EP3010908A1 - Pyrazoles fongicides - Google Patents

Pyrazoles fongicides

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Publication number
EP3010908A1
EP3010908A1 EP14705926.5A EP14705926A EP3010908A1 EP 3010908 A1 EP3010908 A1 EP 3010908A1 EP 14705926 A EP14705926 A EP 14705926A EP 3010908 A1 EP3010908 A1 EP 3010908A1
Authority
EP
European Patent Office
Prior art keywords
independently
alkyl
methyl
ring
haloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP14705926.5A
Other languages
German (de)
English (en)
Inventor
Andrew Edmund Taggi
James Francis Bereznak
Jeffrey Keith Long
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
FMC Corp
Original Assignee
EI Du Pont de Nemours and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by EI Du Pont de Nemours and Co filed Critical EI Du Pont de Nemours and Co
Publication of EP3010908A1 publication Critical patent/EP3010908A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to certain pyrazoles, their N-oxides, salts and compositions, and methods of their use as fungicides.
  • 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:
  • R la is H
  • R la and R 1 are taken together with the carbon atom to which they are attached to form a cyclopropyl ring optionally substituted with up to 2 substituents independently selected from halogen and methyl;
  • R 2 is H, cyano, halogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 haloalkyl,
  • each R a is independently cyano, halogen, hydroxy, nitro, -C4 alkyl, -C4
  • each R 3b is independently C5-C8 alkyl, C5-C8 haloalkyl, C5-C8 alkenyl, C5-C8 alkynyl, C2-Cg haloalkenyl, C2-Cg haloalkynyl, C i -Cg nitroalkyl, C2-Cg nitroalkenyl, C5-Cg cycloalkyl, C 7 -Cg alkylcycloalkyl, C 7 -Cg cycloalkylalkyl, C5-C12 cycloalkylalkenyl, C5-C12 cycloalkylalkynyl, Cg-C ⁇
  • cycloalkylcycloalkyl C4-Cg alkylthio, C4-Cg haloalkythio, Cz j -Cg alkylsulfinyl, C4-Cg haloalkylsulfinyl, C4-Cg alkylsulfonyl, C4-Cg haloalkylsulfonyl, C4-Cg alkoxy, C5-Cg haloalkoxy, C2-Cg alkenyloxy, C2-Cg haloalkenyloxy, C3-Cg alkynyloxy, C3-Cg haloalkynyloxy, C2-Cg cyanoalkoxy, Cg-C ⁇ cycloalkoxy, C3-C12 halocycloalkoxy, C4-C12 cycloalkylalkoxy, C5-C 12
  • cycloalkylalkenyloxy, C5-C 12 cycloalkylalkynyloxy, C3-Cg alkylsulfonyloxy, C3-Cg haloalkylsulfonyloxy, C4-Cg alkylcarbonyloxy, C4-Cg alkylcarbonyl, C2-Cg alkylamino, C4-Cg alkylcarbonylamino, C3-C12 trialkylsilyl, C4-C12 trialkylsilylalkyl, C 4 -C 12 trialkylsilylalkoxy, -C( NR 9a )NR 9a OR 9a ,
  • -CR 10a NOR 10b
  • -CR 10c NNR 9a R 9b
  • each R 3b is independently -A(CR 12a R 12b ) n W;
  • each A is independently O or a direct bond
  • each W is independently a 3- to 7-membered heterocyclic ring containing ring
  • R 5a is H or C r C 6 alkyl
  • R 6 is H, C r C 6 alkyl or C r C 6 haloalkyl
  • each R 9a and R 9b is independently H or Ci -C4 alkyl
  • each R 10a is independently H, C1-C3 alkyl or C1-C3 haloalkyl
  • each R 10b and R 10c is independently H, C r C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C1-C3 haloalkyl, C2-C4 haloalkenyl, C3-C4 cycloalkyl, C4-C8 cycloalkylalkyl or C3-C4 halocycloalkyl;
  • each R l l a and R l lb is independently H, C1-C3 alkyl or C1-C3 haloalkyl;
  • each R 12a is independently H, halogen, cyano or Ci -C4 alkyl
  • each R 12b is independently H or Ci -C4 alkyl
  • each R 13 is independently halogen, cyano, Ci -C2 alkyl, Ci -C2 haloalkyl, Ci -C2 alkoxy or C 1 -C2 haloalkoxy;
  • each R 14 is independently cyano, Ci -C2 alkyl or Ci -C2 alkoxy;
  • R 15 is C r C 6 alkyl or C r C 6 haloalkyl
  • R 16 is Ci -Cg alkyl, C2-Cg alkoxyalkyl, C2-Cg alkylaminoalkyl, C3-C6
  • dialkylaminoalkyl Ci -Cg alkoxy, Ci -Cg alkylthio or C2-Cg alkylthioalkyl;
  • Ci -Cg haloalkyl each optionally substituted with up to 2 substituents independently selected from R 21 ;
  • each R 18 and R 21 is independently cyano, C3-Cg cycloalkyl, Ci -Cg alkoxy, Ci -Cg haloalkoxy, Ci -Cg alkylthio, Ci -Cg alkylsulfinyl or Ci -Cg alkylsulfonyl;
  • R 19 is H, C r C 3 alkyl or C 2 -C 3 haloalkyl
  • R 20 is Ci -Cg alkyl, C2-Cg alkoxyalkyl, C2-Cg alkylaminoalkyl, C3-Cg
  • each R 22 is independently H, Ci -Cg alkyl, Ci -Cg haloalkyl, C2-Cg alkylcarbonyl,
  • each R 23a and R 23b is independently H, C ⁇ -Cg alkyl, C ⁇ -Cg haloalkyl, C2-Cg alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C2-Cg alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-Cg (alkylthio)carbonyl, C2-Cg alkoxy(thiocarbonyl), Cz Cg cycloalkylcarbonyl, C4-C8 cycloalkoxycarbonyl, C4-C8
  • each R 24 and R 25 is independently H, C ⁇ -Cg alkyl, C ⁇ -Cg haloalkyl, C2-Cg alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C2-Cg alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-Cg (alkylthio)carbonyl, C4-C8 cycloalkylcarbonyl, C4-C8 cycloalkoxycarbonyl, C4-C8 (cycloalkylthio)carbonyl, C2-Cg alkoxy(thiocarbonyl) or C4-C8 cycloalkoxy(thio
  • each R 26 is independently halogen, C ⁇ -Cg alkyl, C ⁇ -Cg haloalkyl or C ⁇ -Cg alkoxy; each R 27 is independently H, cyano, Ci -C3 alkyl or C1-C3 haloalkyl;
  • Z is O or S
  • M is K, Na or Li
  • each m is independently 0, 1 or 2;
  • each n is independently 0, 1, 2 or 3;
  • this invention pertains to a compound selected from compounds of Formula 1 (including all stereoisomers) and N-oxides and salts thereof.
  • This invention also relates to a fungicidal composition
  • a fungicidal composition comprising (a) a compound of the invention (i.e. in a fungicidally effective amount); and (b) at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents.
  • This invention also relates to a fungicidal composition
  • a fungicidal composition comprising (a) a compound of the invention; and (b) at least one other fungicide (e.g., at least one other fungicide having a different site of action).
  • This invention further relates to a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof, or to the plant seed, a fungicidally effective amount of a compound of the invention (e.g., as a composition described herein).
  • This invention also relates to a composition
  • a composition comprising a compound of Formula 1, an
  • N-oxide or a salt thereof, and at least one invertebrate pest control compound or agent.
  • compositions comprising, “comprising,” “includes,” “including,” “has,” “having,” “contains”, “containing,” “characterized by” or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated.
  • a composition, mixture, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, method, article, or apparatus.
  • transitional phrase consisting essentially of is used to define a composition, method or apparatus that includes materials, steps, features, components, or elements, in addition to those literally disclosed, provided that these additional materials, steps, features, components, or elements do not materially affect the basic and novel characteristic(s) of the claimed invention.
  • plant includes members of Kingdom Plantae, particularly seed plants (Spermatopsida), at all life stages, including young plants (e.g., germinating seeds developing into seedlings) and mature, reproductive stages (e.g., plants producing flowers and seeds).
  • Portions of plants include geotropic members typically growing beneath the surface of the growing medium (e.g., soil), such as roots, tubers, bulbs and corms, and also members growing above the growing medium, such as foliage (including stems and leaves), flowers, fruits and seeds.
  • seedling used either alone or in a combination of words means a young plant developing from the embryo of a seed.
  • the term “broadlea ' 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.
  • alkylating agent or “alkylating reagent” 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 2 .
  • a molecular fragment i.e. radical
  • a series of atom symbols e.g., C, H, N, O, S
  • the point or points of attachment may be explicitly indicated by a hyphen ("-").
  • -SC ⁇ N indicates that the point of attachment is the sulfur atom (i.e. thiocyanato, not isothiocyanato).
  • alkyl used either alone or in compound words such as “alkylthio” or “haloalkyl” includes straight-chain or branched alkyl such as methyl, ethyl, n-propyl, /-propyl, or the different butyl, pentyl or hexyl isomers.
  • alkenyl includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers.
  • Alkenyl also includes polyenes such as 1 ,2-propadienyl and 2,4-hexadienyl.
  • Alkynyl includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers.
  • Alkynyl can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl.
  • 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.
  • Alkylamino includes an NH radical substituted with straight-chain or branched alkyl.
  • alkylamino include CH 3 CH 2 NH, CH 3 CH 2 CH 2 NH and (CH 3 ) 2 CHNH.
  • dialkylamino include (CH 3 ) 2 N, (CH 3 CH 2 ) 2 N and CH 3 CH 2 (CH 3 )N.
  • Alkylaminoalkyl denotes alkylamino substitution on alkyl.
  • alkylaminoalkyl include CH 3 NHCH 2 , CH 3 NHCH 2 CH 2 and CH 3 CH 2 NHCH 2 .
  • dialkylaminoalkyl include (CH 3 ) 2 NCH 2 , CH 3 CH 2 (CH 3 )NCH 2 and (CH 3 ) 2 NCH 2 CH 2 .
  • Alkoxy includes, for example, methoxy, ethoxy, n-propyloxy, z ' -propyloxy and the different butoxy, pentoxy and hexyloxy isomers.
  • Alkoxyalkyl denotes alkoxy substitution on alkyl. Examples of “alkoxyalkyl” include CH 3 OCH 2 , CH 3 OCH 2 CH 2 , CH 3 CH 2 OCH 2 , CH 3 CH 2 CH 2 CH 2 OCH 2 and CH 3 CH 2 OCH 2 CH 2 .
  • Alkenyloxy includes straight-chain or branched alkenyl attached to and linked through an oxygen atom.
  • alkynyloxy includes straight-chain or branched alkynyl attached to and linked through an oxygen atom. Examples of “alkynyloxy” include HC ⁇ CCH 2 0, CH 3 C ⁇ CCH 2 0 and CH 3 C ⁇ CCH 2 CH 2 0.
  • alkylsulfonyloxy denotes alkylsulfonyl attached to and linked through an oxygen atom.
  • Alkylthio includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio isomers.
  • Alkylthioalkyl denotes alkylthio substitution on alkyl. Examples of “alkylthioalkyl” include CH 3 SCH 2 , CH 3 SCH 2 CH 2 , CH 3 CH 2 SCH 2 , CH 3 CH 2 CH 2 CH 2 SCH 2 and CH 3 CH 2 SCH 2 CH 2 .
  • Alkylsulfmyl includes both enantiomers of an alkylsulfmyl group.
  • cycloalkyl denotes a saturated carbocyclic ring consisting of between 3 to 8 carbon atoms linked to one another by single bonds.
  • examples of “cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • cycloalkylalkyl denotes cycloalkyl substitution on an alkyl group.
  • Examples of “cycloalkylalkyl” include cyclopropylmethyl, cyclopentylethyl, and other cycloalkyl moieties bonded to straight-chain or branched alkyl groups.
  • Alkylcycloalkyl denotes alkyl substitution on a cycloalkyl moiety. Examples include 4-methylcyclohexyl and 3-ethylcyclopentyl.
  • cycloalkylcycloalkyl denotes cycloalkyl substitution on another cycloalkyl ring.
  • cycloalkylcycloalkyl examples include cyclopropylcyclopropyl (such as l,l'-bicyclopropyl-l-yl, l,l'-bicyclopropyl-2-yl), cyclohexylcyclopentyl (such as 4-cyclopentylcyclohexyl) and cyclohexylcyclohexyl (such as ⁇ , ⁇ -bicyclohexyl-l-yl), and the different cis- and trans- cycloalkylcycloalkyl isomers, (such as (li?,25)-l,l'-bicyclopropyl-2-yl and (1R,2R)-1,1'- bicyclopropyl-2-yl).
  • cyclopropylcyclopropyl such as l,l'-bicyclopropyl-l-yl, l,l'-bicyclopropyl-2-yl
  • cycloalkoxy denotes cycloalkyl attached to and linked through an oxygen atom such as cyclopentyloxy and cyclohexyloxy.
  • Cycloalkylalkoxy denotes cycloalkyl substitution on an alkoxy group. Examples of “cycloalkylalkoxy” include cyclopropylmethoxy, cyclopentylethoxy, and other cycloalkyl moieties bonded to straight-chain or branched alkoxy groups.
  • cycloalkylene denotes a cycloalkanediyl ring. Examples of “cycloalkylene” include cyclopropylene, cyclobutylene, cyclopentylene and cyclohexylene.
  • cycloalkenylene denotes a cycloalkenediyl ring containing one olefmic bond. Examples of “cycloalkenylene” include cyclopropenylene and cyclopentenylene.
  • Cyanoalkyl denotes an alkyl group substituted with one cyano group.
  • cyanoalkyl include NCCH 2 , NCCH 2 CH 2 and CH 3 CH(CN)CH 2 .
  • Hydroalkyl denotes an alkyl group substituted with one hydroxy group. Examples of “hydroxyalkyl” include HOCH 2 , HOCH 2 CH 2 and CH 3 CH 2 (OH)CH.
  • Nonroalkyl denotes an alkyl group substituted with one nitro group. Examples of “nitroalkyl” include N0 2 CH 2 and N0 2 CH 2 CH 2 .
  • Trialkylsilyl includes 3 branched and/or straight-chain alkyl radicals attached to and linked through a silicon atom, such as trimethylsilyl, triethylsilyl and tert-butyldimethylsilyl.
  • halogen either alone or in compound words such as “halomethyl”, “haloalkyl”, includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as “haloalkyl”, said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of “haloalkyl” include F3C, CICH2, CF3CH2 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 -Cj The total number of carbon atoms in a substituent group is indicated by the "C -Cj" prefix where i and j are numbers from 1 to 12.
