method for preparing a β-ketoester of Formula 4; and Example 1 , Steps C-D illustrate a method for preparing a hydrazine of formula R'NHNHQ2.
Alternatively, compounds of Formula lb can be prepared via the two step synthesis shown in Scheme 7. Using conditions analogous to those described for Scheme 6, β-ketoesters of Formula 4 are reacted with hydrazines of formula R'NHNH2 to form intermediates of Formula 5. For relevant references see Katrizky et al., J. Chem. Soc. Perkin Trans. II 1987, 969-975; Muller et al., Monatshefte fuer Chemie 1958, 89, 23-35; PCT Patent Application Publication WO 2006/116713 and U.S. Patent Application Publication US 2007/0049574. Intermediates of Formula 5 can then be reacted with halides of formula Q2X2 to provide compounds of Formula lb wherein Q2 is an aryl or heteroaryl ring or ring system. A variety of conditions published in the chemistry literature can be used for introduction of an aryl or heteroaryl ring onto Formula 5 including copper-catalyzed conditions involving the use of a suitable copper source (e.g., copper(I) iodide or copper(I) triflate) and a metal carbonate base (e.g., potassium or cesium carbonate) in a suitable solvent such as xylenes, dioxane or acetonitrile (see Buchwald et al., Tetrahedron Letters 1999, 40, 2657-2660 and Jiang et al., Journal of Organic Chemistry 2007, 72, 8943-8946).
Scheme 7
Figure imgf000034_0001
lb
In another method, compounds of Formula lb are prepared via the two-step synthesis shown in Scheme 8. In the first step, alkynoic esters of Formula 6 are reacted with hydrazines of formula Q'NHNF^ in the presence of a base (e.g., sodium hydroxide or potassium hydroxide) in a solvent such as methanol, ethanol or r/-butanol to provide intermediates of Formula 7 according to the procedure disclosed in PCT Patent Application Publication WO 2008/144463 and U.S. Patent Application Publication US 2007/0049574. Intermediates of Formula 7 can then be reacted with halides of formula R2X2 to provide compounds of Formula lb wherein R2 is alkyl, alkenyl, alkynyl, or the like. Typical reactions conditions involve combining a compound of Formula 7 with R2X2 in a solvent (e.g., N^V-dimethylformamide, methyl sulfoxide or acetone), in the presence of a base (e.g., potassium carbonate, sodium carbonate, /er/-butoxide, sodium hydroxide or potassium hydroxide) and optionally in the presence of a phase transfer catalyst. General procedures for conducting N-alkylations are known in the art and can be readily adapted to prepare compounds of Formula lb (see Wang et al., Organic Letters 2000, 2(20), 3107-3109; Alabaster et al., Journal of Med. Chemistry 1989, 32, 575-583; Kitazaki et al., Chem. Pharm. Bull. 2000, 48{\2), 1935-1946 and Jeon et al., Journal of Fluorine Chemistry 2007, 128, 1 191-1197). Scheme 8
Figure imgf000035_0001
As shown in Scheme 9, intermediates of Formulae 5 and 7 are also useful for preparing intermediates of Formulae 8 and 9, which can then be converted to compounds of Formula la. Using conditions analogous to those described for Method A of Scheme 1 compounds of Formulae 8 and 9 can be obtained from Formulae 5 and 1. Using methods analogous to those described in Schemes 7 and 8 compounds of Formulae 8 and 9 can be converted to compounds of Formula la.
Figure imgf000035_0002
wherein R is halogen
Compounds of Formula 1 wherein Y is O (i.e. Formula la) can be converted to the corresponding thioamides wherein Y is S 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).
One skilled in the art will recognize that for some compounds of Formula 1 the R3a, R3b, R3c and/or R3d substituents attached to the rings and ring systems of Q1 and Q2 may be more conveniently incorporated after forming the central pyrazolone ring with Qj and Q2 attached. In particular, when R3a, R3b, R3c and or R3d is halogen or another suitable leaving group, the leaving group can be replaced using various electrophilic, nucleophilic and organometallic reactions known in the art to introduce other functional groups as R3a, R3b, R3c and/or R3d.
Furthermore, compounds of Formula 1 wherein a ring or ring system of QJor Q2 is substituted with an R3a, R3b, R3c and/or R3d substituent which is -X-U-Z (as defined in the Summary of the Invention) can be prepared from the corresponding compounds of Formula 1 wherein R3a, R3b, R3c and/or R3d is a halogen or other suitable leaving group, such as by the general method described in PCT Patent Application Publication WO 07/149448 (see Scheme 15 therein). This reference also describes other general methods for forming an R3a, R3b, R3c and/or R3d substituent as -X-U-Z (see Schemes 16—19 therein).
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. Parts and percentages for chromatographic solvent mixtures are by volume unless otherwise indicated. The mass spectra (MS) value given in the following Examples 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), observed by mass spectrometry using electrospray ionization (ESI). !H NMR spectra are reported in ppm downfield from tetramethylsilane; "s" means singlet, "d" means doublet, "t" means triplet, "q" means quartet, "m" means multiplet.
EXAMPLE 1
Preparation of 1 -(4-chlorophenyl)-5-(2,6-difluoro-4-methoxyphenyl)-l ,2-dihydro-2-methyl-
3H-pyrazol-3-one (Compound 3)
Step A: Preparation of 2,6-difluoro-4-methoxybenzoyl chloride
To a mixture of 2,6-difluoro-4-methoxybenzoic acid (2.0■ g, 10.6 mmol) in dichloromethane (30 mL) were added oxalyl chloride (1.49 g, 1 1.7 mmol) and A,N-dimethylformamide (1 drop). The reaction mixture was heated at 50 °C for 3 h, cooled to room temperature and concentrated under reduced pressure to provide the title compound as an oil (2.0 g).
Step B: Preparation of ethyl 2,6-difluoro-4-methoxy-P-oxobenzenepropanoate
To a mixture of 3-ethoxy-3-oxopropanoic acid (3.51 g, 26.6 mmol) in tetrahydrofuran (40 mL) at -78 °C was added w-butyl lithium (1.6 M in hexanes, 33.2 mL, 53.2 mmol). The reaction mixture was stirred at -40 °C for 1 h and then cooled to -78 °C, and a solution of 2,6-difluoro-4-methoxybenzoyl chloride (i.e. the product of Step A) in tetrahydrofuran (10 mL) was added dropwise. The reaction mixture was stirred for 5 h at room temperature and then cooled to 0 °C, and hydrochloric acid (1.5 N, 5 mL) was added. The reaction mixture was diluted with water, the layers were separated, and the aqueous layer was extracted with ter/-butyl methyl ether. The combined organic layers were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography (10% /er/-butyl methyl ether in petroleum ether as eluant) to provide the title compound as an oil (2.0 g).
>H NMR (CDC13): 6 6.51-6.46 (m, 2H), 4.25-4.16 (q, 2H), 3.87 (s, 2H), 3.82 (s, 3H), 1.26- 1.23 (t, 3H).
Step C: Preparation of 2-(4-chlorophenyl)hydrazinecarboxaldehyde
To a mixture of 4-chlorophenylhydrazine hydrochloride (5.0 g, 27.9 mmol) in water (8 mL) and methyl formate (30 mL) was added potassium carbonate (5.0 g, 36.1 mmol). The reaction mixture was heated at 50 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with water, the layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was triturated with petroleum ether to provide the title compound as a solid (3.0 g).
*H NMR (DMSO-< 6): δ 9.76 (s, 1H), 8.09 (s, 1H), 7.97 (s, 1H), 7.19-7.15 (d, 2H), 6.71-6.68 (d, 2H).
ES1 MS OT/Z 157.
Step D: Preparation of 1 -(4-chlorophenyl)-2-methylhydrazine
To a mixture of lithium aluminum hydride (1.07 g, 28.1 mmol) in tetrahydrofuran (50 mL) at 0 °C was added a solution of 2-(4-chlorophenyl)hydrazinecarboxaldehyde (i.e. the product of Step C) (3.0 g, 17.6 mmol) in tetrahydrofuran (10 mL). The reaction mixture was heated at 60 °C for 5 h. The reaction mixture was cooled to -10 °C, and then water (1 mL), sodium hydroxide (10%, 1 mL) and more water (1 mL) were added sequentially. The reaction mixture was filtered through a bed of Celite® (diatomaceous filter aid) on a sintered glass frit funnel, and the filtrate was concentrated under reduced pressure to provide the title compound as an oil (2.3 g). . . ,
1 H NMR (CDC13): 6 7.17-7.15 (d, 2H), 6.91 -6.85 (d, 2H), 2.65 (s, 3H).
Step E: Preparation of l-(4-chlorophenyl)-5-(2,6-difluoro-4-methoxyphenyl)- 1 ,2- dihydro-2-methyl-3H-pyrazol-3-one
A mixture of ethyl 2,6-difluoro-4-methoxy- -oxobenzenepropanoate (i.e. the product of Step B) (1.65 g, 6.4 mmol) and l-(4-chlorophenyl)-2-methylhydrazine (i.e. the product of Step D) (1.0 g, 6.4 mmol) in pyridine (15 mL) was heated at 90 °C for 12 h. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. To a mixture of the resulting material in toluene (20 mL) was added /7-toluenesulfonic acid (0.1 g), and the reaction mixture was heated at 140 °C in a Biotage Initiator™ microwave apparatus for 1 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and the layers were separated. The organic layer was washed with aqueous sodium bicarbonate solution (10%), water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography (30% ethyl acetate in petroleum ether as eluant) to provide the title compound, a compound of the present invention, as a light brown solid (0.97 g).
lU NMR (DMSO-rf6): 7.49-7.47 (d, 2H), 7.20-7.18 (d, 2H), 6.80-6.78 (d, 2H) 5.38 (s, 1H),
3.75 (s, 3H), 3.08 (s, 3H).
Figure imgf000038_0001
EXAMPLE 2
Preparation of 4-bromo- 1 -(4-chlorophenyl)-5-(2,6-difluoro-4-methoxyphenyl)- 1 ,2-dihydro- 2-methyl-3H-pyrazol-3-one (Compound 1)
To a mixture of l-(4-chlorophenyl)-5-(2,6-difluoro-4-methoxyphenyl)-l,2-dihydro-2- methyl-3H-pyrazol-3-one (i.e. the product of Example 1, Step E) (0.5 g, 1.4 mmol) in carbon tetrachloride (20 mL) was added N-bromosuccinimide (0.25 g, 1.4 mmol) and 2,2'-azobis(2- methylpropionitrile) (AIBN) (0.023 g, 0.14 mmol). The reaction mixture was heated at 70 °C for 2 h, cooled to room temperature, and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether as eluant) to provide the title compound, a compound of the present invention, as a brown solid (0.5 g).
*H NMR (CDC13): 5 7.34-7.31 (d, 2H), 7.10-7.09 (d, 2H), 6.45-6.42 (d, 2H), 3.79 (s, 3H), 3.27 (s, 3H).
ESI MS w/z 431 (M+l).
EXAMPLE 3
Preparation of 4-chloro- 1 -(4-chlorophenyl)-5-(2.6-difluoro-4-methoxyphenyl)- 1 ,2-dihydro- 2-methyl-3H-pyrazol-3-one (Compound 2)
To a mixture of l-(chlorophenyl)-5-(2,6-difluoro-4-methoxyphenyl)-l,2-dihydro-2- methyl-3H-pyrazol-3-one (i.e. the product of Example 1, Step E) (0.10 g, 0.29 mmol) in carbon tetrachloride (15 mL) was added N-chlorosuccinimide (0.038 g, 0.29 mmol) and AIBN (0.005 g, 0.029 mmol). The reaction mixture was heated at 85 °C for 2 h, cooled to room temperature, and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether as eluant) to provide the title compound, a compound of the present invention, as a brown solid (0.11 g).
Ή NMR (CDCI3): δ 7.34-7.33 (d, 2Η), 7.1 1 -7.09 (d, 2Η), 6.45-6.43 (d, 2Η), 3.79 (s, 3Η), 3.27 (s, 3Η).
