US20120010075A1 - Synergistic fungicidal compositions including hydrazone derivatives and copper - Google Patents

Synergistic fungicidal compositions including hydrazone derivatives and copper Download PDF

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Publication number
US20120010075A1
US20120010075A1 US13/144,684 US201013144684A US2012010075A1 US 20120010075 A1 US20120010075 A1 US 20120010075A1 US 201013144684 A US201013144684 A US 201013144684A US 2012010075 A1 US2012010075 A1 US 2012010075A1
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United States
Prior art keywords
copper
alkyl
group
synergistic mixture
mixture
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US13/144,684
Inventor
David H. Young
Steven Howard Shaber
Cruz Avila-Adame
Nneka T. Breaux
James M. Ruiz
Thomas L. Siddall
Jeffery D. Webster
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Corteva Agriscience LLC
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Dow AgroSciences LLC
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Priority to US13/144,684 priority Critical patent/US20120010075A1/en
Assigned to DOW AGROSCIENCES LLC reassignment DOW AGROSCIENCES LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: AVILA-ADAME, CRUZ, BREAUX, NNEKA T., RUIZ, JAMES M., SIDDALL, THOMAS L., WEBSTER, JEFFERY D., YOUNG, DAVID H., SHABER, GERALD, LEGAL REPRESENTATIVE FOR THE ESTATE OF STEVEN H. SHABER (DECEASED)
Publication of US20120010075A1 publication Critical patent/US20120010075A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N59/00—Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
    • A01N59/16—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
    • A01N33/26—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds containing nitrogen-to-nitrogen bonds, e.g. azides, diazo-amino compounds, diazonium compounds, hydrazine derivatives
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N31/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic oxygen or sulfur compounds
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N31/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic oxygen or sulfur compounds
    • A01N31/04—Oxygen or sulfur attached to an aliphatic side-chain of a carbocyclic ring system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N59/00—Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N59/00—Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
    • A01N59/16—Heavy metals; Compounds thereof
    • A01N59/20—Copper
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/72—Hydrazones
    • C07C251/86—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/33—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring
    • C07C323/35—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group
    • C07C323/36—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group the sulfur atom of the sulfide group being further bound to an acyclic carbon atom

Definitions

  • the present invention relates to the use of hydrazones in combination with copper, copper-based fungicides or other copper-containing materials as synergistic fungicidal mixtures.
  • Copper is used to control the growth of organisms, especially microorganisms, in a variety of applications such as those described in the “Handbook of copper compounds and applications” edited by H. W. Richardson and published by Marcel Dekker, Inc. New York (1997), which is expressly incorporated by reference herein. These applications may include its use in agriculture to control a wide range of fungal and bacterial diseases of plants. Copper products may also be used as aquatic biocides in fresh or marine environments. Copper products may be used in antifouling applications and to control unwanted organisms in ponds and lakes based on the toxicity of copper towards algae, fungi, macrophytes and mollusks. Copper-based materials may also be used as wood preservatives and on other materials to inhibit fungal and bacterial growth. Other uses also include killing plant roots in sewer systems.
  • One exemplary embodiment of the present disclosure includes a synergistic mixture for controlling the growth of fungi, the synergistic mixture including copper and a hydrazone compound of Formula I:
  • A is oxygen or sulfur
  • Z is H or C1-C4 alkyl
  • W is —CHR1-
  • n 0, 1, or 2;
  • R is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl C2-C6 haloalkynyl, or C3-C6 halocycloalkyl;
  • R1 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl C2-C6 haloalkynyl, C3-C6 halocycloalkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, or unsubstituted heteroaryl;
  • X3 and X4, X4 and X5, X5 and X6, Y2 and Y3, or Y3 and Y4 may form a 5 or 6 membered fused ring which may contain up to two heteroatoms selected from the group consisting of O, N, and S.
  • alkyl refers to a branched, unbranched, or cyclic carbon chain, including methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tertiary butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • cycloalkyl refers to a monocyclic or polycyclic, saturated substituent consisting of carbon and hydrogen.
  • alkenyl refers to a branched, unbranched or cyclic carbon chain containing one or more double bonds including ethenyl, propenyl, butenyl, isopropenyl, isobutenyl, cyclohexenyl, and the like.
  • alkynyl refers to a branched or unbranched carbon chain containing one or more triple bonds including propynyl, butynyl and the like.
  • R refers to the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl C2-C6 haloalkynyl, or C3-C6 halocycloalkyl, unless stated otherwise.
  • alkoxy refers to an —OR substituent.
  • alkylthio refers to an —S—R substituent.
  • haloalkylthio refers to an alkylthio, which is substituted with Cl, F, I, or Br or any combination thereof.
  • cyano refers to a —C ⁇ N substituent.
  • hydroxyl refers to an —OH substituent.
  • haloalkoxy refers to an —OR—X substituent, wherein X is Cl, F, Br, or I, or any combination thereof.
  • haloalkyl refers to an alkyl, which is substituted with Cl, F, I, or Br or any combination thereof.
  • halocycloalkyl refers to a monocyclic or polycyclic, saturated substituent consisting of carbon and hydrogen, which is substituted with Cl, F, I, or Br or any combination thereof.
  • haloalkenyl refers to an alkenyl, which is substituted with Cl, F, I, or Br or any combination thereof.
  • haloalkynyl refers to an alkynyl which is substituted with Cl, F, I, or Br or any combination thereof.
  • halogen refers to one or more halogen atoms, defined as F, Cl, Br, and I.
  • aryl refers to a cyclic, aromatic substituent consisting of hydrogen and carbon.
  • heteroaryl refers to a cyclic substituent that may be fully unsaturated, where the cyclic structure contains at least one carbon and at least one heteroatom, where said heteroatom is nitrogen, sulfur, or oxygen.
  • phenoxy refers to an —O substituted with a six-membered fully unsaturated ring consisting of hydrogen and carbon.
  • nitro refers to a —NO 2 substituent.
  • Certain compounds disclosed in this document can exist as one or more isomers.
  • the various isomers include stereoisomers, geometric isomers, diastereomers, and enantiomers.
  • the compounds disclosed in this invention include geometric isomers, racemic mixtures, individual stereoisomers, and optically active mixtures. It will be appreciated by those skilled in the art that one isomer may be more active than the others.
  • the structures disclosed in the present disclosure are drawn in only one geometric form for clarity, but are intended to represent all geometric forms of the molecule.
  • the mixtures of the present invention have fungitoxic activity against phytopathogenic fungi, against fungal pathogens of mammals, including humans, and against wood decay causing fungi.
  • the mixtures of the present invention may have broad spectrum fungitoxic activity, particularly against phytopathogenic fungi. They are active against fungi of a number of classes including Deuteromycetes (Fungi Imperfecti), Basidiomycetes, Oomycetes and Ascomycetes.
  • the method of this invention provides for activity against organisms including, but not limited to, Phytophthora species, Plasmopara viticola, Pseudoperonospora cubensis, Pythium species, Pyricularia oryzae, Colletotrichum species, Helminthosporium species, Alternaria species, Septoria nodorum, Leptosphaeria nodorum, Ustilago maydis, Erysiphe graminis, Puccinia species, Sclerotinia species, Sphaerotheca fuliginea, Cercospora species, Rhizoctonia species, Uncinula necator, Septoria tritici , and Podosphaera leucotricha.
  • organisms including, but not limited to, Phytophthora species, Plasmopara viticola, Pseudoperonospora cubensis, Pythium species, Pyricularia oryzae, Colle
  • the method of the present invention also provides for activity against fungal pathogens of mammals (including humans) including, but not limited to, Candida species such as C. albicans, C. glabrata, C. parapsilosis, C. krusei , and C. tropicalis, Aspergillus species such as Aspergillus fumigatus, Fusarium species, Coccidioides immitis, Cryptococcus neoformans, Histoplasma capsulatum, Microsporum species, and Tricophyton species.
  • the method of the present invention also provides for activity against fungi which cause wood decay such as Gleophyllum trabeur, Phialophora mutabilis, Poria palcenta and Trametes versicolor.
  • the present invention contemplates all vehicles by which the composition of the present invention can be formulated for delivery and use as a pesticide composition, including solutions, suspensions, emulsions, wettable powders and water dispersible granules, emulsifiable concentrates, granules, dusts, baits, and the like.
  • formulations are applied following dilution of the concentrated formulation with water as aqueous solutions, suspensions or emulsions, or combinations thereof.
  • Such solutions, suspensions or emulsions are produced from water-soluble, water-suspended or water-suspendable, water-emulsified or water-emulsifiable formulations or combinations thereof which are solids, including and usually known as wettable powders or water dispersible granules; or liquids including and usually known as emulsifiable concentrates, aqueous suspensions or suspension concentrates, and aqueous emulsions or emulsions in water, or mixtures thereof such as suspension-emulsions.
  • any material to which this composition can be added may be used, provided they yield the desired utility without significant interference with the desired activity of the pesticidally active ingredients as pesticidal agents and improved residual lifetime or decreased effective concentration is achieved.
  • Wettable powders which may be compacted to form water dispersible granules, comprise an intimate mixture of one or more of the pesticidally active ingredients, an inert carrier and surfactants.
  • concentration of the pesticidally active ingredient in the wettable powder is usually from about 10 percent to about 90 percent by weight based on the total weight of the wettable powder, more preferably about 25 weight percent to about 75 weight percent.
  • the pesticidally active ingredients can be compounded with any finely divided solid, such as prophyllite, talc, chalk, gypsum, Fuller's earth, bentonite, attapulgite, starch, casein, gluten, montmorillonite clays, diatomaceous earths, purified silicates or the like.
  • the finely divided carrier and surfactants are typically blended with the compound(s) and milled
  • Emulsifiable concentrates of the pesticidally active ingredient comprise a convenient concentration, such as from about 10 weight percent to about 50 weight percent of the pesticidally active ingredient, in a suitable liquid, based on the total weight of the concentrate.
  • the pesticidally active ingredients are dissolved in an inert carrier, which is either a water miscible solvent or a mixture of water-immiscible organic solvents, and emulsifiers.
  • the concentrates may be diluted with water and oil to form spray mixtures in the form of oil-in-water emulsions.
  • Useful organic solvents include aromatics, especially the high-boiling naphthalenic and olefinic portions of petroleum such as heavy aromatic naphtha. Other organic solvents may also be used, such as, for example, terpenic solvents, including rosin derivatives, aliphatic ketones, such as cyclohexanone, and complex alcohols, such as 2-ethoxyethanol.
  • Emulsifiers which can be advantageously employed herein can be readily determined by those skilled in the art and include various nonionic, anionic, cationic and amphoteric emulsifiers, or a blend of two or more emulsifiers.
  • nonionic emulsifiers useful in preparing the emulsifiable concentrates include the polyalkylene glycol ethers and condensation products of alkyl and aryl phenols, aliphatic alcohols, aliphatic amines or fatty acids with ethylene oxide, propylene oxides such as the ethoxylated alkyl phenols and carboxylic esters esterified with the polyol or polyoxyalkylene.
  • Cationic emulsifiers include quaternary ammonium compounds and fatty amine salts.
  • Anionic emul-sifiers include the oil-soluble salts (e.g., calcium) of alkylaryl sulfonic acids, oil-soluble salts of sulfated polyglycol ethers and appropriate salts of phosphated polyglycol ether.
  • organic liquids which can be employed in preparing emulsifiable concentrates are the aromatic liquids such as xylene, propyl benzene fractions; or mixed naphthalene fractions, mineral oils, substituted aromatic organic liquids such as dioctyl phthalate; kerosene; dialkyl amides of various fatty acids, particularly the dim-ethyl amides; and glycol ethers such as the n-butyl ether, ethyl ether or methyl ether of diethylene glycol, and the methyl ether of triethylene glycol and the like. Mixtures of two or more organic liquids may also be employed in the preparation of the emulsifiable concentrate.
  • aromatic liquids such as xylene, propyl benzene fractions; or mixed naphthalene fractions, mineral oils, substituted aromatic organic liquids such as dioctyl phthalate; kerosene; dialkyl amides of various fatty acids, particularly
  • Surface-active emulsifying agents are typically employed in liquid formulations and in an amount of from 0.1 to 20 percent by weight based on the combined weight of the emulsifying agents.
  • the formulations can also contain other compatible additives, for example, plant growth regulators and other biologically active compounds used in agriculture.
  • Aqueous suspensions comprise suspensions of one or more water-insoluble pesticidally active ingredients dispersed in an aqueous vehicle at a concentration in the range from about 5 to about 50 weight percent, based on the total weight of the aqueous suspension.
  • Suspensions are prepared by finely grinding one or more of the pesticidally active ingredients, and vigorously mixing the ground material into a vehicle comprised of water and surfactants chosen from the same types discussed above.
  • Other components such as inor-ganic salts and synthetic or natural gums, may also be added to increase the density and viscosity of the aqueous vehicle. It is often most effective to grind and mix at the same time by preparing the aqueous mixture and homogenizing it in an implement such as a sand mill, ball mill, or piston-type homogenizer.
  • Aqueous emulsions comprise emulsions of one or more water-insoluble pesticidally active ingredients emulsified in an aqueous vehicle at a concentration typically in the range from about 5 to about 50 weight percent, based on the total weight of the aqueous emulsion. If the pesticidally active ingredient is a solid it must be dissolved in a suitable water-immiscible solvent prior to the preparation of the aqueous emulsion.
  • Emulsions are prepared by emulsifying the liquid pesticidally active ingredient or water-immiscible solution thereof into an aqueous medium typically with inclusion of surfactants that aid in the formation and stabilization of the emulsion as described above. This is often accomplished with the aid of vigorous mixing provided by high shear mixers or homogenizers.
  • compositions of the present invention can also be granular formulations, which are particularly useful for applications to the soil.
  • Granular formulations usually contain from about 0.5 to about 10 weight percent, based on the total weight of the granular formulation of the pesticidally active ingredient(s), dispersed in an inert carrier which consists entirely or in large part of coarsely divided inert material such as attapulgite, bentonite, diatomite, clay or a similar inexpensive substance.
  • Such formulations are usually prepared by dissolving the pesticidally active ingredients in a suitable solvent and applying it to a granular carrier which has been preformed to the appropriate particle size, in the range of from about 0.5 to about 3 mm
  • a suitable solvent is a solvent in which the compound is substantially or completely soluble.
  • Such formulations may also be prepared by making a dough or paste of the carrier and the compound and solvent, and crushing and drying to obtain the desired granular particle.
  • Dusts can be prepared by intimately mixing one or more of the pesticidally active ingredients in powdered form with a suitable dusty agricultural carrier, such as, for example, kaolin clay, ground volcanic rock, and the like. Dusts can suitably contain from about 1 to about 10 weight percent of the compounds, based on the total weight of the dust.
  • a suitable dusty agricultural carrier such as, for example, kaolin clay, ground volcanic rock, and the like. Dusts can suitably contain from about 1 to about 10 weight percent of the compounds, based on the total weight of the dust.
  • the formulations may additionally contain adjuvant surfactants to enhance deposition, wetting and penetration of the pesticidally active ingredients onto the target site such as a crop or organism.
  • adjuvant surfactants may optionally be employed as a component of the formulation or as a tank mix.
  • the amount of adjuvant surfactant will typically vary from 0.01 to 1.0 percent by volume, based on a spray-volume of water, preferably 0.05 to 0.5 volume percent.
  • Suitable adjuvant surfactants include, but are not limited to ethoxylated nonyl phenols, ethoxylated synthetic or natural alcohols, salts of the esters of sulfosuccinic acids, ethoxylated organosilicones, ethoxylated fatty amines and blends of surfactants with mineral or vegetable oils.
  • the formulations may optionally include combinations that contain other pesticidal compounds.
  • additional pesticidal compounds may be fungicides, insecticides, nematocides, miticides, arthropodicides, bactericides or combinations thereof that are compatible with the mixtures of the present invention in the medium selected for application, and not antagonistic to the activity of the present mixtures.
  • the other pesticidal compound is employed as a supplemental toxicant for the same or for a different pesticidal use.
  • the mixtures of the present invention, and the pesticidal compound in the combination can generally be present in a weight ratio of from 1:100 to 100:1.
  • the mixtures described herein may be taken up in pharmaceutically acceptable carriers, such as, for example, solutions, suspensions, tablets, capsules, ointments, elixirs and injectable compositions.
  • Pharmaceutical preparations may contain from 0.1% to 99% by weight of active ingredient.
  • active ingredient refers to mixtures described herein, salts thereof, hydrates, and mixtures with other pharmaceutically active compounds.
  • Dosage unit forms such as, for example, tablets or capsules, typically contain from about 0.05 to about 1.0 g of active ingredient.
  • the mixtures of the present invention can also be combined with other agricultural fungicides to form fungicidal mixtures and synergistic mixtures thereof.
  • the fungicidal mixtures of the present invention are often applied in conjunction with one or more other fungicides to control a wider variety of undesirable diseases.
  • the presently claimed mixtures can be formulated with the other fungicide(s), tank mixed with the other fungicide(s) or applied sequentially with the other fungicide(s).
  • Such other fungicides include amisulbrom 2-(thiocyanatomethylthio)-benzothiazole, 2-phenylphenol, 8-hydroxyquinoline sulfate, antimycin, Ampelomyces, quisqualis, azaconazole, azoxystrobin, Bacillus subtilis , benalaxyl, benomyl, benthiavalicarb-isopropyl, benzylaminobenzene-sulfonate (BABS) salt, bicarbonates, biphenyl, bismerthiazol, bitertanol, bixafen, blasticidin-S, borax, boscalid, bromuconazole, bupirimate, BYF 1047, calcium polysulfide, captafol, captan, carbendazim, carboxin, carpropamid, carvone, chloroneb, chlorothalonil, chlozolinate, Coniothyrium minitans ,
  • the mixtures of the present invention can also be combined with other antifungal compounds used to control infections in mammals to form fungicidal mixtures and synergistic mixtures thereof.
  • the fungicidal mixtures of the present invention can be applied in conjunction with one or more other antifungal compounds or their pharmaceutically acceptable salts to control a wider variety of undesirable diseases.
  • the presently claimed mixtures can be formulated with the other antifungal compound(s), coadministered with the other antifungal compound(s) or applied sequentially with the other antifungal compound(s).
  • Typical antifungal compounds include, but are not limited to compounds selected from the group consisting of an azole such as fluconazole, voriconazole, itraconazole, ketoconazole, and miconazole, a polyene such as amphotericin B, nystatin or liposomal and lipid forms thereof such as Abelcet, AmBisome and Amphocil, a purine nucleotide inhibitor such as 5-fluorocytosine, a polyoxin such as nikkomycin, and pneumocandin or echinocandin derivatives such as caspofungin and micofungin.
  • an azole such as fluconazole, voriconazole, itraconazole, ketoconazole, and miconazole
  • a polyene such as amphotericin B, nystatin or liposomal and lipid forms thereof such as Abelcet, AmBisome and Amphocil
  • a purine nucleotide inhibitor such
  • the mixtures of the present invention can be combined with other pesticides, including insecticides, nematocides, miticides, arthropodicides, bactericides or combinations thereof that are compatible with the mixtures of the present invention in the medium selected for application, and not antagonistic to the activity of the present mixtures to form pesticidal mixtures and synergistic mixtures thereof.
  • the fungicidal mixtures of the present invention are often applied in conjunction with one or more other pesticides to control a wider variety of undesirable pests.
  • the presently claimed mixtures can be formulated with the other pesticide(s), tank mixed with the other pesticide(s) or applied sequentially with the other pesticide(s).
  • Typical insecticides include, but are not limited to: antibiotic insecticides such as allosamidin and thuringiensin; macrocyclic lactone insecticides such as spinosad; avermectin insecticides such as abamectin, doramectin, emamectin, eprinomectin, ivermectin and selamectin; milbemycin insecticides such as lepimectin, milbemectin, milbemycin oxime and moxidectin; arsenical insecticides such as calcium arsenate, copper acetoarsenite, copper arsenate, lead arsenate, potassium arsenite and sodium arsenite; botanical insecticides such as anabasine, azadirachtin, d-limonene, nicotine, pyrethrins, cinerins, cinerin I, cinerin II, jasmolin I, jasmolin II,
  • the mixtures have broad ranges of efficacy as fungicides.
  • the exact amounts of hydrazones and copper-containing materials to be applied is dependent not only on the specific materials being applied and relative amounts of hydrazone and copper in the mixtures, but also on the, the particular action desired, the fungal species to be controlled, and the stage of growth thereof, as well as the part of the plant or other product to be contacted with the mixture.
  • all the mixtures, and formulations containing the same may not be equally effective at similar concentrations or against the same fungal species.
  • the mixtures are effective in use with plants in a disease-inhibiting and phytologically acceptable amount.
  • disease inhibiting and phytologically acceptable amount refers to an amount of a mixture that kills or inhibits the plant disease for which control is desired, but is not significantly toxic to the plant.
  • the exact amount of a mixture required varies with the fungal disease to be controlled, the type of formulation employed, the method of application, the particular plant species, climate conditions, and the like. The dilution and rate of application will depend upon the type of equipment employed, the method and frequency of application desired and diseases to be controlled.
  • the amount of copper used in mixture with hydrazone may range from 0.001 to 5 kg/ha, and preferably from 0.05 to 1 kg/ha.
  • the amount of hydrazone used in mixture with copper may range from 0.001 to 5 kg/ha, and preferably from 0.05 to 1 kg/ha.
  • the molar ratio of copper to hydrazone may range from 0.1:1 to 10, 000:1, preferably from 0.5:1 to 1000:1 and more preferably from 1:1 to 20:1.
  • the preferred amount of a copper material to be mixed with hydrazone in a given application may be influenced by availability of copper from other sources such as copper present in the soil or irrigation water, copper present on the foliage from natural sources, copper applied for fungal or bacterial disease control, copper applied as a fertilizer component, copper present in the water used in preparing fungicide solutions for application such as in spray application, copper present in formulations used in preparing spray solutions or dusts for application, or any other suitable copper source.
  • the hydrazone may be applied before or after the application of copper such that the mixture is generated in the location where fungal control is desired. Additionally, multiple applications of copper or the hydrazone may be applied.
  • the amount of toxicant coated on the seed is usually at a dosage rate of about 10 to about 250 grams (g) and preferably from about 20 to about 60 g per 50 kilograms of seed.
  • the chemical can be incorporated in the soil or applied to the surface usually at a rate of 0.5 to about 20 kg and preferably about 1 to about 5 kg per hectare.
  • 2,4-Dichloro-6-iodophenol (2.0 grams (g), 6.9 millimoles (mmol)) was dissolved in dry tetrahydrofuran (THF; 20 milliliters (mL)), cooled to ⁇ 30 to ⁇ 40° C., treated in portions with isopropyl magnesium chloride-lithium chloride complex (1.3 M in THF; 7.3 mmol) and stirred for 45 minutes (min) as the temperature was allowed to rise to 0° C. The mixture was cooled to ⁇ 30° C., treated with 8 mL (10 mmol) of the Grignard reagent and stirred for 30 min at ⁇ 30° C.
  • Ethyl trifluoroacetate (2.4 mL, 2.8 g, 20 mmol) was added, and the mixture was stirred for 15 min at ⁇ 30° C., warmed to 25° C. and stirred for 2 hours (h).
  • the reaction was quenched by addition of saturated (satd) ammonium chloride (NH 4 C1; 10 mL), diluted with ethyl acetate (EtOAc; 50 mL) and washed with 1 M hydrochloric acid (HCl; 20 mL), satd sodium chloride (NaCl; 10 mL), dried over sodium sulfate (Na 2 SO 4 ) and evaporated.
  • N-(3,5-Dichloro-2-hydroxybenzoyl)benzotriazole (prepared according to Katritizky et al., Synthesis 2007, 20, 3141-3146, which is expressly incorporated by reference herein; 2.0 g, 6.5 mmol) was stirred in dry THF (25 mL), cooled to ⁇ 30° C., treated in portions with cyclopropylmagnesium bromide (0.5 M in THF; 28 mL, 14 mmol) and stirred at ⁇ 30° C. for 30 min. The cooling bath was removed and the mixture was allowed to warm to 25° C. and stir for 3 h.
  • reaction was quenched by addition of 10 mL satd NH 4 Cl, and shaken with EtOAc (50 mL) plus 20% citric acid solution (30 mL). The organic phase was washed with satd NaCl (20 mL), dried (Na 2 SO 4 ) and evaporated.
  • Methyl-3,5-dichlorosalicylate prepared according to Ahmed et al., Medicinal Chemistry 2008, 4, 298-308, which is expressly incorporated by reference herein; 2.0 g, 9.0 mmol
  • the mixture was stirred at ⁇ 20 to ⁇ 40° C. for 45 min, warmed to 25° C. and stirred for 4 h.
  • the excess reagent was quenched by addition of satd NH 4 Cl (10 mL).
  • the reaction was quenched by addition of satd NH 4 Cl solution then diluted with Et 2 O (30 mL).
  • the separated organic phase was washed with satd NaCl (10 mL), dried (Na 2 SO 4 ) and evaporated.
  • the residue was dissolved in dry methanol (CH 3 OH; 10 mL) and treated with 30% sodium methoxide solution in CH 3 OH (14 g).
  • the mixture was stirred at 25° C. for 20 h, diluted with H 2 O (50 mL) and extracted with Et 2 O (2 ⁇ 40 mL).
  • the combined organic phases were washed with satd NaCl solution (20 mL), dried (Na 2 SO 4 ) and evaporated.
  • This material (3.4 g, 16 mmol) was dissolved in dry THF (100 mL), cooled to ⁇ 78° C. and treated dropwise with n-BuLi (2.5 M in hexanes; 16 mL, 39 mmol) over 15 min. After stirring for 90 min at ⁇ 78° C., DMF (3.5 mL, 3.3 g, 45 mmol) was added and stirring was continued for 30 min at ⁇ 78° C. and then warmed to 25° C. over 2 h. Satd NH 4 Cl solution (25 mL) and Et 2 O (100 mL) were added, and the pH was adjusted to 2 with 1 M HCl.
  • This material (2.0 g, 7.3 mmol) was dissolved in dry THF (65 mL), cooled to ⁇ 78° C. and treated dropwise with n-BuLi (2.5 M in hexanes; 6.4 mL, 16 mmol). The mixture was stirred for 90 min at ⁇ 78° C. and treated with DMF (1.4 mL, 1.3 g, 18 mmol). After stirring at ⁇ 78° C. for 30 min, the mixture was warmed to 25° C., quenched with satd NH 4 Cl solution (10 mL) and worked up with H 2 O (30 mL) and Et 2 O (75 mL).
  • 3,5-Bis(trifluoromethyl)anisole (5.0 g 21 mmol) and TMEDA (4.0 mL, 3.0 g, 26 mmol) were dissolved in dry Et 2 O (60 mL), cooled to ⁇ 10° C. and treated in portions with n-BuLi (2.5 M in hexanes; 10 mL, 25 mmol). The mixture was warmed to 25° C. and stirred for 90 min. The mixture was cooled to ⁇ 78° C., treated dropwise with DMF (2.3 mL, 2.2 g, 30 mmol), stirred for 30 min, warmed to 25° C. and stirred for 30 min.
  • DMF 2.3 mL, 2.2 g, 30 mmol
  • 3,4-Dichloro-2-hydroxybenzaldehyde was prepared from commercially available starting materials as described in Gu et al., J. Med. Chem. 2000, 43, 4868-4876, which is expressly incorporated by reference herein.
  • 3-Bromo-2-hydroxy-5-methylsulfanyl-benzaldehyde was prepared from commercially available starting materials as described in Guiles et al., PCT Int. Appl. WO 2008039641 A2, which is expressly incorporated by reference herein.
  • 3,6-Dichloro-2-hydroxybenzaldehyde was prepared from commercially available starting materials as described in Rafferty et al., PCT Int. Appl. WO 2008121602 A1, which is expressly incorporated by reference herein.
  • 2-Hydroxy-4-trifluoromethylbenzaldehyde was prepared from commercially available starting materials as described in Faeh et al., U.S. Pat. Appl. Publ. 2007185113 A1, which is expressly incorporated by reference herein.
  • 2,3-Dichloro-6-hydroxybenzaldehyde was prepared from commercially available starting materials as described in Stokker et al., J. Med. Chem. 1980, 23, 1414-1427, which is expressly incorporated by reference herein.
  • 2-Hydroxy-6-trifluoromethylbenzaldehyde was prepared from commercially available starting materials as described in Stokker et al., J. Med. Chem. 1980, 23, 1414-1427, which is expressly incorporated by reference herein.
  • 2-Hydroxy-6-methylbenzaldehyde was prepared from commercially available starting materials as described in Hofslokken and Skattebol, Acta Chemica Scandinavica 1999, 53, 258-262, which is expressly incorporated by reference herein.
  • Ketone compounds wherein R2 is either i-propyl or t-butyl, were prepared from commercially available starting materials as described in Miller, J. A., J. Org. Chem. 1987, 52, 322-323, which is expressly incorporated by reference herein.
  • hydrazones of the present invention or their metal complexes, in a mixture with inorganic or organic mono- or divalent copper salts or chelates (hereinafter referred to as “copper products”) increase the biological potency of copper products, enabling comparable or improved efficacy at lower copper use rates.
  • copper products which may be mixed with the compounds of the present invention to provide enhanced potency may include the following: copper oxychloride, copper octanoate, copper ammonium carbonate, copper arsenate, copper oxysulfate, copper formate, copper propionate, copper oxyacetate, copper citrate, copper chloride, copper diammonium chloride, copper nitrate, copper carbonate, copper phosphate, copper pyrophosphate, copper disodium EDTA, copper diammonium EDTA, copper oxalate, copper tartrate, copper gluconate, copper glycinate, copper glutamate, copper aspartate, copper adipate, copper palmitate, copper stearate, copper caprylate, copper decanoate, copper undecylenate, copper neodecanoate, copper linoleate, copper oleate, copper borate, copper methanesulfonate, copper sulfamate
  • Salicylaldehyde benzoylhydrazones such as those of the current invention are known in the literature as chelators of metal cations ( Inorganica Chimica Acta 1982, 67, L25-L27, which is expressly incorporated by reference herein), including copper.
  • Antimicrobial activity has been reported for o-hydroxybenzaldehyde-N-salicyloylhydrazone and its copper, nickel and cobalt complexes towards Staphylococcus aureus, Escherichia coli, Aspergillus niger and A. flavus ( Proceedings of the National Academy of Sciences , India 1991, Section A Part IV, Vol. LXI, pp. 447-452, which is expressly incorporated by reference herein).
  • In vitro fungitoxicity assays against Leptosphaeria nodorum were conducted using the liquid growth medium described by Coursen and Sisler ( American Journal of Botany 1960, 47, 541-549) except that copper micronutrient, normally included as CuSO 4 , was omitted.
  • the medium termed “copper-minus”, was prepared by dissolving 10 g glucose, 1.5 g K 2 HPO 4 , 2 g KH 2 PO 4 and 1 g (NH 4 ) 2 SO 4 in 1 liter of deionized water and treating the solution with 0.5 g Chelex 100 resin (Bio-Rad Analytical grade, 50-100 mesh, sodium form, cat# 142-2822) by stiffing at room temperature for 1 h.
  • MgSO 4 .7H 2 O (0.5 g) was added, and stiffing continued for a further hour. Trace elements (minus CuSO 4 ), and vitamins described by Coursen and Sisler were added from concentrated stock solutions and the entire medium was sterilized by filtration.
  • Medium containing copper was prepared by adding CuCl 2 .2H 2 O to the copper-minus medium at 20 ⁇ M. Test compounds were dissolved in dimethylsulfoxide (DMSO) then dilutions in copper-minus and copper-plus growth media were prepared as 100 ⁇ L aliquots in flat-bottomed 96-well microtiter plates.
  • DMSO dimethylsulfoxide
  • LEPTNO was grown on potato dextrose agar in 9 cm diameter petri dishes for 7 days.
  • Sterile deionized water (20 mL) was added to a culture plate and spores suspended by scraping the surface gently with a sterile plastic loop.
  • the resulting suspension was filtered through a double layer of sterile cheesecloth.
  • Filtered spore suspension (5 mL) was centrifuged in a bench centrifuge at 2000 rpm for 2 min.
  • the resulting spore pellet was resuspended in 10 mL sterile deionized water (which had been treated with Chelex 100 resin using 0.5 g resin per liter of water by stirring at room temperature for 1 h), and recentrifuged.
  • the spores were resuspended in copper-minus medium, and the suspension adjusted to 2 ⁇ 10 5 spores per mL.
  • Microtiter plates were inoculated with 100 ⁇ L of this spore suspension and the plates incubated at 25° C. for 72 h before assessing fungal growth by measuring light scattering in a NepheloStar plate reader. Growth inhibition was determined by comparing growth in the presence of test compound with growth in control wells lacking test compound.
  • Results for growth inhibition by test compounds in copper-plus medium (“% Inhn. Plus Copper Observed”) were compared with predicted values (“% Inhn. Plus Copper Predicted”) that were calculated using the formula set forth by S. R. Colby in Weeds 1967, 15, 20-22 based on results obtained for the same compounds in copper-minus medium (“% Inhn. Minus Copper Observed”) and the inhibition attributed to copper chloride alone, as determined by comparing growth in copper-minus and copper-plus media without any test compound across experiments. Data are presented in Table 3. Results illustrate that hydrazones and copper produce a synergistic fungitoxic effect towards LEPTNO.
  • Hydrazone compounds at 50 ppm in combination with 50 ⁇ M CuCl 2 .2H 2 O were evaluated as prophylactic treatments applied 24 h before inoculation. Efficacy was determined based on percentage of disease control against tomato late blight (TLB), causal agent Phytophthora infestans . Treatments were arranged in a completely randomized design with 3 repetitions each. A pot with one tomato plant was considered as an experimental unit. Hydrazones were dissolved in acetone and re-suspended in water containing 0.01% Triton® X-100, 0.1% Atlox 4913 and 50 ⁇ M CuCl 2 .2H 2 O to a final concentration of 10% acetone.
  • the medium termed “copper-minus AS” was prepared by dissolving 2 g asparagine, 0.43 g KH 2 PO 4 , 0.3 g K 2 HPO 4 , 0.4 mL of a 0.5 mg/mL thiamine-HCl solution and 15 g sucrose in 1 liter of deionized water and treating the solution with 0.5 g Chelex 100 resin (Bio-Rad Analytical grade, 50-100 mesh, sodium form, cat# 142-2822) by stiffing at room temperature for 1 h.
  • Chelex 100 resin Bio-Rad Analytical grade, 50-100 mesh, sodium form, cat# 142-2822
  • Phytophthora capsici was grown on petri plates, 9 cm in diameter, containing 15 mL V-8 agar, pH 7.0, containing 200 mL V-8 juice, 4 g CaCO 3 , and 20 g agar per liter. Plates were inoculated with 7-mm plugs from a 1-week old culture, incubated at 25° C. in the dark for 3 days, and then placed under fluorescent lights for 4 days to induce sporulation.
  • Zoospore release from sporangia was induced by adding 15 mL of sterile deionized water (which had been treated with Chelex 100 resin using 0.5 g resin per liter of water by stiffing at room temperature for 1 h) to each plate, and incubating for 10 min at 25° C. followed by 20 min at 4° C. The plates were returned to 25° C. for 10 min and the aqueous suspension of released zoospores was recovered. The zoospore suspension was adjusted to 5 ⁇ 10 4 spores/mL by dilution into Chelex 100-treated water. Microtiter plates were inoculated with 100 ⁇ L of spore suspension and incubated at 25° C. for 48 h before assessing fungal growth by measuring light scattering in a NepheloStar plate reader. Growth inhibition was determined by comparing growth in the presence of test compound with growth in control wells lacking test compound.
  • Results for growth inhibition by test compounds in copper-plus AS medium (“% Inhn. Plus Copper Observed”) were compared with predicted values (“% Inhn. Plus Copper Predicted”) that were calculated using the formula set forth by S. R. Colby in Weeds (1967), 15, 20-22 based on results obtained for the same compounds in copper-minus AS medium (“% Inhn. Minus Copper Observed”) and the inhibition attributed to copper chloride alone, as determined by comparing growth in copper-minus AS and copper-plus AS media without any test compound across experiments. Data are presented in Table 3. Results illustrate that hydrazones and copper produce a synergistic fungitoxic effect towards Phytophthora capsici .
  • In vitro fungitoxicity assays against Ustilago maydis were conducted using the copper-minus medium described in Example 26.
  • Medium containing copper was prepared by adding CuCl 2 .2H 2 O to the copper-minus medium at 20 ⁇ M.
  • Test compounds were dissolved in dimethylsulfoxide (DMSO) at 200 ⁇ g/mL and 1 ⁇ L aliquots were added to two wells of flat-bottomed 96-well microtiter plates. Copper-minus medium (100 ⁇ L) was added to one of the wells and copper-plus medium to the second well. Control wells, included for each medium, received 1 uL DMSO and 100 ⁇ L of medium.
  • DMSO dimethylsulfoxide
  • Ustilago maydis was grown in 50 mL potato dextrose broth with shaking at 25° C. for 24 h. A 10 mL aliquot of the culture was centrifuged at 2000 rpm for 2 min, resuspended in 10 mL of sterile Chelex 100-treated water, and centrifuged again. The spores were resuspended in copper-minus medium, and the suspension adjusted to a concentration of 1 ⁇ 10 5 spores per mL. Microtiter plate wells containing test compound of DMSO (control) as described above were inoculated with 100 ⁇ L of this spore suspension and the plates incubated at 25° C. for 48 h before assessing fungal growth by measuring light scattering in a NepheloStar plate reader. Growth inhibition was determined by comparing growth in the presence of test compound with growth in control wells lacking test compound.
  • Results for growth inhibition by test compounds at 1 ⁇ g/mL in copper-plus medium (“% Inhn. Plus Copper Observed”) were compared with predicted results (“% Inhn. Plus Copper Predicted”) that were calculated using the formula set forth by S. R. Colby in Weeds 1967, 15, 20-22 based on results obtained for the same compounds in copper-minus medium (“% Inhn. Minus Copper Observed”) and the inhibition attributed to copper chloride alone, as determined by comparing growth in copper-minus and copper-plus media without any test compound. Data are presented in Table 4. Results illustrate that hydrazones and copper produce a synergistic fungitoxic effect towards Ustilago maydis .
  • Example 26 In vitro fungitoxicity assays against Septoria tritici were conducted using the copper-minus medium described in Example 26.
  • Medium containing copper was prepared by adding CuCl 2 .2H 2 O to the copper-minus medium at 2 ⁇ M.
  • Test compounds were dissolved in dimethylsulfoxide (DMSO) at 10 ⁇ g/mL and 1 ⁇ L aliquots were added to two wells of flat-bottomed 96-well microtiter plates. Copper-minus medium (100 ⁇ L) was added to one of the wells and copper-plus medium to the second well. Control wells, included for each medium, received 1 uL DMSO and 100 ⁇ L of medium.
  • DMSO dimethylsulfoxide
  • Septoria tritici isolate USA-184 was grown on potato dextrose agar at 18° C. under black lights for 3 days. A loopful of spores was transferred from the culture to a 15 mL tube containing 5 mL of sterile Chelex-treated water. The spores were centrifuged at 2000 rpm for 2 min, resuspended in 10 mL water, and centrifuged again. The spores were resuspended in copper-minus medium, and the suspension adjusted to a concentration of 1 ⁇ 10 5 spores per mL.
  • Microtiter plate wells containing test compound of DMSO (control) as described above were inoculated with 100 ⁇ L of this spore suspension and the plates incubated at 25° C. for 90 h before assessing fungal growth by measuring light scattering in a NepheloStar plate reader. Growth inhibition was determined by comparing growth in the presence of test compound with growth in control wells lacking test compound.
  • Results for growth inhibition by test compounds at 0.05 ⁇ g/mL in copper-plus medium (“% Inhn. Plus Copper Observed”) were compared with predicted results (“% Inhn. Plus Copper Predicted”) that were calculated using the formula set forth by S. R. Colby in Weeds 1967, 15, 20-22 based on results obtained for the same compounds in copper-minus medium (“% Inhn. Minus Copper Observed”) and the inhibition attributed to copper chloride alone, as determined by comparing growth in copper-minus and copper-plus media without any test compound. In this experiment, copper chloride alone (1 ⁇ M) had no effect on growth. Data are presented in Table 5. Results illustrate that hydrazones and copper produce a synergistic fungitoxic effect towards Septoria tritici .
  • Metal complexes of hydrazones were prepared by precipitation from ethanol with various metal salts, at 1:1, 2:1 or 3:1 molar ratios, as described in general by Ainscough, Brodie, Dobbs, Ranford, and Waters ( Inorganica Chimica Acta 1998, 267, 27-38, which is expressly incorporated by reference herein).
  • a general synthesis of 1:1 metal-hydrazone complexes is as follows.
  • the starting salicylaldehyde benzoylhydrazone or 2-hydroxyphenylketone benzoylhydrazone is dissolved (or suspended) in EtOH (generally 0.1 mmol hydrazone per mL solvent) and agitated at a temperature ranging from room temperature to 80° C. for 30 min.
  • EtOH generally 0.1 mmol hydrazone per mL solvent
  • To this solution (or suspension) is added 1 equivalent of the metal salt (generally as a 1 M solution in EtOH). The mixture is agitated for a period ranging from 1 to 24 h at a temperature ranging from room temperature to 80° C.
  • the metal-hydrazone complex generally precipitates during the reaction or upon cooling and is isolated by filtration, washed with EtOH and finally washed with Et 2 O. In the instances where the complex does not precipitate, the solvent is removed and the resulting solid metal-hydrazone complex is washed with Et 2 O. Properties of particular metal complexes of hydrazones are provided in Table 6 below.
  • Example 26 In vitro fungitoxicity assays were conducted using the copper-minus medium described in Example 26. Test compounds were dissolved in dimethylsulfoxide (DMSO) then dilutions in copper-minus medium were prepared as 100 ⁇ L aliquots in flat-bottomed 96-well microtiter plates. Microtiter plates were inoculated with 100 ⁇ L of spore suspension at a concentration of 2 ⁇ 10 5 spores per mL, prepared as in Example 26. The plates were incubated at 25° C. for 72 h before assessing fungal growth by measuring light scattering in a NepheloStar plate reader. Growth inhibition was determined by comparing growth in the presence of test compound with growth in control wells lacking test compound.
  • DMSO dimethylsulfoxide
  • Results for growth inhibition by hydrazones and corresponding isolated metal complexes are shown in Table 7.
  • Hydrazones and their copper complexes were compared with respect to their ability to control glume blotch of wheat.
  • Compound formulation was accomplished by dissolving technical materials in acetone and adding 9 volumes de-ionized water containing 0.01% Triton® X-100.
  • Example 26 In vitro fungitoxicity assays against LEPTNO were conducted using the copper-minus medium described in Example 26.
  • Medium containing copper was prepared by adding CuCl 2 .2H 2 O to the copper minus medium at 20 ⁇ M.
  • Test compounds were dissolved in dimethylsulfoxide (DMSO) then dilutions in copper-minus and copper-plus media were prepared as 100 ⁇ L aliquots in flat-bottomed 96-well microtiter plates.
  • Microtiter plates were inoculated with 100 ⁇ L of spore suspension at a concentration of 2 ⁇ 10 5 spores per mL, prepared as in Example 26. The plates were incubated at 25° C.
  • Results show that fungitoxicity of metal complexes of hydrazones towards LEPTNO is synergistically enhanced in the presence of added copper. Furthermore, the fungitoxicity of copper complexes of hydrazones is synergistically enhanced in the presence of added copper.
  • Example 28 In vitro fungitoxicity assays against Phytophthora capsici were conducted using the copper-minus AS medium described in Example 28. Medium containing copper was prepared by adding CuCl 2 .2H 2 O to the copper-minus AS medium at 100 ⁇ M. Test compounds were dissolved in dimethylsulfoxide (DMSO) then dilutions in copper-minus AS and copper-plus AS media were prepared as 100 ⁇ L aliquots in flat-bottomed 96-well microtiter plates. Microtiter plates were inoculated with 100 ⁇ L of zoospore suspension at a concentration of 5 ⁇ 10 4 spores per mL, prepared as in Example 28. The plates were incubated at 25° C. for 48 h before assessing fungal growth by measuring light scattering in a NepheloStar plate reader. Growth inhibition was determined by comparing growth in the presence of test compound with growth in control wells lacking test compound.
  • DMSO dimethylsulfoxide
  • Results for growth inhibition by test compounds in copper-plus AS medium (“% Inhn. Plus Copper Observed”) were compared with predicted values (“% Inhn. Plus Copper Predicted”) that were calculated using the formula set forth by S. R. Colby in Weeds 1967, 15, 20-22 based on results obtained for the same compounds in copper-minus AS medium (“% Inhn. Minus Copper Observed”) and the inhibition attributed to copper chloride alone, as determined by comparing growth in copper-minus and copper-plus media without any test compound across experiments. Data are presented in Table 10. Results show that fungitoxicity of metal complexes of hydrazones towards Phytophthora capsici is synergistically enhanced in the presence of added copper. Furthermore, the fungitoxicity of copper complexes of hydrazones is synergistically enhanced in the presence of added copper.