  • C 1 -C3 alkylsulfonyl designates methylsulfonyl through propylsulfonyl
  • C2 alkoxyalkyl designates CH 3 OCH 2
  • C 3 alkoxyalkyl designates, for example, CH 3 OCH2CH2 or CH 3 CH20CH2
  • C4 alkoxyalkyl designates the various isomers of an alkyl group substituted with an alkoxy group containing a total of four carbon atoms, examples including CH 3 CH2CH20CH2 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” means that 0, 1, 2, 3, 4 or 5 substituents can be present if the number of available connection points allows.
  • a "ring” or “ring system” as a component of Formula 1 is carbocyclic (e.g., phenyl or naphthalenyl) or heterocyclic (e.g., pyridinyl).
  • ring member refers to an atom (e.g., C, O, N or S) forming the backbone of a ring.
  • ring system denotes two or more fused rings (e.g., quinazolinyl).
  • 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 are essentially in the same plane and have a / ⁇ -orbital perpendicular to the ring plane, and that (4n + 2) ⁇ electrons, where n is a positive integer, are associated with the ring to comply with Huckel's rule.
  • Carbocyclic ring or “carbocycle” denote a ring wherein the atoms forming the ring backbone are selected only from carbon. When a fully unsaturated carbocyclic ring satisfies Huckel's rule, then said ring is also called an "aromatic carbocyclic 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 denotes a ring or ring system 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 3 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 rings can be attached through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.
  • Q 1 and Q 2 comprises a phenyl or 6-membered heterocyclic ring (e.g., pyridinyl)
  • the ortho, meta and para positions of each ring are relative to the connection of the ring to the remainder of Formula 1.
  • Compounds of this invention can exist as one or more stereoisomers.
  • the various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers.
  • one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers.
  • the compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers or as an optically active form.
  • salts of chemical compounds are in equilibrium with their corresponding nonsalt forms, salts share the biological utility of the nonsalt forms.
  • the salts of the compounds of Formula 1 include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids.
  • Formula 1 includes all crystalline and noncrystalline forms of the compounds that Formula 1 represents.
  • Non-crystalline forms include embodiments which are solids such as waxes and gums as well as embodiments which are liquids such as solutions and melts.
  • Crystalline forms include embodiments which represent essentially a single crystal type and embodiments which represent a mixture of polymorphs (i.e. different crystalline types).
  • polymorph refers to a particular crystalline form of a chemical compound that can crystallize in different crystalline forms, these forms having different arrangements and/or conformations of the molecules in the crystal lattice.
  • polymorphs can have the same chemical composition, they can also differ in composition due to the presence or absence of co-crystallized water or other molecules, which can be weakly or strongly bound in the lattice. Polymorphs can differ in such chemical, physical and biological properties as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspensibility, dissolution rate and biological availability.
  • a polymorph of a compound represented by Formula 1 can exhibit beneficial effects (e.g., suitability for preparation of useful formulations, improved biological performance) relative to another polymorph or a mixture of polymorphs of the same compound represented by Formula 1.
  • Preparation and isolation of a particular polymorph of a compound represented by Formula 1 can be achieved by methods known to those skilled in the art including, for example, crystallization using selected solvents and temperatures.
  • Embodiments of the present invention as described in the Summary of the Invention include those described below.
  • Formula 1 includes stereoisomers, N-oxides and salts thereof, and reference to "a compound of Formula 1" includes the definitions of substituents specified in the Summary of the Invention unless further defined in the Embodiments.
  • Embodiment 1 A compound of Formula 1 wherein Q 1 is a phenyl, pyridinyl,
  • pyrimidinyl pyrazinyl or pyridazinyl ring, each ring optionally substituted with up to 3 substituents independently selected from R 3a and R b .
  • Embodiment 2 A compound of Embodiment 1 wherein Q 1 is a phenyl ring optionally substituted with up to 3 substituents independently selected from R 3a and R b .
  • Embodiment 3. A compound of Formula 1 or any one of Embodiments 1 through 2 wherein Q 1 is a phenyl ring optionally substituted with up to 2 substituents independently selected from R 3a and substituted with 1 to 2 substituents independently selected from R 3 ⁇ .
  • Embodiment 4 A compound of Embodiment 3 wherein Q 1 is a phenyl ring optionally substituted with up to 2 substituents independently selected from R 3a and substituted with 1 substituent selected from R b .
  • Embodiment 5 A compound of Embodiment 4 wherein Q 1 is a phenyl ring optionally substituted with up to 1 substituent selected from R a and substituted with 1 substituent selected from R b .
  • Embodiment 6 A compound of Formula 1 or any one of Embodiments 1 through 5 wherein Q 1 is a phenyl ring substituted with 1 to 3 substituents independently selected from R 3a and R 3 ⁇ .
  • Embodiment 7 A compound of Embodiment 6 wherein Q 1 is a phenyl ring substituted with 1 to 2 substituents independently selected from R a and 1 substituent selected from R 3 ⁇ .
  • Embodiment 8 A compound of Embodiment 7 wherein Q 1 is a phenyl ring substituted with 2 substituents independently selected from R a and 1 substituent selected from R 3b .
  • Embodiment 9 A compound of Embodiment 6 wherein Q 1 is a phenyl ring substituted with 1 substituent selected from R a and 1 to 2 substituents independently selected from R 3b .
  • Embodiment 10 A compound of Embodiment 9 wherein Q 1 is a phenyl ring substituted with 1 substituent selected from R a and 1 substituent selected from R b .
  • Embodiment 11 A compound of Formula 1 or any one of Embodiments 1 through 10 wherein Q 1 is a phenyl ring substituted with at least 1 substituent selected from R 3a attached at the 2-position (relative to the connection of the Q 1 ring to the remainder of Formula 1).
  • Embodiment 12 A compound of Formula 1 or any one of Embodiments 1 through 11 wherein Q 1 is a phenyl ring substituted with at least 1 substituent selected from R 3 ⁇ attached at the 4-position (relative to the connection of the Q 1 ring to the remainder of Formula 1).
  • Embodiment 13 A compound of Formula 1 or any one of Embodiments 1 through 12 wherein Q 1 is a phenyl ring substituted with at least 1 substituent selected from R 3 ⁇ attached at the 3-position (relative to the connection of the Q 1 ring to the remainder of Formula 1).
  • Embodiment 14 A compound of Formula 1 or any one of Embodiments 1 through 13 wherein Q 1 is a phenyl ring substituted at the 2-position with a substituent selected from R 3a and at the 4-position with a substitutent selected from R 3b (relative to the connection of the Q 1 ring to the remainder of Formula 1).
  • Embodiment 15 A compound of Formula 1 or any one of Embodiments 1 through 13 wherein Q 1 is a phenyl ring substituted at the 2- and 6-positions with substituents independently selected from R 3a and at the 4-position with a substitutent selected from R 3b (relative to the connection of the Q 1 ring to the remainder of Formula 1).
  • Embodiment 16 A compound of Formula 1 or any one of Embodiments 1 through 13 wherein Q 1 is a phenyl ring substituted at the 2-position with a substituent selected from R 3a and at the 4-position with a substituent selected from R 3b ; or a phenyl ring substituted at the 2- and 6-positions with substituents independently selected from R 3a and at the 4-position with a substituent selected from R 3b .
  • Embodiment 17 A compound of Formula 1 or any one of Embodiments 1 through 13 wherein Q 1 is a phenyl ring substituted at the 2- and 6-positions with substituents independently selected from R a ; or a phenyl ring substituted at the 2-, 4- and 6-positions with substituents independently selected from R a .
  • Embodiment 18 A compound of Formula 1 or any one of Embodiments 1 through 17 wherein Q 2 is a phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl ring, each ring optionally substituted with up to 3 substituents independently selected from R 3a and R 3b .
  • Embodiment 19 A compound of Embodiment 18 wherein Q 2 is a phenyl ring
  • R a and R 3b optionally substituted with up to 3 substituents independently selected from R a and R 3b .
  • Embodiment 20 A compound of Embodiment 19 wherein Q 2 is a phenyl ring
  • R a and R 3b optionally substituted with up to 2 substituents independently selected from R a and R 3b .
  • Embodiment 21 A compound of Formula 1 or any one of Embodiments 1 through 20 wherein Q 2 is a phenyl ring substituted with 1 to 3 substituents independently selected from R 3a and R 3b .
  • Embodiment 22 A compound of Embodiment 21 wherein Q 2 is a phenyl ring
  • Embodiment 23 A compound of Embodiment 22 wherein Q 2 is a phenyl ring
  • Embodiment 24 A compound of Embodiment 22 wherein Q 2 is a phenyl ring
  • Embodiment 25 A compound of Embodiment 21 wherein Q 2 is a phenyl ring
  • Embodiment 26 A compound of Embodiment 25 wherein Q 2 is a phenyl ring substituted with 1 substituent selected from R 3a and 1 substituent selected from R3 .
  • Embodiment 27 A compound of Embodiment 21 wherein Q 2 is a phenyl ring
  • Embodiment 28 A compound of Formula 1 or any one of Embodiments 1 through 27 wherein Q 2 is a phenyl ring substituted with at least 1 substituent selected from R 3a attached at the 2-position (relative to the connection of the Q 2 ring to the remainder of Formula 1).
  • Embodiment 29 A compound of Formula 1 or any one of Embodiments 1 through 28 wherein Q 2 is a phenyl ring substituted with at least 1 substituent selected from R 3 ⁇ attached at the 4-position (relative to the connection of the Q 2 ring to the remainder of Formula 1).
  • Embodiment 30 A compound of Formula 1 or any one of Embodiments 1 through 29 wherein Q 2 is a phenyl ring substituted with at least 1 substituent selected from R 3 ⁇ attached at the 3-position (relative to the connection of the Q 2 ring to the remainder of Formula 1).
  • Embodiment 31 A compound of Formula 1 or any one of Embodiments 1 through 30 wherein Q 2 is a phenyl ring substituted with at least 2 substituents independently selected from R 3a attached at the 2- and 6-positions (relative to the connection of the Q 2 ring to the remainder of Formula 1).
  • Embodiment 32 A compound of Formula 1 or any one of Embodiments 1 through 31 wherein Q 2 is a phenyl ring substituted at the 2- and 6-positions with substituents independently selected from R 3a (relative to the connection of the Q 2 ring to the remainder of Formula 1).
  • Embodiment 33 A compound of Formula 1 or any one of Embodiments 1 through 31 wherein Q 2 is a phenyl ring substituted at the 2-, 4- and 6-postions with substituents independently selected from R 3a (relative to the connection of the Q 2 ring to the remainder of Formula 1).
  • Embodiment 34 A compound of Formula 1 or any one of Embodiments 1 through 32 wherein Q 2 is a phenyl ring substituted at the 2- and 6-positions with substituents independently selected from R a ; or a phenyl ring substituted at the 2-, 4- and 6-positions with substituents independently selected from R a .
  • Embodiment 35 A compound of Formula 1 or any one of Embodiments 1 through 31 wherein Q 2 is a phenyl ring substituted at the 2-position with a substituent selected from R 3a and at the 4-position with a substituent selected from R 3 ⁇ ; or a phenyl ring substituted at the 2- and 6-positions with substituents independently selected from R 3a and at the 4-position with a substituent selected from R 3 b.r Embodiment 36.
  • Embodiment 37. A compound of Formula 1 or any one of Embodiments 1 through 36 wherein X is O, S, NR 4 or CR 5a OR 5b .
  • Embodiment 38 A compound of Embodiment 37 wherein X is O, NR 4 or CHOR 5 ⁇ .
  • Embodiment 39 A compound of Embodiment 38 wherein X is NR 4 or CHOR 5 ⁇ .
  • Embodiment 40 A compound of Embodiment 39 wherein X is CHOR 5 ⁇ .
  • Embodiment 41 A compound of Embodiment 39 wherein X is NR 4 .
  • Embodiment 43 A compound of Embodiment 42 wherein R 1 is H, cyano, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C2-C4 alkoxyalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy.
  • Embodiment 44 A compound of Embodiment 43 wherein R 1 is H, cyano, halogen, Ci -C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy.
  • Embodiment 45 A compound of Embodiment 44 wherein R 1 is H, halogen or C1-C3 alkyl.
  • Embodiment 46 A compound of Embodiment 45 wherein R 1 is H or methyl.
  • Embodiment 47 A compound of Embodiment 46 wherein R 1 is H.
  • Embodiment 48 A compound of Formula 1 or any one of Embodiments 1 through 47 wherein R 1 is taken alone.
  • Embodiment 49 A compound of Formula 1 or any one of Embodiments 1 through 48 wherein R la is H.
  • Embodiment 50 A compound of Formula 1 or any one of Embodiments 1 through 49 wherein R la is taken alone.
  • Embodiment 51 A compound of Formula 1 or any one of Embodiments 1 through 49 wherein when R la and R 1 are taken together with the carbon atom to which they are attached to form a ring, then said ring is cyclopropyl (i.e. unsubstituted).
  • Embodiment 52 A compound of Formula 1 or any one of Embodiments 1 through 47 wherein R la and R 1 are taken together.
  • Embodiment 53 A compound of Formula 1 or any one of Embodiments 1 through 52 wherein R 2 is cyano, halogen, Ci -C2 alkyl, halomethyl, cyanomethyl, hydroxymethyl, methoxy or methylthio; or cyclopropyl optionally substituted with up to 2 substituents independently selected from halogen and methyl.
  • Embodiment 54 A compound of Embodiment 53 wherein R 2 is Br, CI, I or C 1 -C2 alkyl.
  • Embodiment 55 A compound of Embodiment 54 wherein R 2 is Br, CI or methyl.
  • Embodiment 56 A compound of Embodiment 55 wherein R 2 is methyl.
  • Embodiment 57 A compound of Formula 1 or any one of Embodiments 1 through 56 wherein each R 3a is independently cyano, halogen, Ci -C4 alkyl, Ci -C4 haloalkyl, C2-C4 alkenyl, C3-C4 cycloalkyl, C4-C6 cycloalkylalkyl, C4-C6 alkylcycloalkyl, C1-C3 alkylthio, C1-C3 alkylsulfmyl, C1-C3 alkylsulfonyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C3-C7 cycloalkoxy, C1 -C2 alkylsulfonyloxy, C2-C3 alkylcarbonyloxy, C2-C3 alkylcarbonyl, amino, methylamino, C2-C4 dialkylamino, C 2 -C 3 alkylcarbonylamino
  • Embodiment 59 A compound of Embodiment 58 wherein each R 3a is independently cyano, halogen, methyl, halomethyl or methoxy.
  • Embodiment 60 A compound of Embodiment 59 wherein each R 3a is independently cyano, halogen or methoxy.
  • Embodiment 61 A compound of Embodiment 60 wherein each R 3a is independently cyano, Br, CI, F or methoxy.
  • Embodiment 62 A compound of Embodiment 61 wherein each R 3a is independently Br, CI or F.
  • Embodiment 63 A compound of Embodiment 62 wherein each R 3a is F.