ESI MS m/z 3£5 (M+l). EXAMPLE 4
Preparation of 1 -(4-chlorophenyl)-5-(2,6-difluoro-4-methoxypheny 1)- 1 ,2-dihydro-2,4- dimethyl-3H-pyrazol-3-one (Compound 4)
To a mixture of 4-bromo-l-(4-chlorophenyl)-5-(2,6-difluoro-4-methoxyphenyl)-l,2- dihydro-2-methyl-3H-pyrazol-3-one (i.e. the product of Example 2) (0.30 g, 0.7 mmol) in dioxane (10 mL) was added potassium carbonate (0.386 g, 2.79 mmol), tetrakis(triphenylphosphine)palladium (0.04 g, 0.04 mmol) and trimethylboroxine (0.175 g, 1.39 mmol). The reaction mixture was heated at 120 °C in a Biotage Initiator™ microwave apparatus for 2 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, the layers were separated, and the organic layer was washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether as eluant) to provide the title compound, a compound of the present invention, as a brown solid (0.15 g).
]H NMR (CDC13): δ 7.28-7.25 (d, 2H), 7.05-7.03 (d, 2H), 6.44-6.40 (d, 2H), 3.78 (s, 3H),
3.21 (s, 3H), 1.85 (s, 3H).
ESI MS m/z 365 (M+l).
By the procedures described herein together with methods known in the art, the following compounds of Tables 1 to 5 can be prepared. The following abbreviations are used in the Tables which follow: Me means methyl, Et means ethyl, -Pr means isopropyl, c-Pr means cyclopropyl, Ph means phenyl, MeO means methoxy, EtO means ethoxy, MeS is methylthio, CN means cyano, Bn means benzyl and NO2 means nitro.
Table 1
Figure imgf000040_0001
Q2 is 4-Cl-Ph and R1 is CI.
Figure imgf000040_0002
Q2 is 4-Cl-Ph and R1 is CI;
(RJa)m
2-Cl, 6-F, 4-MeO 2-Cl, 6-F, 3-MeO 2-Cl, 6-F, 5-MeO 2,3,4,5,6-penta-F
Figure imgf000041_0001
The present disclosure also includes Tables 1A through 299 A, each of which is constructed the same as Table 1 above except that the row heading in Table 1 (i.e. "Q2 is 4-Cl-Ph and R1 is CI") is replaced with the respective row heading shown below. For example, in Table 1A the row heading is "Q2 is 4-Cl-Ph and R1 is H", and (R3a)m is as defined in Table 1 above. Thus, the first entry in Table l A specifically discloses l-(4- chlorophenyl)-l,2-dihydro-5-[(2-trifluoromethyl)phenyl)]-2-methyl-3H-pyrazol-3-one. Tables 2A through 299A are constructed similarly.
Table Row Heading
1A Q2 4-Cl-Ph and R1 is H.
2A Q2 4-Cl-Ph and R1 is Br.
3A Q2 4-Cl-Ph and R1 is Me.
4A Q2 4-Cl-Ph and R1 is CH2F.
5A Q2 3-Cl-Ph and R1 is H.
6A Q2 3-Cl-Ph and R1 is CI.
7A Q2 3-Cl-Ph and R1 is Br.
8A Q2 3-CI-Ph and R1 is Me.
9A Q2 3-Cl-Ph and R1 is CH2F.
10A Q2 -F-Ph and R1 is H.
11A Q2 -F-Ph and R1 is CI.
12A Q2 -F-Ph and R1 is Br.
13A Q2 -F-Ph and R1 is Me.
14A Q2 -F-Ph and R1 is CH2F
15A Q2 -Et-Ph and R1 is H.
16A Q2 -Et-Ph and R1 is CI.
17A Q2 -Et-Ph and R1 is Br.
18A Q2 -Et-Ph and R1 is Me. Table Row Heading 19A Q2 s 4-Et-Ph and R1 is CH2F.
20A Q2 s 2-CI, 4-F-Ph and R1 is H.
21A Q2 s 2-CI, 4-F-Ph and R1 is CI.
22A Q2 s 2-Cl, 4-F-Ph and R1 is Br.
23A Q2 s 2-Cl, 4-F-Ph and R1 is Me.
24A Q2 s 2-CI, 4-F-Ph and R1 is CH2F.
25A Q2 s 4-F, 3-Me-Ph and R1 is H.
26A Q2 s 4-F, 3-Me-Ph and R1 is CI.
27A Q2 s 4-F, 3-Me-Ph and R1 is Br.
28A Q2 s 4-F, 3-Me-Ph and R1 is Me.
29A Q2 s 4-F, 3-Me-Ph and R1 is CH2F.
30A Q2 s 3,4-d I-F-Ph arid R1 is H.
31A Q2 s 3,4-d: -F-Ph and R1 is CI.
32A Q2 s 3,4-d -F-Ph and R1 is Br.
33A Q2 is 3,4-d -F-Ph and R1 is Me.
34A Q2 s 3,4-d -F-Ph and R1 is CH2F.
35A Q2 s 3,4-d -Cl-Ph and R is H.
36A Q2 s 3,4-d -Cl-Ph and R is CI.
37A Q2 s 3,4-d -Cl-Ph and R is Br.
38A Q2 s 3,4-d Cl-Ph and R is Me.
39A Q2 s 3,4-d Cl-Ph and R is CH2F.
40A Q2 s 3,5-d MeO-Ph and R1 is H.
41A Q2 s 3,5-d -MeO-Ph and R1 is CI.
42A Q2 s 3,5-d MeO-Ph and R1 is Br.
43A Q2 s 3,5-d MeO-Ph and R1 is Me.
44A Q2 s 3,5-d MeO-Ph and R1 is CH2F.
45A Q2 s 2-CI, 3,5-di-MeO-Ph and R1 s H.
46A Q2 s 2-CI, 3,5-di-MeO-Ph and R1 s Cl. 47A Q2 s 2-CI, 3,5-di-MeO-Ph and R1 s Br. 48A Q2 s 2-CI, 3,5-di-MeO-Ph and R1 s Me. 49A Q2 s 2-CI, 3,5-di-MeO-Ph and R1 s CH2F. 50A Q2 s 4-Cl, 3,5-di-MeO-Ph and R1 s H.
5 IA Q2 s 4-CI, 3,5-di-MeO-Ph and R1 s Cl. 52A Q2 s 4-Cl, 3,5-di-MeO-Ph and R1 s Br. 53A s 4-Cl, 3,5-di-MeO-Ph and R1 s Me. Table Row Heading
54A Q2 i s 4-Cl, 3,5-di-MeG-Ph and R1 is CH2F.
55A s 4-GHF20-Ph and R1 is H.
56A s 4-CHF20-Ph and R1 is CI.
57A Q2 i s 4-CHF20-Ph and R1 is Br.
58A Q2 i s 4-CHF20-Ph and R1 is Me.
59A s 4-CHF20-Ph and R1 is CH2F.
60A s 3-CHF20-Ph and R1 is H.
61A Q2 ' s 3-CHF20-Ph and R1 is CI.
62A Q2 i s 3-CHF20-Ph and R1 is Br.
63A Q2 i s 3-CHF20-Ph and R1 is Me.
64A Q2 i s 3-CHF20-Ph and R1 is CH2F.
65A Q2 ! s 4-F-Ph and R1 is H.
66A Q2 ! s 4-F-Ph and R1 is CI.
67A Q2 I s 4-F-Ph and R1 is Br.
68A Q2 1 s 4-F-Ph and R1 is Me.
69A Q2 . s 4-F-Ph and R1 is CH2F.
70A Q2 > s 4-Me-Ph and R1 is H.
71A Q2 - 54-Me-Ph and R1 is CL
72A Q2 s 4-Me-Ph and R1 is Br.
73A Q2 s 4-Me-Ph and R* is Me.
74A Q2 5 4-Me-Ph and R1 is CH2F.
75A Q2 s 4-Cl, 3-F-Ph and R1 is H.
76A Q2 s 4-Cl, 3-F-Ph and R1 is CI.
77A Q2 s 4-Cl, 3-F-Ph and R1 is Br.
78A Q2 s 4-Cl, 3-F-Ph and R1 is Me.
79A Q2 s 4-Cl, 3-F-Ph and R1 is CH2F.
80A Q2 s 3-Cl, 4-F-Ph and R1 is H:
81A Q2 is 3-Cl, 4-F-Ph and R1 is CI.
82A Q2 is 3-Cl, 4-F-Ph and R1 is Br.
83A Q2 is 3-Cl, 4-F-Ph and R1 is Me.
84A Q2 is 3-Cl, 4-F-Ph and R1 is CH2F.
85A Q2 is 6-MeO-3-pyridinyI and R' is H.
86A Q2 is 6-MeO-3-pyridinyl and R1 is CI.
87A Q2 is 6-MeO-3-pyridinyl and R1 is Br.
88A Q2 is 6-MeO-3-pyridinyl and R' is Me. Table Row Heading 89A Q2 is 6-MeO-3-pyridinyl and R1 is CH2F. 90A Q2 is 6-Cl-3-pyridinyl and R1 is H.
91A Q2 is 6-Cl-3-pyridinyl and R1 is CI.
92A Q2 is 6-Cl-3-pyridinyl and R1 is Br.
93A Q2 is 6-Cl-3-pyridinyl and R^ is Me.
94A Q2 is 6-Cl-3-pyridinyl and R1 is CH2F.
95A Q2 is 6-CF3-3-pyridinyl and R1 is H.
96A Q2 is 6-CF3-3-pyridinyl and R1 is CI.
97A Q2 is 6-CF3-3-pyridinyl and R1 is Br.
98A Q2 is 6-CF3-3-pyridinyl and R' is Me.
99A Q2 is 6-CF3-3-pyridinyl and R1 is CH2F. 100A Q2 is 6-Br-3-pyridinyl and R1 is H.
101 A Q2 is 6-Br-3-pyridinyl and R1 is CI.
102 A Q2 is 6-Br-3-pyridinyl and R' is Br.
103 A Q2 s 6-Br-3-pyridiny) and R' is Me.
104A Q2 is 6-Br-3-pyridinyl and R' is CH2F.
105 A Q2 s 6-Me-3-pyridinyl and R' is H.
106 A Q2 is 6-Me-3-pyridinyl and R' is CI.
107 A Q2 is 6-Me-3-pyridiny) and R^ is Br.
108A Q2 s 6-Me-3-pyridinyl and R' is Me.
109 A Q2 is 6-Me-3-pyridinyl and R' is CH2F.
1 10A Q2 is 6-F-3-pyridinyl and R^ is H.
1 1 1 A Q2 s 6-F-3-pyridinyl and R^ is CI.
1 12A Q2 is 6-F-3-pyridinyl and R' is Br.
1 13A Q2 is 6-F-3-pyridinyl and R' is Me.
1 14A Q2 is 6-F-3-pyridinyl and R1 is CH2F.
1 15A Q2 is 2-Cl, 6-Me-4-pyridinyl and R1 is H. 1 16A Q2 is 2-Cl, 6-Me-4-pyridinyl and R1 is CI. 1 17A Q2 is 2-Cl, 6-Me-4-pyridinyl and R1 is Br. 1 18A Q2 is 2-Cl, 6-Me-4-pyridinyl and R' is Me. 1 19A Q2 is 2-Cl, 6-Me-4-pyridinyl and R1 is CH2F. 120A Q2 is 2-Cl, 6-MeO-3-pyridinyl and R1 is H. 121 A Q2 is 2-Cl, 6-MeO-3-pyridinyI and R1 is CI. 122 A Q2 is 2-Cl, 6-MeO-3-pyridinyl and R1 is Br. . 123A Q2 is 2-Cl, 6-MeO-3-pyridinyl and R1 is Me. Table Row Heading 124A Q2 s 2-Cl, 6-MeO-3-pyridinyl and R1 is CH2F. 125A Q2 s 2-Cl, 6-CF3-3-pyridinyt and R1 is H. 126A Q2 s 2-Cl, 6-CF3-3-pyridinyl and R1 is CI.
127 A Q2 s 2-Cl, 6-CF3-3-pyridinyi and R1 is Br.
128 A Q2 s 2-Cl, 6-CF3-3-pyridinyl and R1 is Me. 129A Q2 s 2-Cl, 6-CF3-3-pyridinyl and R1 is CH2F. 130A Q2 s 5-Cl-3-pyridinyl and R^ is H.
131A Q2 s 5-Cl-3-pyridinyl and R^ is CI.
132A Q2 s 5-Cl-3-pyridinyl and R' is Br.
133 A Q2 Is 5-Cl-3-pyridinyl and R' is Me.
134A Q2 s 5-Cl-3-pyridinyl and R1 is CH F.
135A Q2 s 5-F-3-pyridinyi and R' is H.
136A Q2 s 5-F-3-pyridinyl and R' is CI.
137A Q2 s 5-F-3-pyridinyl and R' is Br.
138A Q2 s 5-F-3-pyridinyl and R' is Me.