  • capsici zoospores in Chelex-treated water at 5 ⁇ 10 4 spores per mL was prepared as in Example 28.
  • Microtiter plates were inoculated with 100 ⁇ L of the spore suspension and incubated at 25° C. for 48 h before assessing fungal growth by measuring light scattering in a NepheloStar plate reader.
  • Hydrazone compound 16 was tested alone or in combination with CuCl 2 .2H 2 O, CuSO 4 .5H 2 O, Kocide® 2000 (copper hydroxide), or CUREX 3 (tribasic copper sulfate). All materials and mixtures were evaluated as prophylactic treatments applied 24 h before inoculation. Efficacy was determined based on percentage of disease control against tomato late blight ( Phytophthora infestans ), tomato early blight ( Alternaria solani ), and anthracnose on cucumbers ( Colletotrichum lagenarium ). Treatments were arranged as a factorial experiment in a completely randomized design.
  • Hydrazone and copper were regarded as factors with hydrazone at 10, 50, 200, and 400 ⁇ M, and copper materials at 10, 50, 200, 400, and 800 ⁇ M with respect to their copper content. All treatments were performed in triplicate. Plant varieties used were Outdoor Girl and Bush Pickle, for tomato and cucumber, respectively. Treatments were prepared in 0.01% Triton® X-100 and applied to run-off 24 h before inoculation using a spin-table sprayer. Inoculation was performed with aqueous spore suspensions using a Delta painting sprayer. Percentage of disease control was determined 7 days after inoculation.
  • Test compounds were hydrazone Compound 16, the complex of Compound 16 with copper (“hydrazone-copper”) prepared by precipitation with CuCl 2 .2H 2 O using a 1:1 molar ratio, and CuCl 2 .2H 2 O alone. Hydrazone and hydrazone-copper were formulated in 10% acetone/0.1% Trycol 5941 in de-ionized water. CuCl 2 .2H 2 O was formulated with 0.1% Trycol 5941 in de-ionized water. Grape and tomato plants were sprayed with 160 ⁇ M suspensions of the formulated test compounds at a spray volume of 0.8 mL per plant.
  • Results for disease control by hydrazone-copper were compared with predicted results calculated using the Colby formula based on disease control by the hydrazone alone and CuCl 2 alone. Results, shown in Table 25, show that hydrazone-copper provided greater disease control than predicted based on control observed for hydrazone and CuCl 2 alone.

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Abstract

The present invention relates to the use of mixtures containing hydrazone compounds and copper for controlling the growth of fungi.

Description

    CROSS REFERENCE TO RELATED APPLICATIONS
  • This application claims the benefit of U.S. Provisional Patent Application Ser. No. 61/144,560 filed Jan. 14, 2009, which is expressly incorporated by reference herein.
    • FIELD OF THE INVENTION
  • The present invention relates to the use of hydrazones in combination with copper, copper-based fungicides or other copper-containing materials as synergistic fungicidal mixtures.
    • BACKGROUND
  • Copper is used to control the growth of organisms, especially microorganisms, in a variety of applications such as those described in the “Handbook of copper compounds and applications” edited by H. W. Richardson and published by Marcel Dekker, Inc. New York (1997), which is expressly incorporated by reference herein. These applications may include its use in agriculture to control a wide range of fungal and bacterial diseases of plants. Copper products may also be used as aquatic biocides in fresh or marine environments. Copper products may be used in antifouling applications and to control unwanted organisms in ponds and lakes based on the toxicity of copper towards algae, fungi, macrophytes and mollusks. Copper-based materials may also be used as wood preservatives and on other materials to inhibit fungal and bacterial growth. Other uses also include killing plant roots in sewer systems.
  • Ecological risk assessment studies have shown that copper products, which normally are applied at high use rates, may be toxic to birds, mammals, fish and other aquatic species (“Reregistration Eligibility Decision (RED) for Coppers”, EPA 738-R-06-020, July 2006, which is expressly incorporated by reference herein). Thus, while copper is a highly useful agent for controlling the growth of undesirable organisms in different environments, it is desirable to minimize the amount of copper applied.
    • SUMMARY OF THE INVENTION
  • One exemplary embodiment of the present disclosure includes a synergistic mixture for controlling the growth of fungi, the synergistic mixture including copper and a hydrazone compound of Formula I:
  • Figure US20120010075A1-20120112-C00001
  • wherein A is oxygen or sulfur;
  • Z is H or C1-C4 alkyl;
  • W is —CHR1-;
  • n is 0, 1, or 2;
  • R is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl C2-C6 haloalkynyl, or C3-C6 halocycloalkyl;
  • R1 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl C2-C6 haloalkynyl, C3-C6 halocycloalkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, or unsubstituted heteroaryl;
  • X3, X4, X5, and X6 are each independently selected from the group consisting of H, halogen, nitro, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkylthio, C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C4 haloalkenyl, C2-C4 haloalkynyl, C1-C4 haloalkylthio, —SO2R1, SONR1R1, —CR1=NOR1, —CONR1R1, NR1COOR1, —COOR1, substituted aryl, substituted heteroaryl, unsubstituted aryl, and unsubstituted heteroaryl; and
  • Y2, Y3, Y4, Y5, and Y6 are each independently selected from the group consisting of H, halogen, nitro, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkylthio, C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C4 haloalkenyl, C2-C4 haloalkynyl, C1-C4 haloalkylthio, —SO2R1, SONR1R1, —R1=NOR1, —CONR1R1, NR1COOR1, —COOR1, NR1R1, substituted aryl, substituted heteroaryl, unsubstituted aryl, unsubstituted heteroaryl, and phenoxy;
  • with the proviso that X3 and X4, X4 and X5, X5 and X6, Y2 and Y3, or Y3 and Y4 may form a 5 or 6 membered fused ring which may contain up to two heteroatoms selected from the group consisting of O, N, and S.
  • The term “alkyl” refers to a branched, unbranched, or cyclic carbon chain, including methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tertiary butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • The term “cycloalkyl” refers to a monocyclic or polycyclic, saturated substituent consisting of carbon and hydrogen.
  • The term “alkenyl” refers to a branched, unbranched or cyclic carbon chain containing one or more double bonds including ethenyl, propenyl, butenyl, isopropenyl, isobutenyl, cyclohexenyl, and the like.
  • The term “alkynyl” refers to a branched or unbranched carbon chain containing one or more triple bonds including propynyl, butynyl and the like.
  • As used throughout this specification, the term ‘R’ refers to the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl C2-C6 haloalkynyl, or C3-C6 halocycloalkyl, unless stated otherwise.
  • The term “alkoxy” refers to an —OR substituent.
  • The term “alkylthio” refers to an —S—R substituent.
  • The term “haloalkylthio” refers to an alkylthio, which is substituted with Cl, F, I, or Br or any combination thereof.
  • The term “cyano” refers to a —C≡N substituent.
  • The term “hydroxyl” refers to an —OH substituent.
  • The term “haloalkoxy” refers to an —OR—X substituent, wherein X is Cl, F, Br, or I, or any combination thereof.
  • The term “haloalkyl” refers to an alkyl, which is substituted with Cl, F, I, or Br or any combination thereof.
  • The term “halocycloalkyl” refers to a monocyclic or polycyclic, saturated substituent consisting of carbon and hydrogen, which is substituted with Cl, F, I, or Br or any combination thereof.
  • The term “haloalkenyl” refers to an alkenyl, which is substituted with Cl, F, I, or Br or any combination thereof.
  • The term “haloalkynyl” refers to an alkynyl which is substituted with Cl, F, I, or Br or any combination thereof.
  • The term “halogen” or “halo” refers to one or more halogen atoms, defined as F, Cl, Br, and I.
  • The term “aryl” refers to a cyclic, aromatic substituent consisting of hydrogen and carbon.
  • The term “heteroaryl” refers to a cyclic substituent that may be fully unsaturated, where the cyclic structure contains at least one carbon and at least one heteroatom, where said heteroatom is nitrogen, sulfur, or oxygen.
  • The term “phenoxy” refers to an —O substituted with a six-membered fully unsaturated ring consisting of hydrogen and carbon.
  • The term “nitro” refers to a —NO2 substituent.
  • Certain compounds disclosed in this document can exist as one or more isomers. The various isomers include stereoisomers, geometric isomers, diastereomers, and enantiomers. Thus, the compounds disclosed in this invention include geometric isomers, racemic mixtures, individual stereoisomers, and optically active mixtures. It will be appreciated by those skilled in the art that one isomer may be more active than the others. The structures disclosed in the present disclosure are drawn in only one geometric form for clarity, but are intended to represent all geometric forms of the molecule.
  • Additional features and advantages of the present invention will become apparent to those skilled in the art upon consideration of the following detailed description of the illustrative embodiments exemplifying the best mode of carrying out the invention as presently perceived.
    • DETAILED DESCRIPTION OF THE DISCLOSURE
  • The embodiments of the invention described herein are not intended to be exhaustive or to limit the invention to the precise forms disclosed. Rather, the embodiments selected for description have been chosen to enable one skilled in the art to practice the invention. Although the disclosure is described as a synergistic combination of copper, copper based fungicides, or other copper-containing materials and a hydrazone or hydrazone derivative it should be understood that the concepts presented herein may be used in various applications and should not be limited.
  • The mixtures of the present invention have fungitoxic activity against phytopathogenic fungi, against fungal pathogens of mammals, including humans, and against wood decay causing fungi. The mixtures of the present invention may have broad spectrum fungitoxic activity, particularly against phytopathogenic fungi. They are active against fungi of a number of classes including Deuteromycetes (Fungi Imperfecti), Basidiomycetes, Oomycetes and Ascomycetes. More particularly, the method of this invention provides for activity against organisms including, but not limited to, Phytophthora species, Plasmopara viticola, Pseudoperonospora cubensis, Pythium species, Pyricularia oryzae, Colletotrichum species, Helminthosporium species, Alternaria species, Septoria nodorum, Leptosphaeria nodorum, Ustilago maydis, Erysiphe graminis, Puccinia species, Sclerotinia species, Sphaerotheca fuliginea, Cercospora species, Rhizoctonia species, Uncinula necator, Septoria tritici, and Podosphaera leucotricha.
  • The method of the present invention also provides for activity against fungal pathogens of mammals (including humans) including, but not limited to, Candida species such as C. albicans, C. glabrata, C. parapsilosis, C. krusei, and C. tropicalis, Aspergillus species such as Aspergillus fumigatus, Fusarium species, Coccidioides immitis, Cryptococcus neoformans, Histoplasma capsulatum, Microsporum species, and Tricophyton species. The method of the present invention also provides for activity against fungi which cause wood decay such as Gleophyllum trabeur, Phialophora mutabilis, Poria palcenta and Trametes versicolor.
  • The present invention contemplates all vehicles by which the composition of the present invention can be formulated for delivery and use as a pesticide composition, including solutions, suspensions, emulsions, wettable powders and water dispersible granules, emulsifiable concentrates, granules, dusts, baits, and the like. Typically, formulations are applied following dilution of the concentrated formulation with water as aqueous solutions, suspensions or emulsions, or combinations thereof. Such solutions, suspensions or emulsions are produced from water-soluble, water-suspended or water-suspendable, water-emulsified or water-emulsifiable formulations or combinations thereof which are solids, including and usually known as wettable powders or water dispersible granules; or liquids including and usually known as emulsifiable concentrates, aqueous suspensions or suspension concentrates, and aqueous emulsions or emulsions in water, or mixtures thereof such as suspension-emulsions. As will be readily appreciated, any material to which this composition can be added may be used, provided they yield the desired utility without significant interference with the desired activity of the pesticidally active ingredients as pesticidal agents and improved residual lifetime or decreased effective concentration is achieved.
  • Wettable powders, which may be compacted to form water dispersible granules, comprise an intimate mixture of one or more of the pesticidally active ingredients, an inert carrier and surfactants. The concentration of the pesticidally active ingredient in the wettable powder is usually from about 10 percent to about 90 percent by weight based on the total weight of the wettable powder, more preferably about 25 weight percent to about 75 weight percent. In the preparation of wettable powder formulations, the pesticidally active ingredients can be compounded with any finely divided solid, such as prophyllite, talc, chalk, gypsum, Fuller's earth, bentonite, attapulgite, starch, casein, gluten, montmorillonite clays, diatomaceous earths, purified silicates or the like. In such operations, the finely divided carrier and surfactants are typically blended with the compound(s) and milled
  • Emulsifiable concentrates of the pesticidally active ingredient comprise a convenient concentration, such as from about 10 weight percent to about 50 weight percent of the pesticidally active ingredient, in a suitable liquid, based on the total weight of the concentrate. The pesticidally active ingredients are dissolved in an inert carrier, which is either a water miscible solvent or a mixture of water-immiscible organic solvents, and emulsifiers. The concentrates may be diluted with water and oil to form spray mixtures in the form of oil-in-water emulsions. Useful organic solvents include aromatics, especially the high-boiling naphthalenic and olefinic portions of petroleum such as heavy aromatic naphtha. Other organic solvents may also be used, such as, for example, terpenic solvents, including rosin derivatives, aliphatic ketones, such as cyclohexanone, and complex alcohols, such as 2-ethoxyethanol.
  • Emulsifiers which can be advantageously employed herein can be readily determined by those skilled in the art and include various nonionic, anionic, cationic and amphoteric emulsifiers, or a blend of two or more emulsifiers. Examples of nonionic emulsifiers useful in preparing the emulsifiable concentrates include the polyalkylene glycol ethers and condensation products of alkyl and aryl phenols, aliphatic alcohols, aliphatic amines or fatty acids with ethylene oxide, propylene oxides such as the ethoxylated alkyl phenols and carboxylic esters esterified with the polyol or polyoxyalkylene. Cationic emulsifiers include quaternary ammonium compounds and fatty amine salts. Anionic emul-sifiers include the oil-soluble salts (e.g., calcium) of alkylaryl sulfonic acids, oil-soluble salts of sulfated polyglycol ethers and appropriate salts of phosphated polyglycol ether.
  • Representative organic liquids which can be employed in preparing emulsifiable concentrates are the aromatic liquids such as xylene, propyl benzene fractions; or mixed naphthalene fractions, mineral oils, substituted aromatic organic liquids such as dioctyl phthalate; kerosene; dialkyl amides of various fatty acids, particularly the dim-ethyl amides; and glycol ethers such as the n-butyl ether, ethyl ether or methyl ether of diethylene glycol, and the methyl ether of triethylene glycol and the like. Mixtures of two or more organic liquids may also be employed in the preparation of the emulsifiable concentrate. Surface-active emulsifying agents are typically employed in liquid formulations and in an amount of from 0.1 to 20 percent by weight based on the combined weight of the emulsifying agents. The formulations can also contain other compatible additives, for example, plant growth regulators and other biologically active compounds used in agriculture.
  • Aqueous suspensions comprise suspensions of one or more water-insoluble pesticidally active ingredients dispersed in an aqueous vehicle at a concentration in the range from about 5 to about 50 weight percent, based on the total weight of the aqueous suspension. Suspensions are prepared by finely grinding one or more of the pesticidally active ingredients, and vigorously mixing the ground material into a vehicle comprised of water and surfactants chosen from the same types discussed above. Other components, such as inor-ganic salts and synthetic or natural gums, may also be added to increase the density and viscosity of the aqueous vehicle. It is often most effective to grind and mix at the same time by preparing the aqueous mixture and homogenizing it in an implement such as a sand mill, ball mill, or piston-type homogenizer.
  • Aqueous emulsions comprise emulsions of one or more water-insoluble pesticidally active ingredients emulsified in an aqueous vehicle at a concentration typically in the range from about 5 to about 50 weight percent, based on the total weight of the aqueous emulsion. If the pesticidally active ingredient is a solid it must be dissolved in a suitable water-immiscible solvent prior to the preparation of the aqueous emulsion. Emulsions are prepared by emulsifying the liquid pesticidally active ingredient or water-immiscible solution thereof into an aqueous medium typically with inclusion of surfactants that aid in the formation and stabilization of the emulsion as described above. This is often accomplished with the aid of vigorous mixing provided by high shear mixers or homogenizers.
  • The compositions of the present invention can also be granular formulations, which are particularly useful for applications to the soil. Granular formulations usually contain from about 0.5 to about 10 weight percent, based on the total weight of the granular formulation of the pesticidally active ingredient(s), dispersed in an inert carrier which consists entirely or in large part of coarsely divided inert material such as attapulgite, bentonite, diatomite, clay or a similar inexpensive substance. Such formulations are usually prepared by dissolving the pesticidally active ingredients in a suitable solvent and applying it to a granular carrier which has been preformed to the appropriate particle size, in the range of from about 0.5 to about 3 mm A suitable solvent is a solvent in which the compound is substantially or completely soluble. Such formulations may also be prepared by making a dough or paste of the carrier and the compound and solvent, and crushing and drying to obtain the desired granular particle.
  • Dusts can be prepared by intimately mixing one or more of the pesticidally active ingredients in powdered form with a suitable dusty agricultural carrier, such as, for example, kaolin clay, ground volcanic rock, and the like. Dusts can suitably contain from about 1 to about 10 weight percent of the compounds, based on the total weight of the dust.
  • The formulations may additionally contain adjuvant surfactants to enhance deposition, wetting and penetration of the pesticidally active ingredients onto the target site such as a crop or organism. These adjuvant surfactants may optionally be employed as a component of the formulation or as a tank mix. The amount of adjuvant surfactant will typically vary from 0.01 to 1.0 percent by volume, based on a spray-volume of water, preferably 0.05 to 0.5 volume percent. Suitable adjuvant surfactants include, but are not limited to ethoxylated nonyl phenols, ethoxylated synthetic or natural alcohols, salts of the esters of sulfosuccinic acids, ethoxylated organosilicones, ethoxylated fatty amines and blends of surfactants with mineral or vegetable oils.
  • The formulations may optionally include combinations that contain other pesticidal compounds. Such additional pesticidal compounds may be fungicides, insecticides, nematocides, miticides, arthropodicides, bactericides or combinations thereof that are compatible with the mixtures of the present invention in the medium selected for application, and not antagonistic to the activity of the present mixtures. Accordingly, in such embodiments, the other pesticidal compound is employed as a supplemental toxicant for the same or for a different pesticidal use. The mixtures of the present invention, and the pesticidal compound in the combination can generally be present in a weight ratio of from 1:100 to 100:1.
  • For pharmaceutical use, the mixtures described herein may be taken up in pharmaceutically acceptable carriers, such as, for example, solutions, suspensions, tablets, capsules, ointments, elixirs and injectable compositions. Pharmaceutical preparations may contain from 0.1% to 99% by weight of active ingredient. Preparations which are in single dose form, “unit dosage form”, preferably contain from 20% to 90% active ingredient, and preparations which are not in single dose form preferably contain from 5% to 20% active ingredient. As used herein, the term “active ingredient” refers to mixtures described herein, salts thereof, hydrates, and mixtures with other pharmaceutically active compounds. Dosage unit forms such as, for example, tablets or capsules, typically contain from about 0.05 to about 1.0 g of active ingredient.
  • The mixtures of the present invention can also be combined with other agricultural fungicides to form fungicidal mixtures and synergistic mixtures thereof. The fungicidal mixtures of the present invention are often applied in conjunction with one or more other fungicides to control a wider variety of undesirable diseases. When used in conjunction with other fungicide(s), the presently claimed mixtures can be formulated with the other fungicide(s), tank mixed with the other fungicide(s) or applied sequentially with the other fungicide(s). Such other fungicides include amisulbrom 2-(thiocyanatomethylthio)-benzothiazole, 2-phenylphenol, 8-hydroxyquinoline sulfate, antimycin, Ampelomyces, quisqualis, azaconazole, azoxystrobin, Bacillus subtilis, benalaxyl, benomyl, benthiavalicarb-isopropyl, benzylaminobenzene-sulfonate (BABS) salt, bicarbonates, biphenyl, bismerthiazol, bitertanol, bixafen, blasticidin-S, borax, boscalid, bromuconazole, bupirimate, BYF 1047, calcium polysulfide, captafol, captan, carbendazim, carboxin, carpropamid, carvone, chloroneb, chlorothalonil, chlozolinate, Coniothyrium minitans, cyazofamid, cyflufenamid, cymoxanil, cyproconazole, cyprodinil, coumarin, dazomet, debacarb, diammonium ethylenebis-(dithiocarbamate), dichlofluanid, dichlorophen, diclocymet, diclomezine, dichloran, diethofencarb, difenoconazole, difenzoquat ion, diflumetorim, dimethomorph, dimoxystrobin, diniconazole, diniconazole-M, dinobuton, dinocap, diphenylamine, dithianon, dodemorph, dodemorph acetate, dodine, dodine free base, edifenphos, enestrobin, epoxiconazole, ethaboxam, ethoxyquin, etridiazole, famoxadone, fenamidone, fenarimol, fenbuconazole, fenfuram, fenhexamid, fenoxanil, fenpiclonil, fenpropidin, fenpropimorph, fentin, fentin acetate, fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil, flumorph, fluopicolide, fluopyram, fluoroimide, fluoxastrobin, fluquinconazole, flusilazole, flusulfamide, flutolanil, flutriafol, folpet, formaldehyde, fosetyl, fosetyl-aluminium, fuberidazole, furalaxyl, furametpyr, guazatine, guazatine acetates, GY-81, hexachlorobenzene, hexaconazole, hymexazol, imazalil, imazalil sulfate, imibenconazole, iminoctadine, iminoctadine triacetate, iminoctadine tris(albesilate), ipconazole, iprobenfos, iprodione, iprovalicarb, isoprothiolane, isopyrazam, isotianil, kasugamycin, kasugamycin hydrochloride hydrate, kresoxim-methyl, mancopper, mancozeb, mandipropamid, maneb, mepanipyrim, mepronil, meptyldinocap, mercuric chloride, mercuric oxide, mercurous chloride, metalaxyl, mefenoxam, metalaxyl-M, metam, metam-ammonium, metam-potassium, metam-sodium, metconazole, methasulfocarb, methyl iodide, methyl isothiocyanate, metiram, metominostrobin, metrafenone, mildiomycin, myclobutanil, nabam, nitrothal-isopropyl, nuarimol, octhilinone, ofurace, oleic acid (fatty acids), orysastrobin, oxadixyl, oxine-copper, oxpoconazole fumarate, oxycarboxin, pefurazoate, penconazole, pencycuron, pentachlorophenol, pentachlorophenyl laurate, penthiopyrad, phenylmercury acetate, phosphonic acid, phthalide, picoxystrobin, polyoxin B, polyoxins, polyoxorim, potas-sium bicarbonate, potassium hydroxyquinoline sulfate, probenazole, prochloraz, procymidone, propamocarb, propamocarb hydrochloride, propiconazole, propineb, pro-quinazid, prothioconazole, pyraclostrobin, pyrazophos, pyribencarb, pyributicarb, pyrifenox, pyrimethanil, pyroquilon, quinoclamine, quinoxyfen, quintozene, Reynoutria sachalinensis extract, silthiofam, simeconazole, sodium 2-phenylphenoxide, sodium bicarbonate, sodium pentachlorophenoxide, spiroxamine, sulfur, SYP-Z071, SYP-048, SYP-Z048, tar oils, tebuconazole, tecnazene, tetraconazole, thiabendazole, thifluzamide, thiophanate-methyl, thiram, tiadinil, tolclofos-methyl, tolylfluanid, triadimefon, triadimenol, triazolopyrimidine, triazoxide, tricyclazole, tridemorph, trifloxystrobin, triflumizole, triforine, triticonazole, validamycin, vinclozolin, zineb, ziram, zoxamide, Candida oleophila, Fusarium cocysporum, Gliocladium spp., Phlebiopsis gigantean, Streptomyces griseoviridis, Trichoderma spp., (RS)—N-(3,5-dichlorophenyl)-2-(methoxymethyl)-succinimide, 1,2-dichloropropane, 1,3-dichloro-1,1,3,3-tetrafluoroacetone hydrate, 1-chloro-2,4-dinitronaphthalene, 1-chloro-2-nitropropane, 2-(2-heptadecyl-2-imidazolin-1-yl)ethanol, 2,3-dihydro-5-phenyl-1,4-dithi-ine 1,1,4,4-tetraoxide, 2-methoxyethylmercury acetate, 2-methoxyethylmercury chloride, 2-methoxyethylmercury silicate, 3-(4-chloro-phenyl)-5-methylrhodanine, 4-(2-nitroprop-1-enyl)phenyl thiocyanateme, ampropylfos, anilazine, azithiram, barium polysulfide, Bayer 32394, benodanil, benquinox, bentaluron, benzamacril; benzamacril-isobutyl, benzamorf, binapacryl, his (methylmercury) sulfate, his (tributyltin) oxide, buthiobate, cadmium calcium copper zinc chromate sulfate, carbamorph, CECA, chlobenthiazone, chloraniformethan, chlorfenazole, chlorquinox, climbazole, cyclafuramid, cypendazole, cyprofuram, decafentin, dichlone, dichlozo-line, diclobutrazol, dimethirimol, dinocton, dinosulfon, dinoterbon, dipyrithione, ditalimfos, dodicin, drazoxolon, EBP, ESBP, etaconazole, etem, ethirim, fenaminosulf, fenapanil, fenitropan, 5-fluorocytosine and profungicides thereof, fluotrimazole, furcarbanil, furconazole, furconazole-cis, furmecyclox, furophanate, glyodine, griseofulvin, halacrinate, Hercules 3944, hexylthiofos, ICIA0858, isopamphos, isovaledione, mebenil, mecarbinzid, metazoxolon, methfuroxam, methylmercury dicyandiamide, metsulfovax, milneb, mucochloric anhydride, myclozolin, N-3,5-dichlorophenyl-succinimide, N-3-nitrophenyl-itaconimide, natamycin, N-ethylmercurio-4-toluenesulfonanilide, nickel bis(dimethyldithio-carbamate), OCH, phenylmercury dimethyldithiocarbamate, phenylmercury nitrate, phos-diphen, picolinamide UK-2A and derivatives thereof, prothiocarb; prothiocarb hydrochloride, pyracar-bolid, pyridinitril, pyroxychlor, pyroxyfur, quinacetol; quinacetol sulfate, quinazamid, quinconazole, rabenzazole, salicylanilide, SSF-109, sultropen, tecoram, thiadifluor, thi-cyofen, thiochlorfenphim, thiophanate, thioquinox, tioxymid, triamiphos, triarimol, triazbutil, trichlamide, urbacid, XRD-563, and zarilamide, 1K-1140, propargyl amides and any combinations thereof.
  • The mixtures of the present invention can also be combined with other antifungal compounds used to control infections in mammals to form fungicidal mixtures and synergistic mixtures thereof. The fungicidal mixtures of the present invention can be applied in conjunction with one or more other antifungal compounds or their pharmaceutically acceptable salts to control a wider variety of undesirable diseases. When used in conjunction with other antifungal compounds, the presently claimed mixtures can be formulated with the other antifungal compound(s), coadministered with the other antifungal compound(s) or applied sequentially with the other antifungal compound(s). Typical antifungal compounds include, but are not limited to compounds selected from the group consisting of an azole such as fluconazole, voriconazole, itraconazole, ketoconazole, and miconazole, a polyene such as amphotericin B, nystatin or liposomal and lipid forms thereof such as Abelcet, AmBisome and Amphocil, a purine nucleotide inhibitor such as 5-fluorocytosine, a polyoxin such as nikkomycin, and pneumocandin or echinocandin derivatives such as caspofungin and micofungin.
  • Additionally, the mixtures of the present invention can be combined with other pesticides, including insecticides, nematocides, miticides, arthropodicides, bactericides or combinations thereof that are compatible with the mixtures of the present invention in the medium selected for application, and not antagonistic to the activity of the present mixtures to form pesticidal mixtures and synergistic mixtures thereof. The fungicidal mixtures of the present invention are often applied in conjunction with one or more other pesticides to control a wider variety of undesirable pests. When used in conjunction with other pesticides, the presently claimed mixtures can be formulated with the other pesticide(s), tank mixed with the other pesticide(s) or applied sequentially with the other pesticide(s). Typical insecticides include, but are not limited to: antibiotic insecticides such as allosamidin and thuringiensin; macrocyclic lactone insecticides such as spinosad; avermectin insecticides such as abamectin, doramectin, emamectin, eprinomectin, ivermectin and selamectin; milbemycin insecticides such as lepimectin, milbemectin, milbemycin oxime and moxidectin; arsenical insecticides such as calcium arsenate, copper acetoarsenite, copper arsenate, lead arsenate, potassium arsenite and sodium arsenite; botanical insecticides such as anabasine, azadirachtin, d-limonene, nicotine, pyrethrins, cinerins, cinerin I, cinerin II, jasmolin I, jasmolin II, pyrethrin I, pyrethrin II, quassia, rotenone, ryania and sabadilla; carbamate insecticides such as bendiocarb and carbaryl; benzofuranyl methylcarbamate insecticides such as benfuracarb, carbofuran, carbosulfan, decarbofuran and furathiocarb; dimethylcarbamate insecticides dimitan, dimetilan, hyquincarb and pirimicarb; oxime carbamate insecticides such as alanycarb, aldicarb, aldoxycarb, butocarboxim, butoxy-carboxim, methomyl, nitrilacarb, oxamyl, tazimcarb, thiocarboxime, thiodicarb and thiofanox; phenyl methylcarbamate insecticides such as allyxycarb, aminocarb, bufencarb, butacarb, carbanolate, cloethocarb, dicresyl, dioxacarb, EMPC, ethiofencarb, fenethacarb, fenobucarb, isoprocarb, methiocarb, metolcarb, mexacarbate, promacyl, promecarb, propoxur, trimethacarb, XMC and xylylcarb; dinitrophenol insecticides such as dinex, dinoprop, dinosam and DNOC; fluorine insecticides such as barium hexafluorosilicate, cryolite, sodium fluoride, sodium hexafluorosilicate and sulfluramid; formamidine insecticides such as amitraz, chlordimeform, formetanate and formparanate; fumigant insecticides such as acrylonitrile, carbon disulfide, carbon tetrachloride, chloroform, chloropicrin, para-dichlorobenzene, 1,2-dichloropropane, ethyl formate, ethylene dibromide, ethylene dichloride, ethylene oxide, hydrogen cyanide, iodomethane, methyl bromide, methylchloroform, methylene chloride, naphthalene, phosphine, sulfuryl fluoride and tetrachloroethane; inorganic insecticides such as borax, calcium polysulfide, copper oleate, mercurous chloride, potassium thiocyanate and sodium thiocyanate; chitin synthesis inhibitors such as bistrifluoron, buprofezin, chlorfluazuron, cyromazine, diflubenzuron, flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, novaluron, noviflumuron, penfluoron, teflubenzuron and triflumuron; juvenile hormone mimics such as epofenonane, fenoxycarb, hydroprene, kinoprene, methoprene, pyriproxyfen and triprene; juvenile hormones such as juvenile hormone I, juvenile hormone II and juvenile hormone III; moulting hormone agonists such as chromafenozide, halofenozide, methoxyfenozide and tebufenozide; moulting hormones such as .alpha.-ecdysone and ecdysterone; moulting inhibitors such as diofenolan; precocenes such as precocene I, precocene II and precocene III; unclassified insect growth regulators such as dicyclanil; nereistoxin analogue insecticides such as bensultap, cartap, thiocyclam and thiosultap; nicotinoid insecticides such as flonicamid; nitroguanidine insecticides such as clothianidin, dinotefuran, imidacloprid and thiamethoxam; nitromethylene insecticides such as nitenpyram and nithiazine; pyridylmethyl-amine insecticides such as acetamiprid, imidacloprid, nitenpyram and thiacloprid; organochlorine insecticides such as bromo-DDT, camphechlor, DDT, pp'-DDT, ethyl-DDD, HCH, gamma-HCH, lindane, methoxychlor, pentachlorophenol and TDE; cyclodiene insecticides such as aldrin, bromocyclen, chlorbicyclen, chlordane, chlordecone, dieldrin, dilor, endosulfan, endrin, HEOD, heptachlor, HHDN, isobenzan, isodrin, kelevan and mirex; organophosphate insecticides such as bromfenvinfos, chlorfenvinphos, crotoxyphos, dichlorvos, dicrotophos, dimethylvinphos, fospirate, heptenophos, methocrotophos, mevinphos, monocrotophos, naled, naftalofos, phosphamidon, propaphos, TEPP and tetrachlorvinphos; organothiophosphate insecticides such as dioxabenzofos, fosmethilan and phenthoate; aliphatic organothiophosphate insecticides such as acethion, amiton, cadusafos, chlorethoxyfos, chlormephos, demephion, demephion-O, demephion-S, demeton, demeton-O, demeton-S, demeton-methyl, demeton-O-methyl, demeton-S-methyl, demeton-S-methylsulphon, disulfoton, ethion, ethoprophos, IPSP, isothioate, malathion, methacrifos, oxydemeton-methyl, oxydeprofos, oxydisulfoton, phorate, sulfotep, terbufos and thiometon; aliphatic amide organothiophosphate insecticides such as amidithion, cyanthoate, dimethoate, ethoate-methyl, formothion, mecarbam, omethoate, prothoate, sophamide and vamidothion; oxime organothiophosphate insecticides such as chlorphoxim, phoxim and phoxim-methyl; heterocyclic organothiophosphate insecticides such as azamethiphos, coumaphos, coumithoate, dioxathion, endothion, menazon, morphothion, phosalone, pyraclofos, pyridaphenthion and quinothion; benzothiopyran organothiophosphate insecticides such as dithicrofos and thicrofos; benzotriazine organothiophosphate insecticides such as azinphos-ethyl and azinphos-methyl; isoindole organothiophosphate insecticides such as dialifos and phosmet; isoxazole organothiophosphate insecticides such as isoxathion and zolaprofos; pyrazolopyrimidine organothiophosphate insecticides such as chlorprazophos and pyrazophos; pyridine organothiophosphate insecticides such as chlorpyrifos and chlorpyrifos-methyl; pyrimidine organothiophosphate insecticides such as butathiofos, diazinon, etrimfos, lirimfos, pirimiphos-ethyl, pirimiphos-methyl, primidophos, pyrimitate and tebupirimfos; quinoxaline organothiophosphate insecticides such as quinalphos and quinalphos-methyl; thiadiazole organothiophosphate insecticides such as athidathion, lythidathion, methidathion and prothidathion; triazole organothiophosphate insecticides such as isazofos and triazophos; phenyl organothiophosphate insecticides such as azothoate, bromophos, bromophos-ethyl, carbophenothion, chlorthiophos, cyanophos, cythioate, dicapthon, dichlofenthion, etaphos, famphur, fenchlorphos, fenitrothion fensulfothion, fenthion, fenthion-ethyl, heterophos, jodfenphos, mesulfenfos, parathion, parathion-methyl, phenkapton, phosnichlor, profenofos, prothiofos, sulprofos, temephos, trichlormetaphos-3 and trifenofos; phosphonate insecticides such as butonate and trichlorfon; phosphonothioate insecticides such as mecarphon; phenyl ethylphosphonothioate insecticides such as fonofos and trichloronat; phenyl phenylphosphonothioate insecticides such as cyanofenphos, EPN and leptophos; phosphoramidate insecticides such as crufomate, fenamiphos, fosthietan, mephosfolan, phosfolan and pirimetaphos; phosphoramidothioate insecticides such as acephate, isocarbophos, isofenphos, methamidophos and propetamphos; phosphorodiamide insecticides such as dimefox, mazidox, mipafox and schradan; oxadiazine insecticides such as indoxacarb; phthalimide insecticides such as dialifos, phosmet and tetramethrin; pyrazole insecticides such as acetoprole, cyenopyrafen, ethiprole, fipronil, pyrafluprole, pyriprole, tebufenpyrad, tolfenpyrad and vaniliprole; pyrethroid ester insecticides such as acrinathrin, allethrin, bioallethrin, barthrin, bifenthrin, bioethanomethrin, cyclethrin, cycloprothrin, cyfluthrin, beta-cyfluthrin, cyhalothrin, gamma-cyhalothrin, lambda-cyhalothrin, cypermethrin, alpha-cypermethrin, beta-cypermethrin, theta-cypermethrin, zeta-cypermethrin, cyphenothrin, deltamethrin, dimefluthrin, dimethrin, empenthrin, fenfluthrin, fenpirithrin, fenpropathrin, fenvalerate, esfenvalerate, flucythrinate, fluvalinate, taufluvalinate, furethrin, imiprothrin, metofluthrin, permethrin, biopermethrin, transpermethrin, phenothrin, prallethrin, profluthrin, pyresmethrin, resmethrin, bioresmethrin, cismethrin, tefluthrin, terallethrin, tetramethrin, tralomethrin and transfluthrin; pyrethroid ether insecticides such as etofenprox, flufenprox, halfenprox, protrifenbute and silafluofen; pyrimidinamine insecticides such as flufenerim and pyrimidifen; pyrrole insecticides such as chlorfenapyr; tetronic acid insecticides such as spiromesifen; thiourea insecticides such as diafenthiuron; urea insecticides such as flucofuron and sulcofuron; and unclassified insecticides such as closantel, crotamiton, EXD, fenazaflor, fenoxacrim, flubendiamide, hydramethylnon, isoprothiolane, malonoben, metaflumizone, metoxadiazone, nifluridide, pyridaben, pyridalyl, rafoxanide, triarathene, triazamate, meptyldinocap, pyribencarb and any combinations thereof.
  • The mixtures have broad ranges of efficacy as fungicides. The exact amounts of hydrazones and copper-containing materials to be applied is dependent not only on the specific materials being applied and relative amounts of hydrazone and copper in the mixtures, but also on the, the particular action desired, the fungal species to be controlled, and the stage of growth thereof, as well as the part of the plant or other product to be contacted with the mixture. Thus, all the mixtures, and formulations containing the same, may not be equally effective at similar concentrations or against the same fungal species.
  • The mixtures are effective in use with plants in a disease-inhibiting and phytologically acceptable amount. The term “disease inhibiting and phytologically acceptable amount” refers to an amount of a mixture that kills or inhibits the plant disease for which control is desired, but is not significantly toxic to the plant. The exact amount of a mixture required varies with the fungal disease to be controlled, the type of formulation employed, the method of application, the particular plant species, climate conditions, and the like. The dilution and rate of application will depend upon the type of equipment employed, the method and frequency of application desired and diseases to be controlled. For foliar control of fungal infections on plants, the amount of copper used in mixture with hydrazone may range from 0.001 to 5 kg/ha, and preferably from 0.05 to 1 kg/ha. The amount of hydrazone used in mixture with copper may range from 0.001 to 5 kg/ha, and preferably from 0.05 to 1 kg/ha. The molar ratio of copper to hydrazone may range from 0.1:1 to 10, 000:1, preferably from 0.5:1 to 1000:1 and more preferably from 1:1 to 20:1.
  • It should be understood that the preferred amount of a copper material to be mixed with hydrazone in a given application may be influenced by availability of copper from other sources such as copper present in the soil or irrigation water, copper present on the foliage from natural sources, copper applied for fungal or bacterial disease control, copper applied as a fertilizer component, copper present in the water used in preparing fungicide solutions for application such as in spray application, copper present in formulations used in preparing spray solutions or dusts for application, or any other suitable copper source.
  • For fungal control the hydrazone may be applied before or after the application of copper such that the mixture is generated in the location where fungal control is desired. Additionally, multiple applications of copper or the hydrazone may be applied.
  • As a seed protectant, the amount of toxicant coated on the seed is usually at a dosage rate of about 10 to about 250 grams (g) and preferably from about 20 to about 60 g per 50 kilograms of seed. As a soil fungicide, the chemical can be incorporated in the soil or applied to the surface usually at a rate of 0.5 to about 20 kg and preferably about 1 to about 5 kg per hectare.
  • Methods for preparation of salicylaldehyde benzoylhydrazones and 2-hydroxyphenylketone benzoylhydrazones from salicylaldehydes or 2-hydroxyphenyl ketones and a benzoic hydrazide are well known in the literature. In addition the preparation of metal complexes of these materials is also well known (see for example Journal of Inorganic Biochemistry 1999, 77, 125-133, which is expressly incorporated by reference herein). Methods of preparation of precursor hydrazides are also well known. Hydrazides can be prepared, for example, from carboxylic acids such as in Maxwell et al., J. Med. Chem. 1984, 27, 1565-1570, and from carboxylic esters such as in Dydio et al., J. Org. Chem. 2009, 74, 1525-1530, which are expressly incorporated by reference herein. Thus, the synthesis of any benzoylhydrazone of the present invention and its metal complex(es) is fully described where the starting aldehyde or ketone, and the starting benzoic hydrazide, acid, or ester are described. The hydrazones disclosed may also be in the form of pesticidally acceptable salts and hydrates. Examples 23, 24, and 25 below provide typical methods for the preparation of such benzoylhydrazones. Example 31 below provides a general method for the preparation of their metal complexes.
    • Example 1 Preparation of 1-(3,5-dichloro-2-hydroxyphenyl)-2,2,2-trifluoroethanone
  • Figure US20120010075A1-20120112-C00002
  • 2,4-Dichloro-6-iodophenol (2.0 grams (g), 6.9 millimoles (mmol)) was dissolved in dry tetrahydrofuran (THF; 20 milliliters (mL)), cooled to −30 to −40° C., treated in portions with isopropyl magnesium chloride-lithium chloride complex (1.3 M in THF; 7.3 mmol) and stirred for 45 minutes (min) as the temperature was allowed to rise to 0° C. The mixture was cooled to −30° C., treated with 8 mL (10 mmol) of the Grignard reagent and stirred for 30 min at −30° C. Ethyl trifluoroacetate (2.4 mL, 2.8 g, 20 mmol) was added, and the mixture was stirred for 15 min at −30° C., warmed to 25° C. and stirred for 2 hours (h). The reaction was quenched by addition of saturated (satd) ammonium chloride (NH4C1; 10 mL), diluted with ethyl acetate (EtOAc; 50 mL) and washed with 1 M hydrochloric acid (HCl; 20 mL), satd sodium chloride (NaCl; 10 mL), dried over sodium sulfate (Na2SO4) and evaporated. The residue was purified by silica gel chromatography with 0-20% EtOAc/hexane to give the purified ketone (1.2 g): mp 50-52° C.; 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=2.4 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 5.92 (s, 1H); EIMS m/z 258.
    • Example 2 Preparation of cyclopropyl-(3,5-dichloro-2-hydroxyphenyl)-methanone
  • Figure US20120010075A1-20120112-C00003
  • N-(3,5-Dichloro-2-hydroxybenzoyl)benzotriazole (prepared according to Katritizky et al., Synthesis 2007, 20, 3141-3146, which is expressly incorporated by reference herein; 2.0 g, 6.5 mmol) was stirred in dry THF (25 mL), cooled to −30° C., treated in portions with cyclopropylmagnesium bromide (0.5 M in THF; 28 mL, 14 mmol) and stirred at −30° C. for 30 min. The cooling bath was removed and the mixture was allowed to warm to 25° C. and stir for 3 h. The reaction was quenched by addition of 10 mL satd NH4Cl, and shaken with EtOAc (50 mL) plus 20% citric acid solution (30 mL). The organic phase was washed with satd NaCl (20 mL), dried (Na2SO4) and evaporated. The residue was purified by silica gel chromatography with 0-20% EtOAc/hexane to give the purified ketone (450 mg): 1H NMR (400 MHz, CDCl3) δ 13.03 (s, 1H), 7.87 (d, J=2.5 Hz, 1H), 7.57 (d, J=2.5 Hz, 1H), 2.70-2.54 (m, 1H), 1.41-1.32 (m, 2H), 1.24-1.15 (m, 2H); EIMS m/z 230.
    • Example 3 Preparation of 1-(3,5-dichloro-2-hydroxyphenyl)-2-methylpropan-1-one
  • Figure US20120010075A1-20120112-C00004
  • Methyl-3,5-dichlorosalicylate (prepared according to Ahmed et al., Medicinal Chemistry 2008, 4, 298-308, which is expressly incorporated by reference herein; 2.0 g, 9.0 mmol) was dissolved in dry THF (30 mL), cooled to −40° C. and treated in portions with isopropyl magnesium chloride, 2.0 M in THF; 10 mL, 20 mmol). The mixture was stirred at −20 to −40° C. for 45 min, warmed to 25° C. and stirred for 4 h. The excess reagent was quenched by addition of satd NH4Cl (10 mL). The mixture was diluted with EtOAc (50 mL) and the pH was adjusted to ˜1 by addition of 1 M HCl. The organic phase was washed with satd NaCl solution (20 mL), dried (Na2SO4) and evaporated. The residue was purified by reverse-phase high-performance liquid chromatography (RP-HPLC) with 70% acetonitrile to give the purified ketone (1.1 g): mp: 102-104° C. 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=2.5 Hz, 1H), 7.57 (d, J=2.4 Hz, 1H), 3.54 (dt, J=13.6, 6.8 Hz, 1H), 1.26 (d, J=6.8 Hz, 6H); EIMS m/z 232.