  • Embodiment 64 A compound of Formula 1 or any one of Embodiments 1 through 63 wherein each R 3b is independently C2-C4 haloalkenyl, C5-C8 cycloalkylalkenyl, C5-C8 cycloalkylalkynyl, C4-C6 alkoxy, C2-C6 alkenyloxy, C2-C6
  • Embodiment 67 A compound of Embodiment 66 wherein each R 3b is independently C2-C6 alkenyloxy, C2-Cg haloalkenyloxy, C3-C6 alkynyloxy, C3-C6
  • trialkylsilylalkyl C4-C9 trialkylsilylalkoxy, -CR 1 O ⁇ NOR 1 ob or
  • -ON CR l la R l lb ; or -A(CR 12a R 12b ) n W.
  • -CR 10a NOR 10b
  • Embodiment 71 A compound of Embodiment 70 wherein each R 3b is independently C2-C6 alkenyloxy, C2-C6 haloalkenyloxy, C3-C6 alkynyloxy, C3-C6
  • Embodiment 73 A compound of Formula 1 or any one of Embodiments 1 through 72 wherein each R 3b is -A(CR 12a R 12b ) n W.
  • Embodiment 74 A compound of Formula 1 or any one of Embodiments 1 through 73 wherein each A is O.
  • Embodiment 75 A compound of Formula 1 or any one of Embodiments 1 through 73 wherein each A is a direct bond.
  • Embodiment 78 A compound of Embodiment 76 wherein each W is independently a 3- to 6-membered 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, the ring optionally substituted with up to 3 substituents independently selected from R 13 on carbon atom ring members and R 1 on nitrogen atom ring members.
  • Embodiment 79 A compound of Embodiment 78 wherein each W is independently a 3- to 5-membered heterocyclic ring containing ring members selected from carbon atoms and 1 to 2 heteroatoms independently selected from up to 2 O and up to 2
  • N atoms the ring optionally substituted with up to 2 substituents independently selected from R 13 on carbon atom ring members and R 1 on nitrogen atom ring members.
  • Embodiment 80 A compound of Embodiment 79 wherein each W is independently a 3- to 5-membered heterocyclic ring containing ring members selected from carbon atoms and 1 to 2 heteroatoms independently selected from up to 2 O and up to 2 N atoms.
  • Embodiment 81 A compound of Formula 1 or any one of Embodiments 1 through 80 wherein each W is independently selected from W-1 through W-52 depicted in Exhibit 1;
  • R 1 a is selected from H and R 14 ; and each x is independently 0, 1 or 2.
  • Embodiment 82 A compound of Embodiment 81 wherein each W is independently selected from W-l through W-5, W-8, W-9 and W-12 through W-23.
  • Embodiment 83 A compound of Embodiment 82 wherein each W is independently selected from W-l, W-2, W-3, W-4, W-5, W-8, W-9, W-12, W-13, W-16, W-17,
  • Embodiment 84 A compound of Embodiment 83 wherein each W is independently selected from W-l, W-2, W-3, W-5, W-12, W-13 and W-20.
  • Embodiment 85 A compound of any one of Embodiments 81 through 84 wherein each x is independently 0 or 1.
  • Embodiment 86 A compound of Embodiment 85 wherein each x is 0.
  • Embodiment 88 A compound of Embodiment 87 wherein R 4 is H, cyclopropyl,
  • Embodiment 92 A compound of Embodiment 91 wherein R 4 is H.
  • Embodiment 93 A compound of Formula 1 or any one of Embodiments 1 through 92 wherein R 5a is H or methyl.
  • Embodiment 94 A compound of Embodiment 90 wherein R 5a is H.
  • Embodiment 98 A compound of Embodiment 97 wherein R 5 ⁇ is H.
  • Embodiment 99 A compound of Formula 1 or any one of Embodiments 1 through 98 wherein R 6 is H or C ⁇ -C ⁇ alkyl.
  • Embodiment 100 A compound of Embodiment 99 wherein R 6 is H or Ci -C2 alkyl.
  • Embodiment 101 A compound of Embodiment 100 wherein R 6 is H or methyl.
  • Embodiment 102 A compound of Embodiment 101 wherein R 6 is H.
  • Embodiment 103 A compound of Formula 1 or any one of Embodiments 1 through 102 wherein when R 7 is taken alone (i.e. not taken together with R 8 to form a ring), then R 7 is H or C r C 6 alkyl.
  • Embodiment 104 A compound of Embodiment 103 wherein R 7 is H.
  • Embodiment 105 A compound of Formula 1 or any one of Embodiments 1 through 104 wherein R 7 is taken alone.
  • Embodiment 106 A compound of Formula 1 or any one of Embodiments 1 through 105 wherein when R 8 is taken alone (i.e. not taken together with R 7 to form a ring), then R 8 is H, C ⁇ -C ⁇ alkyl, C ⁇ -C ⁇ haloalkyl or Cz Cg alkylcycloalkyl.
  • Embodiment 107 A compound of Embodiment 106 wherein R 8 is H or C ⁇ -C ⁇ alkyl.
  • Embodiment 108 A compound of Embodiment 107 wherein R 8 is H.
  • Embodiment 109 A compound of Formula 1 or any one of Embodiments 1 through 108 wherein R 8 is taken alone.
  • Embodiment 110 A compound of Formula 1 or any one Embodiments 1 through 109 wherein when R 7 and R 8 are taken together with the nitrogen atom to which they are attached to form a 4- to 7-membered nonaromatic heterocyclic ring, then said ring contains ring members, in addition to the connecting nitrogen atom, selected from carbon atoms and up to 1 ring member selected from O and NR 19 .
  • Embodiment 111 A compound of Embodiment 110 wherein R 7 and R 8 are taken
  • Embodiment 112. A compound of Embodiment 111 wherein R 7 and R 8 are taken
  • Embodiment 113 A compound of Formula 1 or any one of Embodiments 1 through 112 wherein each R 10a is independently H, methyl or halomethyl.
  • Embodiment 113a A compound of Formula 1 or any one of Embodiments 1 through
  • each R 10a is independently H or methyl.
  • Embodiment 114 A compound of Embodiment 113a wherein each R 10a is H.
  • Embodiment 115 A compound of Formula 1 or any one of Embodiments 1 through 114 wherein each R 10 ⁇ and R 10c is independently H, C1-C 3 alkyl, C1-C 3 haloalkyl,
  • Embodiment 116 A compound of Embodiment 115 wherein each R 10 ⁇ and R 10c is independently H, methyl, halomethyl or cyclopropyl.
  • Embodiment 116a A compound of Embodiment 116 wherein each R 10 ⁇ and R 10c is independently H or methyl.
  • Embodiment 117 A compound of Formula 1 or any one of Embodiments 1 through 116a wherein each R 12a is independently H, cyano or methyl.
  • Embodiment 118 A compound of Embodiment 117 wherein each R 12a is
  • Embodiment 119 A compound of Embodiment 118 wherein each R 12a is H.
  • Embodiment 120 A compound of Formula 1 or any one of Embodiments 1 through 119 wherein each R 12 ⁇ is independently H or methyl.
  • Embodiment 121 A compound of Embodiment 120 wherein each R 12 ⁇ is H.
  • Embodiment 122 A compound of Formula 1 or any one of Embodiments 1 through 121 wherein each R 13 is independently halogen, cyano, methyl, halomethyl, methoxy or halomethoxy.
  • Embodiment 123 A compound of Embodiment 122 wherein each R 13 is independently halogen, methyl, halomethyl or methoxy.
  • Embodiment 123a A compound of Embodiment 123 wherein each R 13 is methyl.
  • Embodiment 124. A compound of Formula 1 or any one of Embodiments 1 through 123a wherein each R 14 is independently methyl or methoxy.
  • Embodiment 124a A compound of Embodiment 124a wherein each R 14 is methyl.
  • Embodiment 125 A compound of Formula 1 or any one of Embodiments 1 through
  • R 15 is methyl or halomethyl.
  • Embodiment 126 A compound of Formula 1 or any one of Embodiments 1 through 125 wherein R 16 is C ⁇ -C ⁇ alkyl, C ⁇ -C ⁇ alkoxy or C ⁇ -C ⁇ alkylthio.
  • Embodiment 127 A compound of Embodiment 126 wherein R 16 is methyl, ethyl, methoxy, ethoxy, methylthio or ethylthio.
  • Embodiment 128 A compound of Embodiment 127 wherein R 16 is methyl, methoxy or methylthio.
  • Embodiment 130 A compound of Formula 1 or any one of Embodiments 1 through 129 wherein each R 18 and R 21 is independently cyano, C 3 -C6 cycloalkyl or C1-C 3 alkoxy.
  • Embodiment 131 A compound of Embodiment 130 wherein each R 18 and R 21 is
  • Embodiment 132 A compound of Embodiment 131 wherein each R 18 and R 21 is
  • Embodiment 133 A compound of Formula 1 or any one of Embodiments 1 through 132 wherein R 19 is H or CH 3 .
  • Embodiment 134 A compound of Embodiment 133 wherein R 19 is CH 3 .
  • Embodiment 135. A compound of Formula 1 or any one of Embodiments 1 through 134 wherein R 20 is C ⁇ -C ⁇ alkyl, C ⁇ -C ⁇ alkoxy or C ⁇ -C ⁇ alkylthio.
  • Embodiment 136 A compound of Embodiment 135 wherein R 20 is methyl, ethyl, methoxy, ethoxy, methylthio or ethylthio.
  • Embodiment 137 A compound of Embodiment 136 wherein R 20 is methyl, methoxy or methylthio.
  • Embodiment 138 A compound of Formula 1 or any one of Embodiments 1 through 137 wherein each U is independently O or NR 22 .
  • Embodiment 139 A compound of Embodiment 138 wherein each U is independently O or NH.
  • Embodiment 140 A compound of Formula 1 or any one of Embodiments 1 through 139 wherein each V is C2-C4 alkylene.
  • Embodiment 141 A compound of Formula 1 or any one of Embodiments 1 through 140 wherein each T is independently NR 23a R 23 ⁇ or OR 24 .
  • Embodiment 142 A compound of Formula 1 or any one of Embodiments 1 through 141 wherein each R 23a and R 23 ⁇ is independently H, C ⁇ -C ⁇ alkyl or C ⁇ -C ⁇ haloalkyl.
  • Embodiment 143 A compound of Embodiment 142 wherein each R 23a and R 23 ⁇ is independently H, methyl or halomethyl.
  • Embodiment 144 A compound of Formula 1 or any one of Embodiments 1 through 143 wherein each R 24 is independently H, C ⁇ -C ⁇ alkyl or C ⁇ -C ⁇ haloalkyl.
  • Embodiment 145 A compound of Embodiment 144 wherein each R 24 is methyl.
  • Embodiment 146 A compound of Formula 1 or any one of Embodiments 1 through 145 wherein Z is O.
  • Embodiment 147 A compound of Formula 1 or any one of Embodiments 1 through 146 wherein M is K or Na.
  • Embodiment 148 A compound of Formula 1 or any one of Embodiments 1 through 147 wherein m is 0.
  • Embodiment 149. A compound of Formula 1 or any one of Embodiments 1 through 148 wherein each n is independently 1, 2 or 3.
  • Embodiment 150 A compound of Formula 1 or any one of Embodiments 1 through 148 wherein each n is independently 0, 1 or 2.
  • Embodiment 151 A compound of Embodiment 150 wherein each n is independently 0 or 1.
  • Embodiment 152 A compound of Embodiment 150 wherein each n is independently 1 or 2.
  • Embodiment 153 A compound of Embodiment 152 wherein each n is 1.
  • Embodiments of this invention can be combined in any manner, and the descriptions of variables in the embodiments pertain not only to the compounds of Formula 1 but also to the starting compounds and intermediate compounds useful for preparing the compounds of Formula 1 unless further defined in the Embodiments.
  • embodiments of this invention including Embodiments 1-153 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 1-153 are illustrated by:
  • Embodiment A A compound of Formula 1 wherein
  • Q 1 is a phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl ring, each ring optionally substituted with up to 3 substituents independently selected from R 3a and R 3b ;
  • Q 2 is a phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl ring, each ring optionally substituted with up to 3 substituents independently selected from R 3a and R 3b ;
  • X is O, S, NR 4 or CR 5a OR 5b ;
  • R la is H
  • R 2 is Br, Cl, I or C r C 2 alkyl
  • each R a is independently cyano, halogen, -C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C3-C4 cycloalkyl, C4-C6 cycloalkylalkyl, C4-C6 alkylcycloalkyl, C1-C3 alkylthio, C1-C3 alkylsulfinyl, C1-C3
  • each R 3b is independently C2-C4 haloalkenyl, C5-C8 cycloalkylalkenyl, C5-C8 cycloalkylalkynyl, C4-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 haloalkenyloxy, C3-C6 alkynyl
  • each W is independently a 3- to 6-membered 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, the ring optionally substituted with up to 3 substituents independently selected from R 13 on carbon atom ring members and R 14 on nitrogen atom ring members;
  • R 5a is H or methyl
  • R 6 is H or methyl
  • R 7 is H or C r C 6 alkyl
  • R 8 is H, -Q alkyl, -Cg haloalkyl or C 4 -C 8 alkylcycloalkyl;
  • each R 10a is independently H, methyl or halomethyl
  • each R 10b and R 10c is independently H, C r C 3 alkyl, C r C 3 haloalkyl, C3-C4 cycloalkyl or C3-C4 halocycloalkyl;
  • each R 12a is independently H, cyano or methyl
  • each R 12b is independently H or methyl
  • each R 13 is independently halogen, methyl, halomethyl or methoxy
  • each R 14 is independently methyl or methoxy
  • R 15 is methyl or halomethyl
  • R 16 is methyl, ethyl, methoxy, ethoxy, methylthio or ethylthio;
  • R 20 is methyl, methoxy or methylthio
  • each U is independently O or NR 22 ;
  • each V is independently C2-C4 alkylene
  • each T is independently NR 23a R 23b or OR 24 ;
  • each R 23a and R 23b is independently H, C ⁇ -C ⁇ alkyl or C ⁇ -C ⁇ haloalkyl; each R 24 is independently H, C ⁇ -C ⁇ alkyl or C ⁇ -C ⁇ haloalkyl;
  • Embodiment B A compound of Embodiment A wherein
  • Q 1 is a phenyl ring optionally substituted with up to 3 substituents independently selected from R 3a and from R 3b ;
  • Q 2 is a phenyl ring optionally substituted with up to 3 substituents independently selected from R 3a and R 3b ;
  • X is O, NR 4 or CHOR 5b ;
  • R 1 is H, cyano, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C2-C4 alkoxyalkyl, Ci -C3 alkoxy or C1-C3 haloalkoxy;
  • each W is independently selected from W-l through E-52 (as depicted in Exhibit 1) wherein the bond shown projecting to the left is bonded to the remainder of the Formula 1; R 1 a is selected from H and R 14 ; and each x is independently 0, 1 or 2;
  • each R 12a is independently H or methyl
  • each U is independently O or NH.