139A Q2 s 5-F-3-pyridinyl and R' is CH2F.
140A Q2 s 5-Me-3-pyridinyl and ' is H.
141A Q2 s 5-Me-3-pyridinyl and R ' is CI.
142A Q2 ,s 5-Me-3-pyridinyl and R' is Br.
143A Q2 s 5-Me-3-pyridinyl and R^ is Me.
144A Q2 s 5-Me-3-pyridinyl and R' is CH2F.
145A Q2 s 5-MeO-3-pyridinyl and R' is H.
146 A Q2 s 5-MeO-3-pyridinyl and R1 is CI.
147A Q2 s 5-MeO-3-pyridinyl and R' is Br.
148A Q2 s 5-MeO-3-pyridinyl and R^ is Me.
149A Q2 s 5-MeO-3-pyridinyl and R1 is CH2F. 150A Q2 s 6-CI, 5-MeO-3-pyridinyl and R1 is H. 151A Q2 s 6-Cl, 5-MeO-3-pyridinyl and R1 is CI. 152 A Q2 s 6-Cl, 5-MeO-3-pyridinyl and R1 is Br. 153A Q2 s 6-Cl, 5-MeO-3-pyridinyl and R' is Me.
154 A Q2 s 6-Cl, 5-MeO-3-pyridinyl and R1 is CH2F.
155 A Q2 s 6-Cl-3-pyridazinyl and R' is H.
156A Q2 s 6-Cl-3-pyridazinyl and R' is CI.
157A Q2 s 6-Cl-3-pyridazinyl and R' is Br.
158 A Q2 s 6-Cl-3-pyridazinyl and R' is Me. Row Heading
Q2 s 6-Cl-3-pyridazinyl and R1 is CH2F. Q2 is 6-MeO-3-pyridazinyI and R^ is H.
Q2 s 6-MeO-3-pyridazinyl and R^ is CI. Q2 s 6-MeO-3-pyridazinyl and R* is Br. Q2 s 6-MeO-3-pyridazinyl and R^ is Me. Q2 is 6-MeO-3-pyridazinyl and R1 is CH2F. Q2 s 6-CF3-3-pyridazinyI and R' is H.
Q2 s 6-CF3-3-pyridazinyl and R' is CI.
Q2 s 6-CF3-3-pyridazinyl and R' is Br.
Q2 s 6-CF3-3-pyridazinyl and R^ is Me. Q2 is 6-CF3-3-pyridazinyl and R^ is CH2F. Q2 s 5-Cl-3-pyridazinyl and R1 is H.
Q2 s 5-CI-3-pyridazinyl and R' is CI.
Q2 s 5-Cl-3-pyridazinyl and ^ is Br.
Q2 s 5-Cl-3-pyridazinyl and R^ is Me.
Q2 s 5-Cl-3-pyridazinyl and R1 is CH2F. Q2 s 5-F-3-pyridazinyl and R ' is H.
Q2 s 5-F-3-pyridazinyl and R 1 is CI.
Q2 s 5-F-3-pyridazinyl and R ' is Br.
Q2 s 5-F-3-pyridazinyl and R 1 is Me.
Q2 s 5-F-3-pyridazinyl and R ' is CH2F. Q2 s 5-MeO-3-pyridazinyl and R^ is H.
Q2 s 5-MeO-3-pyridazinyl and R' is CI. Q2 s 5-MeO-3-pyridazinyI and R^ is Br. Q2 s 5-MeO-3-pyridazinyl and R' is Me. Q2 s 5-MeO-3-pyridazinyl and R^ is CH2F. Q2 s 2-Cl-5-pyrimidinyl and R' is H.
Q2 s 2-CJ-5-pyrimidinyl and R1 is CI.
Q2 s 2-Cl-5-pyrimidinyl and R' is Br.
Q2 s 2-Cl-5-pyrimidinyI and R' is Me.
Q2 s 2-Cl-5-pyrimidinyl and ^ is CH2F. Q2 s 2-Me-5-pyrimidiny] and R^ is H.
Q2 s 2-Me-5-pyrimidinyl and R ' is CI.
Q2 s 2-Me-5-pyrimidinyl and R ' is Br.
Q2 is 2-Me-5-pyrimidinyl and R* is Me. Table Row Heading
194 A Q2 is 2-Me-5-pyrimidinyl and R* is CH2F.
195 A Q2 is 2-MeO-5-pyrimidinyl and R^ is H.
196 A Q2 s 2-MeO-5-pyrimidinyl and R^ is CI.
197 A Q2 s 2-MeO-5-pyrimidinyl and R' is Br.
198A Q2 s 2-MeO-5-pyrimidinyl and R^ is Me.
199 A Q2 s 2-MeO-5-pyrim)dinyl and R' is CH2F. 200A Q2 s 2-CF3-5-pyrimidinyl and is H.
201A Q2 s 2-CF3-5-pyrimidinyl and R' is CI.
202A Q2 s 2-CF3-5-pyrimidinyl and R' is Br.
203A Q2 s 2-CF3-5-pyrimidinyl and R' is Me.
204A Q2 s 2^CF3-5-pyrimidinyl and R1 is CH2F. 205A Q2 s 5 Cl-2-pyrimidinyl and R' is H.
206A Q2 s 5-Cl-2-pyrimidinyl and R1 is CI.
207A Q2 is 5-Cl-2-pyrimidinyl and R^ is Br.
208A Q2 s 5-Cl-2-pyrimidinyl and R' is Me.
209A Q2 s 5-Cl-2-pyrimidinyl and R1 is CH2F.
210A Q2 s 5-Me-2-pyrimidinyl and R^ is H.
21 A Q2 s 5-Me-2-pyrimidinyl and R' is CI.
212A Q2 s 5-Me-2-pyrimidinyI and R* is Br.
213A Q2 s 5-Me-2-pyrimidinyl and R' is Me.
214A Q2 s 5-Me-2-pyrimidinyl and R' is CH2F. 215A Q2 s 5-MeO-2-pyrimidinyl and R^ is H.
216A Q2 is 5-MeO-2-pyrimidinyl and R* is CI.
21 7A Q2 s 5-MeO-2-pyrimidinyl and R' is Br.
21 8A Q2 is 5-MeO-2-pyrimidinyl and R ' is Me.
219A Q2 s 5-MeO-2-pyrimidinyl and R' is CH2F. 220A Q2 is 5-CF3-2-pyrimidinyl and R^ is H.
221 A Q2 s 5-CF3-2-pyrimidinyl and R' is CI.
222A Q2 s 5-CF3-2-pyrimidinyl and R^ is Br.
223A Q2 s 5-CF3-2-pyrimidinyl and R ' is Me.
224A Q2 s 5-CF3-2-pyrimidinyI and R1 is CH2F. 225A Q2 s 4,6-di-MeO-l,3,4-triazin-2-yl and R1 is H. 226A Q2 s 4,6-di-MeO-l,3,4-triazin-2-yl and R1 is CI. 227A Q2 s 4,6-di-MeO-l,3,4-triazin-2-yl and R^ is Br. 228A Q2 s 4,6-di-MeO-l,3,4-triazin-2-yl and R' is Me. Table Row Heading
229A Q2 s 4,6-di-MeO-l,3,4-triazin-2-yl and R1 is CH2F.
230A Q2 s 5-Me-2-thienyI and Rl is H.
231A Q2 s 5-Me-2-thienyl and R1 is CI.
232A Q2 s 5-Me-2-thieny] and R1 is Br.
233A Q2 s 5-Me-2-thienyl and R1 is Me.
234A Q2 s 5-Me-2-thienyl and R1 is CH2F.
235A Q2 s 5-Cl-2-thienyl and R1 is H.
236A Q2 s 5-Cl-2-thienyl and R1 is CI.
237A Q2 s 5-Cl-2-thienyl and R1 is Br.
238A Q2 s 5-Cl-2-thienyl and R1 is Me.
239A Q2 s 5-Cl-2-thienyl and R1 is CH2F.
240A Q2 s 5-F-2-thienyl and R1 is H.
241A Q2 s 5-F-2-thienyl and R1 is CI.
242A Q2. s 5-F-2-thienyl and R1 is Br.
243A Q2 s 5-F-2-thienyl and R1 is Me.
244A Q2 s 5-F-2-thienyl and R1 is CH2F.
245A Q2 s 5-Me-3-thienyl and R1 is H.
246A Q2 s 5-Me-3-thienyJ and R1 is CI.
247A Q2 is 5-Me-3-thienyl and R1 is Br.
248A Q2 s 5-Me-3-thienyl and R^ is Me.
249A Q2 s 5-Me-3-thienyl and R1 is CH2F.
250A Q2 s 5-Cl-3-thieny I and R 1 is H.
251A Q2 ,s 5-Cl-3-thienyl and R1 is CI.
252A Q2 is 5-Cl-3-thienyl and R1 is Br.
253A Q2 s 5-Cl-3-thienyl and R1 is Me.
254A Q2 s 5-Cl-3-thienyl and R1 is CH2F.
255A Q2 s 5-F-3-thienyl and R1 is H.
256A Q2 is 5-F-3-thienyl and R1 is CI.
257A Q2 s 5-F-3-thienyl and R1 is Br.
258A Q2 s 5-F-3-thienyl and R* is Me.
259A Q2 s 5-F-3-thienyl and R1 is CH2F.
260A Q2 is l-Me-l /-pyrazoI-3-yl and R1 is H.
261 A Q2 s l-Me-l y-pyrazol-3-yl and R1 is CI.
262A Q2 s l-Me-lW-pyrazol-3-yl and R1 is Br.
263A Q2 s l-Me- l//-pyrazol-3-yl and R1 is Me. Table Row Heading
264A
265A
266A
267A
268A
269A
270A
271 A
272A
273A
274A
275A
276A
277A
278A
279A'
280A
281A
282A
283A
284A
285A
286A
287A
288A
289A
290A
291A
292A
293A
294A
295A
296A
297A
298A
Figure imgf000049_0001
Table Row Heading
299A Q2 is 4-F-Bn and R1 is CH2F.
Table 2
Q1 is 4-Cl-Ph and
Figure imgf000050_0002
Figure imgf000050_0001
The present disclosure also includes Tables IB through 299B, each of which is constructed the same as Table 2 above except that the row heading in Table 2 (i.e. "Q1 is 4-Cl-Ph and R1 is CI") is replaced with the respective row heading shown below. Thus, for example, in Table IB the row heading is "Q1 is 4-Cl-Ph and R1 is H", and (R5b)m is as defined in Table 2 above. Thus, the first entry in Table IB specifically discloses 5-(4- chlorophenyl)-l,2-dihydro-l-[(2-trifluoromethyl)phenyl)]-2-methyl-3H-pyrazol-3-one.
Tables 2B through 299B are constructed similarly.
Table Row Heading
IB Q1 is 4-Cl-Ph and R' is H.
2B Q1 is 4-Cl-Ph and R1 is Br.
3B Q1 is 4-Cl-Ph and R1 is Me. Table Row Heading 4B Q1 54-Cl-PhandR1 isCH2F.
5B Q1 s3-Cl-PhandR5 isH.
6B Q] s 3-Cl-Ph and R1 is CI.
7B Q1 s 3-Cl-Ph and R1 is Br.
8B Q1 s 3-Cl-Ph and R1 is Me.
9B Q1 s3-Cl-PhandR1 isCH2F.
10B Q1 s 3-F-Ph and R1 is H.
1 IB Q1 s 3-F-Ph and R1 is CI.
12B Q1 53-F-PhandR1 is Br.
13B Q1 is 3-F-Ph and R1 is Me.
14B Q1 53-F-PhandR1 isCH2F.
15B Q1 is 4-Et-Ph and R1 is H.
16B Q1 :s 4-Et-Ph and R1 is CI.
17B Q1 s 4-Et-Ph and R1 is Br.
18B Q1 s 4-Et-Ph and R1 is Me.
19B Q1 s 4-Et-Ph and R1 isCH2F.
20B Q1 s2-Cl,4-F-PhandRt isH.
21B Q] s2-Cl,4-F-Phand ' is CI.
22B Q] s2-C!,4-F-PhandR1 is Br.
23B Q1 s2-CI,4-F-PhandR1 is Me.
24B Q1 s 2-CI, 4-F-Ph and R1 is CH2F.
25B Q1 is 4-F, 3-Me- Ph and R1 is H.
26B Q1 s4-F, 3-Me-Ph and R1 is CI.
27B Q1 s 4-F, 3-Me-Ph and R1 is Br.