    • Example 4 Preparation of 2-hydroxy-3,5-bis-trifluoromethylbenzaldehyde
  • Figure US20120010075A1-20120112-C00005
  • 3,5-Bis(trifluoromethyl)anisaldehyde (prepared as in Sui and Macielag, Synth. Commun. 1997, 27, 3581-3590, which is expressly incorporated by reference herein; 2.0 g, 7.7 mmol) was dissolved in dry CH2Cl2 (15 mL), cooled to −78° C. and treated in portions with BBr3 (1 M solution in CH2Cl2; 8.0 mL, 8.0 mmol). The mixture was stirred and allowed to warm to 25° C. After 20 h, the mixture was cooled to −40° C., carefully treated with H2O (10 mL) and warmed to room temperature. The separated organic phase was washed with H2O (10 mL), satd NaCl solution (5 mL), dried (Na2SO4) and evaporated. The residue was purified by silica gel chromatography with a 0 to 20% gradient of EtOAc in hexane to give the purified aldehyde (1.4 g, 70%) as an oil: 1H NMR (400 MHz, CDCl3) δ 12.05 (s, 1H), 10.02 (s, 1H), 8.07 (s, 2H). EIMS m/z 258.
    • Example 5 Preparation 5-chloro-2-hydroxy-3-trifluoromethylbenzaldehyde
  • Figure US20120010075A1-20120112-C00006
  • 5-Chloro-2-fluorobenzotrifluoride (1.5 g, 7.5 mmol) was dissolved in dry THF (10 mL), treated with tetramethylethylenediamine (TMEDA; 1.6 mL, 1.2 g, 11 mmol), cooled to −78° C. and treated in portions with n-butyl lithium (n-BuLi, 2.5 M in hexanes; 3.9 mL, 9.8 mmol). After stirring at −78° C. for 90 min, the mixture was treated with N,N-dimethylformamide (DMF; 770 μL, 730 mg, 10 mmol) and stirred for a further 30 min. The cooling bath was removed and mixture warmed to 25° C. over 30 min. The reaction was quenched by addition of satd NH4Cl solution then diluted with Et2O (30 mL). The separated organic phase was washed with satd NaCl (10 mL), dried (Na2SO4) and evaporated. The residue was dissolved in dry methanol (CH3OH; 10 mL) and treated with 30% sodium methoxide solution in CH3OH (14 g). The mixture was stirred at 25° C. for 20 h, diluted with H2O (50 mL) and extracted with Et2O (2×40 mL). The combined organic phases were washed with satd NaCl solution (20 mL), dried (Na2SO4) and evaporated. The residue was purified by silica gel chromatography using a 0 to 10% EtOAc gradient in hexane to give the benzaldehyde (1.1 g). This material (1.0 g, 4.2 mmol) was dissolved in dry CH2Cl2 (10 mL), cooled to −78° C. and treated with BBr3 (1 M solution in CH2Cl2; 5 mL, 5 mmol). The mixture was allowed to warm to 25° C. and stir for 22 h. After cooling to −45° C., the mixture was treated with H2O (5 mL), warmed to 25° C. and extracted with EtOAc (2×15 mL). The combined extracts were washed with satd NaCl solution (10 mL), dried (Na2SO4) and evaporated. The residue was purified by silica gel chromatography using a 0 to 10% EtOAc gradient in hexane to give the aldehyde (950 mg): 1H NMR (400 MHz, CDCl3) δ 11.61 (s, 1H), 9.91 (s, 1H), 7.77 (dd, J=18.5, 2.6 Hz, 2H); EIMS m/z 224.
    • Example 6 Preparation of 3-chloro-2-hydroxy-5-trifluoromethylbenzaldehyde
  • Figure US20120010075A1-20120112-C00007
  • 3-Chloro-2-fluoro-5-trifluoromethylbenzaldehyde (5.0 g, 22 mmol) was dissolved in dry CH3OH (50 mL), treated with 25% sodium methoxide solution (30 mL) and heated to reflux for 2 h. After cooling the volatiles were removed by evaporation and the residue was taken up in H2O (20 mL) plus Et2O (80 mL). The aqueous phase was extracted with Et2O (50 mL), and the combined organic phases were washed with satd NaCl solution (15 mL), dried (Na2SO4) and evaporated. The residue was dissolved in dry CH2Cl2 (50 mL), cooled to −78° C. and treated with BBr3 (1 M solution in CH2Cl2; 25 mL, 25 mmol). After warming to 25° C., the mixture was stirred for 21 h, cooled to −40° C. and quenched by addition of H2O (30 mL). After warming the aqueous phase was extracted with CH2Cl2 (30 mL), and the combined org. phases were washed with satd NaCl solution (30 mL), dried (Na2SO4) and evaporated. The residue was purified by silica gel chromatography with 0-20% EtOAc gradient in hexane to give the purified aldehyde (2.7 g): 1H NMR (400 MHz, CDCl3) δ 11.81 (s, 1H), 9.96 (s, 1H), 7.87 (d, J=2.1 Hz, 1H), 7.84-7.77 (m, 1H); EIMS m/z 224.
    • Example 7 Preparation of 3-fluoro-5-formyl-4-hydroxybenzonitrile
  • Figure US20120010075A1-20120112-C00008
  • 4-Cyano-2-fluorophenol (5.0 g, 38 mmol) was dissolved in acetic acid (50 mL) and treated dropwise with stirring with bromine (6.4 g, 40 mmol). After 2 h at 25° C., H2O (100 mL) was added. The precipitated product was collected by filtration, washed well with H2O and then taken up in EtOAc (150 mL). The solution was washed with H2O (50 mL), satd NaCl solution (50 dmL), dried (Na2SO4) and evaporated. The residue was crystallized from aqueous ethanol (EtOH) to give the bromophenol (4.1 g). This material (3.4 g, 16 mmol) was dissolved in dry THF (100 mL), cooled to −78° C. and treated dropwise with n-BuLi (2.5 M in hexanes; 16 mL, 39 mmol) over 15 min. After stirring for 90 min at −78° C., DMF (3.5 mL, 3.3 g, 45 mmol) was added and stirring was continued for 30 min at −78° C. and then warmed to 25° C. over 2 h. Satd NH4Cl solution (25 mL) and Et2O (100 mL) were added, and the pH was adjusted to 2 with 1 M HCl. The separated organic phase was washed with satd NaCl solution, dried (Na2SO4) and evaporated. The residue was purified on silica gel chromatography with 10-50% EtOAc/hexane to give the aldehyde (2.1 g): 1H NMR (400 MHz, CDCl3) δ 11.48 (s, 1H), 9.96 (d, J=1.7 Hz, 1H), 7.78 (t, J=1.5 Hz, 2H), 7.61 (dd, J=9.8, 1.9 Hz, 2H); EIMS m/z 165.
    • Example 8 Preparation of 3-chloro-2-hydroxy-6-trifluoromethylbenzaldehyde
  • Figure US20120010075A1-20120112-C00009
  • 4-Chloro-3-fluoro-6-trifluoromethylbenzaldehyde (1.0 g, 4.4 mmol) was dissolved in dry CH3OH (10 mL), treated with 30% sodium methoxide solution in CH3OH (7.9 g, 44 mmol) and heated at reflux for 1 h. After cooling the mixture was diluted with H2O (15 mL) and extracted with Et2O (30 mL). The combined organic extracts were washed with satd NaCl solution (10 mL), dried (Na2SO4), and evaporated. The residue was purified by silica gel chromatography with 0-10% EtOAc/hexane to give the anisole intermediate (1.0 g). This material was dissolved in dry CH2Cl2 (15 mL), cooled to −78° C., treated with BBr3 (1 M in CH2Cl2; 5.0 mL, 5 mmol), allowed to warm to 25° C. and stir for 20 h. The reaction was cooled in ice and quenched by addition of H2O (10 mL). The separated organic phase was washed with satd NaCl solution (10 mL), dried (Na2SO4) and evaporated. The residue was purified by silica gel chromatography with 0-10% EtOAc/hexane to give the aldehyde (980 mg): 1H NMR (400 MHz, CDCl3) δ 12.78 (s, 1H), 10.28 (s, 1H), 7.71 (d, J=8.2 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H); EIMS m/z 224.
    • Example 9 Preparation of 5-chloro-2-hydroxy-4-trifluoromethylbenzaldehyde
  • Figure US20120010075A1-20120112-C00010
  • 2-Chloro-5-hydroxybenzotrifluoride (5.0 g, 25 mmol) was dissolved in acetic acid (50 mL) and treated with bromine (4.8 g, 30 mmol). The mixture was stirred at 25° C. for 6 h and poured into H2O (200 mL) with stirring. The precipitated phenol was collected by filtration and washed well with H2O. The solid was taken up in EtOAc (150 mL), washed with satd NaCl solution (50 mL), dried (Na2SO4) and evaporated to give product (6.0 g, circa 90% pure). This material (2.0 g, 7.3 mmol) was dissolved in dry THF (65 mL), cooled to −78° C. and treated dropwise with n-BuLi (2.5 M in hexanes; 6.4 mL, 16 mmol). The mixture was stirred for 90 min at −78° C. and treated with DMF (1.4 mL, 1.3 g, 18 mmol). After stirring at −78° C. for 30 min, the mixture was warmed to 25° C., quenched with satd NH4Cl solution (10 mL) and worked up with H2O (30 mL) and Et2O (75 mL). The organic phase was washed with satd NaCl (20 mL), dried (Na2SO4) and evaporated. The residue was purified by RP-HPLC to give the product (300 mg, ˜70% purity), which was used without further purification: EIMS m/z 224.
    • Example 10 Preparation of 2-hydroxy-4,6-bis-trifluoromethyl-benzaldehyde
  • Figure US20120010075A1-20120112-C00011
  • 3,5-Bis(trifluoromethyl)anisole (5.0 g 21 mmol) and TMEDA (4.0 mL, 3.0 g, 26 mmol) were dissolved in dry Et2O (60 mL), cooled to −10° C. and treated in portions with n-BuLi (2.5 M in hexanes; 10 mL, 25 mmol). The mixture was warmed to 25° C. and stirred for 90 min. The mixture was cooled to −78° C., treated dropwise with DMF (2.3 mL, 2.2 g, 30 mmol), stirred for 30 min, warmed to 25° C. and stirred for 30 min. The reaction was quenched by addition of H2O (50 mL) and extracted with Et2O (2×75 mL). The combined organic fractions were washed with satd NaCl solution (30 mL), dried (Na2SO4) and evaporated. The residue was purified by silica gel chromatography to give the anisaldehyde derivative (3.3 g). This material (3.0 g, 11 mmol) was dissolved in CH2Cl2 (75 mL), cooled to −78° C. and treated with BBr3 (1 M solution in CH2Cl2; 12 mL, 12 mmol). The mixture was stirred for 30 min at −78° C., warmed to 25° C. and stirred for 90 min H2O (100 mL) was added and stirring was continued for 30 min. The separated organic phase was washed with satd NaCl solution, dried (Na2SO4) and evaporated. The residue was purified by silica gel chromatography with 0-20% EtOAc/hexane to give the purified aldehyde (2.0 g): 1H NMR (400 MHz, CDCl3) δ 12.27 (s, 1H), 10.34 (s, 1H), 7.51 (s, 1H); EIMS m/z 258.
    • Example 11 Preparation of 1-(2-hydroxy-3-methoxyphenyl)-ethanone
  • Figure US20120010075A1-20120112-C00012
  • 1-(2-Hydroxy-3-methoxyphenyl)-ethanone was prepared from commercially available starting materials as described in US 038048, which is expressly incorporated by reference herein.
    • Example 12 Preparation of 1-(2-hydroxy-5-trifluoromethylphenyl)-ethanone
  • Figure US20120010075A1-20120112-C00013
  • 1-(2-Hydroxy-5-trifluoromethylphenyl)-ethanone was prepared from commercially available starting materials as described in EP 129812, which is expressly incorporated by reference herein.
    • Example 13 Preparation of 3,4-dichloro-2-hydroxybenzaldehyde
  • Figure US20120010075A1-20120112-C00014
  • 3,4-Dichloro-2-hydroxybenzaldehyde was prepared from commercially available starting materials as described in Gu et al., J. Med. Chem. 2000, 43, 4868-4876, which is expressly incorporated by reference herein.
    • Example 14 Preparation of 3-bromo-2-hydroxy-5-methylsulfanyl-benzaldehyde
  • Figure US20120010075A1-20120112-C00015
  • 3-Bromo-2-hydroxy-5-methylsulfanyl-benzaldehyde was prepared from commercially available starting materials as described in Guiles et al., PCT Int. Appl. WO 2008039641 A2, which is expressly incorporated by reference herein.
    • Example 15 Preparation of 3-bromo-5-formyl-4-hydroxybenzonitrile
  • Figure US20120010075A1-20120112-C00016
  • 3-Bromo-5-formyl-4-hydroxybenzonitrile was prepared from commercially available starting materials as described in Sakaitani et al., PCT Int. Appl. WO 2004037816 A1, which is expressly incorporated by reference herein.
    • Example 16 Preparation of 3,6-dichloro-2-hydroxybenzaldehyde
  • Figure US20120010075A1-20120112-C00017
  • 3,6-Dichloro-2-hydroxybenzaldehyde was prepared from commercially available starting materials as described in Rafferty et al., PCT Int. Appl. WO 2008121602 A1, which is expressly incorporated by reference herein.
    • Example 17 Preparation of 2-hydroxy-4-trifluoromethylbenzaldehyde
  • Figure US20120010075A1-20120112-C00018
  • 2-Hydroxy-4-trifluoromethylbenzaldehyde was prepared from commercially available starting materials as described in Faeh et al., U.S. Pat. Appl. Publ. 2007185113 A1, which is expressly incorporated by reference herein.
    • Example 18 Preparation of 2-hydroxy-5-trifluoromethylbenzaldehyde
  • Figure US20120010075A1-20120112-C00019
  • 2-Hydroxy-5-trifluoromethylbenzaldehyde was prepared from commercially available starting materials as described in Bonnert et al., PCT Int. Appl. WO 2006056752 A1, which is expressly incorporated by reference herein.
    • Example 19 Preparation of 2,3-dichloro-6-hydroxybenzaldehyde
  • Figure US20120010075A1-20120112-C00020
  • 2,3-Dichloro-6-hydroxybenzaldehyde was prepared from commercially available starting materials as described in Stokker et al., J. Med. Chem. 1980, 23, 1414-1427, which is expressly incorporated by reference herein.
    • Example 20 Preparation of 2-hydroxy-6-trifluoromethylbenzaldehyde
  • Figure US20120010075A1-20120112-C00021
  • 2-Hydroxy-6-trifluoromethylbenzaldehyde was prepared from commercially available starting materials as described in Stokker et al., J. Med. Chem. 1980, 23, 1414-1427, which is expressly incorporated by reference herein.
    • Example 21 Preparation of 2-hydroxy-6-methylbenzaldehyde
  • Figure US20120010075A1-20120112-C00022
  • 2-Hydroxy-6-methylbenzaldehyde was prepared from commercially available starting materials as described in Hofslokken and Skattebol, Acta Chemica Scandinavica 1999, 53, 258-262, which is expressly incorporated by reference herein.
    • Example 22 General Preparation of Ketone Compounds
  • Figure US20120010075A1-20120112-C00023
  • Ketone compounds, wherein R2 is either i-propyl or t-butyl, were prepared from commercially available starting materials as described in Miller, J. A., J. Org. Chem. 1987, 52, 322-323, which is expressly incorporated by reference herein.
    • Example 23 Preparation of 3-trifluoromethoxy-benzoic acid [1-(3,5-dichloro-2-hydroxy-phenyl)-methylidene]-hydrazide
  • Figure US20120010075A1-20120112-C00024
  • A suspension of 3,5-dichloro-2-hydroxy-benzaldehyde (0.200, 1.05 mmol) and 3-trifluoromethoxy-benzoic acid hydrazide (0.243 g, 1.05 mmol) in ethanol (3.3 mL) was heated to 60° C. for 18 hours. The reaction mixture was cooled to room temperature to precipitate the product. The solid was collected via suction filtration and rinsed with ethanol to furnish 3-trifluoromethoxy-benzoic acid [1-(3,5-dichloro-2-hydroxy-phenyl)-methylidene]-hydrazide as an off-white solid (0.412 g, 99%): mp 180-182° C.; 1H NMR (400 MHz, DMSO) δ 12.63 (s, 1H), 12.39 (s, 1H), 8.60 (s, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.91 (s, 1H), 7.76-7.63 (m, 4H); ESIMS m/z 393 ([M+H]+), 391 ([M−H]−).
    • Example 24 Preparation of benzoic acid [1-(3-chloro-2-hydroxyphenyl)-ethylidene]-hydrazide
  • Figure US20120010075A1-20120112-C00025
  • A suspension of 1-(3-chloro-2-hydroxyphenyl)-ethanone (0.100 g, 0.586 mmol), benzoic acid hydrazide (0.080 g, 0.586 mmol), and glacial acetic acid (0.180 mL) in ethanol (1.8 mL) was heated to 60° C. for 18 hours. The reaction mixture was cooled to room temperature to precipitate the product. The solid was collected via suction filtration and rinsed with ethanol to furnish benzoic acid [1-(3-chloro-2-hydroxy-phenyl)-ethylidene]-hydrazide as a yellow solid (0.100 g, 59%): mp 202-203° C.; 1H NMR (400 MHz, DMSO) δ 14.36 (s, 1H), 11.50 (s, 1H), 7.96 (d, J=7.3 Hz, 2H), 7.68-7.61 (m, 2H), 7.56 (t, J=6.7 Hz, 2H), 7.49 (d, J=7.8 Hz, 1H), 6.92 (t, J=8.0 Hz, 1H), 2.52 (s, 3H); ESIMS m/z 289 ([M+H]+), 287 ([M−H]−.
    • Example 25 General Method for the Preparation of Benzoic Hydrazones of alkyl-o-hydroxyphenyl ketones
  • The alkyl-o-hydroxyphenyl ketone (0.5 mmol) and benzoic hydrazide (0.75 mmol) were combined in n-propanol (5 mL) and acetic acid (4-5 drops) and heated to reflux for 20-24 h. Upon cooling the mixture was diluted with water (2-5 mL) in portions to induce precipitation. The solids were collected by filtration, washed with water and dried under vacuum at 80° C. After analysis by HPLC-MS most of the hydrazones were found to be sufficiently pure for testing. The less pure materials were purified by RP-HPLC using acetonitrile-water mixtures on a 10 mm×250 mm YMC-AQ column.
  • TABLE 1
    Com- 1H NMR (400 MHz,
    pound DMSO-d6
    Num- ESIMS ESIMS unless otherwise
    ber Structure mp (° C.) (+) (−) stated), δ
     1
    Figure US20120010075A1-20120112-C00026
         		257 255
     2
    Figure US20120010075A1-20120112-C00027
         		275 273
     3
    Figure US20120010075A1-20120112-C00028
         		270 268
     4
    Figure US20120010075A1-20120112-C00029
         		291 289
     5
    Figure US20120010075A1-20120112-C00030
         		511 509
     6
    Figure US20120010075A1-20120112-C00031
         		353 351
     7
    Figure US20120010075A1-20120112-C00032
         		387 (+Na) 363
     8
    Figure US20120010075A1-20120112-C00033
         		255 253
     9
    Figure US20120010075A1-20120112-C00034
         		368 366
     10
    Figure US20120010075A1-20120112-C00035
         		224-227 318 12.46 (s, 1H), 11.15 (s, 1H), 8.79 (d, J = 1.7 Hz, 1H), 8.68 (s, 1H), 8.51-8.35 (m, 2H), 7.86 (t, J = 8.0 Hz, 1H), 7.71 (d, J = 2.7 Hz, 1H), 7.34 (dd, J = 8.8, 2.7 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H)
     11
    Figure US20120010075A1-20120112-C00036
         		323 321
     12
    Figure US20120010075A1-20120112-C00037
         		259-262 320 318 12.43 (s, 1H), 11.15 (s, 1H), 8.67 (s, 1H), 8.39 (d, J = 8.8 Hz, 2H), 8.18 (d, J = 8.7 Hz, 2H), 7.71 (d, J = 2.7 Hz, 1H), 7.34 (dd, J = 8.8, 2.7 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H)
     13
    Figure US20120010075A1-20120112-C00038
         		381 379
     14
    Figure US20120010075A1-20120112-C00039
         		311 309
     15
    Figure US20120010075A1-20120112-C00040
         		197-198 259 257 12.27 (s, 1H), 11.64 (s, 1H), 8.67 (s, 1H), 8.02-7.89 (m, 2H), 7.68-7.52 (m, 3H), 7.40 (d, J = 7.8 Hz, 1H), 7.35-7.24 (m, 1H), 6.99-6.88 (m, 1H)
     16
    Figure US20120010075A1-20120112-C00041
         		309 307
     17
    Figure US20120010075A1-20120112-C00042
         		209-213 356 354 14.30 (s, 1H), 11.43 (s, 1H), 7.61 (dd, J = 10.3, 2.5 Hz, 2H), 7.37 (dd, J = 7.7, 4.8 Hz, 2H), 7.16 (t, J = 8.9 Hz, 2H), 3.74 (s, 2H), 2.44 (s, 3H)
     18
    Figure US20120010075A1-20120112-C00043
         		299 297
     19
    Figure US20120010075A1-20120112-C00044
         		433 (+Na) 410
     20
    Figure US20120010075A1-20120112-C00045
         		275 273
     21
    Figure US20120010075A1-20120112-C00046
         		285 283
     22
    Figure US20120010075A1-20120112-C00047
         		327 325
     23
    Figure US20120010075A1-20120112-C00048
         		169-172 337 335 12.46 (s, 1H), 12.37 (s, 1H), 8.45 (s, 1H), 7.64 (dd, J = 7.5, 2.5 Hz, 2H), 7.34 (s, 1H), 7.28-7.20 (m, 2H), 2.35 (s, 3H), 2.33 (s, 3H)
     24
    Figure US20120010075A1-20120112-C00049
         		241 239
     25
    Figure US20120010075A1-20120112-C00050
         		271
     26
    Figure US20120010075A1-20120112-C00051
         		381 379
     27
    Figure US20120010075A1-20120112-C00052
         		246-247 337 335 12.51 (s, 1H), 12.34 (s, 1H), 8.45 (s, 1H), 7.64 (dd, J = 9.5, 2.5 Hz, 2H), 7.43 (d, J = 7.6 Hz, 1H), 7.18-7.10 (m, 2H), 2.38 (s, 3H), 2.33 (s, 3H)
     28
    Figure US20120010075A1-20120112-C00053
         		447 (+Na) 423
     29
    Figure US20120010075A1-20120112-C00054
         		283 281
     30
    Figure US20120010075A1-20120112-C00055
         		159-160 297 295 13.48 (s, 1H), 11.43 (s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.30 (t, J = 7.2 Hz, 1H), 7.17-7.09 (m, 2H), 6.94- 6.86 (m, 2H), 2.94 (q, J = 7.5 Hz, 2H), 2.37 (s, 3H), 2.32 (s, 3H), 1.11 (t, J = 7.5 Hz, 3H)
     31
    Figure US20120010075A1-20120112-C00056
         		143-145 373 371 13.43 (s, 1H), 11.42 (s, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.33-7.26 (m, 6H), 7.25- 7.17 (m, 1H), 7.16-7.09 (m, 2H), 6.96-6.89 (m, 2H), 3.31-3.22 (m, 2H), 2.88-2.79 (m, 2H), 2.35 (s, 3H), 2.33 (s, 3H)
     32
    Figure US20120010075A1-20120112-C00057
         		192-194 427 425 12.70 (s, 1H), 12.41 (s, 1H), 8.41 (s, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.79 (d, J = 2.3 Hz, 1H), 7.34 (s, 1H), 7.28-7.19 (m, 2H), 2.35 (s, 3H), 2.33 (s, 3H)
     33
    Figure US20120010075A1-20120112-C00058
         		188-190 283 281 13.37 (s, 1H), 11.38 (s, 1H), 7.62 (dd, J = 7.8, 1.3 Hz, 1H), 7.35-7.27 (m, 2H), 7.26-7.15 (m, 2H), 6.94-6.86 (m, 2H), 2.42 (s, 3H), 2.35 (s, 3H), 2.33 (s, 3H)
     34
    Figure US20120010075A1-20120112-C00059
         		175-176 297 295 13.47 (s, 1H), 11.50 (s, 1H), 7.66-7.59 (m, 1H), 7.33- 7.27 (m, 2H), 7.26-7.16 (m, 2H), 6.95-6.87 (m, 2H), 2.94 (q, J = 7.5 Hz, 2H), 2.33 (s, 6H), 1.11 (t, J = 7.5 Hz, 3H)
     35
    Figure US20120010075A1-20120112-C00060
         		162-166 373 371 13.41 (s, 1H), 11.46 (s, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 4.4 Hz, 5H), 7.25-7.20 (m, 3H), 7.16 (s, 1H), 6.96-6.89 (m, 2H), 3.32-3.24 (m, 2H), 2.87-2.80 (m, 2H), 2.33 (s, 3H), 2.32 (s, 3H)
     36
    Figure US20120010075A1-20120112-C00061
         		269 267
     37
    Figure US20120010075A1-20120112-C00062
         		300 298
     38
    Figure US20120010075A1-20120112-C00063
         		269 267
     39
    Figure US20120010075A1-20120112-C00064
         		283 281
     40
    Figure US20120010075A1-20120112-C00065
         		297 295
     41
    Figure US20120010075A1-20120112-C00066
         		261-263 349 12.58 (s, 1H), 12.46 (s, 1H), 8.57 (s, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 2.5 Hz, 1H), 7.63 (d, J = 2.5 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 2.98 (hept, J = 6.7 Hz, 1H), 1.24 (d, J = 6.9 Hz, 6H)
     42
    Figure US20120010075A1-20120112-C00067
         		270-272 441 439 12.80 (s, 1H), 12.49 (s, 1H), 8.53 (s, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.83 (dd, J = 7.0, 2.2 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 3.04-2.92 (m, 1H), 1.24 (d, J = 6.9 Hz, 6H)
     43
    Figure US20120010075A1-20120112-C00068
         		250-252 377 375 12.77, 12.67, 11.99, and 10.28 (4s, 2H), 8.45 and 8.31 (2s, 1H), 7.75-7.30 (m, 5H); Note: rotational isomers
     44
    Figure US20120010075A1-20120112-C00069
         		148-163 361 359 13.37 (s, 1H), 11.41 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.51 (s, 1H), 7.48-7.41 (m, 2H), 7.30 (t, J = 7.4 Hz, 1H), 7.25 (dd, J = 8.1, 1.9 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 7.10 (d, J = 7.8 Hz, 2H), 6.95- 6.87 (m, 2H), 3.02 (q, J = 7.4 Hz, 2H), 1.13 (t, J = 7.5 Hz, 3H)
     45
    Figure US20120010075A1-20120112-C00070
         		204-208 413 411 13.08, 12.07, 12.00, 10.65 (4s, 2H), 7.70-7.40 (m, 4H), 7.38-7.14 (m, 6H), 7.00-6.65 (m, 2H), 3.29-3.18 (m, 2H), 2.80 (dd, J = 11.0, 5.3 Hz, 2H); Note: rotational isomers
     46
    Figure US20120010075A1-20120112-C00071
         		170-171 401 399 12.54 (s, 1H), 12.47 (s, 1H), 8.57 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 2.5 Hz, 1H), 7.64 (d, J = 2.5 Hz, 1H), 7.61-7.55 (m, 2H), 7.49-7.41 (m, 2H), 7.28 (dd, J = 7.9, 2.2 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 7.12-7.06 (m, 2H)
     47
    Figure US20120010075A1-20120112-C00072
         		178-180 347 345 13.31 (s, 1H), 11.37 (s, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.67-7.62 (m, 1H), 7.60- 7.53 (m, 2H), 7.48-7.41 (m, 2H), 7.34-7.28 (m, 1H), 7.25 (dd, J = 7.9, 2.1 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 7.11-7.07 (m, 2H), 6.94-6.87 (m, 2H), 2.48 (s, 3H)
     48
    Figure US20120010075A1-20120112-C00073
         		181-184 337 335 13.16, 11.95, 11.87, 10.73 (4s, 2H), 7.68-7.17 (m, 5H), 6.97-6.66 (m, 2H), 2.97-2.85 (m, 2H), 1.16-1.04 (m, 3H); Note: rotational isomers
     49
    Figure US20120010075A1-20120112-C00074
         		173-177 379 377 13.24 (s, 1H), 11.74 (s, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.62-7.54 (m, 3H), 7.51- 7.47 (m, 1H), 7.35-7.28 (m, 5H), 7.24-7.19 (m, 1H), 6.97-6.89 (m, 2H), 3.30-3.22 (m, 2H), 2.87-2.79 (m, 2H)
     50
    Figure US20120010075A1-20120112-C00075
         		303 301
     51
    Figure US20120010075A1-20120112-C00076
         		270 268
     52
    Figure US20120010075A1-20120112-C00077
     53
    Figure US20120010075A1-20120112-C00078
         		285 283
     54
    Figure US20120010075A1-20120112-C00079
         		289 287
     55
    Figure US20120010075A1-20120112-C00080
         		333 (+Na) 309
     56
    Figure US20120010075A1-20120112-C00081
         		106-111 377 375 12.62 (s, 1H), 12.17 (s, 1H), 8.45 (s, 1H), 7.92-7.88 (m, 1H), 7.83 (d, J = 7.0 Hz, 1H), 7.80-7.75 (m, 2H), 7.70 (d, J = 2.5 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H)
     57
    Figure US20120010075A1-20120112-C00082
         		220-222 403 401 14.32 (s, 1H), 11.91 (s, 1H), 7.76 (dd, J = 7.8, 1.1 Hz, 1H), 7.67 (d, J = 2.5 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.61 (dd, J = 7.4, 1.8 Hz, 1H), 7.55-7.45 (m, 2H), 2.45 (s, 3H)
     58
    Figure US20120010075A1-20120112-C00083
         		208-210 323 321 13.18, 11.64, 11.59 (3s, 2H), 7.91-7.46 (m, 5H), 7.36- 7.14 (m, 1H), 6.95-6.60 (m, 2H), 2.40. 2.38 (2s, 3H); Note: rotational isomers
     59
    Figure US20120010075A1-20120112-C00084
         		363 (+Na) 339
     60
    Figure US20120010075A1-20120112-C00085
         		345 (+Na) 321
     61
    Figure US20120010075A1-20120112-C00086
         		308 307
     62
    Figure US20120010075A1-20120112-C00087
         		273 271
     63
    Figure US20120010075A1-20120112-C00088
         		334
     64
    Figure US20120010075A1-20120112-C00089
         		333 331
     65
    Figure US20120010075A1-20120112-C00090
         		289
     66
    Figure US20120010075A1-20120112-C00091
         		269 267
     67
    Figure US20120010075A1-20120112-C00092
         		357 355
     68
    Figure US20120010075A1-20120112-C00093
         		343 341
     69
    Figure US20120010075A1-20120112-C00094
         		323
     70
    Figure US20120010075A1-20120112-C00095
         		343 341
     71
    Figure US20120010075A1-20120112-C00096
         		389 387
     72
    Figure US20120010075A1-20120112-C00097
         		323
     73
    Figure US20120010075A1-20120112-C00098
         		202-209 339 337 12.67 (s, 1H), 12.35 (s, 1H), 12.31 (s, 1H), 8.65 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 2.5 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 6.91 (t, J = 7.7 Hz, 1H), 2.20 (s, 3H)
     74
    Figure US20120010075A1-20120112-C00099
         		407 (+Na) 383
     75
    Figure US20120010075A1-20120112-C00100
         		340
     76
    Figure US20120010075A1-20120112-C00101
         		352
     77
    Figure US20120010075A1-20120112-C00102
         		323 321
     78
    Figure US20120010075A1-20120112-C00103
         		377
     79
    Figure US20120010075A1-20120112-C00104
         		248-249 377 375 12.57 (s, 1H), 12.29 (s, 1H), 8.57 (s, 1H), 8.00-7.90 (m, 3H), 7.75- 7.61 (m, 2H)
     80
    Figure US20120010075A1-20120112-C00105
         		385
     81
    Figure US20120010075A1-20120112-C00106
         		238-240 377 375 12.71 (s, 1H), 12.37 (s, 1H), 8.61 (s, 1H), 8.16 (d, J = 8.1 Hz, 2H), 7.96 (d, J = 8.2 Hz, 2H), 7.68 (dd, J = 27.3, 2.5 Hz, 2H)
     82
    Figure US20120010075A1-20120112-C00107
         		339 337
     83
    Figure US20120010075A1-20120112-C00108
         		189-191 377 12.62 (s, 1H), 12.11 (s, 1H), 8.45 (s, 1H), 7.82 (t, J = 1.4 Hz, 1H), 7.71 (d, J = 2.6 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H), 7.65 (d, J = 1.4 Hz, 2H)
     84
    Figure US20120010075A1-20120112-C00109
         		408 (+Na) 387
     85
    Figure US20120010075A1-20120112-C00110
         		369 367
     86
    Figure US20120010075A1-20120112-C00111
         		207-209 353 351 12.52 (s, 1H), 12.47 (s, 1H), 8.58 (s, 1H), 7.68 (d, J = 2.5 Hz, 1H), 7.64 (d, J = 2.5 Hz, 1H), 7.55-7.50 (m, 1H), 7.50-7.43 (m, 2H), 7.19 (dd, J = 7.8, 1.9 Hz, 1H), 4.11 (q, J = 6.9 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H)
     87
    Figure US20120010075A1-20120112-C00112
         		364 363
     88
    Figure US20120010075A1-20120112-C00113
         		369 367
     89
    Figure US20120010075A1-20120112-C00114
         		325
     90
    Figure US20120010075A1-20120112-C00115
         		399
     91
    Figure US20120010075A1-20120112-C00116
         		324 322
     92
    Figure US20120010075A1-20120112-C00117
         		215-217 359 12.70 (s, 1H), 12.60 (s, 1H), 8.63 (s, 1H), 8.60 (s, 1H), 8.13-8.07 (m, 2H), 8.06- 8.00 (m, 2H), 7.73-7.62 (m, 4H)
     93
    Figure US20120010075A1-20120112-C00118
         		343
     94
    Figure US20120010075A1-20120112-C00119
         		337
     95
    Figure US20120010075A1-20120112-C00120
         		321
     96
    Figure US20120010075A1-20120112-C00121
         		353
     97
    Figure US20120010075A1-20120112-C00122
         		279-281 353 351 12.64 (s, 1H), 12.40 (s, 1H), 8.55 (s, 1H), 7.94 (d, J = 8.7 Hz, 2H), 7.67 (d, J = 2.5 Hz, 1H), 7.62 (d, J = 2.5 Hz, 1H), 7.08 (d, J = 8.9 Hz, 2H), 4.13 (q, J = 7.0 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H)
     98
    Figure US20120010075A1-20120112-C00123
         		191-192 421 12.62, 12.57, 12.1, 10.35 (4s, 2H), 8.45, 8.28 (2s, 1H), 8.5-7.4 (m, 5H); Note: rotational isomers
     99
    Figure US20120010075A1-20120112-C00124
         		192-194 353 351 12.40 (s, 2H), 8.44 (s, 1H), 7.64 (dd, J = 7.6, 2.5 Hz, 2H), 7.31 (t, J = 8.0 Hz, 1H), 7.19-7.03 (m, 2H), 3.84 (s, 3H), 2.20 (s, 3H)
    100
    Figure US20120010075A1-20120112-C00125
         		220-229 393 391 12.61 (s, 1H), 12.44 (s, 1H), 8.58 (s, 1H), 8.09 (d, J = 8.8 Hz, 2H), 7.75-7.49 (m, 4H)
    101
    Figure US20120010075A1-20120112-C00126
         		327 325
    102
    Figure US20120010075A1-20120112-C00127
         		207-209 339 337 12.56 (s, 1H), 12.44 (s, 1H), 8.56 (s, 1H), 7.65 (dd, J = 14.1, 2.5 Hz, 2H), 7.57 (s, 2H), 7.27 (s, 1H), 2.36 (s, 6H)
    103
    Figure US20120010075A1-20120112-C00128
         		350
    104
    Figure US20120010075A1-20120112-C00129
         		343
    105
    Figure US20120010075A1-20120112-C00130
         		199-201 365 363 12.06 (s, 1H), 11.18 (s, 1H), 8.46 (s, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.47-7.37 (m, 1H), 7.34-7.21 (m, 1H), 7.07 (dd, J = 27.1, 7.9 Hz, 2H), 6.90 (d, J = 7.6 Hz, 1H), 3.83 (s, 3H), 2.19 (s, 3H)
    106
    Figure US20120010075A1-20120112-C00131
         		210-220 439 437 12.64 (s, 2H), 8.55 (s, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.79-7.69 (m, 1H), 7.58 (d, J = 8.2 Hz, 1H)
    107
    Figure US20120010075A1-20120112-C00132
         		191-195 345
    108
    Figure US20120010075A1-20120112-C00133
         		188-189 443 12.65 (s, 1H), 12.43 (s, 1H), 8.40 (s, 1H), 7.81 (dd, J = 19.3, 2.3 Hz, 2H), 7.31 (t, J = 7.9 Hz, 1H), 7.19-7.02 (m, 2H), 3.84 (s, 3H), 2.14 (s, 3H)
    109
    Figure US20120010075A1-20120112-C00134
         		224-230 483 481 12.66 (s, 2H), 8.54 (s, 1H), 8.09 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 16.3 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H)
    110
    Figure US20120010075A1-20120112-C00135
         		209-211 427
    111
    Figure US20120010075A1-20120112-C00136
         		237-239 449 447 12.81 (s, 1H), 12.74 (s, 1H), 8.60 (m, 2H), 8.19-7.97 (m, 4H), 7.85 (s, 2H), 7.72-7.54 (m, 2H)
    112
    Figure US20120010075A1-20120112-C00137
         		430
    113
    Figure US20120010075A1-20120112-C00138
         		475
    114
    Figure US20120010075A1-20120112-C00139
         		427
    115
    Figure US20120010075A1-20120112-C00140
         		413 411
    116
    Figure US20120010075A1-20120112-C00141
         		415
    117
    Figure US20120010075A1-20120112-C00142
         		267-269 465 12.76-12.63 (m, 1H), 12.59- 12.46 (m, 1H), 8.62-8.46 (m, 1H), 8.05-7.77 (m, 5H)
    118
    Figure US20120010075A1-20120112-C00143
         		476
    119
    Figure US20120010075A1-20120112-C00144
         		415
    120
    Figure US20120010075A1-20120112-C00145
         		431
    121
    Figure US20120010075A1-20120112-C00146
         		421 (+Na) 397
    122
    Figure US20120010075A1-20120112-C00147
         		430
    123
    Figure US20120010075A1-20120112-C00148
         		359 357
    124
    Figure US20120010075A1-20120112-C00149
         		413 411
    125
    Figure US20120010075A1-20120112-C00150
         		324 322
    126
    Figure US20120010075A1-20120112-C00151
         		342 340
    127
    Figure US20120010075A1-20120112-C00152
         		300 298
    128
    Figure US20120010075A1-20120112-C00153
         		269 267
    129
    Figure US20120010075A1-20120112-C00154
         		207-212 406 404 14.24 (s, 1H), 11.50 (s, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.62 (dd, J = 11.3, 2.5 Hz, 2H), 7.57 (d, J = 8.1 Hz, 2H), 3.88 (s, 2H), 2.45 (s, 3H)
    130
    Figure US20120010075A1-20120112-C00155
         		269 267
    131
    Figure US20120010075A1-20120112-C00156
         		283 281
    132
    Figure US20120010075A1-20120112-C00157
         		187-189 397 395 12.63 (s, 1H), 12.43 (s, 1H), 8.41 (s, 1H), 7.75 (d, J = 2.5 Hz, 1H), 7.68 (d, J = 2.5 Hz, 1H),7.31 (t, J = 7.9 Hz, 1H), 7.18-7.04 (m, 2H), 3.84 (s, 3H), 2.20 (s, 3H)
    133
    Figure US20120010075A1-20120112-C00158
         		122-128 317 12.06 (s, 1H), 11.17 (s, 1H), 8.46 (s, 1H), 7.65 (d, J = 2.7 Hz, 1H), 7.30 (ddd, J = 14.5, 7.7, 2.8 Hz, 2H), 7.11 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 7.4 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 3.83 (s, 3H), 2.19 (s, 3H)
    134
    Figure US20120010075A1-20120112-C00159
         		196-199 303 12.11 (s, 1H), 11.30 (s, 1H), 8.62 (s, 1H), 7.66 (d, J = 2.6 Hz, 1H), 7.56 (s, 2H), 7.32 (dd, J = 8.8, 2.7 Hz, 1H), 7.25 (s, 1H), 6.96 (d, J = 8.8 Hz, 1H), 2.34 (s, 6H)
    135
    Figure US20120010075A1-20120112-C00160
         		245-246 357 355 14.38 (s, 1H), 11.68 (s, 1H), 8.02 (s, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.72 (d, J = 9.1 Hz, 1H), 7.70 (d, J = 2.5 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 2.53 (s, 3H)
    136
    Figure US20120010075A1-20120112-C00161
         		260-262 355 14.41 (s, 1H), 11.65 (s, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 2.5 Hz, 1H), 7.66-7.60 (m, 3H), 2.68-2.32 (m, 3H)
    137
    Figure US20120010075A1-20120112-C00162
         		226-230 337 14.50 (s, 1H), 11.70 (s, 1H), 7.65 (dd, J = 11.7, 2.4 Hz, 2H), 7.53 (d, J = 7.5 Hz, 1H), 7.45 (t, J = 7.0 Hz, 1H), 7.39-7.29 (m, 2H), 2.45 (s, 3H), 2.41 (s, 3H).