  • Embodiment C A compound of Embodiment B wherein
  • X is NR 4 or CHOR 5b ;
  • R 1 is H, halogen or C1-C3 alkyl
  • R 2 is Br, CI or methyl
  • each R 3a is independently cyano, halogen or methoxy
  • each R b is independently C2-Cg alkenyloxy, C2-Cg haloalkenyloxy, C3-C6 alkynyloxy, C3-C6 haloalkynyloxy, C4-C8 cycloalkylalkoxy,
  • R 4 is H
  • each R 10a is H
  • each R 10b and R 10c is independently H, methyl, halomethyl or cyclopropyl; each R 12a is H; and
  • each R 12b is H.
  • Embodiment D A compound of Embodiment C wherein
  • Q 1 is a phenyl ring optionally substituted with up to 2 substituents independently selected from R 3a and substituted with 1 substituent selected from R b ;
  • Q 2 is a phenyl ring substituted with 1 to 3 substituents independently selected from R 3a ;
  • R 1 is H
  • R 2 is methyl
  • each R 3a is independently cyano, Br, CI, F or methoxy.
  • Embodiment E A compound of Embodiment D wherein
  • Q 1 is a phenyl ring substituted with at least 1 substituent selected from R a attached at the 2-position;
  • Q 2 is a phenyl ring substituted with at least 1 substituent selected from R a attached at the 2-position;
  • each R 3a is independently Br, CI or F.
  • Embodiment Al A compound of Formula 1 wherein
  • Q 1 is a phenyl ring substituted at the 2-position with a substituent selected from R 3a and at the 4-position with a substituent selected from R 3b ; or a phenyl ring substituted at the 2- and 6-positions with substituents independently selected from R 3a and at the 4-position with a substituent selected from R b ;
  • Q 2 is a phenyl ring substituted at the 2- and 6-positions with substituents independently selected from R a ; or a phenyl ring substituted at the 2-, 4- and 6-positions with substituents independently selected from R a ;
  • X is NR 4 ;
  • R 1 is H
  • R la is H
  • R 2 is methyl
  • each R a is independently cyano, Br, CI or F;
  • each A is independently O or a direct bond
  • each W is independently selected from W-1 through E-52 (as depicted in Exhibit 1) wherein the bond shown projecting to the left is bonded to the remainder of the Formula 1;
  • R 1 a is selected from H and R 14 ; and each x is independently 0, 1 or 2;
  • R 4 is H
  • each R 9a and R 9b is independently H or Ci -C4 alkyl
  • each R 10a is independently H, methyl or halomethyl
  • each R 10b and R 10c is independently H, C r C 3 alkyl, C r C 3 haloalkyl, C3-C4 cycloalkyl or C3-C4 halocycloalkyl;
  • each R l la and R l lb is independently H, -C3 alkyl or C1-C3 haloalkyl; each R 12a is independently H, cyano or methyl;
  • each R 12b is independently H or methyl
  • n 0, 1, 2 or 3.
  • Embodiment B 1. A compound of Embodiment Al wherein
  • each R 3b is independently C2-Cg alkenyloxy, C2-Cg haloalkenyloxy, C3-C6 alkynyloxy, C3-C6 haloalkynyloxy, C4-C8 cycloalkylalkoxy,
  • each W is independently selected from W-1 through W-5, W-8, W-9 and W-12 through W-23;
  • each R 9a and R 9b is independently H or methyl
  • each R 10a is independently H or methyl
  • each R 10b and R 10c is independently H or methyl
  • each R 1 la and R 1 lb is independently H or methyl
  • each R 12a is independently H
  • each R 12b is independently H
  • each R 13 is independently halogen, methyl or halomethyl
  • each R 1 is methyl.
  • Embodiment CI A compound of Formula 1 wherein
  • Q 1 is a phenyl ring substituted at the 2- and 6-positions with substituents independently selected from R 3a ; or a phenyl ring substituted at the 2-,
  • Q 2 is a phenyl ring substituted at the 2-position with a substituent selected from R 3a and at the 4-position with a substituent selected from R 3b ; or a phenyl ring substituted at the 2- and 6-positions with substituents independently selected from R 3a and at the 4-position with a substituent selected from R b ;
  • X is NR 4 ;
  • R 1 is H
  • R la is H
  • R 2 is methyl
  • each R 3a is independently cyano, Br, CI or F;
  • each A is independently O or a direct bond
  • each W is independently selected from W-1 through E-52 (as depicted in Exhibit 1) wherein the bond shown projecting to the left is bonded to the remainder of the Formula 1;
  • R 1 a is selected from H and R 14 ; and each x is independently 0, 1 or 2;
  • R 4 is H
  • each R 9a and R 9b is independently H or Ci -C4 alkyl
  • each R 10a is independently H, methyl or halomethyl
  • each R 10b and R 10c is independently H, C r C 3 alkyl, C r C 3 haloalkyl, C3-C4 cycloalkyl or C3-C4 halocycloalkyl;
  • each R l la and R l lb is independently H, C1-C3 alkyl or C1-C3 haloalkyl; each R 12a is independently H, cyano or methyl;
  • each R 12b is independently H or methyl
  • n 0, 1, 2 or 3.
  • Embodiment D A compound of Embodiment C 1 wherein
  • each R b is independently C2-Cg alkenyloxy, C2-Cg haloalkenyloxy, C3-C6 alkynyloxy, C3-C6 haloalkynyloxy, C4-C8 cycloalkylalkoxy,
  • each W is independently selected from W-1 through W-5, W-8, W-9 and W-12 through W-23;
  • each R 9a and R 9b is independently H or methyl
  • each R 10a is independently H or methyl
  • each R 10b and R 10c is independently H or methyl; each R 1 la and R 1 ⁇ is independently H or methyl;
  • each R 12a is independently H
  • each R 12 ⁇ is independently H
  • each R 13 is independently halogen, methyl or halomethyl
  • each R 1 is methyl.
  • Embodiment A2 A compound of Formula 1 wherein
  • alkylcarbonyl C2-C3 alkoxycarbonyl, C2-C3 alkylaminoalkyl
  • alkylcarbonyl C2-C3 alkoxycarbonyl, C2-C3 alkylaminoalkyl
  • R la is H
  • R l a and R 1 are taken together with the carbon atom to which they are attached to form a cyclopropyl ring optionally substituted with up to 2
  • R 2 is H, cyano, halogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 haloalkyl, C2-C3 haloalkenyl, C2-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy or C1-C3 alkylthio; or cyclopropyl optionally substituted with up to 2 substituents independently selected from halogen and methyl;
  • each R 3a is independently cyano, halogen, hydroxy, nitro, Ci -C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1 -C4 haloalkyl, C3-C4 cycloalkyl, C3-C7 halocycloalkyl, C4-C6 cycloalkylalkyl, C4-C6 alkylcycloalkyl, C1-C3 alkylthio, C 1 -C3 haloalkylthio, C1 -C3 alkylsulfinyl, C1 -C3
  • each R 3b is independently C5-C8 alkyl, C5-C8 haloalkyl, C5-C8 alkenyl,
  • R 5a is H or C r C 6 alkyl
  • cycloalkoxycarbonyl C4-C8 (cycloalkylthio)carbonyl, C 2 -Cg alkoxy(thiocarbonyl) or C4-C8 cycloalkoxy(thiocarbonyl);
  • R 6 is H, C ! -C 6 alkyl or C l -C 6 haloalkyl
  • R 7 and R 8 are each independently H, C ⁇ -Cg alkyl, C ⁇ -Cg haloalkyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl or C4-C8 alkylcycloalkyl; or
  • R 7 and R 8 are taken together with the nitrogen atom to which they are
  • each R 9a and R 9b is independently H or C1-C4 alkyl
  • each R 10a is independently H, C1-C3 alkyl or C1-C3 haloalkyl
  • each R 10b and R 10c is independently H, C r C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C1-C3 haloalkyl, C 2 -C4 haloalkenyl, C3-C4 cycloalkyl, C4-C8 cycloalkylalkyl or C3-C4 halocycloalkyl;
  • each R l la and R l lb is independently H, C1-C3 alkyl or C1-C3 haloalkyl; each R 12a is independently H, halogen, cyano or C1-C4 alkyl;
  • each R 12b is independently H or C1-C4 alkyl
  • each R 13 is independently halogen, cyano, C j -C 2 alkyl, Ci-C 2 haloalkyl,
  • each R 14 is independently cyano, C j -C 2 alkyl or Ci-C 2 alkoxy;
  • R 15 is C r C 6 alkyl or C r C 6 haloalkyl;
  • R 16 is C ⁇ -Cg alkyl, C2-Cg alkoxyalkyl, C2-C6 alkylaminoalkyl, C3-C6
  • dialkylaminoalkyl C ⁇ -C ⁇ alkoxy, C ⁇ -C ⁇ alkylthio or C2-C6
  • each R 18 and R 21 is independently cyano, C3-C6 cycloalkyl, C ⁇ -Cg alkoxy,
  • R 19 is H, C r C 3 alkyl or C 2 -C 3 haloalkyl
  • R 20 is C ⁇ -Cg alkyl, C2-C6 alkoxyalkyl, C2-C6 alkylaminoalkyl, C3-C6
  • dialkylaminoalkyl C ⁇ -C ⁇ alkoxy, C ⁇ -C ⁇ alkylthio or C2-C6
  • each V is independently C ⁇ -Cg alkylene, C2-Cg alkenylene, C3-C6
  • each R 22 is independently H, C ⁇ -Cg alkyl, C ⁇ -Cg haloalkyl, C2-Cg
  • alkylcarbonyl C2-Cg alkoxycarbonyl, C2-Cg (alkylthio)carbonyl, C2-Cg alkoxy(thiocarbonyl), C4-C8 cycloalkylcarbonyl, C4-C8
  • each R 23a and R 23b is independently H, C r C 6 alkyl, C r C 6 haloalkyl, C 2 -C 6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C2-Cg alkylcarbonyl, C2-Cg alkoxycarbonyl, C2-Cg (alkylthio)carbonyl, C2-Cg alkoxy(thiocarbonyl), C4-C8 cycloalkylcarbonyl, C4-C8
  • each R 24 and R 25 is independently H, C ⁇ -Cg alkyl, C ⁇ -Cg haloalkyl, C2-Cg alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C2-Cg alkylcarbonyl, C2-Cg alkoxycarbonyl, C2-Cg (alkylthio)carbonyl, C4-C8 cycloalkylcarbonyl, C4-C8 cycloalkoxycarbonyl, C4-C8 (cycloalkylthio)carbonyl, C2-C6 alkoxy(thiocarbonyl) or C4-C8 cycloalkoxy(thiocarbon
  • each R 26 is independently halogen, C ⁇ -Cg alkyl, C ⁇ -Cg haloalkyl or C ⁇ -Cg alkoxy;
  • each R 27 is independently H, cyano, Ci -C3 alkyl or C1-C3 haloalkyl;
  • Z is O or S
  • M is K, Na or Li
  • each m is independently 0, 1 or 2;
  • each n is independently 1, 2 or 3;
  • Q 1 is a phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl ring, each ring optionally substituted with up to 3 substituents independently selected from R 3a and R 3b ;
  • Q 2 is a phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl ring, each ring optionally substituted with up to 3 substituents independently selected from R 3a and R 3b ;
  • X is O, S, NR 4 or CR 5a OR 5b ;
  • R la is H
  • R 2 is Br, Cl, I or C r C 2 alkyl
  • R 5a is H or methyl
  • R 6 is H or methyl
  • R 7 is H or C r C 6 alkyl
  • R 8 is H, -Q alkyl, -Cg haloalkyl or C 4 -C 8 alkylcycloalkyl;
  • each R 10a is independently H, methyl or halomethyl
  • each R 10b and R 10c is independently H, C r C 3 alkyl, C r C 3 haloalkyl, C3-C4 cycloalkyl or C3-C4 halocycloalkyl;
  • each R 12a is independently H, cyano or methyl
  • each R 12b is independently H or methyl
  • each R 13 is independently halogen, methyl, halomethyl or methoxy
  • each R 14 is independently methyl or methoxy
  • R 15 is methyl or halomethyl
  • R 16 is methyl, ethyl, methoxy, ethoxy, methylthio or ethylthio;
  • R 20 is methyl, methoxy or methylthio; each U is independently O or NR 22 ;
  • each V is independently C2-C4 alkylene
  • each T is independently NR 23a R 23b or OR 24 ;
  • each R 23a and R 23b is independently H, C ⁇ -C ⁇ alkyl or C ⁇ -C ⁇ haloalkyl; each R 24 is independently H, C ⁇ -Cg alkyl or C ⁇ -Cg haloalkyl;
  • Z is O
  • n 1.
  • Embodiment C2 A compound of Embodiment B2 wherein
  • Q 1 is a phenyl ring optionally substituted with up to 3 substituents independently selected from R 3a and from R 3b ;
  • Q 2 is a phenyl ring optionally substituted with up to 3 substituents independently selected from R 3a and R 3b ;
  • X is O, NR 4 or CHOR 5b ;
  • R 1 is H, cyano, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C2-C4 alkoxyalkyl, Ci -C3 alkoxy or C1-C3 haloalkoxy;
  • each R b is independently C4-C6 alkoxy, C2-Cg alkenyloxy, C2-Cg haloalkenyloxy, C3-C6 alkynyloxy, C3-C6 haloalkynyloxy, C4-C8 cycloalkylalkoxy, C3-C6 alkylsulfonyloxy, C3-C6 haloalkylsulfonyloxy, C3-C9 trialkylsilyl, C4-C9 trialkylsilylalkyl, C4-C9 trialkylsilylalkoxy, .
  • each W is independently a 3- to 5-membered heterocyclic ring containing ring members selected from carbon atoms and 1 to 2 heteroatoms
  • each R 12a is independently H or methyl
  • each R 12b is independently H or methyl
  • each U is independently O or NH.
  • Embodiment D2 A compound of Embodiment C2 wherein
  • X is NR 4 or CHOR 5b ;
  • R 1 is H, halogen or C1-C3 alkyl
  • R 2 is Br, CI or methyl
  • each R 3a is independently cyano, halogen or methoxy
  • R 4 is H
  • R 5b is H
  • each R 10a is H
  • each R 10b and R 10c is independently H, methyl, halomethyl or cyclopropyl; each R 12a is H; and
  • each R 12b is H.
  • Embodiment E2 A compound of Embodiment D2 wherein
  • Q 1 is a phenyl ring optionally substituted with up to 2 substituents
  • Q 2 is a phenyl ring substituted with up to 3 substituents independently
  • R 1 is H
  • R 2 is methyl
  • each R 3a is independently cyano, Br, CI, F or methoxy.
  • Embodiment F2 A compound of Embodiment E2 wherein
  • Q 1 is a phenyl ring substituted with at least 1 substituent selected from R a attached at an ortho position;
  • Q2 is a phenyl ring substituted with at least 1 substituent selected from R a attached at an ortho position;
  • each R 3a is independently Br, CI or F.