28B Q] s 4-F, 3-Me- Ph and R1 is Me.
29B Q1 s 4-F, 3-Me-Ph and R1 is CH2F.
30B Q1 s ,4-di-F-PhandR1 is H.
31B Q1 s3,4-di-F-PhandR' is CI.
32B Q1 s3,4-di-F-Ph and R1 is Br.
33B Q1 s 3,4-di-F-Ph and R1 is Me.
34B Q1 is 3,4-di-F-Ph and R1 is CH2F.
35B Q1 is 3,4-di-Cl-Ph and R1 is H.
36B oj s 3,4-di-Cl-Ph and R1 is CI.
37B Q1 s 3,4-di-Cl-Ph and Rl is Br.
38B s 3,4-di-Cl-Ph and R1 is Me. Table Row Heading
39B Q1 is 3,4-di-Cl-Ph and R1 is CH2F.
40B Q1 is 3,5-di-MeO-Ph and R1 is H.
41B Q1 is 3,5-di-MeO-Ph and R1 is CI.
42B Q1 is 3,5-di-MeO-Ph and R1 is Br.
43B Q1 is 3,5-di-MeO-Ph and R1 is Me.
44B Q1 is 3,5-di-MeO-Ph and R^ is CH2F.
45B Q1 is 2-Cl, 3,5-di-MeO-Ph and R1 is H.
46B Q1 is 2-Cl, 3,5-di-MeO-Ph and R 1 is CI.
47B Q1 is 2-Cl, 3,5-di-MeO-Ph and R1 is Br.
48B Q1 is 2-Cl, 3,5-di-MeO-Ph and R1 is Me.
49B Q1 is 2-Cl, 3,5-di-MeO-Ph and R1 is CH2F.
50B Q1 is 4-Cl, 3,5-di-MeO-Ph and R1 is H.
51B Q1 is 4-Cl, 3,5-di-MeO-Ph and R1 is CI.
52B Q1 is 4-Cl, 3,5-di-MeO-Ph and R1 is Br.
53B Q1 is 4-Cl, 3,5-di-MeO-Ph and R1 is Me.
54B Q* is 4-Cl, 3,5-di-MeO-Ph and R1 is CH2F.
55B Q5 is 4-CHF20-Ph and R1 is H.
56B Q1 is 4-CHF20-Ph and R1 is CI.
57B Q1 is 4-CHF20-Ph and R1 is Br.
58B Q' is 4-CHF20-Ph and R1 is Me.
59B Q1 is 4-CHF20-Ph and R1 is CH2F.
60B Q1 is 3-CHF20-Ph and R1 is H.
61B Q1 is 3-CHF20-Ph and R1 is CI.
62B Q1 is 3-CHF20-Ph and R1 is Br.
63B Q1 is 3-CHF20-Ph and R1 is Me.
64B Q1 is 3-CHF20-Ph and R1 is CH2F.
65B Q1 is 4-F-Ph and R1 is H.
66B Q1 is 4-F-Ph and R1 is CI.
67B Q1 is 4-F-Ph and R1 is Br.
68B .Q1 is 4-F-Ph and R' is Me.
69B Q1 is 4-F-Ph and R1 is CH2F.
70B Q1 is 4-Me-Ph and R1 is H.
71B Q1 is 4-Me-Ph and R1 is CI.
72B Q1 is 4-Me-Ph and R1 is Br.
73B Q1 is 4-Me-Ph and R^ is Me. Table Row Heading
74B Q1 is 4-Me-Ph and R1 is CH2F.
75B Q1 is 4-Cl, 3-F-Ph and R1 is H.
76B Q1 is 4-Cl, 3-F-Ph and R1 is CI.
77B Q1 is 4-Cl, 3-F-Ph and R1 is Br.
78B Q1 is 4-Cl, 3-F-Ph and R1 is Me.
79B Q1 is 4-Cl, 3-F-Ph and R1 is CH2F.
80B Q1 is 3-Cl, 4-F-Ph and R1 is H.
8 IB Q1 is 3-Cl, 4-F-Ph and R1 is CI.
82B Q1 is 3-Cl, 4-F-Ph and R1 is Br.
83B Q1 is 3-Cl, 4-F-Ph and R1 is Me.
84B Q1 is 3-Cl, 4-F-Ph and R1 is CH2F.
85B Q1 is 6-MeO-3-pyridinyl and R' is H.
86B Q1 is 6-MeO-3-pyridinyl and R^ is CI.
87B Q1 is 6-MeO-3-pyridinyl and R' is Br.
88B Q1 is 6-MeO-3-pyridinyl and R' is Me.
89B Q1 is 6-MeO-3-pyridinyl and R1 is CH2F.
90B Q1 is 6-Cl-3-pyridinyl and R' is H.
91B Q1 is 6-Cl-3-pyridinyl and R' is CI.
92B Q1 is 6-Cl-3-pyridinyl and R' is Br.
• ·
93B Q1 is 6-Cl-3-pyridinyl and R1 is Me.
94B Q1 is 6-Cl-3-pyridinyl and R1 is CH2F.
95B Q1 is 6-CF3-3-pyridinyl and R' is H.
96B Q1 is 6-CF3-3-pyridinyl and R' is CI.
97B Q1 is 6-CF3-3-pyridinyl and R' is Br.
98B Q1 is 6-CF3-3-pyridinyl and R' is Me.
99B Q' is 6-CF3-3-pyridinyl and R1 is CH2F.
100B Q1 is 6-Br-3-pyridinyl and R* is H.
101B Q1 is 6-Br-3-pyridinyl and R' is CI.
102B Q1 is 6-Br-3-pyridinyl and R' is Br.
103B Q1 is 6-Br-3-pyridinyl and R' is Me.
104B Q1 is 6-Br-3-pyridiny! and R1 is CH2F,
105B Q1 is 6-Me-3-pyridihyl and R' is H.
106B Q1 is 6-Me-3-pyridinyl and R ' is CI.
107B Q1 is 6-Me-3-pyridinyl and R ' is Br.
108B Q1 is 6-Me-3-pyridinyl and R ' is Me. Table Row Heading 109B Q s 6-Me-3-pyridinyl and R^ is CH2F.
HOB Q is 6-F-3-pyridinyl and Rl is H.
1 1 I B Q s 6-F-3-pyridinyl and R1 is CI.
1 I2B Q s 6-F-3-pyridinyl and R' is Br.
1 13B Q is 6-F-3-pyridinyI and R' is Me.
1 14B Q s 6-F-3-pyridinyI and R1 is CH2F.
1 15B Q is 2-Cl, 6-Me-4-pyridinyl and R1 is H. 1 16B Q is 2-CI, 6-Me-4-pyridinyl and R1 is CI. 1 17B Q is 2-Cl, 6-Me-4-pyridiny] and R* is Br. 1 18B Q is 2-C), 6-Me-4-pyridinyl and R' is Me. 119B Q is 2-Cl, 6-Me-4-pyridinyl and R1 is CH2F. 120B Q is 2-Cl, 6-MeO-3-pyridinyl and R1 is H. 121 B Q is 2-Cl, 6-MeO-3-pyridinyl and R1 is CI. 122B Q is 2-Cl, 6-MeO-3-pyridinyl and R1 is Br. 123B Q is 2-Cl, 6-MeO-3-pyridin I and R' is Me. 124B Q is 2-Cl, 6-MeO-3-pyridinyl and R1 is CH2F. 125B Q s 2-Cl, 6-CF3-3-pyridinyI and R1 is H. 126B Q s 2-Ci, 6-CF3-3-pyridinyl and R1 is CI. 127B Q s 2-Cl, 6-CF3-3-pyridinyl and R1 is Br. 128B Q s 2-Cl, 6-CF3-3-pyridinyl and R^ is Me. 129B Q s 2-Cl, 6-CF3-3-pyridinyl and R 1 is CH2F. 130B Q is 5-Cl-3-pyridinyl and R' is H.
131 B Q s 5-Cl-3-pyridinyl and R1 is CI.
132B Q s 5-Cl-3-pyridinyl and R' is Br.
133B Q s 5-Cl-3-pyridinyl and R' is Me.
134B Q is 5-Cl-3-pyridinyl and R1 is CH2F.
135B Q s 5-F-3-pyridinyl and R' is H.
136B Q s 5-F-3-pyridinyl and R' is CI.
137B Q s 5-F-3-pyridinyl and R' is Br.
138B Q s 5-F-3-pyridinyl and R^ is Me. .
139B Q s 5-F-3-pyridinyl and R1 is CH2F
140B Q s 5-Me-3-pyridinyl and R^ is H.
141 B Q s 5-Me-3-pyridinyl and R ^ is CI.
142B Q is 5-Me-3-pyridinyl and R' is Br.
143B Q s 5-Me-3-pyridinyl and R^ is Me. Table Row Heading
144B is 5-Me-3-pyridinyl and R1 is CH2F.
145B is 5-MeO-3-pyridinyI and R1 is H.
146B is 5-MeO-3-pyridinyl and R1 is CI.
147B is 5-MeO-3-pyridinyl and R^ is Br.
148B is 5-MeO-3-pyridinyl and R' is Me. , 149B is 5-MeO-3-pyridinyl and R1 is CH2F. 150B is 6-CJ, 5-MeO-3-pyridinyl and R1 is H. 151B is 6-CI, 5-MeO-3-pyridinyl and R1 is CI. 152B is 6-Cl, 5-MeO-3-pyridinyl and R1 is Br. 153B is 6-Cl, 5-MeO-3-pyridinyl and R^ is Me. 154B is 6-Cl, 5-MeO-3-pyridinyl and R1 is CH2F. 155B is 6-Cl-3-pyridazinyI and R' is H.
156B is 6-CI-3-pyridazinyl and R^ is CI.
I57B s 6-CI-3-pyridazinyl and R' is Br.
158B is 6-Cl-3-pyridazinyI and R^ is Me.
159B is 6-Cl-3-pyridazinyI and R! is CH2F. 160B s 6-MeO-3-pyridazinyI and R^ is H.
161 B s 6-MeO-3-pyridazinyl and R^ is CI.
162B s 6-MeO-3-pyridazinyl and R' is Br. 163B s 6-MeO-3-pyridazinyl and Rl is Me. 164B is 6-MeO-3-pyridazinyl and R^ is CH2F. 165B s 6-CF3-3-pyridazinyI and R' is H.
166B is 6-CF3-3-pyridazinyl and R' is CI.
167B is 6-CF3-3-pyridazinyl and R' is Br.
168B is 6-CF3-3-pyridazinyl and R^ is Me. I69B is 6-CF3-3-pyridazinyl and R^ is CH2F. 170B is 5-Cl-3-pyridazinyl and R' is H.
171B is 5-Cl-3-pyridazinyl and R' is CI.
172B is 5-Cl-3-pyridazinyl and R' is Br.
173B is 5-CI-3-pyridazinyl and R^ is Me.
174B is 5-C)-3-pyridazinyl and R' is CH2F. 175B is 5-F-3-pyridazinyI and R' is H.
176B is 5-F-3-pyridazinyl and ' is CI.
177B is 5-F-3-pytidazinyI and R ' is Br.
178B is 5-F-3-pyridazinyl and R' is Me. Table Row Heading 179B Q1 is 5-F-3-pyridazinyl and R1 is CH2F. 180B Q1 is 5-MeO-3-pyridazinyl and R is H. 181B Q1 s 5-MeO-3-pyridazinyl and R^ is Cl. 182B Q1 s 5-MeO-3-pyridazinyl and R^ is Br. 183B Q1 is 5-MeO-3-pyridazinyJ and is Me. 184B Q1 s 5-MeO-3-pyridazinyl and R* is CH2F. 185B Q1 s 2-CJ-5-pyrimidinyl and R1 is H.
186B Q1 is 2-Cl-5-pyrimidinyI and R* is Cl.
187B Q1 s 2-Cl-5-pyrimidinyl and R1 is Br.
188B Q1 s 2-Cl-5-pyrimidinyl and R' is Me.
189B Q1 is 2-CJ-5-pyrimidinyi and R1 is CH2F. 190B Q1 s 2-Me-5-pyrimidinyl and R' is H.
191B Q1 s 2-Me-5-pyrimidinyl and R* is Cl.
192B Q1 s 2-Me-5-pyrimidinyl and R* is Br.