    138
    Figure US20120010075A1-20120112-C00163
         		247-253 403 401 14.38 (s, 1H), 11.68 (s, 1H), 8.14 (s, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.87-7.83 (m, 1H), 7.70 (d, J = 2.5 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 2.53 (s, 3H)
    139
    Figure US20120010075A1-20120112-C00164
         		401 399
    140
    Figure US20120010075A1-20120112-C00165
         		199-204 338 336 14.27 (s, 1H), 11.44 (s, 1H), 7.61 (dd, J = 10.6, 2.5 Hz, 2H), 7.36-7.32 (m, 4H), 7.30-7.23 (m, 1H), 3.75 (s, 2H), 2.44 (s, 3H)
    141
    Figure US20120010075A1-20120112-C00166
         		307-310 353 14.33 (s, 1H), 11.41 (s, 1H), 7.82-7.78 (m, 1H), 7.70 (d, J = 2.5 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.62- 7.56 (m, 1H), 7.25 (d, J = 8.2 Hz, 1H), 7.13 (t, J = 7.7 Hz, 1H), 3.96 (s, 3H), 2.45 (s, 3H)
    142
    Figure US20120010075A1-20120112-C00167
         		250-253 368 366 14.25 (s, 1H), 11.98 (s, 1H), 8.26-8.20 (m, 1H), 7.94- 7.88 (m, 1H), 7.85-7.78 (m, 2H), 7.67 (q, J = 2.5 Hz, 2H), 2.42 (s, 3H)
    143
    Figure US20120010075A1-20120112-C00168
         		281
    144
    Figure US20120010075A1-20120112-C00169
         		365 363
    145
    Figure US20120010075A1-20120112-C00170
         		286 284
    146
    Figure US20120010075A1-20120112-C00171
         		515 (+Na) 491
    147
    Figure US20120010075A1-20120112-C00172
         		271 269
    148
    Figure US20120010075A1-20120112-C00173
         		317
    149
    Figure US20120010075A1-20120112-C00174
         		271 269
    150
    Figure US20120010075A1-20120112-C00175
         		320 318
    151
    Figure US20120010075A1-20120112-C00176
         		374 (+Na) 351
    152
    Figure US20120010075A1-20120112-C00177
         		284
    153
    Figure US20120010075A1-20120112-C00178
         		362
    154
    Figure US20120010075A1-20120112-C00179
         		271 269
    155
    Figure US20120010075A1-20120112-C00180
         		316 314
    156
    Figure US20120010075A1-20120112-C00181
         		349 347
    157
    Figure US20120010075A1-20120112-C00182
         		289 287
    158
    Figure US20120010075A1-20120112-C00183
         		335 333
    159
    Figure US20120010075A1-20120112-C00184
         		411 (+Na)
    160
    Figure US20120010075A1-20120112-C00185
         		399 397
    161
    Figure US20120010075A1-20120112-C00186
         		387
    162
    Figure US20120010075A1-20120112-C00187
         		367
    163
    Figure US20120010075A1-20120112-C00188
         		456 (+Na)
    164
    Figure US20120010075A1-20120112-C00189
         		250-251 423 419 12.75 (s, 1H), 12.60 (s, 1H), 8.57 (s, 1H), 8.16 (d, J = 8.1 Hz, 2H), 7.96 (d, J = 8.3 Hz, 2H), 7.76 (q, J = 2.5 Hz, 2H)
    165
    Figure US20120010075A1-20120112-C00190
         		218-221 385 383 12.58 (s, 1H), 12.35 (s, 1H), 8.61 (s, 1H), 7.85-7.77 (m, 1H), 7.75 (dd, J = 6.9, 2.5 Hz, 2H), 7.41 (d, J = 7.2 Hz, 1H), 6.91 (t, J = 7.7 Hz, 1H), 2.20 (s, 3H)
    166
    Figure US20120010075A1-20120112-C00191
         		166-168 385 381 12.72 (s, 1H), 12.52 (s, 1H), 8.55 (s, 1H), 7.73 (dd, J = 14.6, 2.5 Hz, 2H), 7.59- 7.43 (m, 3H), 7.27-7.12 (m, 1H), 3.85 (s, 3H)
    167
    Figure US20120010075A1-20120112-C00192
         		203-205 269 12.04 (s, 1H), 11.31 (s, 1H), 8.64 (s, 1H), 7.62-7.49 (m, 3H), 7.36-7.27 (m, 1H), 7.24 (s, 1H), 6.93 (t, J = 8.5 Hz, 2H), 2.36 (s, 6H)
    168
    Figure US20120010075A1-20120112-C00193
         		223-226 382 380 12.76 (s, 1H), 12.47 (s, 1H), 8.53 (s, 1H), 7.73 (dd, J = 18.0, 2.5 Hz, 2H), 7.57 (s, 2H), 7.28 (s, 1H), 2.36 (s, 6H)
    169
    Figure US20120010075A1-20120112-C00194
         		373 371
    170
    Figure US20120010075A1-20120112-C00195
         		354
    171
    Figure US20120010075A1-20120112-C00196
         		354
    172
    Figure US20120010075A1-20120112-C00197
         		307
    173
    Figure US20120010075A1-20120112-C00198
         		318 317
    174
    Figure US20120010075A1-20120112-C00199
         		255 253
    175
    Figure US20120010075A1-20120112-C00200
         		275 273
    176
    Figure US20120010075A1-20120112-C00201
         		375 (+Na) 351
    177
    Figure US20120010075A1-20120112-C00202
    178
    Figure US20120010075A1-20120112-C00203
         		331 (+Na)
    179
    Figure US20120010075A1-20120112-C00204
         		332
    180
    Figure US20120010075A1-20120112-C00205
         		287
    181
    Figure US20120010075A1-20120112-C00206
         		354
    182
    Figure US20120010075A1-20120112-C00207
         		319 317
    183
    Figure US20120010075A1-20120112-C00208
         		339 (+Na) 315
    184
    Figure US20120010075A1-20120112-C00209
         		219-222 388 386 12.36 (s, 1H), 11.19 (s, 1H), 8.65 (s, 1H), 8.04 (dd, J = 80.4, 8.3 Hz, 4H), 7.83 (d, J = 2.5 Hz, 1H), 7.45 (dd, J = 8.8, 2.5 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H)
    185
    Figure US20120010075A1-20120112-C00210
         		349 347
    186
    Figure US20120010075A1-20120112-C00211
         		196-202 389 387 12.25 (s, 1H), 10.99 (s, 1H), 7.82 (d, J = 2.5 Hz, 1H), 7.80-7.76 (m, 1H), 7.66- 7.57 (m, 3H), 7.45 (dd, J = 8.8, 2.6 Hz, 1H), 7.37-7.31 (m, 1H)
    187
    Figure US20120010075A1-20120112-C00212
         		213-218 343 341 12.36 (s, 1H), 11.18 (s, 1H), 8.66 (s, 1H), 8.14 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 8.3 Hz, 2H), 7.71 (d, J = 2.6 Hz, 1H), 7.34 (dd, J = 8.8, 2.7 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H)
    188
    Figure US20120010075A1-20120112-C00213
         		305 303
    189
    Figure US20120010075A1-20120112-C00214
         		185-188 344 342 12.25 (s, 1H), 10.98 (s, 1H), 8.47 (s, 1H), 7.81-7.67 (m, 1H), 7.66-7.57 (m, 2H), 7.34 (dd, J = 8.8, 2.7 Hz, 1H), 7.23 (dt, J = 3.5, 2.3 Hz, 1H), 6.91 (dd, J = 42.1, 8.6 Hz, 1H)
    190
    Figure US20120010075A1-20120112-C00215
         		353 351
    191
    Figure US20120010075A1-20120112-C00216
         		351
    192
    Figure US20120010075A1-20120112-C00217
         		385
    193
    Figure US20120010075A1-20120112-C00218
         		432 431
    194
    Figure US20120010075A1-20120112-C00219
         		369 367
    195
    Figure US20120010075A1-20120112-C00220
         		367
    196
    Figure US20120010075A1-20120112-C00221
         		169-173 423 421 12.67 (s, 1H), 12.32 (s, 1H), 8.42 (s, 1H), 7.82 (t, J = 1.3 Hz, 1H), 7.77 (dd, J = 12.0, 2.5 Hz, 2H), 7.65 (d, J = 1.3 Hz, 2H)
    197
    Figure US20120010075A1-20120112-C00222
         		321 319
    198
    Figure US20120010075A1-20120112-C00223
         		525
    199
    Figure US20120010075A1-20120112-C00224
         		354 352
    200
    Figure US20120010075A1-20120112-C00225
         		305 303
    201
    Figure US20120010075A1-20120112-C00226
         		276-280 399 397 13.87 (s, 1H), 12.82 (s, 1H), 8.71 (s, 1H), 8.65 (d, J = 2.7 Hz, 1H), 8.48 (d, J = 2.7 Hz, 1H), 8.02 (t, J = 1.8 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.73 (dd, J = 8.0, 2.0 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H).
    202
    Figure US20120010075A1-20120112-C00227
         		379
    203
    Figure US20120010075A1-20120112-C00228
         		385 383
    204
    Figure US20120010075A1-20120112-C00229
         		429 427
    205
    Figure US20120010075A1-20120112-C00230
         		383 381
    206
    Figure US20120010075A1-20120112-C00231
         		363 361
    207
    Figure US20120010075A1-20120112-C00232
         		305 303
    208
    Figure US20120010075A1-20120112-C00233
         		283-300 393 391 14.01 (s, 1H), 12.65 (s, 1H), 8.69 (s, 1H), 8.60 (d, J = 2.7 Hz, 1H), 8.47 (d, J = 2.6 Hz, 1H), 7.59 (s, 2H), 7.29 (s, 1H), 2.37 (s, 6H)
    209
    Figure US20120010075A1-20120112-C00234
         		189-193 378 376 12.07 (s, 1H), 10.90 (s, 1H), 8.61 (s, 1H), 7.55 (s, 2H), 7.40 (d, J = 2.2 Hz, 1H), 7.24 (s, 1H), 7.17 (d, J = 2.2 Hz, 1H), 3.85 (s, 3H), 2.35 (s, 6H)
    210
    Figure US20120010075A1-20120112-C00235
         		369 367
    211
    Figure US20120010075A1-20120112-C00236
         		220-227 393 391 11.76 (s, 1H), 8.19 (s, 1H), 7.65 (d, J = 2.5 Hz, 1H), 7.39 (d, J = 2.6 Hz, 1H), 7.04 (s, 2H), 6.94 (s, 1H), 2.18 (s, 6H), 1.53 (s, 9H)
    212
    Figure US20120010075A1-20120112-C00237
         		289 287
    213
    Figure US20120010075A1-20120112-C00238
         		271 269
    214
    Figure US20120010075A1-20120112-C00239
         		285 283
    215
    Figure US20120010075A1-20120112-C00240
         		300 298
    216
    Figure US20120010075A1-20120112-C00241
         		323 321
    217
    Figure US20120010075A1-20120112-C00242
         		 91-104 297 295 10.78 (s, 1H), 8.18 (s, 1H), 7.42-7.37 (m, 2H), 7.34 (dd, J = 7.7, 1.7 Hz, 1H), 7.32-7.24 (m, 4H), 6.80 (td, J = 8.3, 4.4 Hz, 2H), 1.53 (s, 9H)
    218
    Figure US20120010075A1-20120112-C00243
         		222-225 354 352 12.17 (s, 1H), 10.94 (s, 6H), 7.78-7.71 (m, 15H), 7.62-7.57 (m, 9H), 7.53 (dd, J = 8.6, 2.6 Hz, 6H), 7.27 (dddd, J = 27.4, 15.4, 7.9, 1.7 Hz, 14H), 6.96- 6.89 (m, 12H), 6.83-6.76 (m, 7H)
    219
    Figure US20120010075A1-20120112-C00244
         		228-231 423 421 12.60 (s, 1H), 12.10 (s, 1H), 7.80-7.75 (m, 2H), 7.69 (dd, J = 19.8, 2.6 Hz, 2H), 7.57 (dd, J = 2.5, 1.2 Hz, 1H), 7.55 (d, J = 2.6 Hz, 1H)
    220
    Figure US20120010075A1-20120112-C00245
         		215-218 512 510 12.65 (s, 1H), 12.35 (s, 1H), 7.87 (q, J = 2.4 Hz, 2H), 7.82-7.75 (m, 3H), 7.64 (dd, J = 17.0, 2.4 Hz, 1H), 7.55 (ddd, J = 8.5, 6.0, 2.6 Hz, 1H)
    221
    Figure US20120010075A1-20120112-C00246
         		202-205 446 444 12.14 (s, 1H), 10.95 (s, 1H), 8.48 (s, 1H), 7.93 (d, J = 2.1 Hz, 1H), 7.80-7.72 (m, 1H), 7.59 (dd, J = 7.7, 1.5 Hz, 1H), 7.50 (dd, J = 12.0, 8.4 Hz, 1H), 7.35-7.18 (m, 1H), 6.96-6.89 (m, 1H), 6.80 (dd, J = 12.3, 5.2 Hz, 1H)
    222
    Figure US20120010075A1-20120112-C00247
         		201-219 514 512 12.57 (s, 1H), 12.12 (s, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.81 (ddd, J = 11.4, 10.0, 2.2 Hz, 2H), 7.71 (d, J = 2.6 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H), 7.53 (dd, J = 8.4, 2.2 Hz, 1H)
    223
    Figure US20120010075A1-20120112-C00248
         		215-216 603 601 12.62 (s, 1H), 12.36 (s, 1H), 8.40 (s, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.86 (dd, J = 7.4, 2.3 Hz, 2H), 7.82-7.76 (m, 2H), 7.53 (d, J = 8.4 Hz, 1H)
    224
    Figure US20120010075A1-20120112-C00249
         		222-226 401 399 12.15 (s, 1H), 10.94 (s, 1H), 8.49 (s, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.88 (dd, J = 8.4, 2.2 Hz, 1H), 7.85-7.81 (m, 1H), 7.59 (dd, J = 7.7, 1.6 Hz, 1H), 6.97-6.89 (m, 2H), 6.84-6.76 (m, 1H)
    225
    Figure US20120010075A1-20120112-C00250
         		198-201 470 8.44 (s, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.89 (td, J = 8.7, 2.1 Hz, 2H), 7.68 (dd, J = 16.4, 2.5 Hz, 2H), 7.43-7.36 (m, 2H)
    226
    Figure US20120010075A1-20120112-C00251
         		205-212 559 12.64 (s, 1H), 12.36 (s, 1H), 8.40 (s, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.93-7.83 (m, 3H), 7.40 (t, J = 5.0 Hz, 1H)
    227
    Figure US20120010075A1-20120112-C00252
         		 86-122 334 332 12.04 (d, J = 17.6 Hz, 1H), 11.05 (s, 1H), 7.62-7.52 (m, 2H), 7.46 (d, J = 7.7 Hz, 1H), 7.34-7.26 (m, 2H), 6.96-6.88 (m, 2H), 6.80 (t, J = 6.0 Hz, 1H), 2.36 (s, 3H)
    228
    Figure US20120010075A1-20120112-C00253
         		240-242 403 401 12.49 (s, 1H), 12.25 (s, 1H), 8.44 (s, 1H), 7.67 (dd, J = 13.6, 2.5 Hz, 2H), 7.60 (d, J = 4.1 Hz, 1H), 7.56-7.43 (m, 1H), 7.33 (dd, J = 6.3, 2.2 Hz, 1H), 2.37 (d, J = 2.8 Hz, 3H)
    229
    Figure US20120010075A1-20120112-C00254
         		258-261 491 489 12.53 (s, 1H), 12.48 (s, 1H), 8.40 (s, 1H), 7.84 (dd, J = 11.5, 2.4 Hz, 2H), 7.60 (s, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.34 (q, J = 7.8 Hz, 1H), 2.37 (d, J = 3.5 Hz, 3H)
    230
    Figure US20120010075A1-20120112-C00255
         		185-187 255 253 (300 MHz, CDCl3) 12.73 (s, 1H), 9.00 (s, 1H), 7.90- 7.82 (m, 2H), 7.64-7.57 (m, 1H), 7.55-7.47 (m, 3H), 7.35-7.28 (m, 1H), 7.09-7.00 (m, 1H), 6.94- 6.87 (m, 1H), 2.42 (s, 3H)
    231
    Figure US20120010075A1-20120112-C00256
         		188-189 275 273 12.47 (s, 1H), 12.40 (s, 1H), 8.63 (s, 1H), 8.07-7.91 (m, 2H), 7.70-7.61 (m, 1H), 7.58 (t, J = 7.4 Hz, 2H), 7.50 (d, J = 7.9 Hz, 2H), 6.98 (t, J = 7.8 Hz, 1H)
    232
    Figure US20120010075A1-20120112-C00257
         		186-188 255 12.24 (s, 1H), 11.96 (s, 1H), 8.59 (s, 1H), 8.08-7.89 (m, 2H), 7.71-7.43 (m, 3H), 7.26 (dd, J = 24.4, 7.4 Hz, 2H), 6.86 (t, J = 7.5 Hz, 1H), 2.23 (s, 3H)
    233
    Figure US20120010075A1-20120112-C00258
         		218-219 275 273 12.16 (s, 1H), 11.60 (s, 1H), 8.65 (s, 1H), 7.95 (d, J = 7.2 Hz, 2H), 7.59 (dt, J = 14.8, 7.7 Hz, 4H), 7.10-6.83 (m, 2H)
    234
    Figure US20120010075A1-20120112-C00259
         		179-182 255 253 12.08 (s, 1H), 11.32 (s, 1H), 8.61 (s, 1H), 8.08-7.81 (m, 2H), 7.70-7.47 (m, 3H), 7.42 (d, J = 7.8 Hz, 1H), 6.89-6.68 (m, 2H), 2.29 (s, 3H)
    235
    Figure US20120010075A1-20120112-C00260
         		192-193 255 253 12.11 (s, 1H), 11.06 (s, 1H), 8.61 (s, 1H), 8.01-7.84 (m, 2H), 7.59 (dt, J = 27.8, 7.2 Hz, 3H), 7.36 (d, J = 1.4 Hz, 1H), 7.12 (dd, J = 8.3, 1.8 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 2.26 (s, 3H)
    236
    Figure US20120010075A1-20120112-C00261
         		247-248 275 273 12.53 (s, 1H), 12.48 (s, 1H), 9.06 (s, 1H), 8.08-7.90 (m, 2H), 7.62 (dt, J = 28.8, 7.2 Hz, 3H), 7.34 (t, J = 8.2 Hz, 1H), 7.06 (dd, J = 7.9, 0.7 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H)
    237
    Figure US20120010075A1-20120112-C00262
         		215-216 271 269 12.26 (s, 1H), 12.21 (s, 1H), 8.98 (s, 1H), 8.03-7.90 (m, 2H), 7.66-7.49 (m, 3H), 7.28 (t, J = 8.3 Hz, 1H), 6.57 (dd, J = 8.3, 3.6 Hz, 2H), 3.86 (s, 3H)
    238
    Figure US20120010075A1-20120112-C00263
         		249-252 289 287 12.88 (s, 1H), 12.46 (s, 1H), 8.61 (s, 1H), 8.04-7.89 (m, 2H), 7.60 (ddd, J = 12.6, 11.5, 6.4 Hz, 4H), 7.23 (d, J = 8.4 Hz, 1H)
    239
    Figure US20120010075A1-20120112-C00264
         		206-208 289 287 12.18 (s, 1H), 11.29 (s, 1H), 8.59 (s, 1H), 7.95 (dd, J = 11.2, 4.0 Hz, 2H), 7.69- 7.47 (m, 4H), 6.94 (s, 1H), 2.30 (s, 3H)
    240
    Figure US20120010075A1-20120112-C00265
         		238-241 309 307 12.25 (s, 1H), 11.61 (s, 1H), 8.62 (s, 1H), 8.08-7.71 (m, 2H), 7.68-7.29 (m, 4H), 7.19 (s, 1H)
    241
    Figure US20120010075A1-20120112-C00266
         		273-274 309 307 12.76 (s, 1H), 12.55 (s, 1H), 9.06 (s, 1H), 8.09-7.90 (m, 2H), 7.62 (ddd, J = 22.7, 11.1, 7.0 Hz, 4H), 7.00 (d, J = 9.0 Hz, 1H)
    242
    Figure US20120010075A1-20120112-C00267
         		273-274 309 307 12.92 (s, 1H), 12.52 (s, 1H), 8.98 (s, 1H), 8.09-7.88 (m, 2H), 7.73-7.52 (m, 3H), 7.22 (d, J = 2.0 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H)
    243
    Figure US20120010075A1-20120112-C00268
         		187-189 349 347 12.77 (s, 1H), 12.50 (s, 1H), 9.00 (s, 1H), 8.11-7.87 (m, 2H), 7.65 (t, J = 7.3 Hz, 1H), 7.58 (t, J = 7.4 Hz, 2H), 7.16 (d, J = 8.7 Hz, 1H), 6.99 (d, J = 8.7 Hz, 1H), 3.82 (s, 3H)
    244
    Figure US20120010075A1-20120112-C00269
         		206-207 277 275 12.45 (d, J = 10.6 Hz, 1H), 12.42 (s, 1H), 8.77 (s, 1H), 7.97 (d, J = 7.5 Hz, 2H), 7.66 (t, J = 7.3 Hz, 1H), 7.58 (t, J = 7.5 Hz, 2H), 7.44- 7.23 (m, 1H), 6.81 (td, J = 9.5, 3.4 Hz, 1H)
    245
    Figure US20120010075A1-20120112-C00270
         		216-218 259 257 12.35 (s, 1H), 12.10 (s, 1H), 8.82 (s, 1H), 8.04-7.89 (m, 2H), 7.76-7.61 (m, 1H), 7.58 (t, J = 7.4 Hz, 2H), 7.36 (dd, J = 15.2, 8.3 Hz, 1H), 6.91-6.70 (m, 2H)
    246
    Figure US20120010075A1-20120112-C00271
         		212-213 255 253 12.19 (s, 2H), 8.92 (s, 1H), 8.03-7.90 (m, 2H), 7.69- 7.60 (m, 1H), 7.57 (t, J = 7.3 Hz, 2H), 7.20 (t, J = 7.9 Hz, 1H), 6.78 (dd, J = 14.2, 7.8 Hz, 2H), 2.43 (s, 3H)
    247
    Figure US20120010075A1-20120112-C00272
         		204-205 309 307 13.45 (s, 1H), 12.61 (s, 1H), 9.02 (s, 1H), 7.99 (d, J = 7.3 Hz, 2H), 7.66 (t, J = 7.3 Hz, 1H), 7.59 (t, J = 7.5 Hz, 2H), 7.53 (d, J = 8.6 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H)
    248
    Figure US20120010075A1-20120112-C00273
         		234-237 354 352 12.72 (s, 1H), 12.45 (s, 1H), 8.80 (t, J = 1.9 Hz, 1H), 8.62 (s, 1H), 8.51-8.37 (m, 2H), 7.88 (t, J = 8.0 Hz, 1H), 7.69 (dd, J = 24.9, 2.5 Hz, 2H)
    249
    Figure US20120010075A1-20120112-C00274
         		165-169 375 12.70 (s, 1H), 12.38 (s, 1H), 8.60 (s, 1H), 8.32-8.23 (m, 2H), 8.02 (d, J = 7.8 Hz, 1H), 7.83 (t, J = 7.8 Hz, 1H), 7.68 (dd, J = 24.6, 2.5 Hz, 2H)
    250
    Figure US20120010075A1-20120112-C00275
         		180-182 393 391 12.63 (s, 1H), 12.39 (s, 1H), 8.60 (s, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.91 (s, 1H), 7.76-7.63 (m, 4H)
    251
    Figure US20120010075A1-20120112-C00276
         		236-237 289 287 13.78 (s, 1H), 11.43 (s, 1H), 7.94 (d, J = 7.3 Hz, 2H), 7.70-7.51 (m, 2H), 7.03- 6.92 (m, 4H), 2.49 (s, 3H)
    252
    Figure US20120010075A1-20120112-C00277
         		214-215 303 301 13.77 (s, 1H), 11.51 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.43 (dd, J = 10.7, 4.3 Hz, 1H), 7.36-7.29 (m, 2H), 7.01-6.92 (m, 2H), 2.41 (s, 3H), 2.40 (s, 3H)
    253
    Figure US20120010075A1-20120112-C00278
         		210-211 303 301 13.79 (s, 1H), 11.38 (s, 1H), 7.78-7.70 (m, 2H), 7.66 (d, J = 8.5 Hz, 1H), 7.48- 7.40 (m, 2H), 7.01-6.93 (m, 2H), 2.48 (s, 3H), 2.41 (s, 3H)
    254
    Figure US20120010075A1-20120112-C00279
         		254-256 303 301 13.80 (s, 1H), 11.33 (s, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.02-6.91 (m, 2H), 2.48 (s, 3H), 2.40 (s, 3H)
    255
    Figure US20120010075A1-20120112-C00280
         		183-184 323 321 13.60 (s, 1H), 11.72 (s, 1H), 7.67-7.45 (m, 5H), 7.02- 6.94 (m, 2H), 2.41 (s, 3H)
    256
    Figure US20120010075A1-20120112-C00281
         		222-223 323 321 13.69 (s, 1H), 11.52 (s, 1H), 8.02-7.97 (m, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.73-7.65 (m, 2H), 7.59 (t, J = 7.9 Hz, 1H), 7.02-6.94 (m, 2H), 2.49 (s, 3H)
    257
    Figure US20120010075A1-20120112-C00282
         		246-247 323 321 13.72 (s, 1H), 11.48 (s, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.6 Hz, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.02-6.93 (m, 2H), 2.49 (s, 3H)
    258
    Figure US20120010075A1-20120112-C00283
         		277-280 337 12.42 (s, 2H), 11.47 (s, 1H), 8.61 (s, 1H), 7.66 (d, J = 13.7 Hz, 3H), 7.28 (dd, J = 8.4, 1.9 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 2.28 (s, 3H)
    259
    Figure US20120010075A1-20120112-C00284
         		245-253 336 12.81 (s, 1H), 12.16 (s, 1H), 8.51 (s, 1H), 7.77 (d, J = 8.7 Hz, 2H), 7.61 (dd, J = 13.2, 2.5 Hz, 2H), 6.61 (d, J = 8.7 Hz, 2H), 6.50 (q, J = 4.8 Hz, 1H), 2.75 (d, J = 4.9 Hz, 3H)
    260
    Figure US20120010075A1-20120112-C00285
         		286-289 337 335 12.58 (s, 1H), 12.48 (s, 1H), 8.57 (s, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 2.4 Hz, 1H), 7.63 (d, J = 2.5 Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H), 2.70 (q, J = 7.6 Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H)
    261
    Figure US20120010075A1-20120112-C00286
         		150-152 285 283 12.85 (s, 1H), 11.33 (s, 1H), 7.94 (d, J = 7.3 Hz, 2H), 7.63 (t, J = 7.3 Hz, 1H), 7.55 (t, J = 7.4 Hz, 2H), 7.13 (d, J = 2.9 Hz, 1H), 6.95 (dd, J = 8.9, 2.8 Hz, 1H), 6.85 (d, J = 8.9 Hz, 1H), 3.75 (s, 3H), 2.49 (s, 3H)
    262
    Figure US20120010075A1-20120112-C00287
         		146-155 299 297 12.81 (s, 1H), 11.40 (s, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.46-7.40 (m, 1H), 7.33 (dd, J = 7.5, 3.9 Hz, 2H), 7.11 (d, J = 2.9 Hz, 1H), 6.94 (dd, J = 8.9, 2.9 Hz, 1H), 6.85 (d, J = 8.9 Hz, 1H), 3.75 (s, 3H), 2.41 (s, 3H), 2.40 (s, 3H)
    263
    Figure US20120010075A1-20120112-C00288
         		131-141 299 297 12.84 (s, 1H), 11.29 (s, 1H), 7.78-7.70 (m, 2H), 7.43 (d, J = 5.2 Hz, 2H), 7.13 (d, J = 2.9 Hz, 1H), 6.94 (dd, J = 8.9, 2.9 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 3.75 (s, 3H), 2.48 (s, 3H), 2.41 (s, 3H)
    264
    Figure US20120010075A1-20120112-C00289
         		159-162 299 297 12.86 (s, 1H), 11.24 (s, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 2.9 Hz, 1H), 6.94 (dd, J = 8.9, 2.9 Hz, 1H), 6.84 (d, J = 8.9 Hz, 1H), 3.75 (s, 3H), 2.48 (s, 3H), 2.40 (s, 3H)
    265
    Figure US20120010075A1-20120112-C00290
         		170-184 319 317 12.67 (s, 1H), 11.61 (s, 1H), 7.65-7.44 (m, 5H), 7.11 (d, J = 3.0 Hz, 1H), 7.01- 6.92 (m, 1H), 3.75 (s, 3H), 2.41 (s, 3H)
    266
    Figure US20120010075A1-20120112-C00291
         		190-201 319 317 12.75 (s, 1H), 11.43 (s, 1H), 8.00 (s, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.58 (t, J = 7.9 Hz, 1H), 7.14 (d, J = 2.9 Hz, 1H), 6.95 (dd, J = 8.9, 2.9 Hz, 1H), 6.86 (d, J = 8.9 Hz, 1H), 3.75 (s, 3H), 2.50 (s, 3H)
    267
    Figure US20120010075A1-20120112-C00292
         		193-196 319 317 12.79 (s, 1H), 11.39 (s, 1H), 7.97 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 2.9 Hz, 1H), 6.95 (dd, J = 8.9, 2.9 Hz, 1H), 6.85 (d, J = 8.9 Hz, 1H), 3.75 (s, 3H), 2.49 (s, 3H).
    268
    Figure US20120010075A1-20120112-C00293
         		215-224 300 298 15.25 (s, 1H), 11.65 (s, 1H), 8.02-7.91 (m, 4H), 7.66 (t, J = 7.3 Hz, 1H), 7.57 (t, J = 7.6 Hz, 2H), 7.07 (t, J = 8.0 Hz, 1H), 2.56 (s, 3H)
    269
    Figure US20120010075A1-20120112-C00294
         		193-196 314 312 15.27 (s, 1H), 11.76 (s, 1H), 7.95 (dd, J = 13.4, 7.5 Hz, 2H), 7.54 (d, J = 7.5 Hz, 1H), 7.45 (t, J = 7.4 Hz, 1H), 7.35 (dd, J = 7.5, 4.3 Hz, 2H), 7.06 (t, J = 8.0 Hz, 1H), 2.49 (s, 3H), 2.41 (s, 3H)
    270
    Figure US20120010075A1-20120112-C00295
         		235-239 314 312 15.25 (d, J = 8.4 Hz, 1H), 11.60 (s, 1H), 7.96 (ddd, J = 21.0, 8.0, 1.4 Hz, 2H), 7.76 (d, J = 11.3 Hz, 2H), 7.46 (d, J = 6.3 Hz, 2H), 7.06 (t, J = 8.0 Hz, 1H), 2.56 (s, 3H), 2.42 (s, 3H)
    271
    Figure US20120010075A1-20120112-C00296
         		242-249 314 312 15.28 (s, 1H), 11.55 (s, 1H), 7.96 (ddd, J = 20.2, 8.0, 1.4 Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 7.06 (t, J = 8.0 Hz, 1H), 2.56 (s, 3H), 2.41 (s, 3H)
    272
    Figure US20120010075A1-20120112-C00297
         		196-205 334 332 15.04 (s, 1H), 11.97 (s, 1H), 8.00-7.92 (m, 2H), 7.68- 7.53 (m, 3H), 7.49 (td, J = 7.3, 1.3 Hz, 1H), 7.07 (t, J = 8.0 Hz, 1H), 2.48 (s, 3H)
    273
    Figure US20120010075A1-20120112-C00298
         		251-286 334 332 15.13 (s, 1H), 11.73 (s, 1H), 8.04-7.89 (m, 4H), 7.73 (d, J = 7.9 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.07 (t, J = 8.0 Hz, 1H), 2.57 (s, 3H)
    274
    Figure US20120010075A1-20120112-C00299
         		241-251 334 332 15.17 (s, 1H), 11.70 (s, 1H), 7.99 (d, J = 8.5 Hz, 3H), 7.94 (dd, J = 8.1, 1.4 Hz, 1H), 7.65 (d, J = 8.5 Hz, 2H), 7.06 (t, J = 8.0 Hz, 1H), 2.56 (s, 3H)
    275
    Figure US20120010075A1-20120112-C00300
         		216-222 343 341 13.24 (s, 1H), 12.64 (s, 1H), 8.69 (s, 1H), 8.04-7.88 (m, 4H), 7.62 (dt, J = 31.2, 7.3 Hz, 3H)
    276
    Figure US20120010075A1-20120112-C00301
         		144-193 377 375 13.34 (s, 1H), 12.74 (s, 1H), 8.97 (s, 1H), 7.99 (d, J = 7.3 Hz, 2H), 7.72-7.65 (m, 2H), 7.60 (t, J = 7.5 Hz, 3H)
    277
    Figure US20120010075A1-20120112-C00302
         		214-217 309 307 12.25 (s, 1H), 11.84 (s, 1H), 8.73 (s, 1H), 8.01 (s, 1H), 7.95 (d, J = 7.9 Hz, 2H), 7.59 (dt, J = 30.0, 7.5 Hz, 4H), 7.12 (d, J = 8.6 Hz, 1H)
    278
    Figure US20120010075A1-20120112-C00303
         		221-223 337 335 14.48 (s, 1H), 11.54 (s, 1H), 7.79-7.72 (m, 2H), 7.68 (d, J = 2.5 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.47- 7.42 (m, 2H), 2.52 (s, 3H), 2.41 (s, 3H)
    279
    Figure US20120010075A1-20120112-C00304
         		262-264 337 335
    280
    Figure US20120010075A1-20120112-C00305
         		211-213 285 283
    281
    Figure US20120010075A1-20120112-C00306
         		170-172 299 297 13.65 (s, 1H), 11.29 (s, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.42 (t, J = 6.9 Hz, 1H), 7.34-7.28 (m, 2H), 6.51- 6.44 (m, 2H), 3.78 (s, 3H), 2.40 (s, 3H), 2.37 (s, 3H)
    282
    Figure US20120010075A1-20120112-C00307
         		184-185 299 297 13.68 (s, 1H), 11.19 (s, 1H), 7.77-7.68 (m, 2H), 7.56 (d, J = 8.7 Hz, 1H), 7.46- 7.40 (m, 2H), 6.51-6.44 (m, 2H), 3.78 (s, 3H), 2.44 (s, 3H), 2.41 (s, 3H)
    283
    Figure US20120010075A1-20120112-C00308
         		206-207 299 297 13.69 (s, 1H), 11.14 (s, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.7 Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H), 6.52-6.44 (m, 2H), 3.78 (s, 3H), 2.44 (s, 3H), 2.39 (s, 3H)
    284
    Figure US20120010075A1-20120112-C00309
         		174-175 319 317
    285
    Figure US20120010075A1-20120112-C00310
         		212-214 319 317
    286
    Figure US20120010075A1-20120112-C00311
         		227-229 319 317
    287
    Figure US20120010075A1-20120112-C00312
         		204-208 334 332 13.49 (s, 1H), 11.45 (s, 1H), 7.94 (d, J = 7.4 Hz, 2H), 7.76 (d, J = 2.3 Hz, 1H), 7.64 (t, J = 7.3 Hz, 1H), 7.55 (t, J = 7.5 Hz, 2H), 7.45 (dd, J = 8.7, 2.3 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 2.49 (s, 3H)
    288
    Figure US20120010075A1-20120112-C00313
         		201-203 348 346 13.49 (s, 1H), 11.53 (s, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.51 (d, J = 7.4 Hz, 1H), 7.47-7.41 (m, 2H), 7.33 (dd, J = 7.4, 4.5 Hz, 2H), 6.90 (d, J = 8.7 Hz, 1H), 2.42 (s, 3H), 2.40 (s, 3H)
    289
    Figure US20120010075A1-20120112-C00314
         		227-233 348 346 13.50 (s, 1H), 11.40 (s, 1H), 7.75 (t, J = 5.9 Hz, 3H), 7.49-7.41 (m, 3H), 6.90 (d, J = 8.7 Hz, 1H), 2.49 (s, 3H), 2.41 (s, 3H)
    290
    Figure US20120010075A1-20120112-C00315
         		245-248 348 346 13.51 (s, 1H), 11.36 (s, 1H), 7.86 (d, J = 7.9 Hz, 2H), 7.75 (d, J = 2.3 Hz, 1H), 7.45 (dd, J = 8.7, 2.3 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 6.89 (d, J = 8.7 Hz, 1H), 2.48 (s, 3H), 2.40 (s, 3H)
    291
    Figure US20120010075A1-20120112-C00316
         		198-201 368 366 13.31 (s, 1H), 11.73 (s, 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.61-7.54 (m, 2H), 7.47 (dd, J = 13.1, 4.7 Hz, 3H), 6.91 (d, J = 8.7 Hz, 1H), 2.41 (s, 3H)
    292
    Figure US20120010075A1-20120112-C00317
         		235-240 368 366 13.40 (s, 1H), 11.54 (s, 1H), 8.00 (s, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.46 (dd, J = 8.7, 2.3 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 2.50 (s, 3H)
    293
    Figure US20120010075A1-20120112-C00318
         		264-268 366 13.43 (s, 1H), 11.50 (s, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 2.3 Hz, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.46 (dd, J = 8.7, 2.3 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 2.49 (s, 3H)
    294
    Figure US20120010075A1-20120112-C00319
         		215-217 309 307 12.24 (s, 1H), 11.56 (s, 1H), 8.73 (s, 1H), 7.95 (d, J = 7.3 Hz, 2H), 7.87 (d, J = 8.0 Hz, 1H), 7.67-7.60 (m, 1H), 7.60-7.52 (m, 2H), 7.29-7.20 (m, 2H)
    295
    Figure US20120010075A1-20120112-C00320
         		232-234 377 375 13.92 (s, 1H), 12.78 (s, 1H), 8.72 (s, 1H), 8.35 (s, 1H), 7.98 (d, J = 7.4 Hz, 2H), 7.94 (s, 1H), 7.70-7.64 (m, 1H), 7.62-7.56 (m, 2H)
    296
    Figure US20120010075A1-20120112-C00321
         		170-173 309 307 13.03 (s, 1H), 12.49 (s, 1H), 8.65 (s, 1H), 7.97 (d, J = 7.3 Hz, 2H), 7.80 (d, J = 7.5 Hz, 1H), 7.71-7.62 (m, 2H), 7.61-7.53 (m, 2H), 7.11 (t, J = 7.7 Hz, 1H)
    297
    Figure US20120010075A1-20120112-C00322
         		228-230 309 307 12.93 (s, 1H), 12.56 (s, 1H), 8.96 (s, 1H), 8.01-7.94 (m, 2H), 7.70-7.62 (m, 1H), 7.62-7.55 (m, 2H), 7.52 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H)
    298
    Figure US20120010075A1-20120112-C00323
         		207-209 365 363 12.54 (s, 1H), 12.50 (s, 1H), 8.55 (s, 1H), 7.99-7.92 (m, 2H), 7.68-7.61 (m, 1H), 7.61-7.50 (m, 4H), 2.50 (s, 3H)
    299
    Figure US20120010075A1-20120112-C00324
         		146-148 285 283 13.50 (s, 1H), 11.34 (s, 1H), 7.94 (d, J = 7.4 Hz, 2H), 7.66-7.60 (m, 1H), 7.59-7.52 (m, 2H), 7.24 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 6.83 (t, J = 8.0 Hz, 1H), 3.79 (s, 3H), 2.48 (s, 3H)
    300
    Figure US20120010075A1-20120112-C00325
         		208-209 299 297 13.50 (s, 1H), 11.40 (s, 1H), 7.52 (d, J = 7.4 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.36- 7.27 (m, 2H), 7.22 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 6.83 (t, J = 8.1 Hz, 1H), 3.79 (s, 3H), 2.41 (s, 6H)
    301
    Figure US20120010075A1-20120112-C00326
         		121-123 299 297 13.51 (s, 1H), 11.28 (s, 1H), 7.79-7.68 (m, J = 9.6 Hz, 2H), 7.46-7.40 (m, 2H), 7.24 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 6.83 (t, J = 8.0 Hz, 1H), 3.79 (s, 3H), 2.48 (s, 3H), 2.41 (s, 3H)
    302
    Figure US20120010075A1-20120112-C00327
         		146-148 299 297 13.53 (s, 1H), 11.24 (s, 1H), 7.86 (d, J = 7.9 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 7.8 Hz, 1H), 6.83 (t, J = 8.1 Hz, 1H), 3.80 (s, 3H), 2.47 (s, 3H), 2.40 (s, 3H)
    303
    Figure US20120010075A1-20120112-C00328
         		233-234 319 317 13.34 (s, 1H), 11.61 (s, 1H), 7.64 (dd, J = 7.5, 1.5 Hz, 1H), 7.61-7.51 (m, 2H), 7.50-7.44 (m, 1H), 7.25-7.20 (m, 1H), 7.05 (d, J = 7.8 Hz, 1H), 6.83 (t, J = 8.1 Hz, 1H), 3.80 (s, 3H), 2.40 (s, 3H)
    304
    Figure US20120010075A1-20120112-C00329
         		146-148 319 317 13.42 (s, 1H), 11.43 (s, 1H), 8.00 (s, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.25 (d, J = 7.5 Hz, 1H), 7.05 (d, J = 7.9 Hz, 1H), 6.84 (t, J = 8.1 Hz, 1H), 3.79 (s, 3H), 2.49 (s, 3H)
    305
    Figure US20120010075A1-20120112-C00330
         		168-170 319 317 13.44 (s, 1H), 11.39 (s, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H), 6.83 (t, J = 8.1 Hz, 1H), 3.79 (s, 3H), 2.48 (s, 3H)
    306
    Figure US20120010075A1-20120112-C00331
         		290-291 344 13.66 (s, 1H), 12.68 (s, 1H), 8.59 (s, 1H), 8.19 (dd, J = 8.5, 1.8 Hz, 2H), 7.97 (d, J = 7.3 Hz, 2H), 7.66 (t, J = 7.3 Hz, 1H), 7.58 (t, J = 7.5 Hz, 2H)
    307
    Figure US20120010075A1-20120112-C00332
         		262-263 384 382 12.70 (s, 1H), 12.48 (s, 1H), 8.67 (s, 1H), 8.07-7.80 (m, 4H), 7.65 (t, J = 7.3 Hz, 1H), 7.57 (t, J = 7.5 Hz, 2H)
    308
    Figure US20120010075A1-20120112-C00333
         		262-269 339 337 12.44 (s, 1H), 12.31 (s, 1H), 11.71 (s, 1H), 8.62 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.65 (dd, J = 6.5, 2.4 Hz, 2H), 6.81 (d, J = 7.5 Hz, 2H), 2.31 (s, 3H)
    309
    Figure US20120010075A1-20120112-C00334
         		252-271 334 332 12.66 (s, 1H), 12.33 (s, 1H), 8.58 (s, 1H), 8.38 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 7.7 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.72 (s, 1H), 7.63 (d, J = 2.5 Hz, 1H)
    310
    Figure US20120010075A1-20120112-C00335
         		234-270 332 12.82 (s, 1H), 12.37 (s, 1H), 8.11-8.02 (m, 4H), 7.76 (dd, J = 15.4, 2.6 Hz, 3H)
    311
    Figure US20120010075A1-20120112-C00336
         		197-199 269 267 13.11 (s, 1H), 11.31 (s, 1H), 7.94 (d, J = 7.4 Hz, 2H), 7.63 (t, J = 7.3 Hz, 1H), 7.55 (t, J = 7.5 Hz, 2H), 7.44 (s, 1H), 7.12 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 2.48 (s, 3H), 2.28 (s, 3H)
    312
    Figure US20120010075A1-20120112-C00337
         		154-156 283 281 13.11 (s, 1H), 11.37 (s, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.42 (d, J = 5.6 Hz, 2H), 7.32 (dd, J = 7.4, 4.2 Hz, 2H), 7.11 (dd, J = 8.3, 1.6 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 2.40 (s, 6H), 2.27 (s, 3H)
    313
    Figure US20120010075A1-20120112-C00338
         		182-184 283 281 13.12 (s, 1H), 11.26 (s, 1H), 7.74 (d, J = 9.7 Hz, 2H), 7.43 (d, J = 5.2 Hz, 3H), 7.12 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 2.47 (s, 3H), 2.41 (s, 3H), 2.27 (s, 3H)
    314
    Figure US20120010075A1-20120112-C00339
         		206-208 283 281 13.13 (s, 1H), 11.22 (s, 1H), 7.85 (d, J = 7.9 Hz, 2H), 7.44 (s, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 2.47 (s, 3H), 2.40 (s, 3H), 2.27 (s, 3H)
    315
    Figure US20120010075A1-20120112-C00340
         		154-158 303 301 12.95 (s, 1H), 11.59 (s, 1H), 7.65-7.57 (m, 2H), 7.46 (ddd, J = 12.5, 9.1, 1.4 Hz, 3H), 7.12 (dd, J = 8.3, 1.8 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 2.40 (s, 3H), 2.27 (s, 3H)
    316
    Figure US20120010075A1-20120112-C00341
         		231-241 303 301 13.02 (s, 1H), 11.41 (s, 1H), 8.00 (s, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 8.9 Hz, 1H), 7.58 (t, J = 7.9 Hz, 1H), 7.45 (s, 1H), 7.13 (dd, J = 8.3, 1.5 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 2.49 (s, 3H), 2.28 (s, 3H)
    317
    Figure US20120010075A1-20120112-C00342
         		203-210 303 301 13.05 (s, 1H), 11.37 (s, 1H), 7.97 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 7.45 (s, 1H), 7.12 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 2.48 (s, 3H), 2.27 (s, 3H)
    318
    Figure US20120010075A1-20120112-C00343
         		242-243 343 341 12.33 (s, 1H), 11.64 (s, 1H), 8.69 (s, 1H), 7.96 (d, J = 6.2 Hz, 3H), 7.64 (t, J = 7.2 Hz, 1H), 7.56 (t, J = 7.5 Hz, 2H), 7.36 (s, 1H)
    319
    Figure US20120010075A1-20120112-C00344
         		216-218 343 341 13.84 (s, 1H), 12.70 (s, 1H), 8.95 (d, J = 1.2 Hz, 1H), 8.03-7.95 (m, 2H), 7.76- 7.64 (m, 2H), 7.60 (t, J = 7.5 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H)
    320
    Figure US20120010075A1-20120112-C00345
         		225-226 343 341 13.15 (s, 1H), 12.64 (s, 1H), 8.61 (s, 1H), 8.04-7.90 (m, 3H), 7.75-7.52 (m, 4H)
    321
    Figure US20120010075A1-20120112-C00346
         		204-206 357 355 13.74-12.87 (m, 1H), 12.60 (s, 1H), 8.68 (s, 1H), 8.00 (s, 1H), 7.90 (d, J = 1.1 Hz, 1H), 7.82-7.72 (m, 2H), 7.46 (d, J = 5.0 Hz, 2H), 2.41 (s, 3H)
    322
    Figure US20120010075A1-20120112-C00347
         		269-271 357 355 13.15 (s, 1H), 12.69 (s, 1H), 8.69 (s, 1H), 8.03 (s, 1H), 7.91 (d, J = 1.8 Hz, 1H), 7.80 (dd, J = 19.3, 8.7 Hz, 2H), 7.64 (d, J = 5.8 Hz, 1H), 7.52 (d, J = 1.9 Hz, 1H), 2.40 (s, 3H)
    323
    Figure US20120010075A1-20120112-C00348
         		210-212 361 359 13.15 (s, 1H), 12.69 (s, 1H), 8.69 (s, 1H), 8.03 (s, 1H), 7.91 (d, J = 1.8 Hz, 1H), 7.80 (dd, J = 19.3, 8.7 Hz, 2H), 7.64 (d, J = 5.8 Hz, 1H), 7.52 (d, J = 1.9 Hz, 1H)
    324
    Figure US20120010075A1-20120112-C00349
         		200-202 361 359 13.4 (s, 1H), 12.66 (s, 1H), 8.68 (s, 1H), 8.11-7.98 (m, 2H), 7.90 (d, J = 2.1 Hz, 1H), 7.43 (t, J = 8.8 Hz, 2H), 7.35-7.24 (m, 1H)