  • Specific embodiments include compounds of Formula 1 selected from the group consisting of:
  • Compounds of Formula 1 can be prepared by reaction of a compound of Formula 2 (e.g., 5-aminopyrazoles for X being NR 4 , 5-hydroxypyrazoles for X being O or 5-mercaptopyrazoles for X being S) with a compound of Formula 3 wherein L 1 is a leaving group such as halogen (e.g., CI, Br or I) or (halo)alkylsulfonate (e.g., p- toluenesulfonate, methanesulfonate or trifluoromethanesulfonate) optionally in the presence of a metal catalyst, and generally in the presence of a base and a polar aprotic solvent such as N,N-dimethylformamide or dimethyl sulfoxide.
  • a compound of Formula 2 e.g., 5-aminopyrazoles for X being NR 4 , 5-hydroxypyrazoles for X being O or 5-mercaptopyrazoles for X being
  • L 1 is typically CI, Br, I or a sulfonate (e.g., methanesulfonate).
  • Q 2 is an aromactic ring lacking an electron-withdrawing substituent(s), or in general, to improve reaction rate, yield or product purity
  • a metal catalyst e.g., metal or metal salt
  • in amounts ranging from catalytic up to superstoichiometric can facilitate the desired reaction.
  • L 1 is Br or I or a sulfonate such as methyl trifluoromethanesulfonate or -OS(0)2(CF2)3CF3.
  • a metal catalyst such as copper salt complexes (e.g., Cul with N,A/"-dimethylethylenediamine, proline or bipyridyl), palladium complexes (e.g., tris(dibenzylideneacetone)dipalladium(0)) or palladium salts (e.g., palladium acetate) with ligands such as 4,5-bis(diphenylphosphino)- 9,9-dimethylxanthene, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl or 2,2'-bis- (diphenylphosphino)l,l'-binaphthalene, with a base such as potassium carbon
  • 5-thiopyrazoles of Formula 2 the corresponding 5-hydroxypyrazoles can be treated with phosphorus pentasulfide or 2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4- disulfide (Lawesson's reagent) in solvents such as toluene, xylene or tetrahydrofuran.
  • solvents such as toluene, xylene or tetrahydrofuran.
  • compounds of Formula 1 can also be prepared by reacting a compound of Formula 4 wherein L 1 is a leaving group such as halogen (e.g., CI, Br or I) or (halo)alkylsulfonate (e.g., /?-toluenesulfonate, methanesulfonate or trifluoromethane- sulfonate) with a compound of Formula 5 under conditions analogous to those described for Scheme 1.
  • halogen e.g., CI, Br or I
  • haloalkylsulfonate e.g., /?-toluenesulfonate, methanesulfonate or trifluoromethane- sulfonate
  • intermediates of Formula 4 wherein L 1 is Br or I can be prepared by reaction of compounds of Formula 2 wherein X is NH under diazotization conditions optionally in the presence of copper salts containing bromide or iodide.
  • X is NH
  • diazotization conditions optionally in the presence of copper salts containing bromide or iodide.
  • addition of tert-butyl nitrite to a solution of a 5-aminopyrazole of Formula 2 in the presence of CuBr 2 in a solvent such as acetonitrile provides the corresponding 5- bromopyrazole of Formula 4.
  • a 5-aminopyrazole of Formula 2 can be converted to a diazonium salt and then to a corresponding 5-bromo or 5-iodopyrazole of Formula 4 by treatment with sodium nitrite in solvents such as water, acetic acid or trifluoroacetic acid, in the presence of a mineral acid typically containing the same halide atom as L 1 (e.g., aqueous HI solution for L 1 being I), followed by treatment with the corresponding copper(I) or copper(II) salt according to general procedures well-known to those skilled in the art.
  • solvents such as water, acetic acid or trifluoroacetic acid
  • compounds of Formula 4 wherein L 1 is Br can also be prepared by reacting pyrazolones of Formula 6 with phosphorus tribromide using the method described in Tetrahedron Lett. 2000, 47(24), 4713-4716.
  • Pyrazolones of Formula 6 can be prepared by condensation of ketoesters of Formula 7 with alkylhydrazines using the method described in J. Heterocyclic Chem. 1987, 24, 149-153.
  • compounds of Formula 4 wherein L 1 is fluoroalkylsulfonyl can be prepared from compounds of Formula 2 wherein X is O using the method described in Synlett 2004, (5), 795-798.
  • compounds of Formula 1 are prepared by reacting a compound of Formula 8 with an alkylating agent of formula Li-CHRiR 1 ⁇ 1 wherein L 1 is a leaving group such as halogen (e.g., CI, Br or I) or (halo)alkylsulfonate (e.g., /?-toluenesulfonate, methanesulfonate or trifluoromethanesulfonate), preferably in the presence of a base such as l ,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate or potassium hydroxide, and in a solvent such as N,N-dimethylformamide, tetrahydrofuran, toluene or water.
  • halogen e.g., CI, Br or I
  • haloalkylsulfonate e.g., /?-toluenesulfonate, methanesulfonate or
  • alkylations of this type are well-known in the art and can be readily adapted to prepare compounds of the present invention.
  • Particularly useful alkylating agents for preparing compounds of Formula 1 wherein R 1 and R l a are H are diazomethane or iodomethane using general procedures known in the art, such as those described in Canada Journal of Chemistry 1986, 64, 221 1-2219, and Heterocycles 2000, 55(12), 2775-2780.
  • halogenation can be achieved using a variety of halogenating agents known in the art such as elemental halogen (e.g., Cl 2 , Br 2 , 1 ⁇ 2), sulfuryl chloride, iodine monochloride or a N-halosuccinimide (e.g., NBS, NCS, NIS) in an appropriate solvent such as N,N-dimethylformamide, carbon tetrachloride, acetonitrile, dichloromethane or acetic acid.
  • elemental halogen e.g., Cl 2 , Br 2 , 1 ⁇ 2
  • sulfuryl chloride iodine monochloride or a N-halosuccinimide (e.g., NBS, NCS, NIS)
  • an appropriate solvent such as N,N-dimethylformamide, carbon tetrachloride, acetonitrile, dichloromethane or acetic acid.
  • Alkylation is achieved by reacting a compound of
  • L 1 is a leaving group such as CI, Br, I or a sulfonate, for example, /?-toluenesulfonate, methanesulfonate or trifluoromethanesulfonate.
  • Suitable metalating agents include, for example, /? -butyl lithium (ft-BuLi), lithium diisopropylamide (LDA) or sodium hydride (NaH).
  • alkylation and “alkylating agent” are not limited to R 2 being an alkyl group, and include in addition to alkyl such groups as alkylthio, haloalkyl, alkenyl, haloalkenyl, alkynyl, and the like.
  • alkyl such groups as alkylthio, haloalkyl, alkenyl, haloalkenyl, alkynyl, and the like.
  • intermediate compounds of Formula 9 can be prepared by reacting a compound of Formula 10 with hydrazine hydrochloride.
  • the reaction can be run in a variety of solvents, but optimal yields are typically obtained when the reaction is run in ethanol at a temperature between about room temperature and the reflux temperature of the solvent.
  • General procedures for this type of reaction are well documented in the chemical literature; see, for example, Bioorganic & Medicinal Chemistry 2005, 13(6), 2097-2107, Journal of Heterocyclic Chemistry 1989, 26(4), 1147-1158, and PCT Patent Publication WO 2009/137651, Example 39, Step C.
  • L is a leaving group such as 2
  • R is halogen or alkyl halogen or (halo)alkylsulfonate
  • compounds of Formula 10 can be prepared from ketones of Formula 11 and N,N-dimethylformamide dimethyl acetal using the method described by Maya et al, Bioorganic & Medicinal Chemistry 2005, 13(6), 2097-2107.
  • the reaction is typically conducted in a solvent such as benzene, toluene or xylenes at a temperature between about room temperature and the reflux temperature of the solvent.
  • Ketones of Formula 11 can be prepared by reaction of acid chlorides of Formula 12 with a compound of formula Q 2 X-H under Friedel-Crafts condensation reaction conditions. Friedel-Crafts reactions are documented in a variety of published references; see, for example, J. March, Advanced Organic Chemistry, McGraw-Hill, New York, p. 490 and references cited therein, and PCT Patent Publications WO 2005/037758 and WO 2009/137651 (Example 39, Step A).
  • Compounds of Formula 1 can also be prepared as shown in Scheme 10.
  • a compound of Formula 13 is first treated with an organometallic agent of Formula 14 such an alkyl lithium base (e.g., n-butyllithium, s-butyllithium or lithium diisopropylamide) or a Grignard reagent in a solvent such as toluene, ethyl ether, tetrahydrofuran or dimethoxymethane at temperatures ranging from about -78 °C to ambient temperature.
  • Anions of Formula 13a are then contacted with an electrophile of Formulae 15 or 16.
  • an appropriate electrophile of Formulae 15 or 16 will depend on the desired compound of Formula 1 and will be apparent to one skilled in chemical synthesis.
  • aldehydes of the formula Q 2 CHO provide compounds Formula 1 wherein X is CH(OH) and chlorosulfides of formula QiSCl or disulfies formula of QiS-S-Q 1 provide compounds Formula 1 wherein X is S.
  • chlorosulfides of formula QiSCl or disulfies formula of QiS-S-Q 1 provide compounds Formula 1 wherein X is S.
  • Electrophiles of Formulae 15 and 16 are commercially available and can be prepared by methods known in the art.
  • Compounds of Formula 13 are known and can be prepared by methods analogous to those disclosed in Schemes 3 and 4 and by a variety of methods disclosed in the chemical literature.
  • keto compounds of Formula 17 can be treated with alkylmagnesium halides to provide compounds of Formula la (i.e Formula 1 wherein X is CR 5a OR 5b , R 5a is alkyl and R 5b is H).
  • the reaction is run in the presence of zinc chloride and in a solvent such as diethyl ether or tetrahydrofuran at temperatures from about 0 to 100 °C (for references see, for exmple, Organic Lett. 2009, 11, 1659-1662, and J. Am. Chem. Soc. 2006, 128, 9998-9999).
  • compounds of Formula 17 can be prepared by contacting a compound of Formula 18 with an acid chloride of Formula 19 in the presence of a Lewis acid (e.g., aluminum chloride, boron trifluoride diethyl etherate or tin tetrachloride) in a solvent such as dichloromethane, tetrachloroethane, or nitrobenzene, at temperatures ranging between about 0 to 200 °C.
  • a Lewis acid e.g., aluminum chloride, boron trifluoride diethyl etherate or tin tetrachloride
  • a solvent such as dichloromethane, tetrachloroethane, or nitrobenzene
  • compounds of Formula lb (i.e. Formula 1 wherein X is NR 4 and R 4 is H) can be prepared by reacting a compound of Formula 20 with an alkylhydrazine of Formula 21 in a solvent such as ethanol or methanol and optionally in the presence of an acid or base catalyst such as acetic acid, piperidine or sodium methoxide, according to general procedures known in the art.
  • a solvent such as ethanol or methanol
  • an acid or base catalyst such as acetic acid, piperidine or sodium methoxide
  • R ⁇ is H or lower alkyl (e.g.,
  • compounds of Formula 20 can be prepared by reaction of corresponding ketene dithioacetal compounds of Formula 22 with compounds of formula Q 2 -NH 2 optionally in the presence of a base, such as sodium hydride or ethylmagnesium chloride, in solvents such as toluene, tetrahydrofuran or dimethoxymethane, at temperatures ranging from -10 °C to the boiling point of the solvent.
  • a base such as sodium hydride or ethylmagnesium chloride
  • solvents such as toluene, tetrahydrofuran or dimethoxymethane
  • compounds of Formula lb (i.e. Formula 1 wherein X is NR 4 and R 4 is H) can also be prepared by condensing a compound of Formula 23 with an alkylhydrazine of Formula 21 in a solvent such as tetrahyrofuran, ethanol or methanol and optionally in the presence of an acid or base catalyst such as acetic acid, piperidine or sodium methoxide, according to general procedures known in the art (see Chemistry of Heterocyclic Compounds 2011, 47(8), 970-976).
  • a solvent such as tetrahyrofuran, ethanol or methanol
  • an acid or base catalyst such as acetic acid, piperidine or sodium methoxide
  • Compounds of Formula 23 can readily be prepared by reacting enolates of Formula 24 with isothiocyantes followed by methylsulfanylation using the method described by Tong et al, Bioorganic & Medicinal Chemistry Letters 2008, 18, 5206-5208.
  • Compounds of Formula 24 can be prepared from commercially available amines according to procedures described in the art (see Synthetic Communications 2007, 37, 985-991). The method of Scheme 15 is also illustrated by Example 1, Steps A-B.
  • Compounds of Formula 1 can be subjected to various nucleophilic and metallation reactions to add substituents or modify existing substituents, and thus provide other functionalized compounds of Formula 1.
  • compounds of Formula lc i.e. Formula 1 wherein X in NR 4 and R 4 is other than H
  • compounds of Formula lb i.e. Formula 1 wherein X is NR 4 and R 4 is H
  • an electrophile comprising R 4 (i.e. Formula 25) typically in the presence of a base such as NaH and a polar solvent such as N,N-dimethylformamide.
  • electrophile comprising R 4 means a chemical compound capable of transferring an R 4 moiety to a nucleophile (such as the nitrogen atom attached to Q 2 in Formula lb).
  • electrophiles comprising R 4 have the formula R L 2 wherein L 2 is a nucleofuge (i.e. leaving group in nucleophilic reactions).
  • Typical nucleofuges include halogens (e.g., CI, Br, I) and sulfonates (e.g., OS(0) 2 CH 3 , OS(0) 2 CF 3 , OS(0)2-(4-CH 3 -Ph)).
  • electrophiles comprising R 4 do not comprise a nucleofuge; an example is sulfur trioxide (S0 3 ), which after deprotonation (such as by a base of the formulae M + H ⁇ wherein M + is a cation) of the nitrogen atom attached to Q 2 in Formula lb, can bond to the nitrogen atom as a -SO3M substituent.
  • S0 3 sulfur trioxide
  • R is other than H
  • a fluoro can be introduce at the 3-position of the pyrazole ring by treating compounds Formula Id (i.e. Formula 1 wherein R 2 is chlorine) with potassium fluoride or cesium fluoride in presence of a solvent such as dimethyl sulfoxide or A ,N-dimethylformamide at 0-25 °C for time periods of 30 minutes to 4 h, using procedures such as described in Zhurnal Organicheskoi Khimii 1983, 19, 2164-2173.
  • sulfoxides and sulfones of Formula lg can be prepared by oxidation of compounds of Formula If (i.e. Formula 1 wherein X is S).
  • an oxidizing agent in an amount from about 1 to 4 equivalents, depending on the oxidation state of the desired product, is added to a mixture of a compound of Formula If and a solvent.
  • Useful oxidizing agents include Oxone® (potassium peroxymonosulfate), potassium permanganate, hydrogen peroxide, sodium periodate, peracetic acid and 3-chloroperbenzoic acid.
  • the solvent is selected with regard to the oxidizing agent employed.