193B Ql s'2-Me-5-pyrimidinyl and R' is Me. 194B Q1 s 2-Me-5-pyrimidinyl and R' is CH2F. J95B Q1 s 2-MeO-5-pyrimidinyl and R' is H. 196B Q1 is 2-MeO-5-pyrimidinyl and R' is Cl. 197B Q1 s 2-MeO-5-pyrimidinyl and R' is Br. 198B Q1 s 2-MeO-5-pyrimidinyl and R* is Me. 199B Q1 s 2-MeO-5-pyrimidinyI and R5 is CH2F. 200B Q' s 2-CF3-5-pyrimidinyl and R' is H.
201B Q1 s 2-CF3-5-pyrimidinyl and R^ is Cl. 202B Q1 s 2-CF3-5-pyrimidinyl and R^ is Br. 203B Q1 s 2-CF3-5-pyrimidinyl and R' is Me.204B Q1 s 2-CF3-5-pyrimidinyl and R1 is CH2F. 205B Q1 is 5-Cl-2-pyrimidinyl and R' is H.
206B Q1 s 5-Cl-2-pyrimidinyl and R' is Cl.
207B Q1 s 5-Cl-2-pyrimidinyl and R* is Br.
208B Q1 s 5-Cl-2-pyrimidinyl and R' is Me.
209B Q1 s 5-CI-2-pyrimidinyl and R is CH2F. 210B Q1 s 5-Me-2-pyrimidinyl and R' is H.
211B Q1 is 5-Me-2-pyrimidinyl and R' is Cl.
212B Q1 s 5-Me-2-pyrimidinyI and R^- is Br.
213B Q1 s 5-Me-2-pyrimidinyl and R* is Me.
Figure imgf000057_0001
Table Row Heading
249B Q1 s 5-Me-3-thieny] and R1 is CH2F.
250B Q1 s 5-Cl-3-thienyl and R1 is H.
251B Q1 s 5-Cl-3-thienyl and R1 is CI.
252B Q1 s 5-Cl-3-thienyl and R1 is Br.
253B Q1 s 5-Cl-3-thien I and R' is Me.
254B Q1 s 5-Cl-3-thienyl and R1 is CH2F.
255B Q1 s 5-F-3-thienyl and R1 is H.
256B Q1 s 5-F-3-thienyl and R1 is C).
257B Q1 s 5-F-3-thienyl and R1 is Br.
258B Q1 is 5-F-3-thienyl and R* is Me.
259B Q1 s 5-F-3-thienyl and R1 is CH2F.
260B Q1 s l-Me-l//-pyrazol-3-yi and R^ s H.
261B Q1 s l-Me-l//-pyrazol-3-yl and R1 s Cl.
262B Q1 s l-Me-l/ -pyrazol-3-yl and R' s Br.
263B Q1 s I-Me-l//-pyrazol-3-yl and R' s Me.
264B Q1 s ]-Me-l /-pyrazol-3-yl and R' s CH2F.
265B Q1 s l-Me-l//-pyrazol-4-yl and R^ s H.
266B Q1 s ?-Me-l/ -pyrazoI-4-yl and R' s Cl.
267B Q1 s l-Me-I /-pyrazoI-4-yl and R^ s Br.
268B Q1 s l-Me-l -pyrazol-4-yl and R' s Me.
269B Q1 s l-Me-l -pyra2ol-4-yl and R' s CH2F.
270B Q1 s 2-Me-5-thiazolyl and R1 is H.
271B Q1 s 2-Me-5-thiazolyl and R1 is CI.
272B Q1 s 2-Me-5-thiazolyl and R1 is Br.
273B Q1 s 2-Me-5-thiazolyl and R' is Me.
274B Q1 s 2-Me-5-thiazolyl and R1 is CH2F.
275B Q1 is 2-Cl-5-thiazolyl and R1 is H.
276B Q1 is 2-Cl-5-thiazolyl and R1 is CI.
277B Q1 is 2-Cl-5-thiazoIyl and R1 is Br.
278B Q1 s 2-Cl-5-thiazolyl and R1 is Me.
279B O1 is 2-C]-5-thiazolyl and R1 is CH2F.
280B Q1 s 5-Me-3-isot iazolyl and is H.
281 B Q1 is 5-Me-3-isothiazofyl and R^ is Ci.
282B Q1 is 5-Me-3-isothiazolyI and R' is Br.
283B Q1 is 5-Me-3-isothiazolyl and R' is Me. Table Row Heading
284B Q1 s 5-Me-3-isothiazolyl and R1 is CH2F. 285B Q1 s 5-Cl-3-isothiazoIyI and R1 is H.
286B Q1 s 5-Cl-3-isothiazolyl and R1 is CI.
287B Q1 s 5-Cl-3-isothiazolyl and R1 is Br.
288B Q1 s 5-Cl-3-isothiazolyl and R is Me.
289B Q1 is 5-Cl-3-isothiazolyl and R1 is CH2F. 290B Q1 s 4-Cl-Bn and R1 is H.
291B Q1 s 4-Cl-Bn and R1 is CI.
292B Q1 s 4-Cl-Bn and R1 is Br.
293B Q1 s 4-Cl-Bn and R1 is Me.
294B Q1 s 4-Cl-Bn and R1 is CH2F.
295B Q1 s 4-F-Bn and R1 is H.
296B Q1 5 4-F-Bn and R1 is CI.
297B Qi s 4-F-Bn and R1 is Br.
298B Q1 s 4-F-Bn and R' is Me.
299B Ql s 4-F-Bn and R1 is CH2F.
Table 3
Figure imgf000059_0001
Figure imgf000059_0002
Figure imgf000060_0001
Figure imgf000060_0002
Figure imgf000061_0001
Table 5
Figure imgf000061_0002
R1 is CI. R1 is Br.
Q1 Q2 Q1 Q2
2,6-di-F, 4-CN-Ph 4-Cl-Ph 2,6-di-F, 4-CN-Ph 4-Cl-Ph
2,6-di-F, 4-CN-Ph 3-F-Ph 2,6-di-F, 4-CN-Ph 3-F-Ph
2,6-di-F, 4-CN-Ph 4-F-Ph 2,6-di-F, 4-CN-Ph 4-F-Ph
2,6-di-F, 4-CN-Ph 3-CHF20-Ph 2,6-di-F, 4-CN-Ph 3-CHF2O Ph
2,6-di-F, 4-CN-Ph 2,6-di-F-Ph 2,6-di-F, 4-CN-Ph 2,6-di-F-Ph
2,6-di-F, 4-CN-Ph 2-Cl, 6-F-Ph 2,6-di-F, 4-CN-Ph 2-Cl, 6-F-Ph
2,6-di-F, 4-CN-Ph 4-C], 3-F-Ph 2,6-di-F, 4-CN-Ph 4-Cl, 3-F-Ph
2,6-di-F, 4-CN-Ph 3-Cl-Bn 2,6-di-F, 4-CN-Ph 3-Cl-Bn
2,6-di-F, 4-CN-Ph 4-Cl-Bn 2,6-di-F, 4-CN-Ph 4-Cl-Bn
2,6-di-F, 4-CN-Ph 5-MeO-3-pyridinyl 2,6-di-F, 4-CN-Ph 5-MeO-3-pyridinyl
2,6-di-F, 4-CN-Ph 6-MeO-3-pyridinyl 2,6-di-F, 4-CN-Ph 6-MeO-3 -pyridiny) ,6-di-F, 4-MeO-Ph 4-CI-Ph . 2,6-di-F, 4-MeO-Ph 4-Cl-Ph ,6-di-F, 4-MeO-Ph 3-F-Ph 2,6-di-F, 4-MeO-Ph 3-F-Ph ,6-di-F, 4-MeO-Ph 4-F-Ph 2,6-di-F, 4-MeO-Ph 4-F-Ph ,6-di-F, 4-MeO-Ph 3-CHF20-Ph 2,6-di-F, 4-MeO-Ph 3-CHF20-Ph ,6-di-F, 4-MeO-Ph 2,6-di-F-Ph 2,6-di-F, 4-MeO-Ph 2,6-di-F-Ph ,6-di-F, 4-MeO-Ph 2-Cl, 6-F-Ph 2,6-di-F, 4-MeO-Ph 2-Cl, 6-F-Ph ,6-di-F, 4-MeO-Ph 4-Cl, 3-F-Ph 2,6-di-F, 4-MeO-Ph 4-Cl, 3-F-Ph ,6-di-F, 4-MeO-Ph 3-CI-Bn 2,6-di-F, 4-MeO-Ph 3-Cl-Bn ,6-di-F, 4-MeO-Ph 4-Cl-Bn 2,6-di-F, 4-MeO-Ph 4-Cl-Bn ,6-di-F, 4-MeO-Ph 5-MeO-3-pyridinyl 2,6-di-F, 4-MeO-Ph 5-MeO-3-pyridiny] ,6-di-F, 4-MeO-Ph 6-MeO-3-pyridinyl 2,6-di-F, 4-MeO-Ph 6-MeO-3-pyridinyl
2,4,6-tri-F-Ph 4-Cl-Ph 2,4,6-tri-F-Ph 4-Cl-Ph
2,4,6-tri-F-Ph 3-F-Ph 2,4,6-tri-F-Ph 3-F-Ph R1 is CI. Rl is Br.
Q1 Q2 . Q1 Q2
2,4,6-tri-F-Ph 4-F-Ph 2,4,6-tri-F-Ph 4-F-Ph
2,4,6-tri-F-Ph 3-CHF20-Ph 2,4,6-tri-F-Ph 3-CHF20-Ph
2,4,6-tri-F-Ph 2,6-di-F-Ph 2,4,6-tri-F-Ph 2,6-di-F-Ph
2,4,6-tri-F-Ph 2-Cl, 6-F-Ph 2,4,6-tri-F-Ph 2-Cl, 6-F-Ph
2,4,6-tri-F-Ph 4-Cl, 3-F-Ph 2,4,6-tri-F-Ph 4-CI, 3-F-Ph
2,4,6-tri-F-Ph 3-Cl-Bn 2,4,6-tri-F-Ph 3-Cl-Bn
2,4,6-tri-F-Ph 4-CI-Bn 2,4,6-tri-F-Ph 4-Cl-Bn
2,4,6-tri-F-Ph 5-MeO-3 -pyridinyl 2,4,6-tri-F-Ph 5-MeO-3-pyridinyl
2,4,6-tri-F-Ph 6-MeO-3-pyridinyl 2,4,6-tri-F-Ph 6-MeO-3-pyridinyl
Formulation/Utility
A compound of Formula 1 of this invention (including N-oxides and salts thereof) 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^-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, w-butanol, isobutyl alcohol, w-hexanol, 2-ethylhexanol, w-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 Cg-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 diquatemary 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 ai 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 μπι can be wet milled using media mills to obtain particles with average diameters below 3 μπι. 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 urn range. Dusts and powders can be prepared by blending and usually grinding (such as with a hammer mill or fluids-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 Chemica 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 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., Black ell 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 construed as merely illustrative, and not limiting of the disclosure in any way whatsoever. Percentages are by weight except where otherwise indicated.
Example A
High Strength Concentrate
Compound 2 98.5% silica aerogel 0.5% synthetic amorphous fine silica 1.0% Example B
Wettable Powder
Compound 3 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 12 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 14 10.0% polyoxyethylene sorbitol hexoleate 20.0%
C6-C10 fatty acid methyl ester 70.0%
Example F
Microemulsion
Compound 15 5.0% polyvinylpyrrolidone-vinyl acetate copolymer 30.0% alkylpolyglycoside 30.0% glyceryl monooleate 15.0% water 20.0%
Example G
Seed Treatment
Compound 2 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. This aspect of the present invention can also be described as a method for protecting a plant or plant seed from diseases caused by fungal pathogens comprising applying a fungicidally effective amount of a compound of the invention (e.g., as a composition described herein) to the plant (or portion thereof) or plant seed (directly or through the environment (e.g., growing medium) of the plant or plant seed). 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 solahi and Alternaria brassicae, Guignardia diseases such as Guignardia bidwell, Venturia diseases such as Vent ria inaequalis, Sept or ia diseases such as Sept or ia nodorum and Sept or ia tritici, powdery mildew diseases such as Erysiphe spp. (including Erysiphe graminis and Erysiphe polygoni), Uncinula necatur, Sphaerotheca fuligena and Podosphaera leucotricha, Pseudocercosporella herpotrichoides, Botrytis diseases such as Botrytis cinerea, Monilinia fructicola, Sclerotinia diseases such as Sclerotinia sclerotiorum, Magnaporthe grisea, Phomopsis viticola, Helminthosporium diseases such as Helminthosporium tritici repentis, Pyrenophora teres, anthracnose diseases such as Glomerella or Colletotrichum spp. (such as Colletotrichum graminicola and Colletotrichum orbiculare), and Gae mannomyces 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 Sclerontina homoeocarpa); Rhizoctonia spp. (such as Rhizoctonia solani); Fusarium diseases such as Fusarium roseum, Fusarium graminearum and Fusarium oxysporum; Verticillium dahliae; Sclerotium rolfsii; Rynchosporium secalis; Cercosporidium personatum, Cercospora arachidicola and Cercospora beticqla; 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. 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, fruity 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.