    325
    Figure US20120010075A1-20120112-C00350
         		210-212 377 375 13.1 (s, 1H), 12.71 (s, 1H), 8.68 (s, 1H), 8.02 (d, J = 7.2 Hz, 2H), 7.93 (d, J = 10.3 Hz, 2H), 7.72 (s, 1H), 7.63 (d, J = 7.8 Hz, 1H)
    326
    Figure US20120010075A1-20120112-C00351
         		208-210 377 13.25 (s, 1H), 12.70 (s, 1H), 8.68 (s, 1H), 8.07-7.95 (m, 3H), 7.90 (d, J = 1.7 Hz, 1H), 7.66 (d, J = 8.5 Hz, 2H)
    327
    Figure US20120010075A1-20120112-C00352
         		237-238 388 386 12.95 (s, 2H), 8.80 (t, J = 1.8 Hz, 1H), 8.72 (s, 1H), 8.48 (dd, J = 8.2, 1.4 Hz, 1H), 8.40 (d, J = 7.9 Hz, 1H), 8.03 (d, J = 1.7 Hz, 1H), 7.88 (dd, J = 13.6, 5.3 Hz, 2H)
    328
    Figure US20120010075A1-20120112-C00353
         		253-255 388 386 12.96 (s, 2H), 8.71 (s, 1H), 8.41 (d, J = 8.7 Hz, 2H), 8.20 (d, J = 8.7 Hz, 2H), 8.04 (s, 1H), 7.91 (d, J = 1.9 Hz, 1H)
    329
    Figure US20120010075A1-20120112-C00354
         		258-260 359 357 13.11 (s, 1H), 12.35 (s, 1H), 11.45 (s, 1H), 8.73 (s, 1H), 7.98 (d, J = 1.7 Hz, 1H), 7.95-7.83 (m, 2H), 7.54-7.40 (m, 1H), 7.00 (dd, J = 14.0, 7.4 Hz, 2H)
    330
    Figure US20120010075A1-20120112-C00355
         		169-171 411 409 12.84 (s, 1H), 12.73 (s, 1H), 8.56 (s, 1H), 8.03 (s, 1H), 7.94-7.56 (m, 5H)
    331
    Figure US20120010075A1-20120112-C00356
         		255-257 373 371 13.09 (s, 1H), 12.37 (s, 1H), 11.63 (s, 1H), 8.72 (s, 1H), 7.97 (d, J = 1.1 Hz, 1H), 7.90 (d, J = 1.8 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 6.81 (d, J = 8.5 Hz, 3H), 2.32 (d, J = 6.7 Hz, 3H)
    332
    Figure US20120010075A1-20120112-C00357
         		210-213 391 389 13.92 (s, 1H), 12.73 (s, 1H), 8.71 (s, 1H), 8.33 (s, 1H), 7.94 (s, 1H), 7.81-7.74 (m, 2H), 7.50-7.43 (m, 2H), 2.42 (s, 3H)
    333
    Figure US20120010075A1-20120112-C00358
         		274-277 391 389 13.94 (s, 1H), 12.70 (s, 1H), 8.71 (s, 1H), 8.33 (s, 1H), 7.93 (s, 1H), 7.89 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 2.40 (s, 3H)
    334
    Figure US20120010075A1-20120112-C00359
         		240-242 395 393 13.81 (s, 1H), 12.83 (s, 1H), 8.72 (s, 1H), 8.37 (s, 1H), 7.95 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 9.6 Hz, 1H), 7.69-7.61 (m, 1H), 7.53 (td, J = 8.4, 2.1 Hz, 1H)
    335
    Figure US20120010075A1-20120112-C00360
         		226-228 395 393 13.87 (s, 1H), 12.79 (s, 1H), 8.71 (s, 1H), 8.36 (s, 1H), 8.06 (dd, J = 8.7, 5.5 Hz, 2H), 7.94 (s, 1H), 7.47-7.39 (m, 2H)
    336
    Figure US20120010075A1-20120112-C00361
         		230-233 411 409 13.80 (s, 1H), 12.85 (s, 1H), 8.71 (s, 1H), 8.37 (s, 1H), 8.04-8.00 (m, 1H), 7.97- 7.91 (m, 2H), 7.74 (d, J = 9.1 Hz, 1H), 7.66-7.59 (m, 1H)
    337
    Figure US20120010075A1-20120112-C00362
         		233-236 411 409 13.85 (s, 1H), 12.84 (s, 1H), 8.71 (s, 1H), 8.36 (s, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.94 (s, 1H), 7.67 (d, J = 8.5 Hz, 2H)
    338
    Figure US20120010075A1-20120112-C00363
         		256-258 420 13.76 (s, 1H), 13.08 (s, 1H), 8.80 (t, J = 1.8 Hz, 1H), 8.75 (s, 1H), 8.50 (dd, J = 8.2, 1.4 Hz, 1H), 8.41 (d, J = 7.9 Hz, 1H), 8.37 (s, 1H), 7.96 (s, 1H), 7.89 (t, J = 8.0 Hz, 1H)
    339
    Figure US20120010075A1-20120112-C00364
         		244-247 420 13.75 (s, 1H), 13.07 (s, 1H), 8.75 (s, 1H), 8.42 (d, J = 8.8 Hz, 2H), 8.39 (s, 1H), 8.21 (d, J = 8.8 Hz, 2H), 7.96 (s, 1H)
    340
    Figure US20120010075A1-20120112-C00365
         		231-235 393 391 13.79 (s, 1H), 12.50 (s, 1H), 11.47 (s, 1H), 8.77 (s, 1H), 8.30 (s, 1H), 7.95 (s, 1H), 7.87 (dd, J = 7.9, 1.5 Hz, 1H), 7.52-7.44 (m, 1H), 7.05-6.96 (m, 2H)
    341
    Figure US20120010075A1-20120112-C00366
         		210-214 445 443 13.59, 12.89, 12.70, 11.12 (4s, 2H), 8.60, 8.38 (2s, 1H), 8.36, 8.15 (2s, 1H), 7.97-7.63 (m, 5H); Note: rotational isomers
    342
    Figure US20120010075A1-20120112-C00367
         		251-254 407 405 13.80 (s, 1H), 12.48 (s, 1H), 11.60 (s, 1H), 8.76 (s, 1H), 8.30 (s, 1H), 7.94 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 6.87-6.78 (m, 2H), 2.32 (s, 3H)
    343
    Figure US20120010075A1-20120112-C00368
         		188-190 323 321 (300 MHz, DMSO-d6) 13.03 (s, 1H), 12.44 (s, 1H), 8.64 (s, 1H), 7.82-7.72 (m, 3H), 7.67 (d, J = 7.3 Hz, 1H), 7.46 (d, J = 5.0 Hz, 2H), 7.11 (t, J = 7.8 Hz, 1H), 2.41 (s, 3H)
    344
    Figure US20120010075A1-20120112-C00369
         		239-241 323 321 (300 MHz, DMSO-d6) 13.05 (s, 1H), 12.41 (s, 1H), 8.64 (s, 1H), 7.88 (d, J = 8.2 Hz, 2H), 7.79 (d, J = 7.5 Hz, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.38 (d, J = 7.9 Hz, 2H), 7.10 (t, J = 7.8 Hz, 1H), 2.40 (s, 3H)
    345
    Figure US20120010075A1-20120112-C00370
         		176-180 327 325 (300 MHz, DMSO-d6) 12.92 (s, 1H), 12.54 (s, 1H), 8.65 (s, 1H), 7.86-7.73 (m, 3H), 7.72-7.59 (m, 2H), 7.51 (td, J = 8.5, 2.2 Hz, 1H), 7.12 (t, J = 7.7 Hz, 1H)
    346
    Figure US20120010075A1-20120112-C00371
         		187-188 327 (300 MHz, DMSO-d6) 12.96 (s, 1H), 12.52 (s, 1H), 8.64 (s, 1H), 8.10-8.00 (m, 2H), 7.80 (d, J = 7.2 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.43 (t, J = 8.8 Hz, 2H), 7.11 (t, J = 7.7 Hz, 1H)
    347
    Figure US20120010075A1-20120112-C00372
         		185-187 343 341 (300 MHz, DMSO-d6) 12.91 (s, 1H), 12.56 (s, 1H), 8.65 (s, 1H), 8.04-7.98 (m, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 7.1 Hz, 1H), 7.76-7.71 (m, 1H), 7.68 (d, J = 7.3 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H)
    348
    Figure US20120010075A1-20120112-C00373
         		215-216 343 341 12.96 (s, 1H), 12.55 (s, 1H), 8.64 (s, 1H), 7.99 (d, J = 8.6 Hz, 2H), 7.81 (d, J = 7.5 Hz, 1H), 7.71-7.63 (m, 3H), 7.11 (t, J = 7.7 Hz, 1H)
    349
    Figure US20120010075A1-20120112-C00374
         		215-217 354 352 12.84 (s, 2H), 8.83-8.77 (m, 1H), 8.68 (s, 1H), 8.49 (d, J = 8.2 Hz, 1H), 8.41 (d, J = 7.9 Hz, 1H), 7.89 (t, J = 8.0 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.69 (d, J = 7.0 Hz, 1H), 7.12 (t, J = 1.1 Hz, 1H)
    350
    Figure US20120010075A1-20120112-C00375
         		253-255 352 12.86 (s, 2H), 8.67 (s, 1H), 8.42 (d, J = 8.8 Hz, 2H), 8.20 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 7.1 Hz, 1H), 7.69 (d, J = 7.3 Hz, 1H), 7.13 (t, J = 7.7 Hz, 1H)
    351
    Figure US20120010075A1-20120112-C00376
         		230-234 325 323 12.95 (s, 1H), 12.28 (s, 1H), 11.56 (s, 1H), 8.71 (s, 1H), 7.88 (dd, J = 7.9, 1.6 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 7.1 Hz, 1H), 7.52-7.44 (m, 1H), 7.12 (t, J = 7.8 Hz, 1H), 7.05-6.96 (m, 2H)
    352
    Figure US20120010075A1-20120112-C00377
         		248-253 339 337 12.95 (s, 1H), 12.26 (s, 1H), 11.67 (s, 1H), 8.70 (s, 1H), 7.80 (t, J = 9.1 Hz, 2H), 7.67 (d, J = 7.4 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 6.83 (d, J = 7.4 Hz, 2H), 2.31 (s, 3H)
    353
    Figure US20120010075A1-20120112-C00378
         		169-171 377 375 12.78, 12.63, 12.47, 10.39 (4s, 2H), 8.50, 8.29 (2s, 1H), 7.92-7.54 (m, 6H), 7.11, 7.04 (2t, J = 1.1 Hz, 1H); Note: rotational isomers
    354
    Figure US20120010075A1-20120112-C00379
         		212-214 323 321 12.89 (s, 1H), 12.41 (s, 1H), 8.60 (s, 1H), 7.79-7.70 (m, 2H), 7.54 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 4.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 1H), 2.41 (s, 3H)
    355
    Figure US20120010075A1-20120112-C00380
         		254-256 323 321 12.92 (s, 1H), 12.39 (s, 1H), 8.60 (s, 1H), 7.87 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 8.4 Hz, 1H), 2.40 (s, 3H)
    356
    Figure US20120010075A1-20120112-C00381
         		215-218 327 325 12.75 (s, 1H), 12.50 (s, 1H), 8.61 (s, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.79-7.73 (m, 1H), 7.67-7.59 (m, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.51 (td, J = 8.4, 2.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H)
    357
    Figure US20120010075A1-20120112-C00382
         		244-246 325 12.83 (s, 1H), 12.47 (s, 1H), 8.60 (s, 1H), 8.04 (dd, J = 8.7, 5.5 Hz, 2H), 7.56 (d, J = 8.5 Hz, 1H), 7.42 (t, J = 8.8 Hz, 2H), 7.24 (d, J = 8.4 Hz, 1H)
    358
    Figure US20120010075A1-20120112-C00383
         		219-222 343 341 12.73 (s, 1H), 12.52 (s, 1H), 8.60 (s, 1H), 8.00 (t, J = 1.8 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.74-7.69 (m, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H)
    359
    Figure US20120010075A1-20120112-C00384
         		260-262 343 341 12.79 (s, 1H), 12.51 (s, 1H), 8.60 (s, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.5 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H)
    360
    Figure US20120010075A1-20120112-C00385
         		269-271 352 12.70 (s, 2H), 8.79 (s, 1H), 8.65 (s, 1H), 8.50-8.46 (m, 1H), 8.42-8.37 (m, 1H), 7.88 (t, J = 8.0 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H)
    361
    Figure US20120010075A1-20120112-C00386
         		237-243 352 12.69 (s, 2H), 8.63 (s, 1H), 8.40 (d, J = 8.7 Hz, 2H), 8.19 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H)
    362
    Figure US20120010075A1-20120112-C00387
         		280-282 325 323 12.78 (s, 1H), 12.26 (s, 1H), 11.57 (s, 1H), 8.66 (s, 1H), 7.87 (dd, J = 7.9, 1.4 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.50-7.44 (m, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.03-6.96 (m, 2H)
    363
    Figure US20120010075A1-20120112-C00388
         		209-213 377 375 12.56, 12.52, 12.41, 10.48 (4s, 2H), 8.47, 8.26 (2s, 1H), 7.92-7.59 (m, 4H), 7.57, 7.31 (2d, J = 8.5 Hz, 1H), 7.57, 7.31 (2d, J = 8.5 Hz, 1H); Note: rotational isomers
    364
    Figure US20120010075A1-20120112-C00389
         		271-278 339 337 12.79 (s, 1H), 12.24 (s, 1H), 11.69 (s, 1H), 8.66 (s, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 6.84-6.79 (m, 2H), 2.31 (s, 3H)
    365
    Figure US20120010075A1-20120112-C00390
         		214-216 323 13.46 (s, 1H), 12.57 (s, 1H), 9.01 (s, 1H), 7.82-7.75 (m, 2H), 7.53 (d, J = 8.6 Hz, 1H), 7.49-7.45 (m, 2H), 7.10 (d, J = 8.6 Hz, 1H), 2.42 (s, 3H)
    366
    Figure US20120010075A1-20120112-C00391
         		267-269 323 321 13.48 (s, 1H), 12.54 (s, 1H), 9.01 (s, 1H), 7.89 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.6 Hz, 1H), 2.40 (s, 3H)
    367
    Figure US20120010075A1-20120112-C00392
         		203-209 327 325 13.35 (s, 1H), 12.65 (s, 1H), 9.01 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.81-7.76 (m, 1H), 7.69-7.61 (m, 1H), 7.56-7.48 (m, 2H), 7.11 (d, J = 8.6 Hz, 1H)
    368
    Figure US20120010075A1-20120112-C00393
         		264-267 327 325 13.41 (s, 1H), 12.62 (s, 1H), 9.00 (s, 1H), 8.10-8.01 (m, 2H), 7.53 (d, J = 8.6 Hz, 1H), 7.44 (t, J = 8.8 Hz, 2H), 7.10 (d, J = 8.6 Hz, 1H)
    369
    Figure US20120010075A1-20120112-C00394
         		232-234 343 341 13.34 (s, 1H), 12.67 (s, 1H), 9.00 (s, 1H), 8.04-8.00 (m, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H)
    370
    Figure US20120010075A1-20120112-C00395
         		271-273 343 13.38 (s, 1H), 12.66 (s, 1H), 9.00 (s, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 8.6 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H)
    371
    Figure US20120010075A1-20120112-C00396
         		273-277 354 352 13.33 (s, 1H), 12.91 (s, 1H), 9.03 (s, 1H), 8.84-8.81 (m, 1H), 8.50 (dd, J = 8.2, 1.4 Hz, 1H), 8.42 (d, J = 7.8 Hz, 1H), 7.90 (t, J = 8.0 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H)
    372
    Figure US20120010075A1-20120112-C00397
         		260-262 325 323 13.43 (s, 1H), 12.46 (s, 1H), 11.48 (s, 1H), 9.06 (s, 1H), 7.86 (dd, J = 7.9, 1.6 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.52-7.45 (m, 1H), 7.10 (d, J = 8.6 Hz, 1H), 7.05-6.96 (m, 2H)
    373
    Figure US20120010075A1-20120112-C00398
         		221-222 377 375 13.18, 12.73, 12.58, 10.82 (4s, 2H), 8.85, 8.65 (2s, 1H), 7.95-7.62 (m, 4H), 7.56, 7.44 (2d, J = 8.6 Hz, 1H), 7.11, 7.05 (2d, J = 8.6 Hz, 1H); Note: rotational isomers
    374
    Figure US20120010075A1-20120112-C00399
         		248-254 339 337 13.42 (s, 1H), 12.44 (s, 1H), 11.61 (s, 1H), 9.05 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.85-6.81 (m, 2H), 2.32 (s, 3H)
    375
    Figure US20120010075A1-20120112-C00400
         		250- 300 dec 354 352 13.31 (s, 1H), 12.87 (s, 1H), 9.03 (s, 1H), 8.45-8.39 (m, 2H), 8.24-8.18 (m, 2H), 7.55 (d, J = 8.6 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H)
    376
    Figure US20120010075A1-20120112-C00401
         		199-201 357 355 13.21 (s, 1H), 12.61 (s, 1H), 8.60 (s, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.82-7.72 (m, 2H), 7.69 (d, J = 2.4 Hz, 1H), 7.51-7.40 (m, 2H), 2.41 (s, 3H)
    377
    Figure US20120010075A1-20120112-C00402
         		276-278 357 355 13.23 (s, 1H), 12.59 (s, 1H), 8.60 (s, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.88 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 2.5 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 2.40 (s, 3H)
    378
    Figure US20120010075A1-20120112-C00403
         		219-221 361 359 13.09 (s, 1H), 12.72 (s, 1H), 8.61 (s, 1H), 8.03 (d, J = 2.5 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.79-7.74 (m, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.64 (td, J = 8.0, 5.9 Hz, 1H), 7.52 (td, J = 8.4, 2.2 Hz, 1H)
    379
    Figure US20120010075A1-20120112-C00404
         		227-228 361 359 13.16 (s, 1H), 12.68 (s, 1H), 8.60 (s, 1H), 8.26-7.87 (m, 3H), 7.71 (d, J = 2.4 Hz, 1H), 7.43 (t, J = 8.8 Hz, 2H)
    380
    Figure US20120010075A1-20120112-C00405
         		228-229 377 375 13.08 (s, 1H), 12.74 (s, 1H), 8.60 (s, 1H), 8.05-7.97 (m, 2H), 7.93 (d, J = 7.8 Hz, 1H), 7.72 (t, J = 5.3 Hz, 2H), 7.62 (t, J = 7.9 Hz, 1H)
    381
    Figure US20120010075A1-20120112-C00406
         		232-234 377 375 13.13 (s, 1H), 12.72 (s, 1H), 8.60 (s, 1H), 8.00 (dd, J = 10.9, 5.5 Hz, 3H), 7.71 (d, J = 2.4 Hz, 1H), 7.66 (d, J = 8.6 Hz, 2H)
    382
    Figure US20120010075A1-20120112-C00407
         		235-237 388 386 13.00 (s, 1H), 8.83-8.74 (m, 1H), 8.63 (s, 1H), 8.56- 8.44 (m, 1H), 8.40 (d, J = 7.9 Hz, 1H), 8.03 (d, J = 2.5 Hz, 1H), 7.88 (t, J = 8.0 Hz, 1H), 7.72 (d, J = 2.5 Hz, 1H)
    383
    Figure US20120010075A1-20120112-C00408
         		245-247 388 386 12.99 (d, J = 25.6 Hz, 2H), 8.63 (s, 1H), 8.41 (d, J = 8.8 Hz, 2H), 8.20 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 2.5 Hz, 1H), 7.73 (d, J = 2.5 Hz, 1H)
    384
    Figure US20120010075A1-20120112-C00409
         		258-260 359 357 13.10 (s, 1H), 12.43 (s, 1H), 11.51 (s, 1H), 8.66 (s, 1H), 7.97 (d, J = 2.5 Hz, 1H), 7.87 (dd, J = 7.9, 1.5 Hz, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.55-7.39 (m, 1H), 7.06-6.91 (m, 2H)
    385
    Figure US20120010075A1-20120112-C00410
         		203-204 411 409 12.92 (s, 1H), 12.79 (s, 1H), 8.48 (s, 1H), 8.01 (d, J = 2.5 Hz, 1H), 7.95- 7.55 (m, 5H)
    386
    Figure US20120010075A1-20120112-C00411
         		252-254 373 371 13.10 (s, 1H), 12.37 (s, 1H), 11.63 (s, 1H), 8.65 (s, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 6.82 (d, J = 7.6 Hz, 2H), 2.30 (d, J = 8.7 Hz, 3H)
    387
    Figure US20120010075A1-20120112-C00412
         		201-203 289 287 12.10 (s, 1H), 11.58 (s, 1H), 8.63 (s, 1H), 7.78-7.69 (m, 2H), 7.62 (d, J = 8.1 Hz, 1H), 7.43 (d, J = 4.7 Hz, 2H), 7.03-6.95 (m, 2H), 2.40 (s, 3H)
    388
    Figure US20120010075A1-20120112-C00413
         		258-260 289 287 12.09 (s, 1H), 11.62 (s, 1H), 8.63 (s, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.04-6.94 (m, 2H), 2.39 (s, 3H)
    389
    Figure US20120010075A1-20120112-C00414
         		218-222 293 291
    390
    Figure US20120010075A1-20120112-C00415
         		226-228 293 291 12.16 (s, 1H), 11.54 (s, 1H), 8.63 (s, 1H), 8.06-7.98 (m, 2H), 7.64 (d, J = 8.1 Hz, 1H), 7.44-7.35 (m, 2H), 7.03-6.95 (m, 2H)
    391
    Figure US20120010075A1-20120112-C00416
         		212-214 307 12.20 (s, 1H), 11.45 (s, 1H), 8.64 (s, 1H), 8.01-7.96 (m, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.73-7.63 (m, 2H), 7.63-7.55 (m, 1H), 7.02-6.95 (m, 2H)
    392
    Figure US20120010075A1-20120112-C00417
         		257-260 309 307 12.20 (s, 1H), 11.50 (s, 1H), 8.64 (s, 1H), 7.96 (d, J = 8.5 Hz, 2H), 7.67-7.60 (m, 3H), 7.03-6.94 (m, 2H)
    393
    Figure US20120010075A1-20120112-C00418
         		233-238 320 318 12.41 (s, 1H), 11.42 (s, 1H), 8.81-8.77 (m, 1H), 8.69 (s, 1H), 8.46 (dd, J = 8.1, 1.8 Hz, 1H), 8.39 (d, J = 7.8 Hz, 1H), 7.86 (t, J = 8.0 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.04-6.96 (m, 2H)
    394
    Figure US20120010075A1-20120112-C00419
         		278-281 320 318 12.40 (s, 1H), 11.41 (s, 1H), 8.68 (s, 1H), 8.39 (d, J = 8.8 Hz, 2H), 8.18 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8.0 Hz, 1H), 7.03-6.96 (m, 2H)
    395
    Figure US20120010075A1-20120112-C00420
         		210-213 291 289
    396
    Figure US20120010075A1-20120112-C00421
         		197-200 343 341 12.20, 12.13, 11.27, 10.30 (4s, 2H), 8.47, 8.26 (2s, 1H), 7.90-7.16 (m, 5H), 7.01-6.80 (m, 2H); Note: rotational isomers
    397
    Figure US20120010075A1-20120112-C00422
         		283-287 305 303 12.02 (s, 1H), 11.90 (s, 1H), 11.51 (s, 1H), 8.67 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.04-6.95 (m, 2H), 6.83- 6.76 (m, 2H), 2.31 (s, 3H)
    398
    Figure US20120010075A1-20120112-C00423
         		245-248 289 287 12.57 (s, 1H), 12.43 (s, 1H), 9.05 (s, 1H), 7.83-7.73 (m, 2H), 7.46 (d, J = 4.8 Hz, 2H), 7.34 (t, J = 8.2 Hz, 1H), 7.06 (dd, J = 7.9, 0.8 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 2.41 (s, 3H)
    399
    Figure US20120010075A1-20120112-C00424
         		250-252 289 287 12.59 (s, 1H), 12.40 (s, 1H), 9.04 (s, 1H), 7.88 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.33 (t, J = 8.2 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 2.40 (s, 3H)
    400
    Figure US20120010075A1-20120112-C00425
         		257-259 293 291 12.52 (s, 1H), 12.48 (s, 1H), 9.04 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.80-7.75 (m, 1H), 7.68-7.60 (m, 1H), 7.52 (td, J = 8.5, 2.4 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.07 (d, J = 7.9 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H)
    401
    Figure US20120010075A1-20120112-C00426
         		266-268 293 291 12.53 (s, 1H), 12.48 (s, 1H), 9.03 (s, 1H), 8.09-8.00 (m, 2H), 7.47-7.39 (m, 2H), 7.34 (t, J = 8.2 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H)
    402
    Figure US20120010075A1-20120112-C00427
         		250-253 309 307 12.54 (s, 1H), 12.47 (s, 1H), 9.04 (s, 1H), 8.05-7.98 (m, 1H), 7.96-7.90 (m, 1H), 7.76-7.69 (m, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.07 (dd, J = 8.0, 1.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H)
    403
    Figure US20120010075A1-20120112-C00428
         		273-277 309 307 12.53 (s, 1H), 12.51 (s, 1H), 9.04 (s, 1H), 8.03-7.95 (m, 2H), 7.71-7.63 (m, 2H), 7.34 (t, J = 8.2 Hz, 1H), 7.07 (dd, J = 7.9, 0.9 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H)
    404
    Figure US20120010075A1-20120112-C00429
         		269-270 320 318 12.77 (s, 1H), 12.48 (s, 1H), 9.07 (s, 1H), 8.82 (t, J = 1.9 Hz, 1H), 8.52-8.45 (m, 1H), 8.41 (d, J = 7.9 Hz, 1H), 7.89 (t, J = 8.0 Hz, 1H), 7.36 (t, J = 8.2 Hz, 1H), 7.08 (dd, J = 7.9, 0.8 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H)
    405
    Figure US20120010075A1-20120112-C00430
         		>300 320 318 12.73 (s, 1H), 12.44 (s, 1H), 9.06 (s, 1H), 8.46-8.38 (m, 2H), 8.25-8.16 (m, 2H), 7.36 (t, J = 8.2 Hz, 1H), 7.08 (dd, J = 8.0, 0.9 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H)
    406
    Figure US20120010075A1-20120112-C00431
         		277-280 291 289 12.52 (s, 1H), 12.37 (s, 1H), 11.55 (s, 1H), 9.07 (s, 1H), 7.86 (dd, J = 7.9, 1.5 Hz, 1H), 7.52-7.43 (m, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.07 (dd, J = 7.9, 0.9 Hz, 1H), 7.03-6.95 (m, 3H)
    407
    Figure US20120010075A1-20120112-C00432
         		222-226 343 341 12.57, 12.45, 12.30, 10.21 (4s, 2H), 8.88, 8.64 (2s, 1H), 7.92-6.70 (m, 7H); Note: rotational isomers
    408
    Figure US20120010075A1-20120112-C00433
         		273-276 305 303 12.51 (s, 1H), 12.35 (s, 1H), 11.70 (s, 1H), 9.07 (s, 1H), 7.82-7.75 (m, 1H), 7.34 (t, J = 8.2 Hz, 1H), 7.09- 7.03 (m, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 4.2 Hz, 2H), 2.32 (s, 3H)
    409
    Figure US20120010075A1-20120112-C00434
         		297-299 337 335 12.20 (s, 1H), 11.63 (s, 2H), 8.66 (s, 1H), 7.88 (dd, J = 7.9, 1.4 Hz, 1H), 7.66 (d, J = 1.3 Hz, 1H), 7.61 (dd, J = 10.4, 2.3 Hz, 1H), 7.53- 7.38 (m, 1H), 7.07-6.88 (m, 2H)
    410
    Figure US20120010075A1-20120112-C00435
         		211-212 337 335 12.36 (s, 1H), 11.72 (s, 1H), 8.63 (s, 1H), 7.96 (d, J = 7.3 Hz, 2H), 7.72-7.48 (m, 5H)
    411
    Figure US20120010075A1-20120112-C00436
         		228-229 351 349 12.30 (s, 1H), 11.76 (s, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.67 (s, 1H), 7.59 (dd, J = 10.5, 2.1 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 2.39 (s, 3H)
    412
    Figure US20120010075A1-20120112-C00437
         		240-241 405 403 12.51 (s, 1H), 11.58 (s, 1H), 8.66 (s, 1H), 8.15 (d, J = 8.1 Hz, 2H), 7.95 (d, J = 8.3 Hz, 2H), 7.73-7.67 (m, 1H), 7.61 (dd, J = 10.4, 2.3 Hz, 1H)
    413
    Figure US20120010075A1-20120112-C00438
         		279-282 368 12.78 (s, 1H), 12.49 (s, 1H), 8.54 (s, 1H), 7.88 (d, J = 8.1 Hz, 2H), 7.73 (dd, J = 13.1, 2.5 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 2.40 (s, 3H)
    414
    Figure US20120010075A1-20120112-C00439
         		209-215 372 370 12.69 (s, 1H), 12.58 (s, 1H), 8.54 (s, 1H), 8.04 (dd, J = 8.7, 5.5 Hz, 2H), 7.74 (dd, J = 7.7, 2.5 Hz, 2H), 7.42 (t, J = 8.8 Hz, 2H)
    415
    Figure US20120010075A1-20120112-C00440
         		200-211 372 370 12.62 (s, 2H), 8.55 (s, 1H), 7.86-7.71 (m, 4H), 7.67- 7.47 (m, 2H)
    416
    Figure US20120010075A1-20120112-C00441
         		167-226 399 397 12.85 (s, 1H), 12.55 (s, 1H), 8.80 (t, J = 1.8 Hz, 1H), 8.59 (s, 1H), 8.52-8.37 (m, 2H), 7.88 (t, J = 8.0 Hz, 1H), 7.76 (dd, J = 6.4, 2.5 Hz, 2H)
    417
    Figure US20120010075A1-20120112-C00442
         		237-250 399 397 12.68 (s, 2H), 8.58 (s, 1H), 8.41 (d, J = 8.8 Hz, 2H), 8.20 (d, J = 8.8 Hz, 2H), 7.77 (q, J = 2.5 Hz, 2H)
    418
    Figure US20120010075A1-20120112-C00443
         		266-274 422 420 12.66 (s, 1H), 8.42 (s, 1H), 7.94-7.71 (m, 7H)
    419
    Figure US20120010075A1-20120112-C00444
         		188-196 289 287 12.16 (s, 1H), 11.30 (s, 1H), 8.62 (s, 1H), 7.80-7.59 (m, 3H), 7.43 (d, J = 4.6 Hz, 2H), 7.33 (dd, J = 8.7, 2.6 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 2.40 (s, 3H)
    420
    Figure US20120010075A1-20120112-C00445
         		205-224 372 12.23 (s, 1H), 11.21 (s, 1H), 8.64 (s, 1H), 7.83-7.72 (m, 2H), 7.70 (d, J = 2.7 Hz, 1H), 7.61 (td, J = 8.0, 5.9 Hz, 1H), 7.48 (td, J = 8.4, 2.1 Hz, 1H), 7.33 (dd, J = 8.8, 2.7 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H)
    421
    Figure US20120010075A1-20120112-C00446
         		234-243 372 12.21 (s, 1H), 11.26 (s, 1H), 8.62 (s, 1H), 8.03 (dd, J = 8.4, 5.6 Hz, 2H), 7.69 (d, J = 2.5 Hz, 1H), 7.45-7.27 (m, 3H), 6.96 (d, J = 8.8 Hz, 1H)
    422
    Figure US20120010075A1-20120112-C00447
         		154-164 343 341 12.25 (s, 1H), 11.01 (s, 1H), 8.47 (s, 1H), 7.91-7.65 (m, 7H)
    423
    Figure US20120010075A1-20120112-C00448
         		166-169 289 287 (400 MHz, CDCl3) 8.59 (d, J = 12.0 Hz, 1H), 7.76 (d, J = 10.0 Hz, 2H), 7.47 (dd, J = 15.6, 6.2 Hz, 4H), 6.97 (t, J = 7.8 Hz, 1H), 2.39 (d, J = 12.0 Hz, 3H)
    424
    Figure US20120010075A1-20120112-C00449
         		230-232 289 287 (400 MHz, CDCl3) 8.60 (s, 1H), 7.87 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 7.9 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 6.97 (t, J = 7.8 Hz, 1H), 2.40 (s, 3H)
    425
    Figure US20120010075A1-20120112-C00450
         		178-184 293 291 (400 MHz, CDCl3) 8.62 (s, 1H), 7.86-7.72 (m, 2H), 7.63 (dd, J = 13.8, 8.0 Hz, 1H), 7.51 (dd, J = 7.1, 5.5 Hz, 3H), 6.98 (t, J = 7.8 Hz, 1H)
    426
    Figure US20120010075A1-20120112-C00451
         		194-198 293 291 (400 MHz, CDCl3) 8.60 (s, 1H), 8.08-7.99 (m, 2H), 7.54-7.46 (m, 2H), 7.42 (t, J = 8.8 Hz, 2H), 6.98 (t, J = 7.8 Hz, 1H)
    427
    Figure US20120010075A1-20120112-C00452
         		174-178 309 307 (400 MHz, CDCl3) 8.61 (s, 1H), 8.00 (t, J = 1.7 Hz, 1H), 7.95-7.68 (m, 2H), 7.61 (t, J = 7.9 Hz, 1H), 7.55- 7.47 (m, 2H), 6.98 (t, J = 7.8 Hz, 1H)
    428
    Figure US20120010075A1-20120112-C00453
         		217-219 309 307 (400 MHz, CDCl3) 8.61 (s, 1H), 7.98 (d, J = 8.6 Hz, 2H), 7.66 (d, J = 8.6 Hz, 2H), 7.50 (ddd, J = 7.9, 4.5, 1.4 Hz, 2H), 6.98 (t, J = 7.8 Hz, 1H)
    429
    Figure US20120010075A1-20120112-C00454
         		236-239 320 318 (400 MHz, CDCl3) 8.80 (t, J = 1.9 Hz, 1H), 8.66 (s, 1H), 8.52-8.36 (m, 2H), 7.88 (t, J = 8.0 Hz, 1H), 7.53 (ddd, J = 9.7, 7.9, 1.5 Hz, 2H), 6.99 (t, J = 7.8 Hz, 1H)
    430
    Figure US20120010075A1-20120112-C00455
         		284-287 320 318 (400 MHz, CDCl3) 8.64 (s, 1H), 8.41 (d, J = 8.5 Hz, 2H), 8.19 (d, J = 8.6 Hz, 2H), 7.56-7.47 (m, 2H), 6.98 (t, J = 7.8 Hz, 1H)
    431
    Figure US20120010075A1-20120112-C00456
         		266-268 291 289 (400 MHz, CDCl3) 8.66 (s, 1H), 7.87 (dd, J = 7.9, 1.6 Hz, 1H), 7.54-7.42 (m, 3H), 6.98 (ddd, J = 7.8, 5.6, 3.9 Hz, 3H)
    432
    Figure US20120010075A1-20120112-C00457
         		118-121 343 341 (400 MHz, CDCl3) 8.36 (d, J = 82.5 Hz, 1H), 7.95- 7.24 (m, 6H), 6.92 (dt, J = 42.3, 7.9 Hz, 1H)
    433
    Figure US20120010075A1-20120112-C00458
         		258-266 305 303 (400 MHz, CDCl3) 8.66 (s, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.49 (dd, J = 7.9, 2.1 Hz, 2H), 6.98 (t, J = 7.8 Hz, 1H), 6.81 (d, J = 7.3 Hz, 2H), 2.31 (s, 3H)
    434
    Figure US20120010075A1-20120112-C00459
         		262-268 384 382 (400 MHz, CDCl3) 8.58 (s, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.72 (dd, J = 27.0, 2.4 Hz, 2H), 6.81 (d, J = 7.7 Hz, 2H), 2.31 (s, 3H)
    435
    Figure US20120010075A1-20120112-C00460
         		192-194 323 321 12.21 (s, 1H), 11.82 (s, 1H), 8.72 (s, 1H), 8.00 (s, 1H), 7.75 (dd, J = 9.3, 4.5 Hz, 2H), 7.64 (dd, J = 8.7, 1.8 Hz, 1H), 7.44 (d, J = 4.7 Hz, 2H), 7.12 (d, J = 8.6 Hz, 1H), 2.40 (s, 3H)
    436
    Figure US20120010075A1-20120112-C00461
         		245-249 323 321 12.19 (s, 1H), 11.88 (s, 1H), 8.72 (s, 1H), 8.00 (s, 1H), 7.86 (d, J = 8.1 Hz, 2H), 7.63 (dd, J = 8.6, 1.9 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.5 Hz, 1H), 2.39 (s, 3H)
    437
    Figure US20120010075A1-20120112-C00462
         		188-196 327 325 12.28 (s, 1H), 11.75 (s, 1H), 8.73 (s, 1H), 8.03 (d, J = 1.3 Hz, 1H), 7.78 (dd, J = 18.8, 9.0 Hz, 2H), 7.68-7.57 (m, 2H), 7.49 (td, J = 8.7, 2.3 Hz, 1H), 7.12 (d, J = 8.5 Hz, 1H)
    438
    Figure US20120010075A1-20120112-C00463
         		229-231 327 325 12.26 (s, 1H), 11.80 (s, 1H), 8.72 (s, 1H), 8.10-7.96 (m, 3H), 7.64 (dd, J = 8.6, 2.0 Hz, 1H), 7.40 (t, J = 8.8 Hz, 2H), 7.12 (d, J = 8.6 Hz, 1H)
    439
    Figure US20120010075A1-20120112-C00464
         		187-197 343 341 12.30 (s, 1H), 11.73 (s, 1H), 8.73 (s, 1H), 8.06-7.94 (m, 2H), 7.91 (dd, J = 7.8, 1.2 Hz, 1H), 7.74-7.54 (m, 3H), 7.12 (d, J = 8.6 Hz, 1H)
    440
    Figure US20120010075A1-20120112-C00465
         		252-254 343 341 12.30 (s, 1H), 11.77 (s, 1H), 8.72 (s, 1H), 8.06-7.90 (m, 3H), 7.64 (d, J = 8.5 Hz, 3H), 7.12 (d, J = 8.6 Hz, 1H)
    441
    Figure US20120010075A1-20120112-C00466
         		218-220 354 352 12.51 (s, 1H), 11.74 (s, 1H), 8.80 (dd, J = 6.6, 4.8 Hz, 2H), 8.51-8.35 (m, 2H), 8.05 (d, J = 1.8 Hz, 1H), 7.87 (t, J = 8.0 Hz, 1H), 7.65 (dd, J = 8.7, 2.2 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H)
    442
    Figure US20120010075A1-20120112-C00467
         		259-265 354 352 12.47 (s, 1H), 11.71 (s, 1H), 8.76 (s, 1H), 8.44-8.36 (m, 2H), 8.23-8.15 (m, 2H), 8.05 (d, J = 2.0 Hz, 1H), 7.65 (dd, J = 8.7, 2.2 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H)
    443
    Figure US20120010075A1-20120112-C00468
         		277-281 325 323 12.15 (s, 1H), 11.78 (s, 2H), 8.75 (s, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.89 (dd, J = 7.8, 1.2 Hz, 1H), 7.65 (dd, J = 8.6, 2.1 Hz, 1H), 7.50-7.42 (m, 1H), 7.13 (d, J = 8.6 Hz, 1H), 7.03-6.94 (m, 2H)
    444
    Figure US20120010075A1-20120112-C00469
         		174-176 377 375 12.30 (s, 1H), 11.55 (s, 1H), 8.57 (s, 1H), 8.03 (d, J = 2.1 Hz, 1H), 7.91-7.47 (m, 5H), 7.12 (d, J = 8.6 Hz, 1H)
    445
    Figure US20120010075A1-20120112-C00470
         		264-271 339 337 12.12 (s, 1H), 11.89 (s, 1H), 11.78 (s, 1H), 8.75 (s, 1H), 8.00 (s, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.65 (dd, J = 8.6, 2.0 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 6.80 (d, J = 7.0 Hz, 2H), 2.31 (s, 3H)
    446
    Figure US20120010075A1-20120112-C00471
         		282-286 305 303 12.03 (s, 2H), 11.24 (s, 1H), 8.65 (s, 1H), 7.82 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 2.6 Hz, 1H), 7.33 (dd, J = 8.8, 2.6 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.80 (d, J = 7.3 Hz, 2H), 2.31 (d, J = 6.5 Hz, 3H)
    447
    Figure US20120010075A1-20120112-C00472
         		219-221 357 355 13.85 (s, 1H), 12.65 (s, 1H), 8.94 (s, 1H), 7.79 (dd, J = 9.2, 3.4 Hz, 2H), 7.72 (d, J = 8.3 Hz, 1H), 7.47 (dd, J = 8.8, 4.1 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H), 2.42 (s, 3H)
    448
    Figure US20120010075A1-20120112-C00473
         		216-218 357 355 13.86 (s, 1H), 12.62 (s, 1H), 8.93 (s, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 8.3 Hz, 1H), 7.37 (dd, J = 14.8, 8.2 Hz, 3H), 2.40 (s, 3H)
    449
    Figure US20120010075A1-20120112-C00474
         		227-229 361 359 13.79 (s, 1H), 12.69 (s, 1H), 8.92 (s, 1H), 8.11-8.00 (m, 2H), 7.72 (d, J = 8.3 Hz, 1H), 7.44 (dd, J = 12.2, 5.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H)
    450
    Figure US20120010075A1-20120112-C00475
         		231-233 361 359 13.73 (s, 1H), 12.73 (s, 1H), 8.93 (s, 1H), 7.87-7.60 (m, 4H), 7.53 (td, J = 8.3, 2.3 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H)
    451
    Figure US20120010075A1-20120112-C00476
         		242-245 377 375 13.73 (s, 1H), 12.74 (s, 1H), 8.92 (s, 1H), 8.02 (t, J = 1.7 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.78-7.67 (m, 2H), 7.63 (t, J = 7.9 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H)
    452
    Figure US20120010075A1-20120112-C00477
         		236-238 377 375 13.76 (s, 1H), 12.73 (s, 1H), 8.92 (s, 1H), 8.00 (d, J = 8.6 Hz, 2H), 7.72 (d, J = 8.3 Hz, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H)
    453
    Figure US20120010075A1-20120112-C00478
         		277-279 388 386 13.71 (s, 1H), 12.96 (s, 1H), 8.94 (s, 1H), 8.80 (t, J = 1.8 Hz, 1H), 8.49 (dd, J = 8.2, 1.5 Hz, 1H), 8.41 (d, J = 7.8 Hz, 1H), 7.89 (t, J = 8.0 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H)
    454
    Figure US20120010075A1-20120112-C00479
         		305-307 388 386 13.73 (s, 1H), 12.91 (s, 1H), 8.94 (s, 1H), 8.43 (d, J = 8.8 Hz, 2H), 8.22 (d, J = 8.9 Hz, 2H), 7.74 (d, J = 8.3 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H)
    455
    Figure US20120010075A1-20120112-C00480
         		278-280 358 356 13.82 (s, 1H), 12.57 (s, 1H), 11.28 (s, 1H), 8.98 (d, J = 1.3 Hz, 1H), 7.84 (dd, J = 7.9, 1.5 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.53-7.45 (m, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.01 (dd, J = 13.2, 7.7 Hz, 2H)
    456
    Figure US20120010075A1-20120112-C00481
         		203-205 358 356 13.55 (s, 1H), 12.83 (s, 1H), 8.77 (s, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.88-7.70 (m, 4H), 7.38 (d, J = 8.4 Hz, 1H)
    457
    Figure US20120010075A1-20120112-C00482
         		258-260 373 371 13.81 (s, 1H), 12.61 (s, 1H), 11.54 (s, 1H), 8.97 (s, 1H), 7.74 (dd, J = 18.2, 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 5.9 Hz, 2H), 2.31 (d, J = 7.9 Hz, 3H)
    458
    Figure US20120010075A1-20120112-C00483
         		218-221 333 331 13.31 (s, 1H), 11.41 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.67-7.62 (m, 1H), 7.35-7.28 (m, 1H), 6.94-6.87 (m, 2H), 2.49 (s, 3H)
    459
    Figure US20120010075A1-20120112-C00484
         		262-263 319 317 13.84 (s, 1H), 11.26 (s, 1H), 7.94 (d, J = 8.7 Hz, 2H), 7.65 (d, J = 8.5 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 7.00-6.92 (m, 2H), 3.85 (s, 3H), 2.48 (s, 3H)
    460
    Figure US20120010075A1-20120112-C00485
         		258-259 367 365 13.72 (s, 1H), 11.48 (s, 1H), 7.89 (d, J = 8.5 Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.5 Hz, 1H), 7.01-6.94 (m, 2H), 2.48 (s, 3H)
    461
    Figure US20120010075A1-20120112-C00486
         		244-245 357 355 13.69 (s, 1H), 11.63 (s, 1H), 8.13 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 8.5 Hz, 1H), 7.03-6.94 (m, 2H), 2.50 (s, 3H)
    462
    Figure US20120010075A1-20120112-C00487
         		187-188 367 13.61, 11.71, 11.04 (3s, 2H), 7.76-7.40 (m, 5H), 7.00, 6.76 (2d, J = 2.2 Hz, 1H), 6.97, 6.88 (2dd, J = 8.6. 2.2 Hz, 1H), 2.41, 2.37 (2s, 3H); Note: rotational isomers
    463
    Figure US20120010075A1-20120112-C00488
         		311-312 305 13.59 (s, 1H), 11.64 (s, 2H), 7.97 (dd, J = 7.9, 1.7 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.49-7.42 (m, 1H), 7.07-6.95 (m, 4H), 2.43 (s, 3H)
    464
    Figure US20120010075A1-20120112-C00489
         		140-141 315 313 13.55 (s, 1H), 11.17 (s, 1H), 7.94 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 7.5 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 7.8 Hz, 1H), 6.83 (t, J = 8.0 Hz, 1H), 3.85 (s, 3H), 3.79 (s, 3H), 2.47 (s, 3H)
    465
    Figure US20120010075A1-20120112-C00490
         		176-177 362 13.44 (s, 1H), 11.40 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 6.83 (t, J = 8.1 Hz, 1H), 3.79 (s, 3H), 2.48 (s, 3H)
    466
    Figure US20120010075A1-20120112-C00491
         		175-176 353 351 13.40 (s, 1H), 11.54 (s, 1H), 8.14 (d, J = 8.1 Hz, 2H), 7.93 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.1 Hz, 1H), 7.05 (d, J = 7.8 Hz, 1H), 6.84 (t, J = 8.1 Hz, 1H), 3.80 (s, 3H), 2.49 (s, 3H)
    467
    Figure US20120010075A1-20120112-C00492
         		245-247 363 361 13.32, 11.61, 11.55, 10.72 (4s, 2H), 7.76-7.40 (m, 4H), 7.72, 7.10 (2dd, J = 8.2, 1.2 Hz, 1H), 7.05, 6.92 (2d, J = 7.5 Hz, 1H), 6.84, 6.76 (2t, J = 8.1 Hz, 1H), 3.80, 3.66 (2s, 3H), 2.41, 2.37 (2s, 3H). Note: rotational isomers.