  • Aqueous ethanol or aqueous acetone is preferably used with potassium peroxymonosulfate, and dichloromethane is generally preferable with 3-chloroperbenzoic acid.
  • Useful reaction temperatures typically range from about -78 to 90 °C. Oxidation reactions of this type are described by Brand et al, J. Agric. Food Chem. 1984, 32, 221-226 and Ouyang, et al, J. Agric. Food Chem. 2008, 56, 10160-10167.
  • n 1 or 2
  • Compounds of Formula 1, or intermediates for their preparation may contain aromatic nitro groups, which can be reduced to amino groups, and then converted via reactions well-known in the art (e.g., Sandmeyer reaction) to various halides.
  • aromatic amines anilines
  • diazonium salts phenols
  • aromatic halides such as bromides or iodides prepared via the Sandmeyer reaction can react with alcohols under copper-catalyzed conditions, such as the Ullmann reaction or known modifications thereof, to provide compounds of Formula 1 that contain alkoxy substituents.
  • halogen groups such as fluorine or chlorine
  • R 3a is - U-V-T
  • Compounds of Formula 1 or precursors thereof in which R 2 is halide, preferably bromide or iodide, are particularly useful intermediates for transition metal-catalyzed cross-coupling reactions to prepare compounds of Formula 1.
  • Step A Preparation of l-(2,6-difluoro-4-methoxyphenyl)-2-propanone
  • Step B Preparation of 4-(2,6-difluoro-4-methoxyphenyl)-l,3-dimethyl-N-(2,4,6- trifluorophenyl)-lH-pyrazol-5-amine
  • iodomethane (2.11 g, 14.9 mmol) was added to the reaction mixture and the mixture was allowed to warm to room temperature.
  • Glacial acetic acid (2.15 g, 35.7 mmol)
  • water 1.3 g, 72.2 mmol
  • methyl hydrazine (2.74 g. 59.54 mmol) were sequentially added to the reaction mixture, and the mixture was then heated at reflux for about 16 h.
  • the reaction mixture was concentrated under reduced pressure and the resulting material was purified by medium pressure liquid chromatography (0 to 50% gradient of ethyl acetate in hexanes as eluant) to provide the title compound (1.9 g).
  • Step C Preparation of 4-[l,3-dimethyl-5-[(2,4,6-trifluorophenyl)amino]-lH-pyrazol-
  • the reaction mixture was concentrated under reduced pressure and the resulting material was purified by medium pressure liquid chromatography (0 to 50% gradient of ethyl acetate in hexanes as eluant) to provide the title compound (1.9 g), a compound of the present invention.
  • Q 2 is 2,4,6-tri-F-Ph, (R : 3a )p is 2,6-di-F.
  • the present disclosure also includes Tables 1A through 215A, each of which is constructed the same as Table 1 above, except that the row heading in Table 1 (i.e. "Q 2 is 2,4,6-tri-F-Ph, (R a ) p is 2,6-di-F") is replaced with the respective row headings shown below.
  • Table 1A the row heading is "Q 2 is 2,4,6-tri-F-Ph, (R 3a ) p is 2-F", and R 3 ⁇ is as defined in Table 1 above.
  • Table 1A specifically discloses 1 ,3-dimethyl-N-(2,4,6-trifluorophenyl)-4-[2-fluoro-4-(-propyn- 1 -yloxy)phenyl]- lH-pyrazol-5-amine.
  • Tables 2A through 215A are constructed similarly.
  • 6A Q 2 is 2,4,6-tri-F-Ph, (R 3a ) p is 2-Cl, 6-Br.
  • 113A Q 2 is 2,6-di-Cl-4-Me-Ph, (R 3a ) p is 2-F.
  • Q 2 is 2,6-di-F-Ph, (R 3a ) p is 2-F.
  • 116A Q 2 is 2,6-di-Cl-4-Me-Ph, (R 3a ) p is 2-Me.
  • 10A Q 2 is 2,6-di-F-Ph, (R 3a ) p is 2-Cl.
  • 117A Q 2 is 2,6-di-Cl-4-Me-Ph, (R 3a ) p is 2-Cl, 6-F.
  • 11A Q 2 is 2,6-di-F-Ph, (R 3a ) p is 2-Br.
  • 118A Q 2 is 2,6-di-Cl-4-Me-Ph, (R 3a ) p is 2-Cl, 6-Br.
  • Q 2 is 2,6-di-F-Ph, (R 3a ) p is 2-Me. 119A Q 2 is 2,6-di-Cl-4-Me-Ph, (R 3a ) p is 2,6-di-Cl.
  • Q 2 is 2,6-di-F-Ph, (R 3a ) p is 2-Cl, 6-F.
  • 120A Q 2 is 2,6-di-Br-4-Me-Ph, (R 3a ) p is 2,6-di-F.
  • Q 2 is 2,6-di-F-Ph, (R 3a ) p is 2,6-di-Cl.
  • 122 A Q 2 is 2,6-di-Br-4-Me-Ph, (R 3a ) p is 2-Cl.
  • Q 2 is 2,6-di-F-4-MeO-Ph, (R 3a ) p is 2-F.
  • 124 A Q 2 is 2,6-di-Br-4-Me-Ph, (R 3a ) p is 2-Me.
  • 21A Q 2 is 2,6-di F -4-MeO-Ph, (R 3a ) p is 2-Cl, 6-F. 128A Q 2 is 2,4,6-tri-Cl-Ph, (R 3a ) p is 2,6-di-F.
  • Q 2 is 2,6-di F -4-MeO-Ph, (R 3a ) p is 2-Cl, 6-Br. 129 A Q 2 is 2,4,6-tri-Cl-Ph, (R 3a ) p is 2-F.
  • 25A Q 2 is 2,6-di F -4-Me-Ph, (R 3a ) p is 2-F.
  • 132A Q 2 is 2,4,6-tri-Cl-Ph, (R 3a ) p is 2-Me.
  • 26A Q 2 is 2,6-di F -4-Me-Ph, (R 3a ) p is 2-Cl.
  • 133A Q 2 is 2,4,6-tri-Cl-Ph, (R 3a ) p is 2-Cl, 6-F.
  • 31A Q 2 is 2,6-di F -4-Me-Ph, (R 3a ) p is 2,6-di-Cl.
  • 138A Q 2 is 2-C1-4-F, (R 3a ) p is 2-Cl.
  • 33A Q 2 is 2,6-di F -4-CN-Ph, (R 3a ) p is 2-F. 140A Q 2 is 2-C1-4-F, (R 3a ) p is 2-Me.
  • 34A Q 2 is 2,6-di F -4-CN-Ph, (R 3a ) p is 2-Cl.
  • 141A Q 2 is 2-C1-4-F, (R 3a ) p is 2-Cl, 6-F.
  • Q 2 is 2,6-di F -4-CN-Ph, (R 3a ) p is 2-Br. 142 A Q 2 is 2-C1-4-F, (R 3a ) p is 2-Cl, 6-Br.
  • 41A Q 2 is 2,6-di F -4-Cl-Ph, (R 3a ) p is 2-F.
  • 148A Q 2 is 2-Cl-4-Me, (R 3a ) p is 2-Me.
  • 43A Q 2 is 2,6-di F -4-Cl-Ph, (R 3a ) p is 2-Br.
  • 150A Q 2 is 2-Cl-4-Me, (R 3a ) p is 2-Cl, 6-Br.
  • Q 2 is 2,6-di F -4-Cl-Ph, (R 3a ) p is 2-Cl, 6-F.
  • 152A Q 2 is 2-Cl-4-MeO, (R 3a ) p is 2,6-di-F.
  • 49A Q 2 is 2,6-di F -4-Br-Ph, (R 3a ) p is 2-F.
  • 156A Q 2 is 2-Cl-4-MeO, (R 3a ) p is 2-Me.
  • 50A Q 2 is 2,6-di F -4-Br-Ph, (R 3a ) p is 2-Cl.
  • 157A Q 2 is 2-Cl-4-MeO, (R 3a ) p is 2-Cl, 6-F.
  • 51A Q 2 is 2,6-di F -4-Br-Ph, (R 3a ) p is 2-Br.
  • 158A Q 2 is 2-Cl-4-MeO, (R 3a ) p is 2-Cl, 6-Br.
  • Q 2 is 2,6-di F -4-Br-Ph, (R 3a ) p is 2-Cl, 6-F. 160A Q 2 is 2-Br-4-F, (R 3a ) p is 2,6-di-F.
  • Q 2 is 2,6-di F -4-Br-Ph, (R 3a ) p is 2-Cl, 6-Br. 161A Q 2 is 2-Br-4-F, (R 3a ) p is 2-F.
  • 57A Q 2 is 2,4-di-F-Ph, (R 3a ) p is 2-F.
  • 164A Q 2 is 2-Br-4-F, (R 3a ) p is 2-Me.
  • 58A Q 2 is 2,4-di-F-Ph, (R 3a ) p is 2-Cl.
  • 165 A Q 2 is 2-Br-4-F, (R 3a ) p is 2-Cl, 6-F.
  • 59A Q 2 is 2,4-di-F-Ph, (R 3a ) p is 2-Br.
  • 166A Q 2 is 2-Br-4-F,
  • (R 3a ) p is 2-Cl, 6-Br.
  • 60A Q 2 is 2,4-di-F-Ph
  • (R 3a ) p is 2-Me 167A Q 2 is 2-Br-4-F
  • (R 3a ) p is 2,6-di-Cl.
  • 61A Q 2 is 2,4-di-F-Ph, (R 3a ) p is 2-Cl, 6-F. 168A Q 2 is 2-Br-4-Me, (R 3a ) p is 2,6-di-F.
  • 62A Q 2 is 2,4-di-F-Ph, (R 3a ) p is 2-Cl, 6-Br. 169A Q 2 is 2-Br-4-Me, (R 3a ) p is 2-F.
  • 64A Q 2 is 2,4-di-F-6-Cl-Ph, (R 3a ) p is 2,6-di-F. 171A Q 2 is 2-Br-4-Me, (R 3a ) p is 2-Br.
  • 65A Q 2 is 2,4-di-F-6-Cl-Ph, (R 3a ) p is 2-F.
  • 172A Q 2 is 2-Br-4-Me, (R 3a ) p is 2-Me.
  • 66A Q 2 is 2,4-di-F-6-Cl-Ph, (R 3a ) p is 2-Cl. 173A Q 2 is 2-Br-4-Me, (R 3a ) p is 2-Cl, 6-F.
  • 67A Q 2 is 2,4-di-F-6-Cl-Ph, (R 3a ) p is 2-Br.
  • 174A Q 2 is 2-Br-4-Me, (R 3a ) p is 2-Cl, 6-Br.
  • 71A Q 2 is 2,4-di-F-6-Cl-Ph, (R 3a ) p is 2,6-di-Cl.
  • 178A Q 2 is 2-Br-4-MeO, (R 3a ) p is 2-Cl.
  • 74A Q 2 is 2,4-di-F-6-Br-Ph, (R 3a ) p is 2-Cl. 181A Q 2 is 2-Br-4-MeO, (R 3a ) p is 2-Cl, 6-F.
  • 77A Q 2 is 2,4-di-F-6-Br-Ph, (R 3a ) p is 2-Cl, 6-F.
  • 184A Q 2 is 2,4-di-Cl, (R 3a ) p is 2,6-di-F.
  • 81A Q 2 is 2-Cl-4-Me-6-F-Ph, (R 3a ) p is 2-F.
  • 188A Q 2 is 2,4-di-Cl, (R 3a ) p is 2-Me.
  • 82A Q 2 is 2-Cl-4-Me-6-F-Ph, (R 3a ) p is 2-Cl.
  • 189A Q 2 is 2,4-di-Cl, (R 3a ) p is 2-Cl, 6-F.
  • 83A Q 2 is 2-Cl-4-Me-6-F-Ph, (R 3a ) p is 2-Br.
  • 190A Q 2 is 2,4-di-Cl, (R 3a ) p is 2-Cl, 6-Br.
  • Q 2 is 2-Cl-4-Me-6-F-Ph, (R 3a ) p is 2-Cl, 6-F. 192 A Q 2 is 2,6-di-Cl, (R 3a ) p is 2,6-di-F.
  • 89A Q 2 is 2-Cl-4-MeO-6-F-Ph, (R 3a ) p is 2-F.
  • 196A Q 2 is 2,6-di-Cl, (R 3a ) p is 2-Me.
  • Q 2 is 2-Cl-4-MeO-6-F-Ph, (R 3a ) p is 2-Cl.
  • 197A Q 2 is 2,6-di-Cl, (R 3a ) p is 2-Cl, 6-F.
  • 91A Q 2 is 2-Cl-4-MeO-6-F-Ph, (R 3a ) p is 2-Br.
  • 198A Q 2 is 2,6-di-Cl, (R 3a ) p is 2-Cl, 6-Br.
  • 92A Q 2 is 2-Cl-4-MeO-6-F-Ph, (R 3a ) p is 2-Me. 199 A Q 2 is 2,6-di-Cl, (R 3a ) p is 2,6-di-Cl.
  • 96A Q 2 is 2-Br-4-Me-6-F-Ph, (R 3a ) p is 2,6-di-F.
  • 203A Q 2 is 2,4 -di-Me, (R 3a ) p is 2-Br.
  • 98A Q 2 is 2-Br-4-Me-6-F-Ph, (R 3a ) p is 2-Cl.
  • 205A Q 2 is 2,4 -di-Me, (R 3a ) p is 2-Cl, 6-F.
  • Q 2 is 2-Br-4-Me-6-F-Ph, (R 3a ) p is 2-Br.
  • 206A Q 2 is 2,4 -di-Me, (R 3a ) p is 2-Cl, 6-Br.
  • 100A Q 2 is 2-Br-4-Me-6-F-Ph, (R 3a ) p is 2-Me.
  • 207A Q 2 is 2,4 -di-Me, (R 3a ) p is 2,6-di-Cl.
  • 101A Q 2 is 2-Br-4-Me-6-F-Ph, (R 3a ) p is 2-Cl, 6-F.
  • 208A Q 2 is 2,6 -di-Me, (R 3a ) p is 2,6-di-F.
  • Q 2 is 2-Br-4-Me-6-F-Ph
  • (R 3a ) p is 2-Cl
  • 6-Br. 209A Q 2 is 2,6 -di-Me
  • (R 3a ) p is 2-F.
  • a Q 2 is 2-Br-4-Me-6-F-Ph, (R 3a ) p is 2,6-di-Cl.
  • 210A Q 2 is 2,6 -di-Me, (R 3a ) p is 2-Cl.
  • Q 2 is 2-Br-4-MeO-6-F-Ph, (R 3a ) p is 2,6-di-F.
  • 211A Q 2 is 2,6 -di-Me, (R 3a ) p is 2-Br.
  • Q 2 is 2-Br-4-MeO-6-F-Ph, (R 3a ) p is 2-F.
  • 212A Q 2 is 2,6 -di-Me, (R 3a ) p is 2-Me.