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 (DM1) 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) glucopyfanosyl 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) behzene-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 benzimidazole and thiophanate fungicides. The benzimidazoles include benomyl, carbendazim, fuberidazole and thiabendazole. The thiophanates include thiophanate and thiophanate-methyl .
(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. DMI fungicides are divided between several chemical classes: azoles (including triazoles and imidazoles), pyrimidines, piperazines and pyridines. The triazoles include azaconazole, bitertanol, bromuconazole, cyproconazole, difenoconazole, diniconazole (including diniconazole-M), epoxiconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, imibenconazole, ipconazole, metconazole, myclobutanil, penconazole, propiconazole, prothioconazole, simeconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole and uniconazole. The imidazoles include clotrimazole, imazalil, oxpoconazole, prochloraz, pefurazoate and triflumizole. The pyrimidines include fenarimol and nuarimol. The piperazines include triforine. The pyridines include 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.
(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 acylalanine, oxazolidinone and butyrolactone fungicides. 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. Arnine/morpholine fungicides (also known as non-DMI sterol biosynthesis inhibitors) include morpholine, piperidine and spiroketal-amine fungicides. 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 phophorothiolate and dithiolane fungicides. 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 benzamides, furan carboxamides, oxathiin carboxamides, thiazole carboxamides, pyrazole carboxamides and pyridine carboxamides. The benzamides include benodanil, flutolanil and mepronil. 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, N-[2-(lS,2i?)-[l,r-bicyclopropyl]-2-ylphenyl]-3- (difluoromethyl)-l -methyl- lH-pyrazole-4-carboxamide and penflufen (N-[2-(l,3-dimethyl- butyl)phenyl]-5-fluoro-l,3-dimethyl-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) ' -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 1 1) 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 methoxyacrylate, methoxycarbamate, oximinoacetate, oximinoacetamide, oxazolidinedione, dihydrodioxazine, imidazolinone and benzylcarbamate fungicides. The methoxyacrylates include azoxystrobin, enestroburin (SYP-Z071), picoxystrobin and pyraoxystrobin (SYP-3343). The methoxycarbamates include pyraclostrobin and pyrametostrobin (SYP-4155). The oximinoacetates include kresoxim-methyl and trifloxystrobin. The oximinoacetamides include dimoxystrobin, metominostrobin, orysastrobin, a-[methoxyimino]-N-methyl-2-[[[l -[3-(trifluoromethyl)phenyl]ethoxy]imino]- methyljbenzeneacetarnide and 2-[[[3-(2,6-dichlorophenyl)-l-methyl-2-propen-l-ylidene]- ammo]oxy]methyl]-a-(methoxyi^^ The oxazolidinediones include famoxadone. The dihydrodioxazines include fluoxastrobin. The imidazolinones include fenamidone. The benzylcarbamates include pyribencarb.
(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) "Quinoline 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. Quinoxyfen and tebufloquin are examples of this class of fungicide.
(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 carbon and 1,2,4-thiadiazole fungicides. The aromatic carbon fungicides include biphenyl, chloroneb, dicloran, quintozene, tecnazene and tolclofos- methyl. The 1 ,2,4-thiadiazole ungicides 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 isobenzofixranone, pyrroloquinolinone and triazolobenzothiazole fungicides. 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 cyclopropanecarboxamide, carboxamide and propionamide fungicides. The cyclopropanecarboxamides include carpropamid. The carboxamides include diclocymet. The propionamides include fenoxanil.
(17) "Hydroxyanilide 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 thiocarbamate and allylamine fungicides. The thiocarbamates include pyributicarb. The allylamines include naftifine and terbinafine.
(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" (Qj) 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 cyanoimidazole and sulfamoyltriazole fungicides. 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. Propamacarh, 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 isoxazole and isothiazolone fungicides. 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 amide, valinamide carbamate and mandelic acid amide fungicides. The cinnamic acid amides include dimethomorph and flumorpb. The valinamide carbamates include benthiavalicarb, benthiavalicarb-isopropyl, iprovalicarb, valifenalate and valiphenal. 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]butanamide and N-[2-[4-[[3-(4- chlorophenyl)-2-propyn- 1 -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 (b42)" (Fungicide Resistance Action Committer (FRAC) code 42) include methasulfocarb.
(43) "Benzamide fungicides" (Fungicide Resistance Action Committee (FRAC) cod( 43) inhibit growth of fungi by derealization of spectrin-like proteins. Examples includt acylpicolide fungicides such as fluopicolide and fluopyram.
(44) "Host plant defense induction fungicides" (Fungicide Resistance Actio! Committee (FRAC) code P) induce host plant defense mechanisms. Host plant defens induction fungicides include benzo-thiadiazole, benzisothiazole and thiadiazole-carboxamid fungicides. The benzo-thiadiazoles include acibenzolar-S-methyl. The benzisothiazole include probenazole. The thiadiazole-carboxamides include tiadinil and isotianil.
(45) "Multi-site contact fungicides" inhibit fungal growth through multiple sites ( action and have contact/preventive activity. This class of fungicides includes: (45.' "copper fungicides" (Fungicide Resistance Action Committee (FRAC) code Ml)", (45.- "sulfur fungicides" (Fungicide Resistance Action Committee (FRAC) code M2), (45.. "dithiocarbamate fungicides" (Fungicide Resistance Action Committee (FRAC) code M3 (45.4) "phthalimide fungicides" (Fungicide Resistance Action Committee (FRAC) co< M4), (45.5) "chloronitrile fungicides" (Fungicide Resistance Action Committee (FRA< code M5), (45.6) "sulfamide fungicides" (Fungicide Resistance Action Committee (FRA' code M6), (45.7) "guanidine fungicides" (Fungicide Resistance Action Committee (FRA1 code M7), (45.8) "triazine fungicides" (Fungicide Resistance Action Committee (FRA code M8) and (45.9) "quinone fungicides" (Fungicide Resistance Action Committee (FRA code M9). "Copper fungicides" are inorganic compounds containing copper, typically in 1 copper(II) oxidation state; examples include copper oxychloride, copper sulfate and copj hydroxide, including compositions such as Bordeaux mixture (tribasic copper sulfal "Sulfur fungicides" are inorganic chemicals containing rings or chains of sulfur ator examples include elemental sulfur. "Dithiocarbamate fungicides" contain a dithiocarbamate molecular moiety; examples include mancozeb, metiram, propineb, ferbam, manebj 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) "phenyl-acetarnide fungicides" (Fungicide Resistance Action Committee (FRAC) code U6), (46.3) "quinazolinone fungicides" (Fungicide Resistance Action Committee (FRAC) code U7), (46.4) "benzophenone fungicides" (Fungicide Resistance Action Committee (FRAC) code U8) and (46.5) "triazolopyrimidine fungicides". The thiazole carboxamides include ethaboxam. The phenyl-acetamides include cyflufenamid and N-[[(cyclopropylmethoxy)- amino] [6-(difluoromethoxy)-2,3-difluorophenyl]-methylene]benzeneacetamide. The quinazolinones include proquinazid and 2-butoxy-6-iodo-3-propyI-4H-l-benzopyran-4-one. The benzophenones include metrafenone. The triazolopyrimidines include ametoctradin. The (b46) class also includes bethoxazin, neo-asozin (ferric methanearsonate), pyrrolnitrin, quinomethionate, N-[2-[4-[[3-(4-chlorophenyl)-2-propyn-l-yl]oxy]-3-methoxyphenyl]ethyl]- 3-methyl-2-[(methylsulfonyl)amino]butanamide, N-[2-[4-[[3-(4-chlorophenyl)-2-propyn- 1 - 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-tri- fluorophenyl)-7-(4-methylpiperidin- 1 -yl)[ 1 ,2,4]triazolo[l ,5-a]pyrimidine, N-(4-chloro-2- nitrophenyl)-N-ethyl-4-methylbenzenesulfonamide, N-[[(cycIopropylmethoxy)amino][6-(di- fluoromethoxy)-2,3-difluorophenyl]methylene]benzeneacetamide, N'-[4-[4-chloro-3-(tri- fluoromemyl)phenoxy]-2,5-dimethylphenyl]-N-ethyl-N-methylmethanimidamide, 1 -[(2- propenylthio)carbonyl]-2-(l-methylethyl)-4-(2-methylphenyl)-5-amino-lH-pyrazol-3-one and 1 -[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-l -piperidinyl]-2- [5-methyl-3-(trifluoromethy )- lH-pyrazol-1 -yl]-ethanone.
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, metaflumizone, metaldehyde, methamidophos, methidathion, methomyl, methoprene, methoxychlor, metofluthrin, milbemycin oxime, monocrotophos, methoxyfenozide, 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, sulprofos, tebufenozide, teflubenzuron, tefluthrin, terbufos, tetrachlorvinphos, 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.
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) pyrimidinone fungicides; (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.
Pyrimidinone fungicides (group (4)) include compounds of Formula Al
Figure imgf000081_0001
Al
wherein M forms a fused phenyl, thiophene or pyridine ring; R1 1 is Cj-C6 alkyl; R12 is Cj-Cg alkyl or Cj-C^ alkoxy; R13 is halogen; and R1 is hydrogen or halogen.
Pyrimidinone fungicides are described in PCT Patent Application Publication WO 94/26722 and U.S. Patents 6,066,638, 6,245,770, 6,262,058 and 6,277,858. Of note are pyrimidinone fungicides selected from the group: 6-bromo-3-propyl-2-propyloxy- 4(3H)-quinazolinone, 6,8-diiodo-3-propyl-2-propyloxy-4(3H)-quinazolinone, 6-iodo- 3-propyl-2-propyloxy-4(3H)-quinazolinone (proquinazid), 6-chloro-2-propoxy-3-propyI- thieno[2,3-< |pyrimidin-4(3H)-one, 6-bromo-2-propoxy-3-propylthieno[2,3-i/]pyrimidin- 4(3H)-one, 7-bromo-2-propoxy-3-propylthieno[3,2-i ]pyrimidin-4(3H)-one, 6-bromo- 2-propoxy-3-propylpyrido[2,3-i/lpyrimidin-4(3H)-one, 6,7-dibromo-2-propoxy-3-propyl- thieno[3,2-i/Jpyrimidin-4(3H)-one, and 3-(cyclopropylmethyl)-6-iodo-2-(propylthio)pyrido- [2 ,3 -i ]pyrimidin-4(3H)-one.
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.
be] 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 ytochrome c oxidoreductase. This complex is uniquely identified by Enzyme Commission number ECl.10.2.2. The bc\ complex is described in, for example, J. Biol. Chem. 1989, 264, 14543^8; Methods Enzymol. 1986, 726, 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 7V-[2-(l,3-dimethylbutyl)phenyl]-5-fluoro-l,3-dimethyl-lH- pyrazole-4-carboxamide (PCT Patent Publication WG 2003/010149), and are known to inhibit mitochondrial function by disrupting complex II (succinate dehydrogenase) in the respiratory electron transport chain. Copper compounds (group (1 1)) 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 morpholines 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.
Of further note are combinations of compounds of Formula 1 with azoxystrobin, kresoxim-methyl, trifloxystrobin, pyraclostrobin, picoxystrobin, dimoxystrobin, metominostrobin/fenominostrobin, carbendazim, chlorothalonil, quinoxyfen, metrafenone, cyflufenamid, fenpropidine, fenpropimorph, bromuconazole, cyproconazole, difenoconazole, epoxiconazole, fenbuconazole, flusilazole, hexaconazole, ipconazole, metconazole, penconazole, propiconazole, proquinazid, prothioconazole, tebuconazole, triticonazole, famoxadone, prochloraz, penthiopyrad and boscalid (nicobifen).