    468
    Figure US20120010075A1-20120112-C00493
         		255-257 301 299 13.29 (s, 1H), 11.75 (s, 1H), 11.58 (s, 1H), 7.99 (dd, J = 7.8, 1.4 Hz, 1H), 7.50-7.42 (m, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.02 (dd, J = 17.9, 7.7 Hz, 3H), 6.84 (t, J = 8.1 Hz, 1H), 3.80 (s, 3H), 2.43 (s, 3H)
    469
    Figure US20120010075A1-20120112-C00494
         		226-227 353 351 14.53 (s, 1H), 11.43 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 2.5 Hz, 1H), 7.63 (d, J = 2.5 Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H), 2.52 (s, 3H)
    470
    Figure US20120010075A1-20120112-C00495
         		237-238 389 14.37 (s, 1H), 11.80 (s, 1H), 8.15 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 2.4 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 2.54 (s, 3H)
    471
    Figure US20120010075A1-20120112-C00496
         		306-308 339 337
    472
    Figure US20120010075A1-20120112-C00497
         		251-252 352 13.59 (s, 1H), 11.45 (s, 1H), 8.12 (d, J = 8.1 Hz, 2H), 7.93 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.7 Hz, 1H), 6.49 (dt, J = 5.8, 2.5 Hz, 2H), 3.78 (s, 3H), 2.46 (s, 3H)
    473
    Figure US20120010075A1-20120112-C00498
         		276-278 301 299 13.49 (s, 1H), 11.75 (s, 1H), 11.49 (s, 1H), 7.97 (dd, J = 7.9, 1.7 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.48-7.41 (m, 1H), 7.06-6.96 (m, 2H), 6.53-6.45 (m, 2H), 3.78 (s, 3H), 2.40 (s, 3H)
    474
    Figure US20120010075A1-20120112-C00499
         		276-279 359 357 12.45 (s, 2H), 11.90 (s, 1H), 8.60 (s, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.68-7.62 (m, 2H), 7.08-7.02 (m, 2H)
    475
    Figure US20120010075A1-20120112-C00500
         		287-92  359 357
    476
    Figure US20120010075A1-20120112-C00501
         		205-206 363 363 13.50, 11.50, 11.05 (3s, 2H), 7.75-7.38 (m, 5H), 6.51- 6.22 (m, 2H), 3.78, 3.68 (2s, 3H), 2.37, 2.34 (2s, 3H); Note: rotational isomers
    477
    Figure US20120010075A1-20120112-C00502
         		310-312 369 367 14.32 (s, 1H), 11.99 (s, 1H), 11.54 (s, 1H), 7.96 (d, J = 8.9 Hz, 1H), 7.70 (d, J = 2.5 Hz, 1H), 7.63 (d, J = 2.5 Hz, 1H), 6.62 (dd, J = 8.9, 2.4 Hz, 1H), 6.55 (d, J = 2.4 Hz, 1H), 3.80 (s, 3H), 2.45 (s, 3H)
    478
    Figure US20120010075A1-20120112-C00503
         		327-331 367 14.28 (s, 1H), 11.76 (s, 1H), 11.39 (s, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.48 (d, J = 3.2 Hz, 1H), 7.10 (dd, J = 8.9, 3.2 Hz, 1H), 7.00 (d, J = 8.9 Hz, 1H), 3.76 (s, 3H), 2.45 (s, 3H)
    479
    Figure US20120010075A1-20120112-C00504
         		  245 352 14.55, 11.80, 11.69, 11.46, 9.82, 9.72 (6s, 3H), 7.64- 7.50 (m, 2H), 7.16 (t, J = 7.9 Hz, 1H), 6.77-6.71 (m, 2H), 2.40, 2.38 (2s, 3H), 2.22, 2.14 (2s, 3H); Note: rotational isomers
    480
    Figure US20120010075A1-20120112-C00505
         		264-246 387 14.34 (s, 1H), 13.31 (s, 1H), 11.83 (s, 1H), 8.34 (d, J = 8.3 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 2.5 Hz, 1H), 7.72-7.65 (m, 2H), 7.64-7.58 (m, 1H), 7.50 (d, J = 8.9 Hz, 1H), 2.59 (s, 3H)
    481
    Figure US20120010075A1-20120112-C00506
         		260-262 373 371 14.28 (s, 1H), 11.96 (s, 2H), 7.93-7.88 (m, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.70- 7.64 (m, 2H), 7.02 (t, J = 7.9 Hz, 1H), 2.52 (s, 3H)
    482
    Figure US20120010075A1-20120112-C00507
         		226-227 315 313 13.72 (s, 1H), 11.07 (s, 1H), 7.93 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 8.7 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.51-6.44 (m, 2H), 3.84 (s, 3H), 3.78 (s, 3H), 2.44 (s, 3H)
    483
    Figure US20120010075A1-20120112-C00508
         		239-241 363 361 13.70 (s, 1H), 11.30 (s, 1H), 7.88 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.8 Hz, 1H), 6.51-6.42 (m, 2H), 3.77 (s, 3H), 2.44 (s, 3H)
    484
    Figure US20120010075A1-20120112-C00509
         		258-259 369 367 14.46 (s, 1H), 11.58 (s, 2H), 7.69 (d, J = 2.5 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.53 (dd, J = 8.0, 1.2 Hz, 1H), 7.21 (d, J = 7.0 Hz, 1H), 6.95 (t, J = 8.0 Hz, 1H), 3.86 (s, 3H), 2.45 (s, 3H)
    485
    Figure US20120010075A1-20120112-C00510
         		217-219 339 337 12.48, 12.31, 12.12, 10.62, 9.85, 9.72 (6s, 3H), 8.37, 8.17 (2s, 1H), 7.64-7.46 (m, 2H), 7.16 (t, J = 7.9 Hz, 1H), 6.78-6.70 (m, 2H), 2.21, 2.14 (2s, 3H); Note: rotational isomers
    486
    Figure US20120010075A1-20120112-C00511
         		267-269 355 353 12.46 (s, 1H), 12.30 (s, 1H), 12.17 (s, 1H), 8.60 (s, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H), 7.64 (d, J = 2.5 Hz, 1H), 6.59 (dd, J = 8.9, 2.4 Hz, 1H), 6.53 (d, J = 2.4 Hz, 1H), 3.81 (s, 3H)
    487
    Figure US20120010075A1-20120112-C00512
         		250-252 355 353 12.41 (s, 1H), 12.29 (s, 1H), 11.13 (s, 1H), 8.63 (s, 1H), 7.69-7.61 (m, 2H), 7.41 (d, J = 3.1 Hz, 1H), 7.11 (dd, J = 9.0, 3.1 Hz, 1H), 6.95 (d, J = 9.0 Hz, 1H), 3.76 (s, 3H)
    488
    Figure US20120010075A1-20120112-C00513
         		276-278 375 373 13.74 (s, 1H), 12.79 (s, 1H), 12.41 (s, 1H), 8.70 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 8.9 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.75 (d, J = 2.5 Hz, 1H), 7.73-7.68 (m, 1H), 7.67 (d, J = 2.5 Hz, 1H), 7.63-7.58 (m, 1H), 7.49 (d, J = 8.9 Hz, 1H)
    489
    Figure US20120010075A1-20120112-C00514
         		314-317 375 373 14.26 (s, 1H), 12.18 (s, 1H), 11.66 (s, 1H), 7.95 (d, J = 9.0 Hz, 1H),7.71 (d, J = 2.5 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.10-7.04 (m, 2H), 2.45 (s, 3H)
    490
    Figure US20120010075A1-20120112-C00515
         		322-325 374 14.28 (s, 1H), 12.07-11.66 (m, 2H), 7.90 (d, J = 2.8 Hz, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.51 (dd, J = 8.8, 2.8 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 2.46 (s, 3H)
    491
    Figure US20120010075A1-20120112-C00516
         		320-323 353 14.31 (s, 1H), 11.69 (s, 2H), 7.89 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 6.88-6.79 (m, 2H), 2.45 (s, 3H), 2.31 (s, 3H)
    492
    Figure US20120010075A1-20120112-C00517
         		202-203 289 287 14.36 (s, 1H), 11.50 (s, 1H), 7.96 (d, J = 7.3 Hz, 2H), 7.68-7.61 (m, 2H), 7.56 (t, J = 6.7 Hz, 2H), 7.49 (d, J = 7.8 Hz, 1H), 6.92 (t, J = 8.0 Hz, 1H), 2.52 (s, 3H)
    493
    Figure US20120010075A1-20120112-C00518
         		193-198 303 301 14.37 (s, 1H), 11.59 (s, 1H), 7.63 (dd, J = 8.0, 1.3 Hz, 1H), 7.55-7.41 (m, 3H), 7.34 (dd, J = 7.5, 4.3 Hz, 2H), 6.92 (t, J = 8.0 Hz, 1H), 2.45 (s, 3H), 2.41 (s, 3H)
    494
    Figure US20120010075A1-20120112-C00519
         		164-178 303 301 14.36 (s, 1H), 11.45 (s, 1H), 7.76 (d, J = 9.6 Hz, 2H), 7.65 (dd, J = 8.1, 1.4 Hz, 1H), 7.48 (dt, J = 15.0, 3.6 Hz, 3H), 6.92 (t, J = 8.0 Hz, 1H), 2.52 (s, 3H), 2.42 (s, 3H)
    495
    Figure US20120010075A1-20120112-C00520
         		195-200 303 301 14.38 (s, 1H), 11.40 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.64 (dd, J = 8.1, 1.5 Hz, 1H), 7.49 (dd, J = 7.9, 1.3 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 6.92 (t, J = 8.0 Hz, 1H), 2.51 (s, 3H), 2.40 (s, 3H)
    496
    Figure US20120010075A1-20120112-C00521
         		189-193 323 321 14.19 (s, 1H), 11.81 (s, 1H), 7.68-7.53 (m, 4H), 7.52- 7.47 (m, 2H), 6.93 (t, J = 8.0 Hz, 1H), 2.44 (s, 3H)
    497
    Figure US20120010075A1-20120112-C00522
         		197-219 323 321 14.26 (s, 1H), 11.59 (s, 1H), 8.01 (s, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.75-7.55 (m, 3H), 7.50 (dd, J = 7.9, 1.1 Hz, 1H), 6.93 (t, J = 8.0 Hz, 1H), 2.53 (s, 3H)
    498
    Figure US20120010075A1-20120112-C00523
         		208-209 323 321 14.29 (s, 1H), 11.55 (s, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.65 (ddd, J = 4.9, 3.8, 1.7 Hz, 3H), 7.50 (dd, J = 7.9, 1.2 Hz, 1H), 6.93 (t, J = 8.0 Hz, 1H), 2.52 (s, 3H)
    499
    Figure US20120010075A1-20120112-C00524
         		203-204 319 317 14.40 (s, 1H), 11.33 (s, 1H), 7.96 (d, J = 8.7 Hz, 2H), 7.64 (dd, J = 8.0, 1.3 Hz, 1H), 7.48 (dd, J = 7.9, 1.2 Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H), 6.92 (t, J = 8.0 Hz, 1H), 3.85 (s, 3H), 2.51 (s, 3H)
    500
    Figure US20120010075A1-20120112-C00525
         		226-232 368 366 14.29 (s, 1H), 11.55 (s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.5 Hz, 2H), 7.65 (dd, J = 8.1, 1.4 Hz, 1H), 7.49 (dd, J = 7.9, 1.1 Hz, 1H), 6.92 (t, J = 8.0 Hz, 1H), 2.52 (s, 3H)
    501
    Figure US20120010075A1-20120112-C00526
         		250-256 357 355 14.26 (s, 1H), 11.70 (s, 1H), 8.15 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 8.3 Hz, 2H), 7.66 (dd, J = 8.1, 1.3 Hz, 1H), 7.51 (dd, J = 7.9, 1.1 Hz, 1H), 6.93 (t, J = 8.0 Hz, 1H), 2.53 (s, 3H)
    502
    Figure US20120010075A1-20120112-C00527
         		178-183 368 366 14.20 (s, 1H), 11.80 (s, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.66-7.59 (m, 2H), 7.53- 7.46 (m, 3H), 6.93 (t, J = 8.0 Hz, 1H), 2.44 (s, 3H)
    503
    Figure US20120010075A1-20120112-C00528
         		283-287 305 303 14.17 (s, 1H), 11.68 (s, 2H), 7.99 (dd, J = 7.9, 1.7 Hz, 1H), 7.67 (dd, J = 8.1, 1.4 Hz, 1H), 7.48 (ddd, J = 14.2, 7.4, 1.5 Hz, 2H), 7.09- 6.99 (m, 2H), 6.93 (t, J = 8.0 Hz, 1H), 2.46 (s, 3H)
    504
    Figure US20120010075A1-20120112-C00529
         		207-208 289 287 13.46 (s, 1H), 11.45 (s, 1H), 7.95 (d, J = 7.3 Hz, 2H), 7.64 (dd, J = 13.0, 4.9 Hz, 2H), 7.55 (t, J = 7.5 Hz, 2H), 7.34 (dd, J = 8.8, 2.5 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 2.50 (s, 3H)
    505
    Figure US20120010075A1-20120112-C00530
         		192-193 303 301 13.46 (s, 1H), 11.53 (s, 1H), 7.64 (d, J = 2.6 Hz, 1H), 7.52 (d, J = 7.5 Hz, 1H), 7.44 (td, J = 7.6, 1.2 Hz, 1H), 7.33 (dt, J = 7.3, 2.4 Hz, 3H), 6.95 (d, J = 8.8 Hz, 1H), 2.42 (s, 3H), 2.40 (s, 3H)
    506
    Figure US20120010075A1-20120112-C00531
         		222-228 303 301 13.47 (s, 1H), 11.40 (s, 1H), 7.75 (d, J = 10.4 Hz, 2H), 7.66 (d, J = 2.5 Hz, 1H), 7.44 (d, J = 5.9 Hz, 2H), 7.34 (dd, J = 8.7, 2.5 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 2.49 (s, 3H), 2.41 (s, 3H)
    507
    Figure US20120010075A1-20120112-C00532
         		221-228 303 13.48 (s, 1H), 11.35 (s, 1H), 7.86 (d, J = 7.9 Hz, 2H), 7.65 (d, J = 2.5 Hz, 1H), 7.34 (dd, J = 13.8, 5.2 Hz, 3H), 6.94 (d, J = 8.8 Hz, 1H), 2.49 (s, 3H), 2.40 (s, 3H)
    508
    Figure US20120010075A1-20120112-C00533
         		210-217 323 321 13.28 (s, 1H), 11.73 (s, 1H), 7.56 (dddd, J = 30.0, 21.9, 7.6, 1.5 Hz, 5H), 7.35 (dd, J = 8.8, 2.6 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 2.42 (s, 3H)
    509
    Figure US20120010075A1-20120112-C00534
         		244-249 323 321 13.37 (s, 1H), 11.53 (s, 1H), 8.01 (s, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.69 (dd, J = 16.9, 5.2 Hz, 2H), 7.59 (t, J = 7.9 Hz, 1H), 7.35 (dd, J = 8.8, 2.5 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 2.50 (s, 3H)
    510
    Figure US20120010075A1-20120112-C00535
         		248-252 323 321 13.40 (s, 1H), 11.50 (s, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.65 (dd, J = 11.0, 5.5 Hz, 3H), 7.35 (dd, J = 8.7, 2.5 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 2.49 (s, 3H)
    511
    Figure US20120010075A1-20120112-C00536
         		203-228 319 317 13.51 (s, 1H), 11.28 (s, 1H), 7.95 (d, J = 8.7 Hz, 2H), 7.65 (d, J = 2.6 Hz, 1H), 7.33 (dd, J = 8.8, 2.6 Hz, 1H), 7.09 (t, J = 5.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 1H), 3.85 (s, 3H), 2.49 (s, 3H)
    512
    Figure US20120010075A1-20120112-C00537
         		269-271 368 366 13.39 (s, 1H), 11.50 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 2.5 Hz, 1H), 7.35 (dd, J = 8.8, 2.5 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 2.49 (s, 3H)
    513
    Figure US20120010075A1-20120112-C00538
         		271-273 357 355 13.35 (s, 1H), 11.65 (s, 1H), 8.14 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 8.3 Hz, 2H), 7.67 (d, J = 2.5 Hz, 1H), 7.36 (dd, J = 8.8, 2.5 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 2.51 (s, 3H)
    514
    Figure US20120010075A1-20120112-C00539
         		222-225 368 366 13.29 (s, 1H), 11.73 (s, 1H), 7.75 (dd, J = 7.8, 1.1 Hz, 1H), 7.66-7.58 (m, 2H), 7.49 (ddd, J = 9.5, 7.5, 1.5 Hz, 2H), 7.35 (dd, J = 8.8, 2.6 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 2.42 (s, 3H)
    515
    Figure US20120010075A1-20120112-C00540
         		298-318 305 303 13.25 (s, 1H), 11.67 (d, J = 54.4 Hz, 2H), 7.98 (dd, J = 7.8, 1.6 Hz, 1H), 7.67 (d, J = 2.5 Hz, 1H), 7.50-7.42 (m, 1H), 7.34 (dd, J = 8.7, 2.5 Hz, 1H), 7.08-6.93 (m, 3H), 2.43 (s, 3H)
    516
    Figure US20120010075A1-20120112-C00541
         		202-252 364 362 13.56 (s, 1H), 11.28 (s, 1H), 7.95 (d, J = 8.7 Hz, 2H), 7.75 (d, J = 2.4 Hz, 1H), 7.44 (dd, J = 8.7, 2.4 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.7 Hz, 1H), 3.85 (s, 3H), 2.48 (s, 3H)
    517
    Figure US20120010075A1-20120112-C00542
         		270-275 413 411 13.44 (s, 1H), 11.50 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.81-7.72 (m, 4H), 6.90 (d, J = 8.7 Hz, 1H), 2.49 (s, 3H)
    518
    Figure US20120010075A1-20120112-C00543
         		272-280 402 400 13.38 (s, 1H), 11.65 (s, 1H), 8.14 (d, J = 8.1 Hz, 2H), 7.93 (d, J = 8.3 Hz, 2H), 7.78 (d, J = 2.4 Hz, 1H), 7.47 (dd, J = 8.7, 2.3 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 2.50 (s, 3H)
    519
    Figure US20120010075A1-20120112-C00544
         		216-218 413 411 13.31 (s, 1H), 11.73 (s, 1H), 7.75 (dd, J = 6.2, 1.7 Hz, 2H), 7.62-7.58 (m, 1H), 7.50-7.43 (m, 3H), 6.91 (d, J = 8.8 Hz, 1H), 2.41 (s, 3H)
    520
    Figure US20120010075A1-20120112-C00545
         		281-303 350 348 13.27 (s, 1H), 11.67 (d, J = 51.7 Hz, 2H), 7.98 (dd, J = 7.9, 1.6 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.50-7.43 (m, 2H), 7.07-6.98 (m, 2H), 6.91 (d, J = 8.7 Hz, 1H), 2.43 (s, 3H)
    521
    Figure US20120010075A1-20120112-C00546
         		204-212 330 328 15.32 (s, 1H), 11.48 (s, 1H), 8.01-7.90 (m, 4H), 7.13- 7.01 (m, 3H), 3.86 (s, 3H), 2.56 (s, 3H)
    522
    Figure US20120010075A1-20120112-C00547
         		244-252 379 15.16 (s, 1H), 11.70 (s, 1H), 8.02-7.87 (m, 4H), 7.79 (d, J = 8.5 Hz, 2H), 7.06 (t, J = 8.0 Hz, 1H), 2.56 (s, 3H)
    523
    Figure US20120010075A1-20120112-C00548
         		267-278 368 366 15.11 (s, 1H), 11.85 (s, 1H), 8.15 (d, J = 8.1 Hz, 2H), 8.00 (dd, J = 8.0, 1.4 Hz, 1H), 7.95 (d, J = 8.1 Hz, 3H), 7.08 (t, J = 8.0 Hz, 1H), 2.57 (s, 3H)
    524
    Figure US20120010075A1-20120112-C00549
         		186-188 379 377 15.06 (s, 1H), 11.97 (s, 1H), 7.95 (dd, J = 8.3, 1.2 Hz, 2H), 7.76 (dd, J = 7.8, 1.1 Hz, 1H), 7.62 (dd, J = 7.4, 1.8 Hz, 1H), 7.53 (ddd, J = 7.4, 6.8, 1.5 Hz, 2H), 7.07 (t, J = 8.0 Hz, 1H), 2.49 (s, 3H)
    525
    Figure US20120010075A1-20120112-C00550
         		274-283 314 15.02 (s, 1H), 11.73 (s, 1H), 11.69 (s, 1H), 8.05-7.89 (m, 3H), 7.51-7.43 (m, 1H), 7.11-6.98 (m, 3H), 2.50 (s, 3H)
    526
    Figure US20120010075A1-20120112-C00551
         		76.9-187  315 313 13.80 (s, 1H), 7.92 (d, J = 7.3 Hz, 1H), 7.64-7.42 (m, 2H), 6.15 (dd, J = 9.6, 7.4 Hz, 1H), 6.10 (dd, J = 12.6, 2.3 Hz, 2H), 3.86 (s, 3H), 3.81 (s, 3H), 3.77 (s, 1H), 3.74 (d, J = 1.3 Hz, 1H), 2.55 (s, 3H)
    527
    Figure US20120010075A1-20120112-C00552
         		226-229 323 321 14.07 (s, 1H), 11.53 (s, 1H), 8.02-7.87 (m, 3H), 7.69- 7.59 (m, 2H), 7.58-7.50 (m, 2H), 7.11 (d, J = 8.5 Hz, 1H), 2.56 (s, 3H)
    528
    Figure US20120010075A1-20120112-C00553
         		200-203 337 335 14.06 (s, 1H), 11.61 (s, 1H), 7.89 (s, 1H), 7.65 (dd, J = 8.6, 2.0 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.44 (t, J = 6.9 Hz, 1H), 7.37-7.28 (m, 2H), 7.11 (d, J = 8.6 Hz, 1H), 2.48 (s, 3H), 2.41 (s, 3H)
    529
    Figure US20120010075A1-20120112-C00554
         		235-238 337 335 14.08 (s, 1H), 11.48 (s, 1H), 7.92 (s, 1H), 7.80-7.72 (m, 2H), 7.65 (d, J = 7.0 Hz, 1H), 7.48-7.43 (m, 2H), 7.11 (d, J = 8.6 Hz, 1H), 2.56 (s, 3H), 2.41 (s, 3H)
    530
    Figure US20120010075A1-20120112-C00555
         		225-229 337 335 14.09 (s, 1H), 11.44 (s, 1H), 7.91 (s, 1H), 7.87 (d, J = 7.9 Hz, 2H), 7.64 (dd, J = 8.6, 1.8 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.6 Hz, 1H), 2.55 (s, 3H), 2.40 (s, 3H)
    531
    Figure US20120010075A1-20120112-C00556
         		189-191 357 355 13.86 (s, 1H), 11.82 (s, 1H), 7.90 (s, 1H), 7.69-7.45 (m, 5H), 7.12 (d, J = 8.6 Hz, 1H), 2.48 (s, 3H)
    532
    Figure US20120010075A1-20120112-C00557
         		241-245 357 355 13.96 (s, 1H), 11.61 (s, 1H), 8.02 (s, 1H), 7.94-7.89 (m, 2H), 7.71 (d, J = 8.8 Hz, 1H), 7.68-7.63 (m, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 2.57 (s, 3H)
    533
    Figure US20120010075A1-20120112-C00558
         		263-265 357 355 14.00 (s, 1H), 11.58 (s, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.92 (s, 1H), 7.68-7.61 (m, 3H), 7.11 (d, J = 8.7 Hz, 1H), 2.56 (s, 3H)
    534
    Figure US20120010075A1-20120112-C00559
         		228-231 353 351 14.12 (s, 1H), 11.36 (s, 1H), 7.96 (d, J = 8.7 Hz, 2H), 7.90 (s, 1H), 7.64 (dd, J = 8.7, 1.9 Hz, 1H), 7.12-7.06 (m, 3H), 3.85 (s, 3H), 2.55 (s, 3H)
    535
    Figure US20120010075A1-20120112-C00560
         		256-259 402 400 13.99 (s, 1H), 11.58 (s, 1H), 7.94-7.89 (m, 3H), 7.78 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 2.56 (s, 3H)
    536
    Figure US20120010075A1-20120112-C00561
         		228-234 391 389 13.95 (s, 1H), 11.73 (s, 1H), 8.15 (d, J = 8.1 Hz, 2H), 7.97-7.91 (m, 3H), 7.69-7.64 (m, 1H), 7.12 (d, J = 8.6 Hz, 1H), 2.57 (s, 3H)
    537
    Figure US20120010075A1-20120112-C00562
         		192-200 402 400 13.87, 11.81, 11.70, 11.28 (4s, 2H), 7.91-7.39 (m, 6H), 7.21, 6.87 (2d, J = 8.6 Hz, 1H), 2.48, 2.42 (2s, 3H); Note: rotational isomers
    538
    Figure US20120010075A1-20120112-C00563
         		277-297 361 (+Na) 13.84 (s, 1H), 11.71 (s, 2H), 7.98 (dd, J = 7.9, 1.6 Hz, 1H), 7.93 (s, 1H), 7.68-7.63 (m, 1H), 7.50-7.43 (m, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.08-6.98 (m, 2H), 2.49 (s, 3H)
    539
    Figure US20120010075A1-20120112-C00564
         		242-245 414
    540
    Figure US20120010075A1-20120112-C00565
         		221-222 425 14.64 (s, 1H), 11.71 (s, 1H), 7.84 (d, J = 2.2 Hz, 1H), 7.79 (d, J = 2.3 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.49-7.41 (m, 1H), 7.37- 7.29 (m, 2H), 2.44 (s, 3H), 2.40 (s, 3H)
    541
    Figure US20120010075A1-20120112-C00566
         		236-238 427 425 14.62 (s, 1H), 11.55 (s, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.78-7.72 (m, 2H), 7.48-7.41 (m, 2H), 2.52 (s, 3H), 2.41 (s, 3H)
    542
    Figure US20120010075A1-20120112-C00567
         		258-259 425 14.64 (s, 1H), 11.50 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 2.3 Hz, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 2.51 (s, 3H), 2.40 (s, 3H)
    543
    Figure US20120010075A1-20120112-C00568
         		207-209 447 445 14.46 (s, 1H), 11.92 (s, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.80 (d, J = 2.3 Hz, 1H), 7.66-7.53 (m, 3H), 7.51-7.46 (m, 1H), 2.44 (s, 3H)
    544
    Figure US20120010075A1-20120112-C00569
         		255-256 447 14.52 (s, 1H), 11.69 (s, 1H), 8.02 (s, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.74-7.70 (m, 1H), 7.60 (t, J = 7.9 Hz, 1H), 2.53 (s, 3H)
    545
    Figure US20120010075A1-20120112-C00570
         		255-258 445 14.55 (s, 1H), 11.65 (s, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.85 (d, J = 2.2 Hz, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.67-7.61 (m, 2H), 2.52 (s, 3H)
    546
    Figure US20120010075A1-20120112-C00571
         		247-248 441 14.66 (s, 1H), 11.43 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 2.3 Hz, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.12-7.06 (m, 2H), 3.85 (s, 3H), 2.51 (s, 3H)
    547
    Figure US20120010075A1-20120112-C00572
         		264-266 493 491 14.55 (s, 1H), 11.65 (s, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.85 (d, J = 2.2 Hz, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.80-7.76 (m, 2H), 2.52 (s, 3H)
    548
    Figure US20120010075A1-20120112-C00573
         		255-257 481 14.51 (s, 1H), 11.80 (s, 1H), 8.15 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 8.3 Hz, 2H), 7.86 (d, J = 2.2 Hz, 1H), 7.83 (d, J = 2.3 Hz, 1H), 2.53 (s, 3H)
    549
    Figure US20120010075A1-20120112-C00574
         		214-216 491 489 14.46 (s, 1H), 11.91 (s, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.80 (d, J = 2.3 Hz, 1H), 7.76 (dd, J = 7.8, 1.2 Hz, 1H), 7.61 (dd, J = 7.4, 1.8 Hz, 1H), 7.53 (td, J = 7.4, 1.3 Hz, 1H), 7.47 (td, J = 7.6, 1.9 Hz, 1H), 2.44 (s, 3H)
    550
    Figure US20120010075A1-20120112-C00575
         		305-306 427 14.43 (s, 1H), 11.71 (s, 2H), 7.97 (dd, J = 7.9, 1.7 Hz, 1H), 7.86-7.82 (m, 2H), 7.50- 7.43 (m, 1H), 7.08-6.98 (m, 2H), 2.45 (s, 3H)
    551
    Figure US20120010075A1-20120112-C00576
         		154-155 315 313 13.71 (s, 1H), 11.27 (s, 1H), 7.93 (d, J = 7.2 Hz, 2H), 7.65-7.59 (m, 1H), 7.58- 7.51 (m, 2H), 7.38 (d, J = 9.0 Hz, 1H), 6.60 (d, J = 9.0 Hz, 1H), 3.82 (s, 3H), 3.71 (s, 3H), 2.45 (s, 3H)
    552
    Figure US20120010075A1-20120112-C00577
         		150-152 329 327 13.71 (s, 1H), 11.34 (s, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.46-7.39 (m, 1H), 7.32 (dt, J = 11.7, 8.4 Hz, 3H), 6.60 (d, J = 9.0 Hz, 1H), 3.82 (s, 3H), 3.71 (s, 3H), 2.40 (s, 3H), 2.38 (s, 3H)
    553
    Figure US20120010075A1-20120112-C00578
         		158-162 329 327 13.70 (s, 1H), 11.22 (s, 1H), 7.77-7.68 (m, 2H), 7.46- 7.41 (m, 2H), 7.37 (d, J = 9.0 Hz, 1H), 6.61 (d, J = 9.1 Hz, 1H), 3.82 (s, 3H), 3.71 (s, 3H), 2.45 (s, 3H), 2.41 (s, 3H)
    554
    Figure US20120010075A1-20120112-C00579
         		245-249 329 327 13.71 (s, 1H), 11.18 (s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.41-7.31 (m, 3H), 6.60 (d, J = 9.1 Hz, 1H), 3.82 (s, 3H), 3.71 (s, 3H), 2.44 (s, 3H), 2.40 (s, 3H)
    555
    Figure US20120010075A1-20120112-C00580
         		77-86 349 347 13.54, 11.55, 10.92 (3s, 2H), 7.63-7.44 (m, 4H), 7.36, 7.25 (2d, J = 9.1 Hz, 1H), 6.61, 6.53 (2d, J = 9.1 Hz, 1H), 3.82, 3.75, 3.71, 3.50 (4s, 6H), 2.38, 2.35 (2s, 3H); Note: rotational isomers
    556
    Figure US20120010075A1-20120112-C00581
         		194-201 349 347 13.60 (s, 1H), 11.37 (s, 1H), 8.00-7.97 (m, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.72- 7.67 (m, 1H), 7.58 (t, J = 7.9 Hz, 1H), 7.39 (d, J = 9.0 Hz, 1H), 6.61 (d, J = 9.1 Hz, 1H), 3.83 (s, 3H), 3.71 (s, 3H), 2.46 (s, 3H)
    557
    Figure US20120010075A1-20120112-C00582
         		230-235 349 347 13.63 (s, 1H), 11.33 (s, 1H), 7.96 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 9.0 Hz, 1H), 6.61 (d, J = 9.1 Hz, 1H), 3.82 (s, 3H), 3.71 (s, 3H), 2.45 (s, 3H)
    558
    Figure US20120010075A1-20120112-C00583
         		230-232 345 343 13.73 (s, 1H), 11.11 (s, 1H), 7.93 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 9.0 Hz, 1H), 7.08 (d, J = 8.9 Hz, 2H), 6.60 (d, J = 9.1 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.71 (s, 3H), 2.44 (s, 3H)
    559
    Figure US20120010075A1-20120112-C00584
         		241-245 393 391 13.62 (s, 1H), 11.33 (s, 1H), 7.89 (d, J = 8.5 Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 9.0 Hz, 1H), 6.61 (d, J = 9.1 Hz, 1H), 3.82 (s, 3H), 3.71 (s, 3H), 2.45 (s, 3H)
    560
    Figure US20120010075A1-20120112-C00585
         		229-233 383 381 13.60 (s, 1H), 11.48 (s, 1H), 8.12 (d, J = 8.1 Hz, 2H), 7.93 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 9.0 Hz, 1H), 6.62 (d, J = 9.1 Hz, 1H), 3.83 (s, 3H), 3.71 (s, 3H), 2.46 (s, 3H)
    561
    Figure US20120010075A1-20120112-C00586
         		195-200 393 391 13.54, 11.55, 10.90 (3s, 2H), 7.76-7.42 (m, 4H), 7.36, 7.25 (2d, J = 9.1 Hz, 1H), 6.61, 6.53 (2d, J = 9.1 Hz, 1H), 3.82, 3.75, 3.71, 3.50 (4s, 6H), 2.38, 2.34 (2s, 3H); Note: rotational isomers
    562
    Figure US20120010075A1-20120112-C00587
         		279-297 331 329 13.51 (s, 1H), 11.74 (s, 1H), 11.51 (s, 1H), 7.98 (dd, J = 7.9, 1.5 Hz, 1H), 7.49-7.42 (m, 1H), 7.40 (d, J = 9.0 Hz, 1H), 7.07-6.97 (m, 2H), 6.62 (d, J = 9.0 Hz, 1H), 3.83 (s, 3H), 3.71 (s, 3H), 2.40 (s, 3H)
    563
    Figure US20120010075A1-20120112-C00588
         		287-292 375 373 (300 MHz, DMSO-d6) 12.48 (s, 1H), 11.17 (s, 1H), 8.63 (s, 1H), 8.44 (s, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.71-7.64 (m, 2H), 7.58-7.49 (m, 1H), 7.42-7.32 (m, 2H)
    564
    Figure US20120010075A1-20120112-C00589
         		312-315 387 14.42 (s, 1H), 12.04-11.57 (m, 2H), 8.60 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 2.5 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H), 7.56-7.51 (m, 1H), 7.41-7.35 (m, 2H), 2.50 (s, 3H)
    565
    Figure US20120010075A1-20120112-C00590
         		278-279 351 14.33 (s, 1H), 11.75 (s, 2H), 7.86 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 2.5 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 6.92 (t, J = 7.7 Hz, 1H), 2.54 (s, 3H), 2.23 (s, 3H)
    566
    Figure US20120010075A1-20120112-C00591
         		177-184 329 327 12.89 (s, 1H), 11.04 (s, 1H), 7.83 (d, J = 7.9 Hz, 2H), 7.34 (d, J = 7.9 Hz, 2H), 6.12 (d, J = 5.0 Hz, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 2.39 (s, 3H), 2.37 (s, 3H)
    567
    Figure US20120010075A1-20120112-C00592
         		206-215 349 347 10.05 (s, 1H), 9.70 (s, 1H), 7.59 (dd, J = 8.9, 2.1 Hz, 2H), 7.47 (d, J = 5.7 Hz, 2H), 6.17 (d, J = 2.0 Hz, 1H), 6.14 (d, J = 2.1 Hz, 1H), 3.74 (s, 6H), 2.15 (s, 2H)
    568
    Figure US20120010075A1-20120112-C00593
         		136-140 349 347 12.80 (s, 1H), 11.19 (s, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.3 Hz, 2H), 6.14-6.09 (m, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 2.38 (s, 3H)
    569
    Figure US20120010075A1-20120112-C00594
         		143-146 345 343 12.91 (s, 1H), 10.98 (s, 1H), 7.92 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 6.12 (dd, J = 7.6, 2.3 Hz, 2H), 3.84 (s, 3H), 3.80 (s, 3H), 3.76 (s, 3H), 2.37 (s, 3H)
    570
    Figure US20120010075A1-20120112-C00595
         		134-159 394 392 12.78 (s, 1H), 11.19 (s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 6.12 (dd, J = 7.8, 2.2 Hz, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 2.37 (s, 3H)
    571
    Figure US20120010075A1-20120112-C00596
         		131-133 383 381 12.70 (s, 1H), 11.33 (s, 1H), 8.11 (d, J = 8.1 Hz, 2H), 7.92 (d, J = 8.3 Hz, 2H), 6.13 (dd, J = 7.1, 2.3 Hz, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 2.38 (s, 3H)
    572
    Figure US20120010075A1-20120112-C00597
         		222-225 291 289 13.55 (s, 1H), 11.54 (s, 1H), 7.95 (d, J = 7.4 Hz, 2H), 7.65 (t, J = 7.3 Hz, 1H), 7.56 (t, J = 7.5 Hz, 2H), 7.43- 7.34 (m, 2H), 2.50 (s, 3H)
    573
    Figure US20120010075A1-20120112-C00598
         		186-188 305 303 13.56 (s, 1H), 11.63 (s, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.40-7.29 (m, 4H), 2.42 (s, 3H), 2.40 (s, 3H)
    574
    Figure US20120010075A1-20120112-C00599
         		215-216 305 303 13.56 (s, 1H), 11.49 (s, 1H), 7.75 (d, J = 11.6 Hz, 2H), 7.45 (d, J = 6.2 Hz, 2H), 7.39 (td, J = 8.9, 2.8 Hz, 2H), 2.49 (s, 3H), 2.41 (s, 3H)
    575
    Figure US20120010075A1-20120112-C00600
         		220-22  305 303 13.57 (s, 1H), 11.44 (s, 1H), 7.87 (d, J = 7.9 Hz, 2H), 7.38 (dd, J = 13.4, 6.6 Hz, 4H), 2.49 (s, 3H), 2.40 (s, 3H)
    576
    Figure US20120010075A1-20120112-C00601
         		205-209 325 323 13.38 (s, 1H), 11.83 (s, 1H), 7.60 (dddd, J = 15.2, 9.7, 7.7, 1.6 Hz, 3H), 7.48 (td, J = 7.3, 1.4 Hz, 1H), 7.44- 7.34 (m, 2H), 2.42 (s, 3H)
    577
    Figure US20120010075A1-20120112-C00602
         		279-282 325 323 13.45 (s, 1H), 11.62 (s, 1H), 8.02 (s, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.41 (dd, J = 9.5, 7.1 Hz, 2H), 2.50 (s, 3H)
    578
    Figure US20120010075A1-20120112-C00603
         		276-280 325 323 13.48 (s, 1H), 11.59 (s, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H), 7.43-7.36 (m, 2H), 2.50 (s, 3H)
    579
    Figure US20120010075A1-20120112-C00604
         		243-247 321 319 13.59 (s, 1H), 11.36 (s, 1H), 7.96 (d, J = 8.7 Hz, 2H), 7.37 (dd, J = 9.4, 3.2 Hz, 2H), 7.09 (d, J = 8.9 Hz, 2H), 3.85 (s, 3H), 2.49 (s, 3H)
    580
    Figure US20120010075A1-20120112-C00605
         		268-270 370 368 13.48 (s, 1H), 11.59 (s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.5 Hz, 2H), 7.44-7.36 (m, 2H), 2.49 (s, 3H)
    581
    Figure US20120010075A1-20120112-C00606
         		287-291 359 357 13.44 (s, 1H), 11.73 (s, 1H), 8.14 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 8.3 Hz, 2H), 7.41 (dd, J = 9.5, 7.5 Hz, 2H), 2.51 (s, 3H)
    582
    Figure US20120010075A1-20120112-C00607
         		190-195 370 368 13.38 (s, 1H), 11.84 (s, 1H), 7.75 (dd, J = 7.8, 1.0 Hz, 1H), 7.62 (d, J = 1.8 Hz, 1H), 7.60 (d, J = 1.8 Hz, 1H), 7.55-7.48 (m, 2H), 7.37 (dd, J = 8.4, 2.2 Hz, 1H), 2.42 (s, 3H)
    583
    Figure US20120010075A1-20120112-C00608
         		308-323 307 305 13.37 (s, 1H), 11.70 (s, 2H), 7.98 (dd, J = 7.9, 1.7 Hz, 1H), 7.44 (ddd, J = 28.3, 14.3, 6.0 Hz, 3H), 7.07-6.98 (m, 2H), 2.43 (s, 3H)
    584
    Figure US20120010075A1-20120112-C00609
         		269-274 329 327 9.96 (s, 1H), 9.24 (s, 1H), 7.35- 7.27 (m, 2H), 7.19 (t, J = 3.6 Hz, 2H), 6.08 (d, J = 10.7 Hz, 2H), 3.72 (s, 3H), 3.69 (s, 3H), 2.26 (s, 3H), 2.12 (s, 3H)
    585
    Figure US20120010075A1-20120112-C00610
         		207-209 329 327 12.87 (s, 1H), 11.09 (s, 1H), 7.72 (d, J = 9.4 Hz, 2H), 7.42 (d, J = 4.6 Hz, 2H), 6.12 (dd, J = 7.8, 2.1 Hz, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 2.40 (s, 3H), 2.38 (s, 3H)
    586
    Figure US20120010075A1-20120112-C00611
         		182-199 331 329 13.80 (s, 1H), 12.50 (s, 1H), 11.54 (s, 1H), 7.96 (dd, J = 7.8, 1.5 Hz, 1H), 7.47- 7.35 (m, 1H), 7.08-6.91 (m, 2H), 6.14 (d, J = 2.3 Hz, 1H), 6.08 (d, J = 2.4 Hz, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 2.35 (s, 3H)
    587
    Figure US20120010075A1-20120112-C00612
         		195-96  377 375 11.38 (s, 1H), 10.47 (s, 1H), 7.71 (dd, J = 15.3, 4.9 Hz, 3H), 7.58 (d, J = 7.4 Hz, 1H), 7.49 (t, J = 7.5 Hz, 2H), 7.35 (d, J = 2.3 Hz, 1H)
    588
    Figure US20120010075A1-20120112-C00613
         		gum 351 349 12.49 (s, 1H), 9.88 (s, 1H), 7.96 (d, J = 2.2 Hz, 1H), 7.86 (d, J = 2.2 Hz, 1H), 7.62-7.31 (m, 4H), 7.13 (s, 1H), 3.78-3.65 (m, 1H), 1.07 (d, J = 9.5 Hz, 6H)
    589
    Figure US20120010075A1-20120112-C00614
         		218-219 349 347 13.96 (s, 1H), 11.71 (s, 1H), 7.95 (d, J = 7.1 Hz, 2H), 7.88 (s, 1H), 7.62 (dt, J = 23.1, 7.2 Hz, 4H), 2.08-1.91 (m, 1H), 1.28 (d, J = 7.4 Hz, 2H), 0.79 (d, J = 4.4 Hz, 2H)
    590
    Figure US20120010075A1-20120112-C00615
         		214-215 337 335 14.55 (s, 1H), 11.67 (s, 1H), 7.91 (d, J = 7.4 Hz, 2H), 7.75-7.61 (m, 3H), 7.57 (t, J = 7.5 Hz, 2H), 3.06 (q, J = 7.4 Hz, 2H), 1.14 (t, J = 7.5 Hz, 3H)
    591
    Figure US20120010075A1-20120112-C00616
         		208-210 309 307 10.75 (s, 1H), 10.47 (s, 1H), 7.73-7.63 (m, 2H), 7.62- 7.53 (m, 1H), 7.47 (dd, J = 10.4, 4.6 Hz, 2H), 7.43- 7.35 (m, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 6.96 (td, J = 7.6, 0.9 Hz, 1H)
    592
    Figure US20120010075A1-20120112-C00617
         		241-243 297 295 9.90 (s, 1H), 8.78 (s, 1H), 7.57-7.24 (m, 6H), 7.11- 6.87 (m, 3H), 1.18 (s, 9H)
  • As exemplified below, hydrazones of the present invention, or their metal complexes, in a mixture with inorganic or organic mono- or divalent copper salts or chelates (hereinafter referred to as “copper products”) increase the biological potency of copper products, enabling comparable or improved efficacy at lower copper use rates. While not intending to be all-inclusive, copper products which may be mixed with the compounds of the present invention to provide enhanced potency may include the following: copper oxychloride, copper octanoate, copper ammonium carbonate, copper arsenate, copper oxysulfate, copper formate, copper propionate, copper oxyacetate, copper citrate, copper chloride, copper diammonium chloride, copper nitrate, copper carbonate, copper phosphate, copper pyrophosphate, copper disodium EDTA, copper diammonium EDTA, copper oxalate, copper tartrate, copper gluconate, copper glycinate, copper glutamate, copper aspartate, copper adipate, copper palmitate, copper stearate, copper caprylate, copper decanoate, copper undecylenate, copper neodecanoate, copper linoleate, copper oleate, copper borate, copper methanesulfonate, copper sulfamate, copper acetate, copper hydroxide, copper oxide, copper oxychloride-sulfate, copper sulfate, basic copper sulfate, copper-oxine, copper 3-phenylsalicylate, copper chloride hydroxide, copper dimethyldithiocarbamate, ammonium copper sulfate, copper magnesium sulfate, coppernaphthenate, copper ethanolamine, chromated copper arsenate, ammoniacal copper arsenate, ammoniacal copper zinc arsenate, ammoniacal copper borate, Bordeaux mixture, copper zinc chromate, cufraneb, cupric hydrazinium sulfate, cuprobam, nano-copper materials and copper didecyldimethylammonium chloride and where appropriate the hydrates of such compounds.