  • 106A Q 2 is 2-Br-4-MeO-6-F-Ph, (R 3a ) p is 2-Cl. 213A Q 2 is 2,6 -di-Me, (R 3a ) p is 2-Cl, 6-F.
  • 107A Q 2 is 2-Br-4-MeO-6-F-Ph, (R 3a ) p is 2-Br.
  • 214A Q 2 is 2,6 -di-Me, (R 3a ) p is 2-Cl, 6-Br.
  • Q 2 is 2,6 -di-Me
  • (R 3a ) p is 2,6-di-Cl.
  • a compound of this invention will generally be used as a fungicidal active ingredient in a composition, i.e. formulation, with at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents, which serve as a carrier.
  • 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.
  • compositions are dusts, powders, granules, pellets, prills, pastilles, tablets, filled films (including seed coatings) and the like, which can be water-dispersible ("wettable") or water-soluble. Films and coatings formed from film- forming solutions or flowable suspensions are particularly useful for seed treatment.
  • Active ingredient can be (micro)encapsulated and further formed into a suspension or solid formulation; alternatively the entire formulation of active ingredient can be encapsulated (or "overcoated”). Encapsulation can control or delay release of the active ingredient.
  • An emulsifiable granule combines the advantages of both an emulsifiable concentrate formulation and a dry granular formulation. High-strength compositions are primarily used as intermediates for further formulation.
  • Sprayable formulations are typically extended in a suitable medium before spraying. Such liquid and solid formulations are formulated to be readily diluted in the spray medium, usually water. Spray volumes can range from about one to several thousand liters per hectare, but more typically are in the range from about ten to several hundred liters per hectare. Sprayable formulations can be tank mixed with water or another suitable medium for foliar treatment by aerial or ground application, or for application to the growing medium of the plant. Liquid and dry formulations can be metered directly into drip irrigation systems or metered into the furrow during planting. Liquid and solid formulations can be applied onto seeds of crops and other desirable vegetation as seed treatments before planting to protect developing roots and other subterranean plant parts and/or foliage through systemic uptake.
  • the formulations will typically contain effective amounts of active ingredient, diluent and surfactant within the following approximate ranges which add up to 100 percent by weight.
  • Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, gypsum, cellulose, titanium dioxide, zinc oxide, starch, dextrin, sugars (e.g., lactose, sucrose), silica, talc, mica, diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate, and sodium sulfate.
  • Typical solid diluents are described in Watkins et al., Handbook of Insecticide Dust Diluents and Carriers, 2nd Ed., Dorland Books, Caldwell, New Jersey.
  • Liquid diluents include, for example, water, N,N-dimethylalkanamides (e.g., N,N-dimethylformamide), limonene, dimethyl sulfoxide, N-alkylpyrrolidones (e.g., N-methylpyrrolidinone), ethylene glycol, triethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, propylene carbonate, butylene carbonate, paraffins (e.g., white mineral oils, normal paraffins, isoparaffins), alkylbenzenes, alkylnaphthalenes, glycerine, glycerol triacetate, sorbitol, aromatic hydrocarbons, dearomatized aliphatics, alkylbenzenes, alkylnaphthalenes, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy- 4-methyl-2-pentan
  • Liquid diluents also include glycerol esters of saturated and unsaturated fatty acids (typically C6-C22), such as plant seed and fruit oils (e.g., oils of olive, castor, linseed, sesame, corn (maize), peanut, sunflower, grapeseed, safflower, cottonseed, soybean, rapeseed, coconut and palm kernel), animal-sourced fats (e.g., beef tallow, pork tallow, lard, cod liver oil, fish oil), and mixtures thereof.
  • plant seed and fruit oils e.g., oils of olive, castor, linseed, sesame, corn (maize), peanut, sunflower, grapeseed, safflower, cottonseed, soybean, rapeseed, coconut and palm kernel
  • animal-sourced fats e.g., beef tallow, pork tallow, lard, cod liver oil, fish oil
  • Liquid diluents also include alkylated fatty acids (e.g., methylated, ethylated, butylated) wherein the fatty acids may be obtained by hydrolysis of glycerol esters from plant and animal sources, and can be purified by distillation.
  • alkylated fatty acids e.g., methylated, ethylated, butylated
  • Typical liquid diluents are described in Marsden, Solvents Guide, 2nd Ed., Interscience, New York, 1950.
  • the solid and liquid compositions of the present invention often include one or more surfactants.
  • surfactants also known as “surface-active agents”
  • surface-active agents generally modify, most often reduce, the surface tension of the liquid.
  • surfactants can be useful as wetting agents, dispersants, emulsifiers or defoaming agents.
  • Nonionic surfactants useful for the present compositions include, but are not limited to: alcohol alkoxylates such as alcohol alkoxylates based on natural and synthetic alcohols (which may be branched or linear) and prepared from the alcohols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof; amine ethoxylates, alkanolamides and ethoxylated alkanolamides; alkoxylated triglycerides such as ethoxylated soybean, castor and rapeseed oils; alkylphenol alkoxylates such as octylphenol ethoxylates, nonylphenol ethoxylates, dinonyl phenol ethoxylates and dodecyl phenol ethoxylates (prepared from the phenols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); block polymers prepared from ethylene oxide or propylene
  • Useful anionic surfactants include, but are not limited to: alkylaryl sulfonic acids and their salts; carboxylated alcohol or alkylphenol ethoxylates; diphenyl sulfonate derivatives; lignin and lignin derivatives such as lignosulfonates; maleic or succinic acids or their anhydrides; olefin sulfonates; phosphate esters such as phosphate esters of alcohol alkoxylates, phosphate esters of alkylphenol alkoxylates and phosphate esters of styryl phenol ethoxylates; protein-based surfactants; sarcosine derivatives; styryl phenol ether sulfate; sulfates and sulfonates of oils and fatty acids; sulfates and sulfonates of ethoxylated alkylphenols; sulfates of alcohols; sulfates of e
  • Useful cationic surfactants include, but are not limited to: amides and ethoxylated amides; amines such as N-alkyl propanediamines, tripropylenetriamines and dipropylenetetramines, and ethoxylated amines, ethoxylated diamines and propoxylated amines (prepared from the amines and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); amine salts such as amine acetates and diamine salts; quaternary ammonium salts such as quaternary salts, ethoxylated quaternary salts and diquaternary salts; and amine oxides such as alkyldimethylamine oxides and bis-(2-hydroxyethyl)-alkylamine oxides.
  • amines such as N-alkyl propanediamines, tripropylenetriamines and dipropylenetetramines, and ethoxylated amine
  • Nonionic, anionic and cationic surfactants and their recommended uses are disclosed in a variety of published references including McCutcheon 's Emulsifiers and Detergents, annual American and International Editions published by McCutcheon's Division, The Manufacturing Confectioner Publishing Co.; Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964; and A. S. Davidson and B. Milwidsky, Synthetic Detergents, Seventh Edition, John Wiley and Sons, New York, 1987.
  • compositions of this invention may also contain formulation auxiliaries and additives, known to those skilled in the art as formulation aids (some of which may be considered to also function as solid diluents, liquid diluents or surfactants).
  • formulation auxiliaries and additives may control: pH (buffers), foaming during processing (antifoams such polyorganosiloxanes), sedimentation of active ingredients (suspending agents), viscosity (thixotropic thickeners), in-container microbial growth (antimicrobials), product freezing (antifreezes), color (dyes/pigment dispersions), wash-off (film formers or stickers), evaporation (evaporation retardants), and other formulation attributes.
  • Film formers include, for example, polyvinyl acetates, polyvinyl acetate copolymers, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohols, polyvinyl alcohol copolymers and waxes.
  • formulation auxiliaries and additives include those listed in McCutcheon 's Volume 2: Functional Materials, annual International and North American editions published by McCutcheon's Division, The Manufacturing Confectioner Publishing Co.; and PCT Publication WO 03/024222.
  • the compound of Formula 1 or Formula 1A 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 ⁇ range. Dusts and powders can be prepared by blending and usually grinding (such as with a hammer mill or fluid-energy mill). Granules and pellets can be prepared by spraying the active material upon preformed granular carriers or by agglomeration techniques.
  • Pellets can be prepared as described in U.S. 4,172,714.
  • Water-dispersible and water-soluble granules can be prepared as taught in U.S. 4,144,050, U.S. 3,920,442 and DE 3,246,493.
  • Tablets can be prepared as taught in U.S. 5,180,587, U.S. 5,232,701 and U.S. 5,208,030.
  • Films can be prepared as taught in GB 2,095,558 and U.S. 3,299,566.
  • Compound 10 65.0% dodecylphenol polyethylene glycol ether 2.0%> sodium ligninsulfonate 4.0%> sodium silicoaluminate 6.0%> montmorillonite (calcined) 23.0%
  • Compound 2 10.0% attapulgite granules (low volatile matter, 0.71/0.30 mm; 90.0% U.S.S. No. 25-50 sieves)
  • Compound 3 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.
  • 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, Sclerotinia minor, Magnaporthe grisea, and Phomopsis viticola, Helminthosporium diseases such as Helminthosporium tritici repentis and Pyrenophora teres, anthracnose diseases such as Glomerella or Colletotrichum spp.
  • Puccinia spp. such as Puccinia recondita, Puccinia striiformis, Puccinia hordei, Puccinia graminis and Puccinia arachidis
  • Rutstroemia floccosum also known as Sclerotinia homoeocarpa
  • Rhizoctonia solani Fusarium diseases such as Fusarium roseum, Fusarium graminearum and Fusarium oxysporumVerticillium dahliae; Sclerotium rolfsii; Rynchosporium secalis; Cercosporidium personatum, Cercospora arachidicola and Cercospora beticola; Rhizopus spp. (such as Rhizopus stolonifer); Aspergillus spp. (such as Aspergillus flavus and Aspergillus parasiticus); and other genera and species closely related to these pathogens.
  • compositions or combinations also have activity against bacteria such as Erwinia amylovora, Xanthomonas campestris, Pseudomonas syringae, and other related species.
  • the compounds of this invention are useful in treating postharvest diseases of fruits and vegetables caused by fungi and bacteria. These infections can occur before, during and after harvest. For example, infections can occur before harvest and then remain dormant until some point during ripening (e.g., host begins tissue changes in such a way that infection can progress); also infections can arise from surface wounds created by mechanical or insect injury. In this respect, the compounds of this invention can reduce losses (i.e.
  • Treatment of postharvest diseases with compounds of the invention can increase the period of time during which perishable edible plant parts (e.g, fruits, seeds, foliage, stems, bulbs, tubers) can be stored refrigerated or un-refrigerated after harvest, and remain edible and free from noticeable or harmful degradation or contamination by fungi or other microorganisms.
  • Treatment of edible plant parts before or after harvest with compounds of the invention can also decrease the formation of toxic metabolites of fungi or other microorganisms, for example, mycotoxins such as aflatoxins.
  • Plant disease control is ordinarily accomplished by applying an effective amount of a compound of this invention either pre- or post-infection, to the portion of the plant to be protected such as the roots, stems, foliage, fruits, seeds, tubers or bulbs, or to the media (soil or sand) in which the plants to be protected are growing.
  • the compounds can also be applied to seeds to protect the seeds and seedlings developing from the seeds.
  • the compounds can also be applied through irrigation water to treat plants. Control of postharvest pathogens which infect the produce before harvest is typically accomplished by field application of a compound of this invention, and in cases where infection occurs after harvest the compounds can be applied to the harvested crop as dips, sprays, fumigants, treated wraps and box liners.
  • Rates of application for these compounds 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 (DMI) fungicides; (4) phenylamide fungicides; (5) amine/morpholine fungicides; (6) phospholipid biosynthesis inhibitor fungicides; (7) carboxamide fungicides; (8) hydroxy(2-amino-)pyrimidine fungicides; (9) anilinopyrimidine fungicides; (10) N-phenyl carbamate fungicides; (11) quinone outside inhibitor (Qol) fungicides; (12) phenylpyrrole fungicides; (13) quinoline fungicides; (14) lipid peroxidation inhibitor fungicides; (15) melanin biosynthesis inhibitors-reductase (MBI-R) fungicides; (15)
  • 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 benzimidazoles and thiophanates.
  • the benzimidazoles include benomyl, carbendazim, fuberidazole and thiabendazole.
  • the thiophanates include thiophanate and thiophanate-methy 1.
  • Demethylation inhibitor (DMI) fungicides (Fungicide Resistance Action Committee (FRAC) code 3) inhibit C14-demethylase, which plays a role in sterol production.
  • Sterols such as ergosterol, are needed for membrane structure and function, making them essential for the development of functional cell walls. Therefore, exposure to these fungicides results in abnormal growth and eventually death of sensitive fungi.
  • Demethylation fungicides include piperazines, pyridines, pyrimidines, imidazoles and triazoles.
  • the piperazines include triforine.
  • the pyridines include buthiobate and pyrifenox.
  • the pyrimidines include fenarimol, nuarimol and triarimol.
  • the imidazoles include clotrimazole, imazalil, oxpoconazole, prochloraz, pefurazoate and triflumizole.
  • the triazoles include azaconazole, bitertanol, bromuconazole, cyproconazole, difenoconazole, diniconazole (including diniconazole-M), epoxiconazole, etaconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, imibenconazole, ipconazole, metconazole, myclobutanil, penconazole, propiconazole, prothioconazole, quinconazole, simeconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole, uniconazole, 1 -
  • the imidazoles include clotrimazole, imazalil, oxpoconazole, prochloraz, pefurazoate and triflumizole.
  • Biochemical investigations have shown that all of the above mentioned fungicides are DMI fungicides as described by K. ⁇ . Kuck et al. in Modern Selective Fungicides - Properties, Applications and Mechanisms of Action, ⁇ . Lyr (Ed.), Gustav Fischer Verlag: New York, 1995, 205-258.
  • Phenylamide fungicides are specific inhibitors of RNA polymerase in Oomycete fungi. Sensitive fungi exposed to these fungicides show a reduced capacity to incorporate uridine into rRNA. Growth and development in sensitive fungi is prevented by exposure to this class of fungicide.
  • Phenylamide fungicides include acylalanines, oxazolidinones and butyrolactones.
  • the acylalanines include benalaxyl, benalaxyl-M, furalaxyl, metalaxyl and metalaxyl- M/mefenoxam.
  • the oxazolidinones include oxadixyl.
  • the butyrolactones include ofurace.
  • Amine/morpholine fungicides include morpholines, piperidines and spiroketal-amines.
  • the morpholines include aldimorph, dodemorph, fenpropimorph, tridemorph and trimorphamide.
  • the piperidines include fenpropidin and piperalin.
  • the spiroketal-amines include spiroxamine.
  • Phospholipid biosynthesis fungicides include phophorothiolates and dithiolanes.
  • the phosphorothiolates include edifenphos, iprobenfos and pyrazophos.
  • the dithiolanes include isoprothiolane.