Preferred for better control of plant diseases caused by fungal plant pathogens (e.g., lower use rate or broader spectrum of plant pathogens controlled) or resistance management are mixtures of a compound of this invention with a fungicide selected from the group: azoxystrobin, kresoxim-methyl, trifloxystrobin, pyraclostrobin, picoxystrobin, dimoxystrobin, metominostrobin/fenominostrobin, quinoxyfen, metrafenone, cyflufenamid, fenpropidine, fenpropimorph, cyproconazole, epoxiconazole, flusilazole, metconazole, propiconazole, proquinazid, prothioconazole, tebuconazole, triticonazole, famoxadone and penthiopyrad. Specifically preferred mixtures (compound numbers refer to compounds in Index Table A) are selected from the group: combinations of Compound 1 , Compound 2, Compound 4, Compound 12, Compound 14 or Compound 15 with azoxystrobin, combinations of Compound 1, Compound 2, Compound 4, Compound 12, Compound 14 or Compound 15 with kresoxim-methyl, combinations of Compound 1, Compound 2, Compound 4, Compound 12, Compound 14 or Compound 15 with trifloxystrobin, combinations of Compound 1, Compound 2, Compound 4, Compound 12, Compound 14 or Compound 15 with picoxystrobin, combinations of Compound 1, Compound 2, Compound 4, Compound 12, Compound 14 or Compound 15 with metominostrobin/fenominostrobin, combinations of Compound 1, Compound 2, Compound 4, Compound 12, Compound 14 or Compound 15 with quinoxyfen, combinations of Compound 1, Compound 2, Compound 4, Compound 12, Compound 14 or Compound 15 with metrafenone, combinations of Compound 1 , Compounds, Compound 4, Compound 12, Compound 14 or Compound 15 with fenpropidine, combinations of Compound 1 , Compound 2, Compound 4, Compound 12, Compound 14 or Compound 15 with fenpropimorph, combinations of Compound 1 , Compound 2, Compound 4, Compound 12, Compound 14 or Compound 15 with cyproconazole, combinations of Compound 1, Compound 2, Compound 4, Compound 12, Compound 14 or Compound 15 with epoxiconazole, combinations of Compound 1, Compound 2, Compounds, Compound 12, Compound 14 or Compound 15 with flusilazole, combinations of Compound 1 , Compound 2, Compound 4; Compound 12, Compound 14 or Compound 15 with metconazole, combinations of Compound 1, Compound s, Compound 4, Compound 12, Compound 14 or Compound 15 with propiconazole, combinations of Compound 1 , Compound 2, Compound 4, Compound 12, Compound 14 or Compound 15 with proquinazid, combinations of Compound 1, Compound 2, Compound A, Compound 12, Compound 14 or Compound 15 with prothioconazole, combinations of Compound 1 , Compound 2, Compound 4, Compound 12, Compound 14 or Compound 15 with tebuconazole, combinations of Compound 1, Compound 2, Compound 4, Compound 12, Compound 14 or Compound 15 with triticonazole, combinations of Compound 1, Compound 2, Compound 4, Compound 12, Compound 14 or Compound 15 with famoxadone, Compound 1 , Compound 2, Compound 4, Compound 12, Compound 14 or Compound 15 with penthiopyrad, combinations of Compound 1 , Compound 2, Compound 4, Compound 12, Compound 14 or Compound 15 with 3-(difluoromethyl)-l -methyl-N-(3',4',5'- trifluoro[l,r-biphenyl]-2-yl)-lH-pyrazole-4-carboxamide, combinations of Compound 1 , Compound 2, Compound 4, Compound 12, Compound. 14 or Compound 15 with 5-ethyl-6- octyl-[l,2,4]triazole[ l ,5-fl]pyrimidin-7-amine, combinations of Compound 1 , Compound 2, Compound 4, Compound 12, Compound 14 or Compound 15 with ametoctradin and combinations of Compound 1 , Compound 2, Compound 4, Compound 12, Compound 14 or Compound 15 with l -[4-[4-[5-(2,6-difluorophenyl)-4j5-dihydro-3-isoxazolyl]-2-thiazolyl]-l- piperidinyl]-2-[5-memyl-3-(trifluoromethyl)-lH-pyrazol-l -yl]-ethanone.
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 compound descriptions. See Index Table B for NMR data. The following abbreviations are used in the Index Table: Me is methyl, Ph is phenyl, Bn is benzyl and MeO is methoxy. 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. In Index Table A 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., 37C, 81C) is not reported. The reported M+1 peaks were observed by mass spectrometry using atmospheric pressure chemical ionization (AP+).
Figure imgf000085_0001
Cmpd. Q1 Q2 Rl AP+ (M+1)
1 (Ex. 2) 2,6-di-F, 4-MeO-Ph 4-CI-Ph Br **
2 (Ex. 3) 2,6-di-F, 4-MeO-Ph 4-CI-Ph CI **
3 (Ex. 1) 2,6-di-F, 4-MeO-Ph 4-Cl-Ph H **
4 (Ex. 4) 2,6-di-F, 4-MeO-Ph 4-Cl-Ph Me **
5 2,6-di-F, 4-MeO-Ph Bn CI 365
6 2,6-di-F, 4-MeO-Ph Bn Me 345
7 2,6-di-F, 4-MeO-Ph Bn H 331
8 2,6-di-F, 4-MeO-Ph Bn Br 409
9 2,6-di-F, 3-MeO-Ph 4-CI-Ph Me *
10 2,6-di-F, 3-MeO-Ph 4-Cl-Ph Br *
1 1 2,6-di-F, 3-MeO-Ph 4-Cl-Ph H *
12 2,6-di-F, 3-MeO-Ph 4-Cl-Ph CI *
13 2,6-di-F, 3-MeO-Ph 3-F-Ph H 335
14 2,6-di-F, 3-MeO-Ph 3-F-Ph Br 323
15 2,6-di-F, 3-MeO-Ph 3-F-Ph CI 369
16 4-Cl-Ph 2,6-di-F, 4-MeO-Ph Br 429
17 4-Cl-Ph 2,6-di-F, 4-MeO-Ph CI 385
18 2,6-di-F, 4-MeO-Ph 6-MeO-3 -p ridiny 1 CI 382
19 2,6-di-F, 4-MeO-Ph 6-MeO-3 -pyridinyl Br 326
20 4-Cl-Ph 2,6-di-F, 4-MeO-Ph H 351
21 2,6-di-F, 4-MeO-Ph 6-MeO-3 -pyridinyl H 348
* See Index Table B for 1 H NMR data.
** See synthesis example forΉ NMR data. INDEX TABLE B
Compd. No. 1 H NMR Data (CDCI3 solution unless indicated otherwise)3
9 δ 7.27-7.25 (d, 2H), 7:07-7.04 (d, 2H), 6.93-6.90 (m, 1H), 6.8-6.77 (m, 1H), 3.84 (s, 3H),
3.21 (s, 3H), 1.86 (s, 3H).
10 δ 7.33-7.30 (d, 2H), 7.12-7.10 (d, 2H), 7.01-6.96 (m, 1H), 6.86-6.81 (m, 1H), 3.86 (s, 3H),
3.28 (s, 3H).
1 1 8 7.33-7.29 (d, 2H), 7.12-7.09 (d, 2H), 6.95-6.89 (m, 1H), 6.81-6.75 (m, 1 H); 5.88 (s, 1H),
3.83 (s, 3H), 3.23 (s, 3H).
12 δ 7.34-7.30 (d, 2H), 7.14-7: 10 (d, 2H), 6.99-6.95 (m, 1H), 6.86-6.81 (m, 1H), 3.85 (s, 3H),
3.27 (s, 3H).
a ' H NMR data are in ppm downfield from tetramethylsilane. Couplings are designated by "s"singlet, "d"doublet, "m"multiplet.
BIOLOGICAL EXAMPLES OF THE INVENTION
General protocol for preparing test suspensions for Tests A-F: 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-F. Spraying a 200 ppm test suspension to the point of run-off on the test plants was the equivalent of a rate of 500 g/ha.
TEST A
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 Botrytis cinerea (the causal agent of tomato Botrytis) and incubated in saturated atmosphere at 20 °C for 48 h, and then moved to a growth chamber at 24 °C for 3 days, after which time disease ratings were visually made.
TEST B
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 Alternaria solani (the causal agent of tomato early blight) and incubated in a saturated atmosphere at 27 °C for 48 h, and then moved to a growth chamber at 20 °C for 5 days, after which time visual disease ratings were made.
TEST C
The test suspension was sprayed to the point of run-off on wheat seedlings. The following day the seedlings were inoculated with a spore suspension of Septoria nodorum (the causal agent of wheat glume blotch) and incubated in a saturated atmosphere at 24 °C for 48 h, and then moved to a growth chamber at 20 °C for 9 days, after which time disease ratings were visually made.
TEST D
The test suspension was sprayed to the point of run-off on wheat seedlings. The following day the seedlings were inoculated with a spore suspension of Septoria tritici (the causal agent of wheat leaf blotch) and incubated in saturated atmosphere at 24 °C for 48 h, and then moved to a growth chamber at 20 °C for 19 days, after which time visual disease ratings were made.
TEST El
Wheat seedlings were inoculated with a spore suspension of Puccinia recondita f. sp. tritici (the causal agent of wheat leaf rust) and incubated in a saturated atmosphere at 20 °C for 24 h, and then moved to a growth chamber at 20 °C for 2 days. At the end of this time the test suspension was sprayed to the point of run-off on the wheat seedlings, and then the seedlings were moved to a growth chamber at 20 °C for 4 days, after which time visual disease ratings were made.
TEST E2
The test suspension was sprayed to the point of run-off on wheat seedlings. The following day the seedlings were inoculated with a spore suspension of Puccinia recondita (the causal agent of wheat leaf rust) and incubated in a saturated atmosphere at 20 °C for 24 h, and then moved to a growth chamber at 20 °C for 6 days, after which time visual disease ratings were made
TEST F
The test suspension was sprayed to the point of run-off on wheat seedlings. The following day the seedlings were inoculated with a spore dust of Erysiphe graminis f. sp. tritici, (the causal agent of wheat powdery mildew) and incubated in a growth chamber at 20 °C for 7 days, after which time disease ratings were visually made.
Results for Tests A-F 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). A dash (-) indicates no test results. All results are for 200 ppm except where followed by "*", which indicates 40 ppm.