  • Salicylaldehyde benzoylhydrazones such as those of the current invention are known in the literature as chelators of metal cations (Inorganica Chimica Acta 1982, 67, L25-L27, which is expressly incorporated by reference herein), including copper. Antimicrobial activity has been reported for o-hydroxybenzaldehyde-N-salicyloylhydrazone and its copper, nickel and cobalt complexes towards Staphylococcus aureus, Escherichia coli, Aspergillus niger and A. flavus (Proceedings of the National Academy of Sciences, India 1991, Section A Part IV, Vol. LXI, pp. 447-452, which is expressly incorporated by reference herein). However, data in this report showed that the copper complex of o-hydroxybenzaldehyde-N-salicyloylhydrazone had a similar level of antimicrobial activity to that of o-hydroxybenzaldehyde-N-salicyloylhydrazone alone and the nickel and cobalt complexes, and provided no indication that salicylaldehyde benzoylhydrazones might show any synergistic antimicrobial effect in combination with copper.
    • Example 26 Effect of Copper on Fungitoxicity of Hydrazones Towards Leptosphaeria nodorum
  • In vitro fungitoxicity assays against Leptosphaeria nodorum (LEPTNO) were conducted using the liquid growth medium described by Coursen and Sisler (American Journal of Botany 1960, 47, 541-549) except that copper micronutrient, normally included as CuSO4, was omitted. The medium, termed “copper-minus”, was prepared by dissolving 10 g glucose, 1.5 g K2HPO4, 2 g KH2PO4 and 1 g (NH4)2SO4 in 1 liter of deionized water and treating the solution with 0.5 g Chelex 100 resin (Bio-Rad Analytical grade, 50-100 mesh, sodium form, cat# 142-2822) by stiffing at room temperature for 1 h. MgSO4.7H2O (0.5 g) was added, and stiffing continued for a further hour. Trace elements (minus CuSO4), and vitamins described by Coursen and Sisler were added from concentrated stock solutions and the entire medium was sterilized by filtration. Medium containing copper was prepared by adding CuCl2.2H2O to the copper-minus medium at 20 μM. Test compounds were dissolved in dimethylsulfoxide (DMSO) then dilutions in copper-minus and copper-plus growth media were prepared as 100 μL aliquots in flat-bottomed 96-well microtiter plates.
  • LEPTNO was grown on potato dextrose agar in 9 cm diameter petri dishes for 7 days. Sterile deionized water (20 mL) was added to a culture plate and spores suspended by scraping the surface gently with a sterile plastic loop. The resulting suspension was filtered through a double layer of sterile cheesecloth. Filtered spore suspension (5 mL) was centrifuged in a bench centrifuge at 2000 rpm for 2 min. The resulting spore pellet was resuspended in 10 mL sterile deionized water (which had been treated with Chelex 100 resin using 0.5 g resin per liter of water by stirring at room temperature for 1 h), and recentrifuged. The spores were resuspended in copper-minus medium, and the suspension adjusted to 2×105 spores per mL. Microtiter plates were inoculated with 100 μL of this spore suspension and the plates incubated at 25° C. for 72 h before assessing fungal growth by measuring light scattering in a NepheloStar plate reader. Growth inhibition was determined by comparing growth in the presence of test compound with growth in control wells lacking test compound.
  • Results for growth inhibition by test compounds in copper-plus medium (“% Inhn. Plus Copper Observed”) were compared with predicted values (“% Inhn. Plus Copper Predicted”) that were calculated using the formula set forth by S. R. Colby in Weeds 1967, 15, 20-22 based on results obtained for the same compounds in copper-minus medium (“% Inhn. Minus Copper Observed”) and the inhibition attributed to copper chloride alone, as determined by comparing growth in copper-minus and copper-plus media without any test compound across experiments. Data are presented in Table 3. Results illustrate that hydrazones and copper produce a synergistic fungitoxic effect towards LEPTNO.
    • Example 27 Efficacy of Hydrazones in Mixture with Copper Against Tomato Blight (Phytophthora infestans)
  • Hydrazone compounds at 50 ppm in combination with 50 μM CuCl2.2H2O were evaluated as prophylactic treatments applied 24 h before inoculation. Efficacy was determined based on percentage of disease control against tomato late blight (TLB), causal agent Phytophthora infestans. Treatments were arranged in a completely randomized design with 3 repetitions each. A pot with one tomato plant was considered as an experimental unit. Hydrazones were dissolved in acetone and re-suspended in water containing 0.01% Triton® X-100, 0.1% Atlox 4913 and 50 μM CuCl2.2H2O to a final concentration of 10% acetone. All treatments were applied to run off 24 h before inoculation using a spin-table sprayer. Inoculation with an aqueous suspension of P. infestans sporangia was performed using a Delta painting sprayer. Percentage of disease control was determined 7 days after inoculation. Data are presented in Table 2, and illustrate the efficacy of hydrazones in mixture with copper for control of tomato late blight.
  • TABLE 2
    LEPTNO LEPTNO LEPTNO
    % Inhn. % Inhn. % Inhn.
    Minus Plus Plus
    Compound Concn. Copper Copper Copper TLB %
    Number (μg/mL) Observed Observed Predicted Control
    1 0.05 0.7 96.2 7.8 64.0
    2 0.05 0.0 95.1 7.1 61.4
    3 0.05 2.3 93.0 9.3 47.0
    4 0.05 4.4 94.5 11.2 67.8
    5 0.05 4.8 56.1 11.6 22.0
    6 0.05 3.9 96.4 10.7 88.1
    7 0.05 2.6 97.2 9.5 54.6
    8 0.05 0.0 92.6 7.1 59.6
    9 0.05 0.0 93.6 7.1 67.3
    10 0.05 6.9 97.2 13.5 96.0
    11 0.05 0.3 97.2 7.4 42.1
    12 0.05 0.5 97.4 7.6 94.0
    13 0.05 0.0 96.2 7.1 33.3
    14 0.156 2.9 59.1 9.8 7.5
    15 0.05 4.4 96.6 11.1 58.5
    16 0.05 0.0 97.1 7.1 94.0
    17 0.05 9.4 95.9 15.9 69.0
    18 0.05 0.0 96.9 7.1 38.6
    19 0.05 2.9 88.8 9.8 25.0
    20 0.05 2.8 96.5 9.7 96.5
    21 0.05 0.1 94.1 7.2 65.5
    22 0.05 16.0 97.6 22.0 93.2
    23 0.05 2.3 95.4 9.2 53.3
    24 0.05 7.6 92.8 14.1 8.9
    25 0.05 0.0 97.3 7.1 35.1
    26 0.05 2.1 98.4 9.1 12.3
    27 0.05 16.5 97.9 22.4 43.3
    28 0.05 7.0 96.8 13.6 62.7
    29 0.05 0.0 98.0 7.1 50.8
    30 0.05 0.0 97.0 7.1 40.7
    31 0.05 2.2 89.0 9.2 33.3
    32 0.05 0.0 94.4 7.1 74.6
    33 0.05 0.0 93.1 7.1 50.9
    34 0.05 0.0 97.8 7.1 68.4
    35 0.05 3.8 96.5 10.6 0.0
    36 0.05 5.9 98.4 12.6 33.9
    37 0.05 3.3 97.0 10.2 33.0
    38 0.05 2.4 98.3 9.4 17.0
    39 0.05 1.3 97.9 8.3 18.6
    40 0.05 0.0 94.8 7.1 64.9
    41 0.05 0.0 97.2 7.1 87.0
    42 0.05 9.2 93.2 15.6 60.0
    43 0.156 14.2 75.4 20.3 68.8
    44 0.05 0.3 93.0 7.3 0.7
    45 0.05 0.0 96.2 7.1 49.0
    46 0.05 20.5 95.9 26.1 72.7
    47 0.05 0.0 97.1 7.1 33.0
    48 0.05 0.3 94.6 7.4 40.0
    49 0.05 14.6 97.1 20.7 0.7
    50 0.05 3.5 97.4 10.4 43.5
    51 0.05 0.0 97.6 7.1 4.8
    52 0.2 12.3 96.4 18.5 NT
    53 0.05 0.0 96.8 7.1 62.0
    54 0.05 0.0 95.7 7.1 17.0
    55 0.05 0.0 95.5 7.1 43.9
    56 0.05 2.1 96.3 9.1 81.3
    57 0.05 0.0 97.3 7.1 89.5
    58 0.05 0.0 95.0 7.1 49.0
    59 0.05 12.8 97.5 19.0 79.7
    60 0.05 7.3 97.5 13.9 85.0
    61 0.05 3.8 93.6 10.6 60.0
    62 0.05 0.0 96.3 7.1 56.1
    63 0.05 0.0 96.7 7.1 40.4
    64 0.05 0.0 97.8 7.1 43.0
    65 0.05 0.0 98.3 7.1 10.0
    66 0.05 0.1 97.4 7.2 51.0
    67 0.05 2.6 91.8 9.5 75.0
    68 0.05 15.8 97.0 21.8 75.9
    69 0.05 19.3 96.9 25.1 90.8
    70 0.05 19.6 98.2 25.3 93.1
    71 0.05 2.6 91.2 9.5 78.0
    72 0.05 14.1 91.3 20.2 81.3
    73 0.05 8.6 98.0 15.1 87.3
    74 0.05 3.0 95.7 9.8 63.6
    75 0.05 0.0 98.4 7.1 15.8
    76 0.05 0.0 97.0 7.1 89.8
    77 0.05 7.6 96.1 14.1 55.5
    78 0.05 7.9 96.3 14.4 70.9
    79 0.05 12.2 97.1 18.4 84.4
    80 0.05 0.0 98.4 7.1 91.5
    81 0.05 2.4 96.1 9.3 97.0
    82 0.05 8.4 97.4 14.9 60.6
    83 0.05 5.9 98.0 12.5 60.6
    84 0.05 5.6 95.5 12.3 83.6
    85 0.05 5.3 90.0 12.0 51.5
    86 0.05 0.3 97.6 7.4 80.7
    87 0.05 8.1 98.6 14.7 69.5
    88 0.05 10.7 96.7 17.0 4.8
    89 0.05 17.5 95.9 23.3 85.8
    90 0.05 9.5 96.4 15.9 54.6
    91 0.05 0.0 79.3 7.1 18.0
    92 0.05 1.9 98.2 8.8 71.9
    93 0.05 6.0 95.2 12.7 77.2
    94 0.05 0.0 92.9 7.1 37.0
    95 0.05 14.1 94.0 20.2 81.2
    96 0.05 1.2 93.6 8.2 78.2
    97 0.05 18.2 98.3 24.0 76.3
    98 0.05 16.8 98.1 22.7 79.7
    99 0.05 8.9 94.5 15.4 50.3
    100 0.05 8.2 97.0 14.7 74.2
    101 0.05 7.8 97.3 14.3 85.3
    102 0.05 0.0 93.4 7.1 74.0
    103 0.05 17.9 98.1 23.8 63.2
    104 0.05 27.7 98.2 32.8 70.2
    105 0.05 5.8 95.2 12.5 74.6
    106 0.05 0.0 94.6 7.1 88.7
    107 0.05 0.0 97.2 7.1 74.6
    108 0.05 21.3 97.6 26.9 50.9
    109 0.05 27.8 98.3 32.9 89.1
    110 0.05 19.9 98.2 25.6 76.4
    111 0.05 16.8 97.4 22.7 63.6
    112 0.05 8.1 97.8 14.6 78.2
    113 0.05 17.0 98.0 22.9 94.7
    114 0.05 0.0 36.9 7.1 7.5
    115 0.05 6.1 97.4 12.7 78.2
    116 0.05 8.4 98.2 14.9 88.8
    117 0.05 28.8 98.5 33.9 89.5
    118 0.05 10.6 98.3 16.9 85.3
    119 0.05 2.2 95.7 9.1 91.9
    120 0.05 19.9 98.2 25.6 92.6
    121 0.05 0.0 98.3 7.1 88.1
    122 0.05 13.5 98.7 19.6 92.7
    123 0.05 7.5 95.5 14.1 71.0
    124 0.05 0.0 88.2 7.1 23.0
    125 0.05 2.4 94.4 9.3 87.0
    126 0.05 13.2 92.4 19.4 73.0
    127 0.05 0.0 97.1 7.1 40.0
    128 0.05 10.8 88.6 17.1 38.0
    129 0.05 5.5 97.8 12.2 49.0
    130 0.05 1.2 98.6 8.2 50.8
    131 0.05 0.0 96.8 7.1 62.0
    132 0.05 9.1 97.7 15.5 65.5
    133 0.05 8.8 98.5 15.3 71.9
    134 0.05 4.2 95.3 11.0 57.0
    135 0.05 0.2 98.6 7.3 96.0
    136 0.05 9.7 98.6 16.2 95.0
    137 0.05 4.5 98.5 11.3 74.0
    138 0.05 4.0 98.1 10.8 91.0
    139 0.05 1.7 97.1 8.6 93.0
    140 0.05 6.7 96.7 13.3 81.0
    141 0.05 1.5 96.2 8.5 52.0
    142 0.05 1.1 98.2 8.1 79.0
    143 0.05 2.1 98.2 9.0 64.4
    144 0.05 0.0 98.5 7.1 87.0
    145 0.05 2.4 97.2 9.3 55.9
    146 0.05 0.0 96.2 7.1 71.2
    147 0.05 0.0 95.6 7.1 13.5
    148 0.05 15.4 97.9 21.5 72.9
    149 0.05 0.0 97.1 7.1 22.1
    150 0.05 10.0 97.5 16.4 87.5
    151 0.05 11.8 97.6 18.1 83.0
    152 0.05 0.0 89.1 7.1 26.0
    153 0.05 0.0 97.0 7.1 34.6
    154 0.05 3.4 70.7 10.3 36.6
    155 0.05 1.9 78.3 8.9 32.0
    156 0.05 7.4 94.8 14.0 51.5
    157 0.05 7.8 96.9 14.3 61.8
    158 0.05 6.2 96.9 12.9 84.7
    159 0.05 11.4 98.5 17.7 91.9
    160 0.05 3.4 96.1 10.2 65.5
    161 0.05 7.0 97.7 13.6 58.2
    162 0.05 0.0 96.9 7.1 94.0
    163 0.05 5.9 98.0 12.6 87.7
    164 0.05 10.8 98.6 17.1 96.5
    165 0.05 14.9 98.4 21.0 88.4
    166 0.05 2.6 97.9 9.5 71.9
    167 0.05 0.0 95.8 7.1 67.3
    168 0.05 13.3 97.7 19.5 59.6
    169 0.05 2.7 98.1 9.6 78.9
    170 0.05 0.0 94.5 7.1 65.5
    171 0.05 4.0 98.3 10.8 15.8
    172 0.05 13.2 97.9 19.4 27.1
    173 0.05 8.3 97.7 14.8 12.2
    174 0.05 0.0 97.0 7.1 72.7
    175 0.05 4.9 97.9 11.6 80.0
    176 0.05 8.8 98.2 15.2 61.4
    177 0.05 12.5 95.2 18.7 91.0
    178 0.05 8.5 98.3 15.0 59.3
    179 0.05 18.7 98.0 24.4 35.1
    180 0.05 10.8 95.1 17.1 43.9
    181 0.05 16.0 97.6 22.0 90.5
    182 0.05 0.0 97.6 7.1 74.6
    183 0.05 0.0 96.7 7.1 66.7
    184 0.05 7.1 97.0 13.7 70.9
    185 0.05 0.0 95.2 7.1 54.6
    186 0.05 0.0 97.6 7.1 61.8
    187 0.05 20.7 97.5 26.3 92.7
    188 0.05 7.9 96.5 14.5 74.6
    189 0.05 19.2 95.9 24.9 72.7
    190 0.05 5.6 95.7 12.3 70.9
    191 0.05 15.4 98.1 21.4 29.8
    192 0.05 7.8 94.7 14.3 84.2
    193 0.05 0.0 95.1 7.1 80.0
    194 0.05 16.1 96.9 22.0 80.4
    195 0.05 19.2 97.9 24.9 89.5
    196 0.05 4.4 97.7 11.2 94.5
    197 0.05 0.0 97.1 7.1 43.7
    198 0.05 11.8 97.7 18.1 75.4
    199 0.05 4.0 98.0 10.8 56.1
    200 0.05 0.0 95.0 7.1 78.9
    201 0.05 4.0 96.0 10.8 50.9
    202 0.05 2.0 96.6 9.0 49.1
    203 0.05 6.9 95.7 13.5 56.4
    204 0.05 7.3 95.5 13.8 77.2
    205 0.05 15.4 97.2 21.5 78.9
    206 0.05 16.4 98.4 22.3 80.7
    207 0.05 0.0 95.3 7.1 52.7
    208 0.05 5.4 97.0 12.1 32.8
    209 0.05 17.6 95.9 23.4 67.3
    210 0.05 1.9 94.1 8.9 37.0
    211 0.05 7.0 97.1 13.6 16.0
    212 0.05 0.0 95.2 7.1 14.0
    213 0.05 3.7 98.8 10.6 56.1
    214 0.05 7.0 98.0 13.6 60.0
    215 0.05 0.5 98.6 7.5 37.0
    216 0.05 6.3 98.4 12.9 57.9
    217 0.05 0.0 92.7 7.1 0.0
    218 0.05 0.0 92.5 7.1 70.9
    219 0.05 34.5 97.9 39.2 68.4
    220 0.05 0.0 95.3 7.1 89.1
    221 0.05 0.0 92.4 7.1 66.0
    222 0.05 0.0 94.5 7.1 67.3
    223 0.05 26.9 97.2 32.1 54.0
    224 0.05 0.0 91.0 7.1 67.3
    225 0.05 0.0 96.6 7.1 78.2
    226 0.05 0.0 94.5 7.1 71.0
    227 0.05 5.0 95.0 11.7 52.7
    228 0.05 2.6 97.0 9.6 68.4
    229 0.05 6.0 98.0 12.7 70.9
    230 0.05 9.0 98.3 15.5 65.0
    231 0.05 0.0 98.5 7.1 81.3
    232 0.05 2.3 97.5 9.3 57.6
    233 0.05 5.6 98.1 12.3 88.1
    234 0.05 0.0 94.3 7.1 72.9
    235 0.05 0.0 96.3 7.1 80.0
    236 0.05 3.5 97.0 10.4 88.1
    237 0.05 0.0 91.8 7.1 45.0
    238 0.05 0.5 97.6 7.5 92.5
    239 0.05 0.1 97.8 7.2 66.1
    240 0.05 0.0 98.1 7.1 74.6
    241 0.05 0.5 97.0 7.5 62.7
    242 0.05 6.9 98.0 13.5 78.0
    243 0.05 5.3 96.7 12.1 86.4
    244 0.05 0.0 96.1 7.1 62.7
    245 0.05 0.0 96.7 7.1 52.7
    246 0.05 0.0 95.3 7.1 50.9
    247 0.05 10.1 94.0 16.5 84.7
    248 0.05 12.4 96.3 18.7 98.0
    249 0.05 27.8 95.8 32.9 100.0
    250 0.05 8.7 98.1 15.2 97.0
    251 0.05 3.5 98.1 10.3 33.0
    252 0.05 7.8 98.4 14.4 28.0
    253 0.05 4.9 98.0 11.6 14.0
    254 0.05 8.3 98.1 14.8 0.0
    255 0.05 3.6 98.2 10.4 28.0
    256 0.05 3.0 98.7 9.8 18.0
    257 0.05 6.0 94.4 12.6 21.0
    258 0.05 34.1 97.4 38.8 87.0
    259 0.05 9.9 97.9 16.3 32.0
    260 0.05 11.2 97.1 17.5 81.0
    261 0.05 2.7 97.9 9.6 10.0
    262 0.05 3.1 94.0 9.9 4.6
    263 0.05 4.1 97.9 10.9 14.0
    264 0.05 6.0 98.4 12.7 21.0
    265 0.05 0.0 98.1 7.1 15.0
    266 0.05 4.5 95.4 11.3 28.0
    267 0.05 5.7 98.3 12.4 33.0
    268 0.05 1.2 98.7 8.2 31.0
    269 0.05 0.0 98.8 7.1 21.0
    270 0.05 6.9 98.6 13.5 61.0
    271 0.05 6.9 98.9 13.5 61.0
    272 0.05 2.0 98.1 8.9 37.0
    273 0.05 0.4 97.7 7.5 44.0
    274 0.05 0.0 96.3 7.1 89.0
    275 0.05 0.0 98.4 7.1 79.7
    276 0.05 5.5 97.8 12.2 71.2
    277 0.05 1.9 97.5 8.9 86.4
    278 0.05 1.7 97.7 8.7 90.0
    279 0.05 5.1 98.6 11.8 96.0
    280 0.05 2.2 98.2 9.1 88.0
    281 0.05 1.4 98.4 8.4 67.0
    282 0.05 0.0 94.7 7.1 52.0
    283 0.05 0.0 95.9 7.1 67.0
    284 0.05 0.0 97.1 7.1 74.0
    285 0.05 3.4 97.5 10.3 51.0
    286 0.05 2.3 98.4 9.2 75.0
    287 0.05 0.0 98.3 7.1 65.0
    288 0.05 1.8 98.2 8.8 26.0
    289 0.05 0.0 97.6 7.1 45.0
    290 0.05 0.4 95.5 7.5 21.0
    291 0.05 2.2 95.4 9.2 67.0
    292 0.05 5.0 97.6 11.7 21.0
    293 0.05 7.9 95.7 14.4 19.0
    294 0.05 1.7 94.2 8.7 72.9
    295 0.05 5.8 98.0 12.5 89.8
    296 0.05 8.3 97.7 14.8 84.7
    297 0.05 0.0 96.4 7.1 69.5
    298 0.05 0.7 95.0 7.8 74.6
    299 0.05 0.0 97.9 7.1 74.0
    300 0.05 0.0 97.2 7.1 70.0
    301 0.05 0.0 97.9 7.1 82.0
    302 0.05 0.0 96.4 7.1 82.0
    303 0.05 0.0 98.0 7.1 45.0
    304 0.05 0.0 97.9 7.1 77.0
    305 0.05 0.5 98.3 7.5 61.0
    306 0.05 0.0 95.2 7.1 35.0
    307 0.05 0.0 91.3 7.1 25.0
    308 0.05 37.2 97.7 41.6 96.0
    309 0.05 5.5 97.4 12.2 74.0
    310 0.05 2.4 96.6 9.3 64.0
    311 0.05 3.3 98.3 10.2 37.0
    312 0.05 3.8 97.8 10.6 1.4
    313 0.05 8.5 98.5 15.0 28.0
    314 0.05 0.0 97.7 7.1 8.8
    315 0.05 2.7 95.8 9.6 18.0
    316 0.05 4.5 97.1 11.3 14.0
    317 0.05 16.3 97.9 22.3 24.0
    318 0.05 3.1 97.3 10.0 71.2
    319 0.05 18.1 96.6 23.9 78.0
    320 0.05 17.1 96.4 23.0 100.0
    321 0.05 11.7 96.6 18.0 100.0
    322 0.05 20.9 97.9 26.5 95.0
    323 0.05 16.1 98.1 22.1 100.0
    324 0.05 2.3 96.3 9.2 98.0
    325 0.05 0.0 95.7 7.1 100.0
    326 0.05 6.9 95.6 13.5 93.0
    327 0.05 1.2 95.7 8.3 98.0
    328 0.05 0.0 95.1 7.1 99.0
    329 0.05 14.0 93.5 20.1 99.0
    330 0.05 5.3 92.9 12.1 99.0
    331 0.05 22.8 97.8 28.2 100.0
    332 0.05 2.0 93.9 8.9 89.0
    333 0.05 16.2 93.2 22.1 85.0
    334 0.05 10.9 97.8 17.2 98.0
    335 0.05 10.2 96.8 16.6 95.0
    336 0.05 16.6 97.8 22.5 98.0
    337 0.05 22.4 98.0 27.9 97.0
    338 0.05 9.0 98.1 15.5 96.0
    339 0.05 1.5 95.4 8.5 100.0
    340 0.05 18.0 96.2 23.8 95.0
    341 0.05 1.2 88.9 8.2 63.0
    342 0.05 9.1 98.3 15.6 86.0
    343 0.05 2.8 95.4 9.7 97.0
    344 0.05 31.5 91.8 36.4 100.0
    345 0.05 18.8 97.9 24.6 97.0
    346 0.05 30.0 96.7 34.9 96.0
    347 0.05 13.8 98.4 19.9 97.0
    348 0.05 16.3 98.3 22.2 100.0
    349 0.05 17.4 96.9 23.3 97.0
    350 0.05 11.3 94.9 17.6 97.0
    351 0.05 7.7 96.1 14.3 100.0
    352 0.05 8.8 98.4 15.3 100.0
    353 0.05 0.0 94.8 7.1 81.0
    354 0.05 18.4 95.4 24.2 98.0
    355 0.05 19.6 89.8 25.3 87.0
    356 0.05 18.6 98.0 24.4 93.0
    357 0.05 56.7 97.4 59.7 93.0
    358 0.05 12.7 98.3 18.9 100.0
    359 0.05 41.4 97.3 45.6 92.0
    360 0.05 17.6 96.9 23.4 97.0
    361 0.05 3.3 96.4 10.2 97.0
    362 0.05 11.1 97.2 17.4 97.0
    363 0.05 4.3 94.7 11.1 92.0
    364 0.05 8.4 95.8 14.9 97.0
    365 0.05 13.8 95.6 19.9 95.0
    366 0.05 14.2 96.6 20.3 100.0
    367 0.05 13.1 97.9 19.2 95.0
    368 0.05 0.0 96.9 7.1 98.0
    369 0.05 7.0 95.5 13.6 98.0
    370 0.05 3.5 97.5 10.4 91.0
    371 0.05 12.6 96.1 18.8 98.0
    372 0.05 15.1 97.4 21.1 98.0
    373 0.05 0.0 97.3 7.1 90.0
    374 0.05 11.1 98.2 17.4 98.0
    375 0.05 7.2 98.2 13.7 90.0
    376 0.05 13.6 96.5 19.8 98.0
    377 0.05 29.9 97.6 34.9 100.0
    378 0.05 26.3 98.4 31.6 97.0
    379 0.05 26.7 98.2 31.9 100.0
    380 0.05 36.1 98.3 40.6 100.0
    381 0.05 31.8 98.6 36.6 100.0
    382 0.05 19.3 98.5 25.0 96.0
    383 0.05 20.3 95.7 25.9 100.0
    384 0.05 28.6 95.8 33.6 100.0
    385 0.05 5.4 94.6 12.1 100.0
    386 0.05 41.1 98.4 45.3 100.0
    387 0.05 13.5 96.9 19.6 87.0
    388 0.05 17.2 98.1 23.1 61.0
    389 0.05 7.7 97.6 14.2 95.0
    390 0.05 4.2 97.5 11.0 95.0
    391 0.05 6.0 96.9 12.7 92.0
    392 0.05 15.8 97.9 21.8 46.0
    393 0.05 4.3 96.1 11.1 73.0
    394 0.05 8.0 95.9 14.6 71.0
    395 0.05 8.2 93.9 14.8 76.0
    396 0.05 0.0 95.5 7.1 49.0
    397 NT NT NT 6.7
    398 0.05 5.4 94.7 12.1 98.0
    399 0.05 5.8 97.1 12.5 88.0
    400 0.05 0.5 97.9 7.6 96.0
    401 0.05 0.0 94.8 7.1 98.0
    402 0.05 0.0 95.2 7.1 100.0
    403 0.05 0.0 97.3 7.1 97.0
    404 0.05 0.0 94.9 7.1 97.0
    405 0.05 2.8 96.2 9.7 98.0
    406 0.05 6.7 96.1 13.3 98.0
    407 0.05 0.0 92.0 7.1 70.0
    408 0.05 8.4 79.7 14.9 94.0
    409 0.05 7.9 96.3 14.4 98.0
    410 0.05 1.9 97.6 8.9 95.0
    411 0.05 8.2 97.9 14.7 85.0
    412 0.05 7.7 97.8 14.3 100.0
    413 0.05 18.9 97.9 24.7 94.0
    414 0.05 14.6 97.9 20.7 90.0
    415 0.05 2.9 96.1 9.8 100.0
    416 0.05 4.3 97.5 11.1 93.0
    417 0.05 10.7 98.2 17.0 100.0
    418 0.05 0.0 97.3 7.1 93.0
    419 0.05 3.2 94.9 10.1 90.0
    420 0.05 11.4 97.5 17.7 100.0
    421 0.05 8.2 96.6 14.7 94.0
    422 0.05 0.0 95.5 7.1 90.0
    423 0.05 0.8 98.0 7.9 98.0
    424 0.05 22.3 97.0 27.8 100.0
    425 0.05 17.5 97.6 23.4 95.0
    426 0.05 34.8 97.3 39.5 98.0
    427 0.05 26.1 97.9 31.3 98.0
    428 0.05 44.1 98.4 48.1 97.0
    429 0.05 10.4 97.4 16.8 94.0
    430 0.05 16.6 98.2 22.5 100.0
    431 0.05 8.5 95.1 15.0 91.0
    432 0.05 0.0 95.9 7.1 72.0
    433 0.05 10.8 97.8 17.2 100.0
    434 0.05 25.6 97.4 30.9 100.0
    435 0.05 4.7 97.2 11.5 100.0
    436 0.05 14.6 98.2 20.7 94.0
    437 0.05 9.2 97.0 15.6 100.0
    438 0.05 0.0 94.2 7.1 98.0
    439 0.05 0.0 100.0 7.1 96.0
    440 0.05 2.9 100.0 9.8 98.0
    441 0.05 0.0 100.0 7.1 96.0
    442 0.05 0.0 100.0 7.1 98.0
    443 0.05 14.6 100.0 20.7 83.0
    444 0.05 0.0 100.0 7.1 91.0
    445 0.05 13.2 100.0 19.4 90.0
    446 0.05 23.5 95.4 29.0 57.0
    447 0.05 20.0 96.6 25.7 100.0
    448 0.05 27.1 97.5 32.3 100.0
    449 0.05 7.2 98.5 13.8 92.0
    450 0.05 1.1 93.5 8.1 100.0
    451 0.05 4.6 100.0 11.4 100.0
    452 0.05 12.9 100.0 19.1 100.0
    453 0.05 5.6 100.0 12.3 100.0
    454 0.05 12.4 100.0 18.6 100.0
    455 0.05 16.7 100.0 22.6 100.0
    456 0.05 0.0 100.0 7.1 100.0
    457 0.05 6.7 100.0 13.3 100.0
    458 0.05 3.7 96.6 10.6 46.0
    459 0.05 7.3 96.9 13.8 20.0
    460 0.05 0.0 97.6 7.1 39.0
    461 0.05 3.4 96.7 10.3 54.0
    462 0.05 0.0 95.0 7.1 86.0
    463 0.05 5.1 96.3 11.9 61.0
    464 0.05 6.7 94.8 13.4 93.0
    465 0.05 1.7 96.5 8.6 93.0
    466 0.05 2.7 97.9 9.6 69.0
    467 0.05 0.0 95.7 7.1 80.0
    468 0.05 6.2 98.1 12.8 92.0
    469 0.05 1.0 97.8 8.1 95.0
    470 0.05 4.0 98.0 10.8 93.0
    471 0.05 7.9 97.8 14.4 83.0
    472 0.05 0.0 97.7 7.1 49.0
    473 0.05 0.0 97.5 7.1 78.0
    474 0.05 39.2 97.6 43.5 100.0
    475 0.05 33.8 97.1 38.5 100.0
    476 0.05 0.0 93.9 7.1 69.0
    477 0.05 6.2 83.4 12.8 93.0
    478 0.05 0.7 94.7 7.7 65.0
    479 0.05 0.0 97.5 7.1 97.0
    480 0.05 9.5 95.3 15.9 4.7
    481 0.05 10.3 97.8 16.7 76.0
    482 0.05 0.0 96.4 7.1 66.0
    483 0.05 0.0 97.9 7.1 63.0
    484 0.05 12.6 93.2 18.8 88.0
    485 0.05 8.0 96.7 14.5 95.0
    486 0.05 12.8 96.6 19.0 95.0
    487 0.05 11.2 93.9 17.5 100.0
    488 0.05 20.1 92.6 25.7 72.0
    489 0.05 15.8 97.8 21.8 85.0
    490 0.05 31.5 97.0 36.4 55.0
    491 0.05 25.0 97.5 30.3 75.0
    492 0.05 0.0 98.1 7.1 93.0
    493 0.05 0.0 97.8 7.1 95.0
    494 0.05 0.0 97.7 7.1 96.0
    495 0.05 0.0 97.3 7.1 91.0
    496 0.05 0.7 97.8 7.8 94.0
    497 0.05 0.0 98.1 7.1 75.0
    498 0.05 0.0 97.5 7.1 85.0
    499 0.05 0.0 97.4 7.1 85.0
    500 0.05 9.2 93.2 15.6 80.0
    501 0.05 0.5 98.0 7.6 89.0
    502 0.05 4.2 97.2 11.0 85.0
    503 0.05 5.2 97.0 11.9 66.0
    504 0.05 1.3 97.6 8.3 94.0
    505 0.05 7.1 97.3 13.7 46.0
    506 0.05 2.7 97.5 9.6 44.0
    507 0.05 7.6 97.0 14.1 66.0
    508 0.05 9.4 97.1 15.9 92.0
    509 0.05 0.0 96.2 7.1 85.0
    510 0.05 6.2 95.5 12.8 56.0
    511 0.05 0.0 97.8 7.1 73.0
    512 0.05 7.4 97.8 13.9 59.0
    513 0.05 14.0 98.0 20.1 53.0
    514 0.05 0.0 97.7 7.1 75.0
    515 0.05 0.0 97.6 7.1 47.0
    516 0.05 0.0 97.9 7.1 59.0
    517 0.05 0.0 96.7 7.1 56.0
    518 0.05 24.2 97.4 29.6 58.0
    519 0.05 9.1 95.7 15.6 88.0
    520 0.05 14.9 96.7 20.9 49.0
    521 0.05 5.0 95.9 11.8 83.0
    522 0.05 9.4 97.3 15.9 95.0
    523 0.05 7.0 97.7 13.6 92.0
    524 0.05 9.3 95.8 15.7 39.0
    525 0.05 5.4 97.4 12.1 78.0
    526 0.05 1.8 16.2 8.7 41.0
    527 0.05 7.6 97.6 14.2 78.0
    528 0.05 8.7 97.7 15.2 73.0
    529 0.05 15.3 97.7 21.3 46.0
    530 0.05 9.8 96.2 16.2 59.0
    531 0.05 0.0 97.3 7.1 80.0
    532 0.05 4.9 91.4 11.7 56.0
    533 0.05 6.2 97.0 12.9 34.0
    534 0.05 5.1 95.7 11.9 61.0
    535 0.05 10.1 97.7 16.5 56.0
    536 0.05 21.1 93.4 26.7 24.0
    537 0.05 12.2 96.2 18.5 90.0
    538 0.05 12.4 96.5 18.6 44.0
    539 0.05 1.6 98.0 8.6 100.0
    540 0.05 0.0 97.5 7.1 95.0
    541 0.05 0.0 97.5 7.1 93.0
    542 0.05 0.0 95.8 7.1 100.0
    543 0.05 1.3 93.9 8.3 100.0
    544 0.05 6.9 97.6 13.5 97.0
    545 0.05 19.6 97.9 25.3 95.0
    546 0.05 7.6 97.7 14.2 100.0
    547 0.05 10.8 97.7 17.1 88.0
    548 0.05 6.7 97.5 13.3 98.0
    549 0.05 0.0 97.3 7.1 94.0
    550 0.05 4.6 97.2 11.4 63.0
    551 0.05 1.7 96.0 8.7 90.0
    552 0.05 0.0 94.2 7.1 71.0
    553 0.05 0.0 93.2 7.1 88.0
    554 0.05 0.0 97.3 7.1 100.0
    555 0.05 3.7 92.5 10.5 46.0
    556 0.05 7.7 95.9 14.2 75.0
    557 0.05 13.0 95.7 19.2 90.0
    558 0.05 3.8 95.7 10.6 80.0
    559 0.05 10.0 97.3 16.4 93.0
    560 0.05 1.3 90.7 8.3 65.0
    561 0.05 0.0 92.2 7.1 60.0
    562 0.05 1.4 97.3 8.4 91.0
    563 0.05 20.6 96.9 26.2 70.0
    564 0.05 17.4 94.2 23.3 1.3
    565 0.05 12.2 97.4 18.4 98.0
    566 0.05 6.8 95.9 13.4 70.0
    567 0.05 2.5 42.3 9.5 14.0
    568 0.05 8.0 94.3 14.6 61.0
    569 0.05 6.1 15.8 12.7 70.0
    570 0.05 3.2 97.2 10.1 39.0
    571 0.05 0.0 84.7 7.1 31.0
    572 0.05 2.5 97.4 9.5 94.0
    573 0.05 2.4 98.4 9.3 93.0
    574 0.05 2.8 98.3 9.7 93.0
    575 0.05 0.0 98.1 7.1 100.0
    576 0.05 0.7 97.9 7.7 90.0
    577 0.05 1.9 97.9 8.8 100.0
    578 0.05 7.2 98.0 13.8 100.0
    579 0.05 0.0 97.6 7.1 97.0
    580 0.05 3.1 98.1 10.0 97.0
    581 0.05 13.6 98.2 19.7 93.0
    582 0.05 12.2 97.8 18.4 94.0
    583 0.05 13.2 98.0 19.4 100.0
    584 0.05 3.0 11.8 9.9 7.6
    585 0.05 6.3 86.3 13.0 62.0
    586 0.05 0.0 87.3 7.1 31.0
    587 0.05 6.2 96.6 12.8 2.4
    588 0.05 7.6 96.3 14.2 5.6
    589 0.05 8.7 97.9 15.2 61.0
    590 0.05 10.0 98.6 16.4 88.0
    591 0.05 0.0 9.9 7.1 11.0
    592 0.05 0.0 25.4 7.1 1.4
    CuCl2 10 μM 7.1 ± 6.0
    NT = not tested
    • Example 28 Effect of Copper on Fungitoxicity of Hydrazones Towards Phytophthora capsici
  • In vitro fungitoxicity assays against Phytophthora capsici were conducted using the asparagine-sucrose (AS) medium described in Canadian Journal of Microbiology 1961, 7, 15-25, except that copper micronutrient, normally included as CuSO4, was omitted. The medium, termed “copper-minus AS”, was prepared by dissolving 2 g asparagine, 0.43 g KH2PO4, 0.3 g K2HPO4, 0.4 mL of a 0.5 mg/mL thiamine-HCl solution and 15 g sucrose in 1 liter of deionized water and treating the solution with 0.5 g Chelex 100 resin (Bio-Rad Analytical grade, 50-100 mesh, sodium form, cat# 142-2822) by stiffing at room temperature for 1 h. The pH was adjusted to 6.4, then MgSO4.7H2O (100 μg/mL), FeSO4.7H2O (1 μg/mL), CaCl2 (50 μg/mL), ZnSO4.7H2O (1 μg/mL), NaMoO4.2H2O (0.2 μg/mL) and MnCl2.4H2O (0.2 μg/mL) were added and the entire medium was sterilized by filtration. “Copper-plus AS” medium was prepared by adding CuCl2.2H2O to the copper-minus AS medium at 100 μM. Test compounds were dissolved in DMSO then dilutions in copper-minus AS and copper-plus AS media were prepared as 100 μL aliquots in flat-bottomed 96-well microtiter plates.
  • Phytophthora capsici was grown on petri plates, 9 cm in diameter, containing 15 mL V-8 agar, pH 7.0, containing 200 mL V-8 juice, 4 g CaCO3, and 20 g agar per liter. Plates were inoculated with 7-mm plugs from a 1-week old culture, incubated at 25° C. in the dark for 3 days, and then placed under fluorescent lights for 4 days to induce sporulation. Zoospore release from sporangia was induced by adding 15 mL of sterile deionized water (which had been treated with Chelex 100 resin using 0.5 g resin per liter of water by stiffing at room temperature for 1 h) to each plate, and incubating for 10 min at 25° C. followed by 20 min at 4° C. The plates were returned to 25° C. for 10 min and the aqueous suspension of released zoospores was recovered. The zoospore suspension was adjusted to 5×104 spores/mL by dilution into Chelex 100-treated water. Microtiter plates were inoculated with 100 μL of spore suspension and incubated at 25° C. for 48 h before assessing fungal growth by measuring light scattering in a NepheloStar plate reader. Growth inhibition was determined by comparing growth in the presence of test compound with growth in control wells lacking test compound.
  • Results for growth inhibition by test compounds in copper-plus AS medium (“% Inhn. Plus Copper Observed”) were compared with predicted values (“% Inhn. Plus Copper Predicted”) that were calculated using the formula set forth by S. R. Colby in Weeds (1967), 15, 20-22 based on results obtained for the same compounds in copper-minus AS medium (“% Inhn. Minus Copper Observed”) and the inhibition attributed to copper chloride alone, as determined by comparing growth in copper-minus AS and copper-plus AS media without any test compound across experiments. Data are presented in Table 3. Results illustrate that hydrazones and copper produce a synergistic fungitoxic effect towards Phytophthora capsici.
  • TABLE 3
    % Inhn % Inhn % Inhn
    Minus Plus Plus
    Compound Concentration copper copper copper
    Number (μg/mL) Observed Observed Predicted
    1 0.039 9.7 87.2 13.8
    3 0.039 0.0 88.5 4.5
    5 0.039 18.6 93.9 22.3
    6 0.039 28.8 95.8 32.0
    14 0.039 0.0 87.2 4.5
    15 0.039 80.4 91.8 81.2
    16 0.050 0.0 91.9 4.5
    20 0.050 2.1 90.4 6.5
    21 0.039 0.0 90.0 4.5
    23 0.039 10.8 93.8 14.8
    24 0.039 10.2 92.4 14.2
    28 0.039 11.4 93.8 15.4
    43 0.039 54.2 90.3 56.2
    52 0.039 40.6 91.2 43.3
    56 0.039 57.5 94.1 59.4
    60 0.050 4.1 76.4 8.4
    61 0.039 17.6 95.6 21.3
    69 0.050 0.0 87.6 4.5
    74 5 17.2 89.4 20.9
    83 0.039 27.9 96.2 31.1
    84 0.039 47.5 95.0 49.8
    91 0.039 52.1 93.2 54.3
    96 0.039 55.2 91.9 57.2
    99 0.039 23.6 94.0 27.1
    100 0.039 10.0 88.8 14.0
    101 0.039 70.0 88.2 71.4
    102 0.039 15.7 93.6 19.4
    119 0.039 37.9 95.1 40.7
    121 0.050 0.0 90.4 4.5
    123 0.039 16.3 94.8 20.0
    124 0.039 25.0 89.7 28.3
    125 0.039 66.6 89.4 68.1
    129 0.039 10.6 96.3 14.6
    131 0.039 5.6 93.7 9.9
    140 0.050 0.0 91.4 4.5
    143 0.039 6.0 94.5 10.3
    146 0.039 11.8 91.4 15.8
    162 0.050 5.2 91.6 9.5
    177 0.050 0.0 92.4 4.5
    182 0.039 25.9 90.9 29.2
    183 0.039 0.0 88.9 4.5
    204 0.050 6.0 81.9 10.2
    207 0.039 0.0 88.9 4.5
    210 0.039 36.6 92.7 39.4
    218 0.050 10.7 93.3 14.7
    219 0.050 15.3 90.6 19.1
    220 0.050 13.4 85.5 17.3
    221 0.050 12.0 92.2 15.9
    222 0.050 11.3 76.8 15.3
    223 0.050 2.5 51.3 6.9
    224 0.050 6.2 93.3 10.4
    225 0.050 11.4 82.8 15.4
    226 0.050 2.3 62.1 6.7
    227 0.050 1.7 93.4 6.2
    228 0.050 10.0 86.9 14.0
    229 0.050 1.6 89.1 6.0
    230 0.050 5.8 93.6 10.1
    275 0.050 0.0 91.2 4.5
    277 0.050 0.0 88.2 4.5
    320 0.050 2.9 81.4 7.3
    337 0.050 4.7 42.1 9.0
    351 0.050 0.0 87.9 4.5
    364 0.050 0.0 23.2 4.5
    369 0.050 0.0 44.5 4.5
    384 0.050 0.0 71.1 4.5
    405 0.050 0.6 85.9 5.1
    427 0.050 9.1 88.6 13.2
    443 0.050 2.4 91.2 6.8
    455 0.050 0.0 30.8 4.5
    578 0.050 2.8 90.4 7.2
    CuCl2, 50 μM 4.5 ± 7.9
    • Example 29 Effect of Copper on Fungitoxicity of Hydrazones Towards Ustilago maydis
  • In vitro fungitoxicity assays against Ustilago maydis were conducted using the copper-minus medium described in Example 26. Medium containing copper was prepared by adding CuCl2.2H2O to the copper-minus medium at 20 μM. Test compounds were dissolved in dimethylsulfoxide (DMSO) at 200 μg/mL and 1 μL aliquots were added to two wells of flat-bottomed 96-well microtiter plates. Copper-minus medium (100 μL) was added to one of the wells and copper-plus medium to the second well. Control wells, included for each medium, received 1 uL DMSO and 100 μL of medium.