  • Carboxamide fungicides (Fungicide Resistance Action Committee (FRAC) code 7) inhibit Complex II (succinate dehydrogenase) fungal respiration by disrupting a key enzyme in the Krebs Cycle (TCA cycle) named succinate dehydrogenase. Inhibiting respiration prevents the fungus from making ATP, and thus inhibits growth and reproduction.
  • Carboxamide fungicides include phenyl benzamides, pyridinyl ethyl benzamides, furan carboxamides, oxathiin carboxamides, thiazole carboxamides, pyrazole carboxamides and pyridine carboxamides.
  • the phenyl benzamides include benodanil, flutolanil and mepronil.
  • the pyridinyl ethyl benzamides include fluopyram.
  • the furan carboxamides include fenfuram.
  • the oxathiin carboxamides include carboxin and oxycarboxin.
  • the thiazole carboxamides include thifluzamide.
  • the pyrazole carboxamides include furametpyr, penthiopyrad, bixafen, isopyrazam, benzovindiflupyr, N-[2-(lS,2R)- [1,1 '-bicyclopropyl]-2-ylphenyl]-3-(difluoromethyl)- 1 -methyl- lH-pyrazole-4-carboxamide, penflufen, (N-[2-(l ,3-dimethylbutyl)phenyl]-5-fluoro- 1 ,3-dimethyl- lH-pyrazole-4- carboxamide), N-[2-(2,4-dichlorophenyl)-2-methoxy-l-methylethyl]-3-(difluoromethyl)-l- methyl- lH-pyrazole-4-carboxamide and N-cyclopropyl-3 -(difluoromethyl)-5 -fluoro- 1 - methyl-N-[[2-(
  • FRAC Federal Communications Commission
  • 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.
  • N-Phenyl carbamate fungicides (Fungicide Resistance Action Committee (FRAC) code 10) 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 diethofencarb.
  • Quinone outside inhibitor fungicides include methoxyacrylates, methoxycarbamates, oximinoacetates, oximinoacetamides, oxazolidinediones, dihydrodioxazines, imidazolinones and benzylcarbamates.
  • the methoxyacrylates include azoxystrobin, coumoxystrobin, enestroburin, flufenoxystrobin, picoxystrobin and pyraoxystrobin.
  • the methoxycarbamates include pyraclostrobin, pyrametostrobin and triclopyricarb.
  • the oximinoacetates include kresoxim-methyl and trifloxystrobin.
  • the oximinoacetamides include dimoxystrobin, metominostrobin, orysastrobin, a-[methoxyimino]-N-methyl-2-[[[ 1 -[3-(trifluoromethyl)phenyl]ethoxy]imino]- methyljbenzeneacetamide and 2-[[[3-(2,6-dichlorophenyl)- 1 -methyl-2-propen- 1 -ylidene]- amino]oxy]methyl]-a-(methoxyimino)-N-methylbenzeneacetamide.
  • the oxazolidinediones include famoxadone.
  • the dihydrodioxazines include fluoxastrobin.
  • the imidazolinones include fenamidone.
  • the benzylcarbamates include pyribencarb.
  • Class (11) also includes 2- [(2,5-dimethylphenoxy)methyl]-a-methoxy-N-benzeneacetamide.
  • Azanaphthalene fungicides (Fungicide Resistance Action Committee (FRAC) code 13) are proposed to inhibit signal transduction by affecting G-proteins in early cell signaling. They have been shown to interfere with germination and/or appressorium formation in fungi that cause powder mildew diseases.
  • Azanaphthalene fungicides include aryloxyquinolines and quinazolinone.
  • the aryloxyquinolines include quinoxyfen and tebufloquin.
  • the quinazolinones include proquinazid.
  • Lipid peroxidation fungicides include aromatic carbons and 1,2,4-thiadiazoles.
  • the aromatic carbon fungicides include biphenyl, chloroneb, dicloran, quintozene, tecnazene and tolclofos-methyl.
  • the 1,2,4-thiadiazole fungicides include etridiazole.
  • MMI-R Melanin biosynthesis inhibitors-reductase fungicides
  • FRAC Field Action Committee
  • MBI-D Melanin biosynthesis inhibitors-dehydratase
  • FRAC Field Action Committee
  • scytalone dehydratase in melanin biosynthesis Melanin in required for host plant infection by some fungi.
  • Melanin biosynthesis inhibitors-dehydratase fungicides include cyclopropanecarboxamides, carboxamides and propionamides.
  • the cyclopropanecarboxamides include carpropamid.
  • the carboxamides include diclocymet.
  • the propionamides include fenoxanil.
  • "Hydroxy anilide fungicides (Fungicide Resistance Action Committee (FRAC) code 17) inhibit C4-demethylase which plays a role in sterol production. Examples include fenhexamid.
  • Squalene- epoxidase inhibitor fungicides include thiocarbamates and allylaminess.
  • the thiocarbamates include pyributicarb.
  • the allylamines include naftifine and terbinafme.
  • Polyoxin fungicides (Fungicide Resistance Action Committee (FRAC) code 19) inhibit chitin synthase. Examples include polyoxin.
  • FRAC Function III mitochondrial respiration in fungi by affecting ubiquinol reductase. Reduction of ubiquinol is blocked at the "quinone inside" (Qi) site of the cytochrome bc ⁇ complex, which is located in the inner mitochondrial membrane of fungi. Inhibiting mitochondrial respiration prevents normal fungal growth and development.
  • Quinone inside inhibitor fungicides include cyanoimidazoles and sulfamoyltriazoles.
  • the cyanoimidazoles include cyazofamid.
  • the sulfamoyltriazoles include amisulbrom.
  • 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.
  • FRAC code 24
  • Glucopyranosyl antibiotic protein synthesis fungicides
  • FRAC Field Resistance Action Committee
  • “Carbamate fungicides” (Fungicide Resistance Action Committee (FRAC) code 28) are considered multi-site inhibitors of fungal growth. They are proposed to interfere with the synthesis of fatty acids in cell membranes, which then disrupts cell membrane permeability. Propamacarb, propamacarb-hydrochloride, iodocarb, and prothiocarb are examples of this fungicide class.
  • 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.
  • 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 (Fungicide Resistance Action Committee (FRAC) code 32) are proposed to affect DNA/ribonucleic acid (RNA) synthesis.
  • Heteroaromatic fungicides include isoxazoles and isothiazolones.
  • the isoxazoles include hymexazole and the isothiazolones include octhilinone.
  • 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 (Fungicide Resistance Action Committee (FRAC) code 40) are proposed to inhibit phospholipid biosynthesis and cell wall deposition. Inhibition of these processes prevents growth and leads to death of the target fungus.
  • Carboxylic acid amide fungicides include cinnamic acid amides, valinamide carbamates, carbamates and mandelic acid amides. The cinnamic acid amides include dimethomorph and flumorph.
  • the valinamide carbamates include benthiavalicarb, benthiavalicarb-isopropyl, iprovalicarb, valifenalate and valiphenal.
  • the carbamates include tolprocarb.
  • the mandelic acid amides include mandipropamid, N-[2-[4-[[3-(4- chlorophenyl)-2-propyn-l-yl]oxy]-3-methoxyphenyl]ethyl]-3-methyl-2-[(methylsulfonyl)- amino Jbutanamide and N-[2-[4-[[3-(4-chlorophenyl)-2-propyn-l-yl]oxy]-3-methoxyphenyl]- ethyl] -3 -methyl-2- [(ethylsulfonyl)amino]butanamide.
  • 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.
  • Benzamide fungicides (Fungicide Resistance Action Committee (FRAC) code 43) inhibit growth of fungi by derealization of spectrin-like proteins.
  • Examples include acylpicolide fungicides such as fluopicolide.
  • Host plant defense induction fungicides include benzothiadiazoles, benzisothiazoles and thiadiazolecarboxamides.
  • the benzothiadiazoles include acibenzolar-S-methyl.
  • the benzisothiazoles include probenazole.
  • the thiadiazolecarboxamides include tiadinil and isotianil.
  • Multi-site contact fungicides inhibit fungal growth through multiple sites of action and have contact/preventive activity.
  • This class of fungicides includes: (45.1) “copper fungicides" (Fungicide Resistance Action Committee (FRAC) code Ml)", (45.2) “sulfur fungicides” (Fungicide Resistance Action Committee (FRAC) code M2), (45.3) “dithiocarbamate fungicides” (Fungicide Resistance Action Committee (FRAC) code M3), (45.4) "phthalimide fungicides” (Fungicide Resistance Action Committee (FRAC) code M4), (45.5) "chloronitrile fungicides” (Fungicide Resistance Action Committee (FRAC) code M5), (45.6) “sulfamide fungicides” (Fungicide Resistance Action Committee (FRAC) code M6), (45.7) "guanidine fungicides” (Fungicide Resistance Action Committee (FRAC) code M7), (45.8) “triazine fungicides” (Fungicides)
  • Copper fungicides are inorganic compounds containing copper, typically in the copper(II) oxidation state; examples include copper oxychloride, copper sulfate and copper hydroxide, including compositions such as Bordeaux mixture (tribasic copper sulfate).
  • Sulfur fungicides are inorganic chemicals containing rings or chains of sulfur atoms; examples include elemental sulfur.
  • Dithiocarbamate fungicides contain a dithiocarbamate molecular moiety; examples include mancozeb, metiram, propineb, ferbam, maneb, thiram, zineb and ziram.
  • Phthalimide fungicides contain a phthalimide molecular moiety; examples include folpet, captan and captafol.
  • Chloronitrile fungicides contain an aromatic ring substituted with chloro and cyano; examples include chlorothalonil.
  • Sulfamide fungicides include dichlofluanid and tolyfluanid.
  • Guanidine fungicides include dodine, guazatine, iminoctadine albesilate and iminoctadine triacetate.
  • Triazine fungicides include anilazine.
  • Quinone fungicides include dithianon.
  • Fungicides other than fungicides of classes (1) through (45) include certain fungicides whose mode of action may be unknown. These include: (46.1) “thiazole carboxamide fungicides” (Fungicide Resistance Action Committee (FRAC) code U5), (46.2) “phenylacetamide fungicides” (Fungicide Resistance Action Committee (FRAC) code U6), (46.3) “arylphenylketone fungicides” (Fungicide Resistance Action Committee (FRAC) code U8) and (46.4) "triazolopyrimidine fungicides”.
  • the thiazole carboxamides include ethaboxam.
  • the phenylacetamides include cyflufenamid and N-[[(cyclopropylmethoxy)- amino][6-(difluoromethoxy)-2,3-difluorophenyl]-methylene]benzeneacetamide.
  • the arylphenylketones include benzophenones such as metrafenone and benzoylpyridines such as pyriofenone.
  • the triazolopyrimidines include ametoctradin. Class (46) (i.e.
  • “Fungicides other than classes (1) through (45)" also includes bethoxazin, fluxapyroxad, neo-asozin (ferric methanearsonate), pyrrolnitrin, quinomethionate, tebufloquin, isofetamid, N-[2-[4-[[3- (4-chlorophenyl)-2-propyn- 1 -yl]oxy] -3 -methoxyphenyl] ethyl] -3 -methyl-2- [(methylsulfonyl)amino]butanamide, N-[2-[4-[[3-(4-chlorophenyl)-2-propyn-l-yl]oxy]-3- methoxyphenyl] ethyl]-3 -methyl-2- [(ethylsulfonyl)amino]butanamide, 2- [ [2-fluoro-5 -
  • 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 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.
  • NPV nucleopolyhedro virus
  • 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).
  • 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 a compound of Formula 1 include at least one compound selected from the group consisting of (1) alkylenebis(dithiocarbamate) fungicides; (2) cymoxanil; (3) phenylamide fungicides; (4) proquinazid (6-iodo-3-propyl-2-propyloxy-4(3H)-quinazolinone); (5) chlorothalonil; (6) carboxamides acting at complex II of the fungal mitochondrial respiratory electron transfer site; (7) quinoxyfen; (8) metrafenone; (9) cyflufenamid; (10) cyprodinil; (11) copper compounds; (12) phthalimide fungicides; (13) fosetyl-aluminum; (14) benzimidazole fungicides; (15) cyazofamid; (16) fluazinam; (17) iprovalicarb; (18) propamocarb; (19) validomycin; (20) dich
  • Sterol biosynthesis inhibitors 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. ⁇ . Kuck et al. in Modern Selective Fungicides - Properties, Applications and Mechanisms of Action, ⁇ . Lyr (Ed.), Gustav Fischer Verlag: New York, 1995, 205-258.
  • bc ⁇ Complex Fungicides (group 28) have a fungicidal mode of action which inhibits the be i complex in the mitochondrial respiration chain.
  • the bc ⁇ complex is sometimes referred to by other names in the biochemical literature, including complex III of the electron transfer chain, and ubihydroquinone: cytochrome c oxidoreductase. This complex is uniquely identified by Enzyme Commission number EC 1.10.2.2.
  • the bc ⁇ complex is described in, for example, J. Biol. Chem. 1989, 264, 14543-48; Methods Enzymol. 1986, 126, 253-71; and references cited therein.
  • Strobilurin fungicides such as azoxystrobin, dimoxystrobin, enestroburin (SYP-Z071), fluoxastrobin, kresoxim-methyl, metominostrobin, orysastrobin, picoxystrobin, pyraclostrobin, pyrametostrobin, pyraoxystrobin and trifloxystrobin are known to have this mode of action (H. Sauter et al., Angew. Chem. Int. Ed. 1999, 38, 1328-1349).
  • Other fungicidal compounds that inhibit the bc ⁇ complex in the mitochondrial respiration chain include famoxadone and fenamidone.
  • Alkylenebis(dithiocarbamate)s 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 N-[2-(l,3-dimethylbutyl)phenyl]-5-fluoro-l,3-dimethyl-lH- pyrazole-4-carboxamide (PCT Patent Publication WO 2003/010149), and are known to inhibit mitochondrial function by disrupting complex II (succinate dehydrogenase) in the respiratory electron transport chain.
  • 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 morpho lines and piperidines are sterol biosynthesis inhibitors that have been shown to inhibit steps in the sterol biosynthesis pathway at a point later than the inhibitions achieved by the DMI sterol biosynthesis (group (27)).
  • the morpho lines include aldimorph, dodemorph, fenpropimorph, tridemorph and trimorphamide.
  • the piperidines include fenpropidin.
  • test suspensions for Tests A-E 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-E. Spraying a 200 ppm test suspension to the point of run-off on the test plants was the equivalent of a rate of 800 g/ha.
  • test suspension was sprayed to the point of run-off on wheat seedlings.
  • 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 7 days, after which time visual disease ratings were made.

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Abstract

L'invention concerne des composés de formule 1, y compris tous les isomères géométriques et stéréoisomères, N-oxydes et sels de ceux-ci, Q1, Q2, X, R1, R1a et R2 étant tels que définis dans la description. La présente invention concerne en outre des compositions contenant les composés de formule 1, et des procédés pour lutter contre une maladie de plante causée par un agent pathogène fongique, consistant à appliquer une quantité efficace d'un composé ou d'une composition selon l'invention.
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