Table A
Cmpd. No. Test A Test B Test C Test D Test El Test E2 Test F . 1 100 100 98 99 7 100 94
2 100 100 99 100 0 99 90 Cmpd. No. Test A Test B Test C Test D Test El Test E2 Test F
3 100 99 0 99 0 86 89
4 100 99 - 100 59 99 99
5 100 93 0 95 8 91 58
6 99 24 0 96 96 24 0
7 99 0 0 87 0 0 62
8 100 98 0 95 10 94 73
9 100 93 87 100 47 98 98
10 99 99 97 100 37 99 99
11 100 99 0 99 8 17 96
12 100 99 98 99 52 99 98
13 94 17 0 91 8 27 0
14 99 95 72 99 0 99 99
15 100 99 64 99 0 100 100
16 99 93 0 83* 0 74 97
17 99 99 0 93* 0 68 69
18 99 97 0 86* 0 100 98
19 99 98 0 96* 0 100 98
20 98 40 0 30* 0 89 79
21 95 0 0 0* 0 91 95

Claims

What is claimed is:
1. A compound selected from Formula 1 , N-oxides and salts thereof,
Figure imgf000089_0001
1
wherein
Y is O or S;
Q1 is a phenyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 5 substituents independently selected from R3a; or a 5- to 6-membered fully unsaturated heterocyclic ring or an 8- to 10-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, 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(=0)q(=NR4)p, each ring or ring system optionally substituted with up to 5 substituents independently selected from R3a on carbon atom ring members and R3b on nitrogen atom ring members; or C(R5aR5b)W"l, N(R5c)Wl, OW» or S(=0)nWl;
WMs a phenyl ring optionally substituted with up to 5 substituents independently selected from R3a; or a 5- to 6-membered fully unsaturated heterocyclic 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, wherein up to 2 carbon atom ring members are independently selected from C(=0) and C(=S), and the sulfur atom ring members are independently selected from S(=0)q(=NR4)p, the ring optionally substituted with up to 5 substituents independently selected from R3a on carbon atom ring members and R3b on nitrogen atom ring members;
Q2 is a phenyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 5 substituents independently selected from R3c; or a 5- to 6-membered fully unsaturated heterocyclic ring or an 8- to 10-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, 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(=0)q(=NR4)p, each ring or ring system optionally substituted with up to 5 substituents independently selected from R3c on carbon atom ring members and R3d on nitrogen atom ring ¾ members; or C(R5aR5B)W2;
W2 is^a phenyl ring optionally substituted with up to 5 substituents independently
selected from R3c; or a 5- to 6-membered fully unsaturated heterocyclic 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 2 carbon atom ring members are independently selected from C(=0) and C(=S), and the sulfur atom ring members are independently selected from S(=0)q(=NR )p, the ring optionally substituted with up to 5 substituents independently selected from R3c on carbon atom ring members and R3d on nitrogen atom ring members;
R1 is H, halogen, cyano, amino, nitro, -CHO, -SCN, C1-C7 alkyl, <¾-C7 alkenyl,
C2-C7 alkynyl, C,-C7 haloalkyl, C2-C7 haloalkenyl, C3-C7 cycloalkyl, C3-C7 halocycloalkyl, C4-C J O alkylcycloalkyl, C4-C10 cycloalkylalkyl, C^-C^ cycloalkylcycloalkyl, C2-C7 alkoxyalkyl, Cj-C7 alkoxy, C]-C7 haloalkoxy, CrC7 alkylthio, CrC7 haloalkylthio, C2-C7 alkylthioalkyl, CrC7 alkylsulfinyl, C]-C7 alkylsulfonyl, Cj-C7 haloalkylsulfinyl, Cj-C7 haloalkylsulfonyl, C]-C7 alkylamino, C2-C7 dialkylamino or C]-C7 hydroxyalkyl;
R2 is cyano, C,-C7 alkyl, C3-C7 alkenyl, C3-C7 alkynyl, C,-C7 haloalkyl, C3-C7
haloalkenyl, C3-C7 cycloalkyl, C3-C7 halocycloalkyl, C4-Cj 0 alkylcycloalkyl, C4"C]o cycloalkylalkyl, Cg-C^ cycloalkylcycloalkyl, C2-C7 alkoxyalkyl, C2-C7 alkylthioalkyl, CrC7 alkylsulfinyl, CrC7 alkylsulfonyl, CrC7
haloalkylsulfinyl, C]-C7 haloalkylsulfonyl or Cj-C7 hydroxyalkyl;
each R3a and R3c is independently halogen, cyano, hydroxy, nitro, Cj-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C]-C7 haloalkyl, C2-C7 haloalkenyl, C3-C7 cycloalkyl, C3-C7 halocycloalkyl, C^CJQ alkylcycloalkyl, C4-C10 cycloalkylalkyl, C6-C 14 cycloalkylcycloalkyl, Cj-C7 alkoxy, Cj-C7 haloalkoxy, C3-C7 cycloalkoxy, C3-C7 halocycloalkoxy, C]-C7 alkylthio, Cj-C7 haloalkylthio, Cj-C7 alkylsulfinyl, Cj-C7 alkylsulfonyl, C]-C7 haloalkylsulfinyl, Cj-C7
haloalkylsulfonyl, Cj-C7 alkylamino, C2-C-7 dialkylamino, C -C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C2-C7 alkylcarbonylamino, C3-Cjo trialkylsilyl, SF5,
-SCN, -C(=S)NH2, -C(=O)NH0H or -X-U-Z;
each R3b and R3d is independently cyano, CrC6 alkyl, C3-C6 alkenyl, C3-Cg alkynyl,
C3-C6 cycloalkyl, Cj-C6 alkoxy, C2-C6 alkoxyalkyl, C2-C£ alkylcarbonyl,
C2-C6 alkoxycarbonyl, C2-Cg alkylaminoalkyl or C3-Cg dialkylaminoalkyl; each X is independently O, S(-0)n, NR6 or a direct bond;
each U is independently Cj-C6 alkylene, C2-Cg alkenylene, C3-C5 alkynylene, C3-Cg cyj loalkylene or C3-Cg cycloalkenylene, wherein up to 3 carbon atoms are independently selected from C(=0), each optionally substituted with up to 5 substituents independently selected from halogen, cyano, nitro, hydroxy, Cj-Cg alkyl, C j -Cg haloalkyl, C j -Cg alkoxy and C 1 -C^ haloalkoxy;
each Z is independently NR7aR7b, OR8 or S(=0)nR8;
each R4 is independently H, cyano, C C3 alkyl, C j-C3 alkoxy or Cj-C3 haloalkyl; each R5a and R5c is independently H, cyano or C1-C4 alkyl;
each R5b is independently H or Cj-C4 alkyl; or
a pair of R5a and R5b attached to the same carbon atom are taken together with the carbon atom to form a 3- to 6-membered saturated carbocyclic ring;
each R6 is independently H, Cj-Cg alkyl, CrC6 haloalkyl, C2-C6 alkylcarbonyl, C2-CG alkoxycarbonyl, C2-C6 (alkylthio)carbonyl, C2-Cg alkoxy(thiocarbonyl), C4-Cg cycloalkylcarbonyl, C4-C8 cycloalkoxycarbonyl, C4-Cg (cycloalkylthio)carbonyl or C4-Cg cycloalkoxy(thiocarbonyl);
each R7a and R7b is independently H, C,-C6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C2-C6 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 (alkylthio)carbonyl, C2-C6 alkoxy(thiocarbonyl), C4-C8 cycloalkylcarbonyl, C4-Cg cycloalkoxycarbonyl, C4-C
(cycloalkylthio)carbonyl or C4-Cg cycloalkoxy(thiocarbonyl); or
a pair of R7a and R7b attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3- to 6-membered heterocyclic ring, the ring optionally substituted with up to 5 substituents independently selected from R9;
each R8 is independently H, Cj-Cg alkyl, Cj-Cg haloalkyl, C2-C$ alkenyl, C3-Cg
alkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C2-C6 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 (alkylthio)carbonyl, C2-C6 alkoxy(thiocarbonyl), C4-Cg cycloalkylcarbonyl, C4-C8 cycloalkoxycarbonyl, C4-Cg (cycloalkylthio)carbonyl or C4-Cg cycloalkoxy(thiocarbonyl);
each R9 is independently halogen, Cj-Cg alkyl, Cj-Cg haloalkyl or Cj-Cg alkoxy; each n is independently 0, 1 or 2; and each q and p are independently 0, 1 or 2 in each instance of S(=0)q(=NR )p, provided that the sum of q and p is 0, 1 or 2;
provided that the compound is other than l,2-dihydro-2-methyl-l-(3-nitrophenyl)-5- phenyl-3H-pyrazol-3-one, i,2-dihydro-2-memyl-I,5-diphenyl-3H-pyrazol-3-one or 2-(3-chloropropyl)-l,2-dihydro-l,5-diphenyl-3H-pyrazol-3-one.
2. A compound of Claim 1 wherein:
Y is O;
Q1 is a phenyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 3 substituents independently selected from R3a; or a 5- to 6-membered fully unsaturated heterocyclic ring containing ring members selected from carbon atoms and 1 to 3 heteroatoms independently selected from up to 2 O, up to 2 S and up to 3 N atoms, wherein up to 2 carbon atom ring members are independently selected from C(=0) and C(=S), and the sulfur atom ring members are independently selected from S(=0)q(=NR4)p, the ring optionally substituted with up to 3 substituents independently selected from R3a on carbon atom ring members and R3b on nitrogen atom ring members; or C(R5aR5b)W!, N(R5c)Wl, OW1 or S(=0)nW 1 ;
W1 is a phenyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazolyl ring optionally substituted with up to 3 substituents independently selected from R3a on carbon atom ring members and R3b on nitrogen atom ring members;
Q2 is a phenyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 3 substituents independently selected from R3c; >r a 5- to 6-membered fully unsaturated heterocyclic ring containing ring members selected from carbon atoms and 1 to 3 heteroatoms independently selected from up to 2 O, up to 2 S and up to 3 N atoms, wherein up to 2 carbon atom ring members are independently selected from C(=0) and C(=S), and the sulfur atom ring members are independently selected from S(=0)q(=NR4)p, the ring optionally substituted with up to 3 substituents independently selected from R3c on carbon atom ring members and R3d on nitrogen atom ring members; or C(R5aR5b)W2;
W2 is a phenyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazolyl ring optionally substituted with up to 3 substituents independently selected from R3c on carbon atom ring members and R3d on nitrogen atom ring members;
R1 is H, halogen, CrC3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, CrC3
haloalkyl, C2-C3 haloalkenyl, C3-Cg cycloalkyl, Cj-C3 alkoxy, Cj-C3 alkylthio, C C3 alkylamino, C2-C4 dialkylamino or Cj-C3
hydroxyalkyl;
R2 is cyano, C]-C3 alkyl, C3 alkenyl, cyclopropyl or Cj-C3 hydroxyalkyl; each R3b and R3d is methyl;
each R5a is independently H, cyano or methyl;
each R5b is independently H or methyl; or
a pair of R5a and R5b attached to the same carbon atom are taken together with the carbon atom to form a cyclopropyl ring; and
R5c is H or methyl.
compound of Claim 2 wherein:
Q1 is a phenyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazolyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 3 substituents independently selected from R3a on carbon atom ring members and R3b on nitrogen atom ring members; or C(R5aR5b)W ;
W1 is a phenyl or pyridinyl ring optionally substituted with up to 3
substituents independently selected from R3a;
Q2 is a phenyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazolyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 3 substituents independently selected from R3c on carbon atom ring members and R3d on nitrogen atom ring members; or C(R5aR5b)W2;
W2 is a phenyl or pyridinyl ring optionally substituted with up to 3
substituents independently selected from R3c;
each R3a and R3c is independently halogen, cyano, C C3 alkyl, C2-C3
alkenyl, C2-C3 alkynyl, C C3 haloalkyl, C3 cycloalkyl, CrC3 alkoxy, Ci"C3 haloalkoxy, Cj-C3 alkylthio, Cj-C3 alk'ylamino, C2-C dialkylamino C2-C4 alkylcarbonyl, C2-C4 alkoxycarbonyl, C2-C4 alkylcarbonylamino or -X-U-Z;
X is O or NH;
U is C2-C4 alkylene;
Z is NR7aR7b or OR8; each R5a is independently H or methyl- each R7a and R7b is independently H, C C6 alkyl or CrC6 haloalkyl; and each R8 is independently H, Cj-C$ alkyl or Cj-C6 haloalkyl.
4. A compound of Claim 3 wherein:
Q1 is a phenyl or pyridinyl ring optionally substituted with up to 3 substituents independently selected from R3a;
Q2 is a phenyl or pyridinyl ring optionally substituted with up to 3 substituents independently selected from R3c;
R1 is H, halogen, cyano or Cj-C3 alkyl; and
R2 is Cj-C3 alkyl.
5. A compound of Claim 4 wherein:
each R3a and R3c is independently halogen, cyano, Ci-C3 alkyl, Cj-C3
haloalkyl, Cj-C3 alkoxy or C]-C3 haloalkoxy.
6. A compound of Claim 5 wherein:
R1 is independently CI, Br, I or Cj-C2 alkyl;
R2 is methyl; '
each R3a and R3c is independently Br, CI, F, cyano, Cj-C2 alkyl, Cj-C2 haloalkyl, C C2 alkoxy or Cj-C2 haloalkoxy; and
one of Q1 and Q2 is substituted with 2 to 3 substituents and the other of Q1 and Q2 is substituted with 0 to 3 substituents.
7. The compound of Claim 1 which is selected from the group:
4-bromo-l-(4-chlorophenyl)-5-(2,6-difluoro-4-methoxyphenyl)-l,2-dihydro-2- methyl-3H-pyrazol-3-one;
4-chloro-l-(4-chlorophenyl)-5-(2,6-difluoro-4-methoxyphenyl)-l ,2-dihydro-2- methyl-3H-pyrazol-3-one;
l-(4-chlorophenyl)-5'(2,6-difluoro-4-methoxyphenyl)-l,2-dihydro-2,4-dimethyl- 3H-pyrazol-3-one;
4-chloro-l-(4-chlorophenyl)-5-(2,6-difluoro-3-methoxyphenyl)-l,2-dihydro-2- methyl -3 -pyrazol-3-one;
4-bromo-5-(2,6-difluoro-3-methoxyphenyl)- 1 -(3-fluorophenyl)- 1 ,2-dihydrcr-2- methyl-3//-pyrazol-3-one; and
4-chloro-5-(2,6-difluoro-3-methoxyphenyl)- 1 -(3 -fluorophenyl)- 1 ,2-dihydro-2- methyl-3//-pyrazol-3-one.
8. A fungicidal composition comprising (a) a compound of Claim 1 ; and (b) at least one other fungicide.
9. 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.
10. 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/IN2009/000616 2009-10-30 2009-10-30 Fungicidal pyrazolones WO2011051958A1 (en)

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