  • Ustilago maydis was grown in 50 mL potato dextrose broth with shaking at 25° C. for 24 h. A 10 mL aliquot of the culture was centrifuged at 2000 rpm for 2 min, resuspended in 10 mL of sterile Chelex 100-treated water, and centrifuged again. The spores were resuspended in copper-minus medium, and the suspension adjusted to a concentration of 1×105 spores per mL. Microtiter plate wells containing test compound of DMSO (control) as described above were inoculated with 100 μL of this spore suspension and the plates incubated at 25° C. for 48 h before assessing fungal growth by measuring light scattering in a NepheloStar plate reader. Growth inhibition was determined by comparing growth in the presence of test compound with growth in control wells lacking test compound.
  • Results for growth inhibition by test compounds at 1 μg/mL in copper-plus medium (“% Inhn. Plus Copper Observed”) were compared with predicted results (“% Inhn. Plus Copper Predicted”) that were calculated using the formula set forth by S. R. Colby in Weeds 1967, 15, 20-22 based on results obtained for the same compounds in copper-minus medium (“% Inhn. Minus Copper Observed”) and the inhibition attributed to copper chloride alone, as determined by comparing growth in copper-minus and copper-plus media without any test compound. Data are presented in Table 4. Results illustrate that hydrazones and copper produce a synergistic fungitoxic effect towards Ustilago maydis.
  • TABLE 4
    % Inhn. % Inhn. % Inhn.
    Compound Minus copper Plus copper Plus copper
    Number Observed Observed Predicted
    16 0.0 80.0 11.9
    20 1.2 91.0 12.9
    60 0.0 93.5 11.9
    69 0.0 96.2 11.9
    121 0.0 96.9 11.9
    140 0.0 95.7 11.9
    162 8.8 96.4 19.7
    177 0.0 33.3 11.9
    204 0.0 77.0 11.9
    230 11.9 94.4 22.4
    275 0.0 92.2 11.9
    277 1.7 83.5 13.4
    320 0.0 95.2 11.9
    329 16.2 41.8 26.2
    337 22.0 97.8 31.3
    351 27.1 97.7 35.8
    364 65.5 92.9 69.6
    369 3.1 93.6 14.7
    384 13.6 96.6 23.9
    405 9.6 90.0 20.4
    427 34.3 89.3 42.1
    443 10.2 35.3 20.9
    455 0.0 96.0 11.9
    578 47.4 93.8 53.6
    CuCl2, 10 μM 11.9
    • Example 30 Effect of Copper on Fungitoxicity of Hydrazones Towards Septoria tritici
  • In vitro fungitoxicity assays against Septoria tritici were conducted using the copper-minus medium described in Example 26. Medium containing copper was prepared by adding CuCl2.2H2O to the copper-minus medium at 2 μM. Test compounds were dissolved in dimethylsulfoxide (DMSO) at 10 μg/mL and 1 μL aliquots were added to two wells of flat-bottomed 96-well microtiter plates. Copper-minus medium (100 μL) was added to one of the wells and copper-plus medium to the second well. Control wells, included for each medium, received 1 uL DMSO and 100 μL of medium.
  • Septoria tritici isolate USA-184 was grown on potato dextrose agar at 18° C. under black lights for 3 days. A loopful of spores was transferred from the culture to a 15 mL tube containing 5 mL of sterile Chelex-treated water. The spores were centrifuged at 2000 rpm for 2 min, resuspended in 10 mL water, and centrifuged again. The spores were resuspended in copper-minus medium, and the suspension adjusted to a concentration of 1×105 spores per mL. Microtiter plate wells containing test compound of DMSO (control) as described above were inoculated with 100 μL of this spore suspension and the plates incubated at 25° C. for 90 h before assessing fungal growth by measuring light scattering in a NepheloStar plate reader. Growth inhibition was determined by comparing growth in the presence of test compound with growth in control wells lacking test compound.
  • Results for growth inhibition by test compounds at 0.05 μg/mL in copper-plus medium (“% Inhn. Plus Copper Observed”) were compared with predicted results (“% Inhn. Plus Copper Predicted”) that were calculated using the formula set forth by S. R. Colby in Weeds 1967, 15, 20-22 based on results obtained for the same compounds in copper-minus medium (“% Inhn. Minus Copper Observed”) and the inhibition attributed to copper chloride alone, as determined by comparing growth in copper-minus and copper-plus media without any test compound. In this experiment, copper chloride alone (1 μM) had no effect on growth. Data are presented in Table 5. Results illustrate that hydrazones and copper produce a synergistic fungitoxic effect towards Septoria tritici.
  • TABLE 5
    % Inhibition % Inhibition % Inhibition
    Compound Minus copper Plus copper Plus copper
    Number Observed Observed Predicted
    16 35.8 93.6 35.8
    20 0.0 95.3 0.0
    60 20.6 94.8 20.6
    69 0.0 96.7 0.0
    121 9.7 96.5 9.7
    140 0.0 96.6 0.0
    162 36.3 97.1 36.3
    177 0.2 95.2 0.2
    204 0.0 84.4 0.0
    230 43.6 96.7 43.6
    275 16.2 93.5 16.2
    277 3.6 88.0 3.6
    320 9.5 92.1 9.5
    329 14.9 55.1 14.9
    337 46.8 97.1 46.8
    351 44.4 97.1 44.4
    364 22.4 93.7 22.4
    369 9.3 93.2 9.3
    384 57.5 97.0 57.5
    405 18.8 89.9 18.8
    427 43.8 96.7 43.8
    443 5.8 92.0 5.8
    455 27.5 92.4 27.5
    578 26.7 90.7 26.7
    CuCl2, 1 μM 0
    • Example 31 Comparative Efficacy of Isolated Metal-Hydrazone Complexes and Parent Hydrazones Towards Leptosphaeria nodorum
  • Hydrazones and their isolated metal complexes were compared with respect to their in vitro fungitoxicity towards LEPTNO. Metal complexes of hydrazones were prepared by precipitation from ethanol with various metal salts, at 1:1, 2:1 or 3:1 molar ratios, as described in general by Ainscough, Brodie, Dobbs, Ranford, and Waters (Inorganica Chimica Acta 1998, 267, 27-38, which is expressly incorporated by reference herein).
  • A general synthesis of 1:1 metal-hydrazone complexes is as follows. The starting salicylaldehyde benzoylhydrazone or 2-hydroxyphenylketone benzoylhydrazone is dissolved (or suspended) in EtOH (generally 0.1 mmol hydrazone per mL solvent) and agitated at a temperature ranging from room temperature to 80° C. for 30 min. To this solution (or suspension) is added 1 equivalent of the metal salt (generally as a 1 M solution in EtOH). The mixture is agitated for a period ranging from 1 to 24 h at a temperature ranging from room temperature to 80° C. The metal-hydrazone complex generally precipitates during the reaction or upon cooling and is isolated by filtration, washed with EtOH and finally washed with Et2O. In the instances where the complex does not precipitate, the solvent is removed and the resulting solid metal-hydrazone complex is washed with Et2O. Properties of particular metal complexes of hydrazones are provided in Table 6 below.
  • TABLE 6
    Ratio
    Com- Hydra-
    plex Com- zone:
    Num- pound Metal
    ber Number Metal Salt Salt Description mp (° C.)
    593 77 FeCl3•6H2O 1:1 brown 199-202
    black solid
    594 77 FeCl3•6H2O 2:1 dark green 258-260
    solid
    595 78 FeCl3•6H2O 3:1 dark green 258-261
    solid
    596 16 Cu(OCOCH3)2•H2O 1:1 dark green
    solid
    597 16 Cu(OCOCH3)2•H2O 2:1 tan solid 310-312
    598 16 CuSO4•5H2O 1:1 dark green 307-308
    solid
    599 16 CuSO4•5H2O 2:1 dark green 310-312
    solid
    600 16 CuCl2•2H2O 1:1 light green 311-312
    olive solid
    601 16 CuCl2•2H2O 2:1 light green 288-290
    solid
    602 69 CuCl2•2H2O 1:1 olive- 250-255
    brown
    solid
    603 84 CuCl2•2H2O 1:1 olive green 278-280
    solid
    604 83 CuCl2•2H2O 1:1 olive 282-285
    brown
    solid
    605 77 CuCl2•2H2O 1:1 olive green 273-274
    solid
    606 96 CuCl2•2H2O 1:1 olive green 258-260
    solid
    607 70 CuCl2•2H2O 1:1 olive 278-279
    brown
    glass
    608 43 CuCl2•2H2O 1:1 green black 310-312
    solid
    609 76 CuCl2•2H2O 1:1 brown 272-273
    solid
    610 100 Cu(OCOCH3)2•H2O 1:1 brown 315-317
    black solid
    611 16 MnCl2 2:1 mustard- 250
    colored
    solid
    612 16 ZnCl2 2:1 yellow- 250
    green solid
    613 299 CuCl2•2H2O 1:1 dark green 160-163
    solid
    614 300 CuCl2•2H2O 1:1 dark green 129-132
    solid
    615 301 CuCl2•2H2O 1:1 dark brown 73-78
    solid
    616 302 CuCl2•2H2O 1:1 dark green 167-170
    solid
    617 303 CuCl2•2H2O 1:1 dark green 137-139
    solid
    618 304 CuCl2•2H2O 1:1 dark green 177-225
    solid
    619 305 CuCl2•2H2O 1:1 dark brown 201-211
    solid
    620 16 CuCl2•2H2O 1:1 olive green 293-302
    solid
    621 151 CuCl2•2H2O 1:1 olive green 283-294
    solid
    622 238 CuCl2•2H2O 1:1 olive green 299-308
    solid
    623 231 CuCl2•2H2O 1:1 olive green 260-275
    solid
    624 233 CuCl2•2H2O 1:1 olive green 286-290
    solid
    625 20 CuCl2•2H2O 1:1 olive green 286-288
    solid
    626 236 CuCl2•2H2O 1:1 olive green 259-263
    solid
    627 277 CuCl2•2H2O 1:1 olive green 286-289
    solid
    628 320 CuCl2•2H2O 1:1 olive green 280-286
    solid
    629 68 CuCl2•2H2O 1:1 olive green 226-228
    solid
    630 159 CuCl2•2H2O 1:1 olive green 224-235
    solid
    631 359 CuCl2•2H2O 1:1 olive green 240-254
    solid
    632 370 CuCl2•2H2O 1:1 olive green 257-267
    solid
    633 428 CuCl2•2H2O 1:1 olive green 212-270
    solid
    634 392 CuCl2•2H2O 1:1 olive green 262-293
    solid
    635 348 CuCl2•2H2O 1:1 olive green 295-305
    solid
    636 440 CuCl2•2H2O 1:1 olive green 259-281
    solid
    637 337 CuCl2•2H2O 1:1 olive green 279-281
    solid
    638 381 CuCl2•2H2O 1:1 olive green 279-281
    solid
    639 452 CuCl2•2H2O 1:1 olive green 270-274
    solid
    640 69 CuCl2•2H2O 1:1 olive green 298-299
    solid
    641 151 CuCl2•2H2O 1:1 olive green 287-289
    solid
    642 172 CuCl2•2H2O 1:1 olive green 311-313
    solid
    643 403 CuCl2•2H2O 1:1 olive green 296-297
    solid
    644 60 CuCl2•2H2O 1:1 olive green 215-219
    solid
    645 137 CuCl2•2H2O 1:1 olive green 207-211
    solid
    646 278 CuCl2•2H2O 1:1 olive green 242-246
    solid
    647 279 CuCl2•2H2O 1:1 olive green 236-239
    solid
    648 67 CuCl2•2H2O 1:1 olive green 176-87 
    solid
    649 135 CuCl2•2H2O 1:1 olive green 245-248
    solid
    650 136 CuCl2•2H2O 1:1 olive green 242-247
    solid
    651 411 CuCl2•2H2O 1:1 olive green 292-295
    solid
    652 412 CuCl2•2H2O 1:1 olive green 309-310
    solid
    653 68 Cu(OCOCH3)2•H2O 1:1 brown- >350  
    black solid
  • In vitro fungitoxicity assays were conducted using the copper-minus medium described in Example 26. Test compounds were dissolved in dimethylsulfoxide (DMSO) then dilutions in copper-minus medium were prepared as 100 μL aliquots in flat-bottomed 96-well microtiter plates. Microtiter plates were inoculated with 100 μL of spore suspension at a concentration of 2×105 spores per mL, prepared as in Example 26. The plates were incubated at 25° C. for 72 h before assessing fungal growth by measuring light scattering in a NepheloStar plate reader. Growth inhibition was determined by comparing growth in the presence of test compound with growth in control wells lacking test compound.
  • Results for growth inhibition by hydrazones and corresponding isolated metal complexes (each at 0.1 μg/mL) are shown in Table 7. The results illustrate that isolated Cu complexes of hydrazones are much more fungitoxic than the corresponding hydrazones and also are much more active than isolated Fe, Mn and Zn complexes of hydrazones.
  • TABLE 7
    Com- Com- Hydrazone Complex
    plex pound Ra- % Inhibi- % Inhibi-
    Number Number Metal Salt tio* tion tion
    593 77 FeCl3•6H2O 1:1 10.6 7.1
    594 77 FeCl3•6H2O 2:1 10.6 4.9
    595 77 FeCl3•6H2O 3:1 10.6 3.1
    596 16 Cu(OCOCH3)2•H2O 1:1 19.9 98.4
    597 16 Cu(OCOCH3)2•H2O 2:1 19.9 94.6
    599 16 CuSO4•5H2O 2:1 19.9 97.3
    600 16 CuCl2•2H2O 1:1 19.9 95.3
    601 16 CuCl2•2H2O 2:1 19.9 97.0
    602 69 CuCl2•2H2O 1:1 32.4 94.9
    603 84 CuCl2•2H2O 1:1 6.7 95.6
    604 83 CuCl2•2H2O 1:1 27.9 95.1
    605 77 CuCl2•2H2O 1:1 10.6 97.2
    606 96 CuCl2•2H2O 1:1 10.7 90.3
    607 70 CuCl2•2H2O 1:1 29.4 48.3
    608 43 CuCl2•2H2O 1:1 3.6 21.2
    609 76 CuCl2•2H2O 1:1 92.8 95.5
    610 100 Cu(OCOCH3)2•H2O 1:1 24.7 96.7
    611 16 MnCl2•4H2O 2:1 19.9 31.3
    612 16 ZnCl2 2:1 19.9 21.4
    613 299 CuCl2•2H2O 1:1 18.6 96.3
    614 300 CuCl2•2H2O 1:1 2.5 66.9
    615 301 CuCl2•2H2O 1:1 3.5 87.3
    616 302 CuCl2•2H2O 1:1 22.9 95.5
    617 303 CuCl2•2H2O 1:1 10.6 88.0
    618 304 CuCl2•2H2O 1:1 13.3 94.1
    619 305 CuCl2•2H2O 1:1 27.1 96.3
    621 151 CuCl2•2H2O 1:1 30.9 97.4
    622 238 CuCl2•2H2O 1:1 20.0 97.5
    623 231 CuCl2•2H2O 1:1 10.7 98.0
    624 233 CuCl2•2H2O 1:1 8.4 96.8
    625 20 CuCl2•2H2O 1:1 14.7 96.9
    626 236 CuCl2•2H2O 1:1 4.7 94.9
    627 277 CuCl2•2H2O 1:1 0.6 91.9
    628 320 CuCl2•2H2O 1:1 22.1 94.6
    629 68 CuCl2•2H2O 1:1 7.1 97.8
    630 159 CuCl2•2H2O 1:1 27.4 97.8
    631 359 CuCl2•2H2O 1:1 24.1 98.0
    632 370 CuCl2•2H2O 1:1 23.1 97.5
    633 428 CuCl2•2H2O 1:1 29.9 97.3
    634 392 CuCl2•2H2O 1:1 22.8 75.8
    635 348 CuCl2•2H2O 1:1 23.9 91.8
    636 440 CuCl2•2H2O 1:1 23.8 95.8
    637 337 CuCl2•2H2O 1:1 39.9 97.9
    638 381 CuCl2•2H2O 1:1 43.9 97.1
    639 452 CuCl2•2H2O 1:1 19.3 96.7
    641 195 CuCl2•2H2O 1:1 21.7 95.2
    642 172 CuCl2•2H2O 1:1 28.7 97.2
    643 403 CuCl2•2H2O 1:1 12.1 93.9
    644 60 CuCl2•2H2O 1:1 23.3 98.0
    645 137 CuCl2•2H2O 1:1 27.2 97.7
    646 278 CuCl2•2H2O 1:1 16.2 97.5
    647 279 CuCl2•2H2O 1:1 19.9 96.9
    648 67 CuCl2•2H2O 1:1 4.2 95.9
    649 135 CuCl2•2H2O 1:1 20.6 96.0
    650 136 CuCl2•2H2O 1:1 34.7 98.3
    651 411 CuCl2•2H2O 1:1 32.1 97.5
    652 412 CuCl2•2H2O 1:1 40.4 97.0
    653 68 Cu(OCOCH3)2•H2O 1:1 7.1 96.9
    *Molar ratio of hydrazone:metal used to prepare complexes.
    • Example 32 Comparative efficacy of isolated Cu-hydrazone complexes and parent hydrazones against glume blotch of wheat (Leptosphaeria nodorum)
  • Hydrazones and their copper complexes were compared with respect to their ability to control glume blotch of wheat. Compound formulation was accomplished by dissolving technical materials in acetone and adding 9 volumes de-ionized water containing 0.01% Triton® X-100.
  • Wheat (cultivar Yuma) was grown in a soilless peat-based potting mixture (“Metromix”) until the seedlings were 10-20 cm tall. These plants were then sprayed to run-off with the test compound at a rate of 200 ppm. After 24 h, the test plants were inoculated by spraying with an aqueous suspension of LEPTNO spores and kept in a dew chamber overnight. The plants were then transferred to the greenhouse until disease developed in the untreated control plants. Results, shown in Table 8, show that copper complexes of hydrazones have higher fungicidal activity towards glume blotch than the corresponding hydrazones without copper.
  • TABLE 8
    Com- Com-
    plex pound Ra- Hydrazone Complex
    Number Number Metal Salt tio* % Control % Control
    600 16 CuCl2•2H2O 1:1 41 93
    602 69 CuCl2•2H2O 1:1 25 83
    603 84 CuCl2•2H2O 1:1 37 92
    604 83 CuCl2•2H2O 1:1 38 75
    605 77 CuCl2•2H2O 1:1 0 75
    606 96 CuCl2•2H2O 1:1 0 91
    607 70 CuCl2•2H2O 1:1 0 91
    608 43 CuCl2•2H2O 1:1 0 84
    609 76 CuCl2•2H2O 1:1 0 97
    610 100 Cu(OCOCH3)2•H2O 1:1 0 94
    *Molar ratio of hydrazone:metal used to prepare complexes.
    • Example 33 Effect of Copper on Fungitoxicity of Metal-Hydrazone Complexes Towards Leptosphaeria nodorum
  • In vitro fungitoxicity assays against LEPTNO were conducted using the copper-minus medium described in Example 26. Medium containing copper was prepared by adding CuCl2.2H2O to the copper minus medium at 20 μM. Test compounds were dissolved in dimethylsulfoxide (DMSO) then dilutions in copper-minus and copper-plus media were prepared as 100 μL aliquots in flat-bottomed 96-well microtiter plates. Microtiter plates were inoculated with 100 μL of spore suspension at a concentration of 2×105 spores per mL, prepared as in Example 26. The plates were incubated at 25° C. for 72 h before assessing fungal growth by measuring light scattering in a NepheloStar plate reader. Growth inhibition was determined by comparing growth in the presence of test compound with growth in control wells lacking test compound. Results for growth inhibition by test compounds in copper-plus medium (“% Inhn. Plus Copper Observed”) were compared with predicted values (“% Inhn. Plus Copper Predicted”) that were calculated using the formula set forth by S. R. Colby in Weeds 1967, 15, 20-22 based on results obtained for the same compounds in copper-minus medium (“% Inhn. Minus Copper Observed”) and the inhibition attributed to copper chloride alone, as determined by comparing growth in copper-minus and copper-plus media without any test compound across experiments. Data are presented in Table 9. Results show that fungitoxicity of metal complexes of hydrazones towards LEPTNO is synergistically enhanced in the presence of added copper. Furthermore, the fungitoxicity of copper complexes of hydrazones is synergistically enhanced in the presence of added copper.
  • TABLE 9
    % Inhn. % Inhn. % Inhn.
    Minus Plus Plus
    Complex Compound Concn. copper copper copper
    Number Number Metal salt Ratio* (μg/mL) Observed Observed Predicted
    593 77 FeCl3•6H2O 1:1 0.05 31.3 93.7 33.6
    594 77 FeCl3•6H2O 2:1 0.05 0.8 92.7 4.1
    595 77 FeCl3•6H2O 3:1 0.05 9.8 93.3 12.8
    596 16 Cu(OCOCH3)2•H2O 1:1 0.0125 4.5 56.7 7.7
    596 16 Cu(OCOCH3)2•H2O 1:1 0.0125 6.4 85.4 9.5
    598 16 CuSO4•5H2O 1:1 0.10 57.3 91.2 58.7
    599 16 CuSO4•5H2O 2:1 0.0125 28.6 55.2 31.0
    600 16 CuCl2•2H2O 1:1 0.0125 29.6 84.3 31.9
    601 16 CuCl2•2H2O 2:1 0.0125 27.2 68.9 29.6
    611 16 MnCl2•4H2O 2:1 0.05 36.6 96.1 38.8
    612 16 ZnCl2 2:1 0.05 36.3 67.5 38.5
    CuCl2, 10 3.3
    μM
    *Molar ratio of hydrazone:metal used to prepare complexes.
    • Example 34 Effect of Copper on Fungitoxicity of Metal-Hydrazone Complexes Towards Phytophthora capsici
  • In vitro fungitoxicity assays against Phytophthora capsici were conducted using the copper-minus AS medium described in Example 28. Medium containing copper was prepared by adding CuCl2.2H2O to the copper-minus AS medium at 100 μM. Test compounds were dissolved in dimethylsulfoxide (DMSO) then dilutions in copper-minus AS and copper-plus AS media were prepared as 100 μL aliquots in flat-bottomed 96-well microtiter plates. Microtiter plates were inoculated with 100 μL of zoospore suspension at a concentration of 5×104 spores per mL, prepared as in Example 28. The plates were incubated at 25° C. for 48 h before assessing fungal growth by measuring light scattering in a NepheloStar plate reader. Growth inhibition was determined by comparing growth in the presence of test compound with growth in control wells lacking test compound.
  • Results for growth inhibition by test compounds in copper-plus AS medium (“% Inhn. Plus Copper Observed”) were compared with predicted values (“% Inhn. Plus Copper Predicted”) that were calculated using the formula set forth by S. R. Colby in Weeds 1967, 15, 20-22 based on results obtained for the same compounds in copper-minus AS medium (“% Inhn. Minus Copper Observed”) and the inhibition attributed to copper chloride alone, as determined by comparing growth in copper-minus and copper-plus media without any test compound across experiments. Data are presented in Table 10. Results show that fungitoxicity of metal complexes of hydrazones towards Phytophthora capsici is synergistically enhanced in the presence of added copper. Furthermore, the fungitoxicity of copper complexes of hydrazones is synergistically enhanced in the presence of added copper.
  • TABLE 10
    % Inhn. % Inhn. % Inhn.
    Minus Plus Plus
    Complex Compound Concn. copper copper copper
    Number Number Metal salt Ratio* (μg/mL) Observed Observed Predicted
    593 77 FeCl3•6H2O 1:1 0.025 7.0 93.7 11.3
    594 77 FeCl3•6H2O 2:1 0.025 0.0 93.6 4.6
    595 77 FeCl3•6H2O 3:1 0.025 0.0 93.7 4.6
    596 16 Cu(OCOCH3)2•H2O 1:1 0.0125 0.9 95.4 5.5
    596 16 Cu(OCOCH3)2•H2O 1:1 0.025 10.1 95.8 14.3
    598 16 CuSO4•5H2O 1:1 0.025 0.0 94.8 4.6
    599 16 CuSO4•5H2O 2:1 0.025 8.4 96.1 12.6
    601 16 CuCl2•2H2O 2:1 0.025 4.1 94.0 8.5
    602 16 CuCl2•2H2O 1:1 0.025 12.7 94.4 16.7
    611 16 MnCl2•4H2O 2:1 0.025 9.3 95.1 13.5
    612 16 ZnCl2 2:1 0.025 5.2 90.2 9.6
    CuCl2, 50 0.025 4.6
    μM
    *Molar ratio of hydrazone:metal used to prepare complexes.
    • Example 35 Fungitoxicity of Copper-Hydrazone Mixtures Containing Different Ratios of Components Towards Leptosphaeria nodorum
  • In vitro fungitoxicity assays against LEPTNO were conducted using the copper-minus medium described in Example 26. Mixtures containing hydrazone compound 16 at 200 nM and CuCl2 at 0.2 μM (1:1 molar ratio), 0.8 μM (1:4 ratio), 12.5 μM (1:62.5 ratio) and 200 μM (1:1000 ratio) were prepared in copper-minus medium. Two-fold dilution series of these mixtures were then prepared in 100 μL aliquots of copper-minus medium in flat-bottomed 96-well microtiter plates. A suspension of LEPTNO spores in copper-minus medium at 2×105 spores per mL was prepared as in Example 26. Microtiter plates were inoculated with 100 μL of the spore suspension and the plates were incubated at 25° C. for 72 h before assessing fungal growth by measuring light scattering in a NepheloStar plate reader.
  • Growth inhibition was determined by comparing growth in the presence of copper-hydrazone mixture with growth in control wells lacking the copper-hydrazone mixture. EC50 values were calculated from dose-response curves, and are expressed as the amounts of hydrazone or copper in each test mixture at the rates providing 50% inhibition of growth as compared to a control lacking the copper-hydrazone mixture. Data are presented in Table 11. The results show that copper-hydrazone mixtures representing a wide range of molar ratios of copper:hydrazone are substantially more efficacious against LEPTNO than either hydrazone or copper alone.
  • TABLE 11
    Amounts of hydrazone and CuCl2
    at EC50 values
    Hydrazone CuCl2
    Hydrazone:Cu ratio EC50 (nM) EC50 (μM)
    Hydrazone without CuCl2 >3200
    1 to 1 72.2 0.072
    1 to 4 43.0 0.172
    1 to 62.5 28.4 1.77
    1 to 1000 14.0 14.0
    CuCl2 without hydrazone 117.9
    • Example 36 Fungitoxicity of Copper-Hydrazone Mixtures Containing Different Ratios of Components Towards Phytophthora capsici
  • In vitro fungitoxicity assays against Phytophthora capsici were conducted using the copper-minus AS medium described in Example 28. Mixtures containing hydrazone compound 16 at 200 nM and CuCl2.2H2O at 0.2 μM (1:1 molar ratio), 0.8 μM (1:4 ratio), 3.2 μM (1:16 ratio), 12.5 μM (1:62.5 ratio), 50 μM (1:200 ratio) and 200 μM (1:1000 ratio) were prepared in copper-minus AS medium. Two-fold dilution series of these mixtures were then prepared in 100 μL aliquots of copper-minus AS medium in flat-bottomed 96-well microtiter plates. A suspension of P. capsici zoospores in Chelex-treated water at 5×104 spores per mL was prepared as in Example 28. Microtiter plates were inoculated with 100 μL of the spore suspension and incubated at 25° C. for 48 h before assessing fungal growth by measuring light scattering in a NepheloStar plate reader.
  • Growth inhibition was determined by comparing growth in the presence of copper-hydrazone mixture with growth in control wells lacking the copper-hydrazone mixture. EC50 values were calculated from dose-response curves, and are expressed as the amounts of hydrazone or copper in each test mixture at the rates providing 50% inhibition of growth as compared to a control lacking the copper-hydrazone mixture. Data are presented in Table 12. The results show that copper-hydrazone mixtures representing a wide range of molar ratios of copper:hydrazone are substantially more efficacious against Phytophthora capsici than either hydrazone or copper alone.
  • TABLE 12
    Amounts of hydrazone and CuCl2
    at EC50 values
    Hydrazone CuCl2
    Hydrazone:Cu ratio EC50 (nM) EC50 (μM)
    Hydrazone without CuCl2 143.2
    1 to 1 71.1 0.071
    1 to 4 47.1 0.189
    1 to 16 27.5 0.441
    1 to 62.5 16.6 1.04
    1 to 250 7.6 1.90
    1 to 1000 4.6 4.56
    CuCl2 without hydrazone 720.0
    • Example 37 Synergistic Effect Between Hydrazone Compound 16 and Various Copper Materials Against Tomato Late Blight (Phytophthora infestans), Tomato Early Blight (Alternaria solani), and Cucumber Anthracnose (Colletotrichum lagenarium)
  • Hydrazone compound 16 was tested alone or in combination with CuCl2.2H2O, CuSO4.5H2O, Kocide® 2000 (copper hydroxide), or CUREX 3 (tribasic copper sulfate). All materials and mixtures were evaluated as prophylactic treatments applied 24 h before inoculation. Efficacy was determined based on percentage of disease control against tomato late blight (Phytophthora infestans), tomato early blight (Alternaria solani), and anthracnose on cucumbers (Colletotrichum lagenarium). Treatments were arranged as a factorial experiment in a completely randomized design. Hydrazone and copper were regarded as factors with hydrazone at 10, 50, 200, and 400 μM, and copper materials at 10, 50, 200, 400, and 800 μM with respect to their copper content. All treatments were performed in triplicate. Plant varieties used were Outdoor Girl and Bush Pickle, for tomato and cucumber, respectively. Treatments were prepared in 0.01% Triton® X-100 and applied to run-off 24 h before inoculation using a spin-table sprayer. Inoculation was performed with aqueous spore suspensions using a Delta painting sprayer. Percentage of disease control was determined 7 days after inoculation.
  • Results (Tables 13-24) for disease control by hydrazone-copper mixtures were compared with predicted values (shown in brackets) which were calculated using the Colby formula based on disease control by the hydrazone alone and copper material alone. The data show that hydrazone-copper mixtures provided greater disease control than predicted based on control delivered by the individual components of the mixtures.
  • TABLE 13
    Synergistic fungicidal effect between hydrazone Compound 16 and
    CuCl2•2H2O against tomato late blight (Phytophthora infestans)
    % Control of Tomato Late Blight
    CuCl2 Hydrazone (μM)
    (μM) 0 10 50 200 400
    0 0.0 1.5 11.3 21.4 25.7
    10 1.7 33.5 (3.1)  41.9 (12.8) 67.8 (22.7) 64.4 (26.9)
    50 8.5 39.7 (9.9)  63.0 (18.8) 96.6 (28.1) 91.7 (32.0)
    200 38.2 69.0 (39.2) 91.5 (45.2) 95.8 (51.5) 91.7 (54.1)
    400 56.0 75.7 (56.6) 91.7 (60.9) 90.8 (65.4) 99.8 (67.3)
    800 70.2 94.2 (70.7) 98.3 (73.6) 96.7 (76.6) 100.0 (77.9) 
  • TABLE 14
    Synergistic fungicidal effect between hydrazone Compound 16 and
    CuSO4•5H2O against tomato late blight (Phytophthora infestans)
    % Control of Tomato Late Blight
    CuSO4 Hydrazone (μM)
    (μM) 0 10 50 200 400
    0 0 1.5 11.3 21.4 25.7
    10 1.7 26.3 (3.1)  56.8 (12.8) 78.0 (22.7) 41.5 (26.9)
    50 4.8 28.1 (6.2)  67.7 (15.5) 81.3 (25.1) 54.5 (29.2)
    200 49.7 56.0 (50.4) 72.9 (55.4) 93.2 (60.4) 87.2 (62.6)
    400 76.0 77.3 (76.4) 78.0 (78.8) 95.8 (81.2) 96.6 (82.2)
    800 82.9 72.2 (83.1) 91.6 (84.8) 97.5 (86.5) 98.3 (87.3)
  • TABLE 15
    Synergistic fungicidal effect between hydrazone Compound 16 and Kocide ® 2000
    against tomato late blight (Phytophthora infestans)
    % Control of Tomato Late Blight
    Kocide ® Hydrazone (μM)
    (μM) 0 10 50 200 400
    0 0 1.5 11.3 21.4 25.7
    10 5.8 26.8 (7.2)  41.2 (16.4) 53.4 (26.0) 65.3 (30.0)
    50 6.8 43.1 (8.2)  46.4 (17.3) 77.3 (26.7) 79.6 (30.8)
    200 30.4 51.6 (31.4) 65.8 (38.3) 94.8 (45.3) 93.2 (48.3)
    400 63.1 64.9 (63.7) 78.3 (67.3) 89.9 (71.0) 94.9 (72.6)
    800 67.4 80.8 (67.9) 95.6 (71.1)  100 (74.4)  100 (75.8)
  • TABLE 16
    Synergistic fungicidal effect between hydrazone Compound 16 and
    CUREX 3 against tomato late blight (Phytophthora infestans)
    % Control of Tomato Late Blight
    CUREX 3 Hydrazone (μM)
    (μM) 0 10 50 200 400
    0 0 1.5 11.3 21.4 25.7
    10 0.0 42.4 (1.5)  72.9 (11.3) 77.9 (21.4) 61.7 (25.7)
    50 0.0 61.0 (1.5)  88.0 (11.3) 88.0 (21.4) 85.5 (25.7)
    200 26.2 63.6 (27.3) 88.9 (34.5) 100.0 (42.0)  93.5 (45.1)
    400 41.2 77.3 (42.0) 96.7 (47.8) 96.7 (53.8) 98.3 (56.3)
    800 60.8 89.8 (61.4) 97.4 (65.3) 99.5 (69.2) 99.1 (70.9)
  • TABLE 17
    Synergistic fungicidal effect between hydrazone Compound 16 and
    CuCl2•2H2O against tomato early blight (Alternaria solani)
    % Control of Tomato Early Blight
    CuCl2 Hydrazone (μM)
    (μM) 0 10 50 200 400
    0 0.0 3.9 8.0 28.4 32.4
    10 0.0 38.4 (3.9)  39.8 (8.0)  46.1 (28.4) 59.2 (32.4)
    50 0.0 44.5 (3.9)  56.0 (8.0)  69.9 (28.4) 86.3 (32.4)
    200 50.4 62.1 (52.4) 73.2 (54.5) 82.0 (64.5) 94.7 (66.5)
    400 72.5 80.3 (73.6) 79.7 (74.7) 94.2 (80.3) 98.1 (81.4)
    800 83.3 86.0 (83.9) 89.6 (84.6) 98.8 (88.0) 98.3 (88.7)
  • TABLE 18
    Synergistic fungicidal effect between hydrazone Compound 16 and
    CuSO4•5H2O against tomato early blight (Alternaria solani)
    % Control of Tomato Early Blight
    CuSO4 Hydrazone (μM)
    (μM) 0 10 50 200 400
    0 0 3.9 8.0 28.4 32.4
    10 0.0 48.7 (3.9)  53.8 (8.0)  55.6 (28.4) 54.7 (32.4)
    50 7.1 53.0 (10.7) 70.5 (14.5) 74.6 (33.5) 80.9 (37.2)
    200 54.4 66.0 (56.2) 83.0 (58.1) 89.7 (67.4) 89.4 (69.2)
    400 64.1 82.1 (65.5) 89.5 (67.0) 93.3 (74.3) 96.8 (75.7)
    800 71.6 83.5 (72.7) 93.0 (73.9) 96.0 (79.7) 97.7 (80.8)
  • TABLE 19
    Synergistic fungicidal effect between hydrazone Compound 16 and Kocide ® 2000
    against tomato early blight (Alternaria solani)
    % Control of Tomato Early Blight
    Kocide ® Hydrazone (μM)
    (μM) 0 10 50 200 400
    0 0 3.9 8 28.4 32.4
    10 1.1 35.6 (5.0)  52.4 (9.0)  29.8 (29.2) 27.2 (33.1)
    50 3.9 55.4 (7.6)  77.6 (11.6) 69.8 (31.2) 75.3 (35.0)
    200 36 66.1 (38.5) 92.4 (41.1) 84.8 (54.2) 81.4 (56.7)
    400 52.7 74.7 (54.5) 92.2 (56.5) 92.4 (66.1) 90.6 (68.0)
    800 62.9 83.4 (64.3) 93.6 (65.9) 93.4 (73.4) 95.1 (74.9)
  • TABLE 20
    Synergistic fungicidal effect between hydrazone Compound 16 and
    CUREX 3 against tomato early blight (Alternaria solani)
    % Control of Tomato Early Blight
    CUREX 3 Hydrazone (μM)
    (μM) 0 10 50 200 400
    0 0 3.9 8.0 28.4 32.4
    10 0.0 39.6 (3.9)  29.2 (8.0) 46.0 (28.4) 44.2 (32.4)
    50 4.9 48.5 (8.6)  64.4 (12.5) 74.8 (31.9) 65.1 (35.7)
    200 36.6 54.7 (39.1) 74.7 (41.7) 85.1 (54.6) 82.3 (57.2)
    400 49.1 65.6 (51.1) 80.0 (53.2) 94.9 (63.6) 93.4 (65.6)
    800 40.2 63.6 (42.5) 88.0 (45.0) 96.6 (57.2) 94.9 (59.6)
  • TABLE 21
    Synergistic fungicidal effect between hydrazone
    Compound 16 and CuCl2•2H2O against cucumber
    anthracnose (Colletotrichum lagenarium).
    % Control of Cucumber Anthracnose
    CuCl2 Hydrazone (μM)
    (μM) 0 10 50 200 400
    0 0 10.0 33.8 63.8 70.8
    10 9.6 46.9 (18.6) 72.5 (40.1) 82.8 (67.3) 83.6 (73.6)
    50 1.4 47.8 (11.3) 81.0 (34.8) 86.2 (64.3) 89.0 (71.2)
    200 37.2 73.0 (43.5) 85.3 (58.4) 95.4 (77.3) 98.9 (81.7)
    400 76.2 87.2 (78.6) 94.9 (84.2) 98.8 (91.4) 99.6 (93.0)
    800 90.0 91.0 (91.0) 97.5 (93.4) 97.8 (96.4) 98.6 (97.1)
  • TABLE 22
    Synergistic fungicidal effect between hydrazone
    Compound 16 and CuSO4•5H2O against cucumber
    anthracnose (Colletotrichum lagenarium).
    % Control of Cucumber Anthracnose
    CuSO4 Hydrazone (μM)
    (μM) 0 10 50 200 400
    0 0 10.0 33.8 63.8 70.8
    10 1.4 55.8 (11.2) 67.5 (34.7) 94.5 (64.3) 90.7 (71.2)
    50 0.0 58.9 (10.0) 78.3 (33.8) 92.0 (63.8) 98.7 (70.8)
    200 61.3 70.6 (65.2) 89.8 (74.4) 97.5 (86.0) 99.6 (88.7)
    400 75.7 92.0 (78.1) 95.2 (83.9) 98.4 (91.2) 99.7 (92.9)
    800 87.1 96.2 (88.4) 95.6 (91.5) 96.5 (95.3) 99.6 (96.2)
  • TABLE 23
    Synergistic fungicidal effect between hydrazone Compound 16 and Kocide ® 2000
    against cucumber anthracnose (Colletotrichum lagenarium)
    % Control of Cucumber Anthracnose
    Kocide ® Hydrazone (μM)
    (μM) 0 10 50 200 400
    0 0 10 33.8 63.8 70.8
    10 15.9 40.4 (24.3) 56.5 (44.3) 83.7 (69.6) 72.2 (75.4)
    50 15 64.9 (23.5) 83.7 (43.7) 93.9 (69.2)  97 (75.2)
    200 28.9  80 (36.0) 95.3 (52.9) 97.2 (74.3) 97.5 (79.2)
    400 68.8 79.9 (71.9) 89.5 (79.3) 99.4 (88.7) 98.5 (90.9)
    800 67.5 90.3 (70.8) 95.9 (78.5) 99.2 (88.2) 99.3 (90.5)
  • TABLE 24
    Synergistic fungicidal effect between hydrazone Compound 16 and CUREX
    3 against cucumber anthracnose (Colletotrichum lagenarium)
    % Control of Cucumber Anthracnose
    CUREX 3 Hydrazone (μM)
    (μM) 0 10 50 200 400
    0 0 10.0 33.8 63.8 70.8
    10 7.8 42.1 (17.0) 78.0 (39.0) 84.4 (66.6) 93.0 (73.1)
    50 10.9 51.9 (19.8) 91.4 (41.0) 92.8 (67.7) 95.8 (74.0)
    200 23.0 58.6 (30.7) 93.5 (49.0) 99.1 (72.1) 99.2 (77.5)
    400 38.7 71.1 (44.8) 92.9 (59.4) 99.4 (77.8) 98.3 (82.1)
    800 31.5 55.2 (38.4) 84.0 (54.7) 96.2 (75.2) 95.0 (80.0)
    • Example 38 Control of Grape Downy Mildew (Plasmopara viticola) and Tomato Late Blight (Phytophthora infestans) by Compound 16, its Copper Complex, and Copper Chloride
  • Test compounds were hydrazone Compound 16, the complex of Compound 16 with copper (“hydrazone-copper”) prepared by precipitation with CuCl2.2H2O using a 1:1 molar ratio, and CuCl2.2H2O alone. Hydrazone and hydrazone-copper were formulated in 10% acetone/0.1% Trycol 5941 in de-ionized water. CuCl2.2H2O was formulated with 0.1% Trycol 5941 in de-ionized water. Grape and tomato plants were sprayed with 160 μM suspensions of the formulated test compounds at a spray volume of 0.8 mL per plant. After 24 h, the undersides of the grape leaves were inoculated with an aqueous suspension of Plasmopara viticola sporangia and tomato plants were inoculated with an aqueous suspension of Phytophthora infestans sporangia. Plants were kept in high humidity overnight, then transferred to a greenhouse (grapes) or growth room (tomatoes) until disease developed on untreated control plants.
  • Results for disease control by hydrazone-copper were compared with predicted results calculated using the Colby formula based on disease control by the hydrazone alone and CuCl2 alone. Results, shown in Table 25, show that hydrazone-copper provided greater disease control than predicted based on control observed for hydrazone and CuCl2 alone.
  • TABLE 25
    % Control % Control
    Disease Treatment μM Observed Predicted
    Downy mildew Hydrazone 16 160 29
    Hydrazone-copper 600 160 78 30
    CuCl2 160 1
    Late blight Hydrazone 16 160 49
    Hydrazone-coppper 600 160 100 84
    CuCl2 160 69
  • While this disclosure has been described as having exemplary compounds, the present disclosure can be further modified within the spirit and scope of this disclosure. For example, all of the disclosed components of the preferred and alternative embodiments are interchangeable providing disclosure herein of many systems having combinations of all the preferred and alternative embodiment components. This application is therefore intended to cover any variations, uses, or adaptations of the disclosure using its general principles. Further, this application is intended to cover such departures from the present disclosure as come within known or customary practice in the art to which this disclosure pertains and which fall within the limits of the appended claims.

Claims (16)

1. A synergistic mixture for controlling the growth of fungi, the synergistic mixture including copper and a hydrazone compound of Formula 1:
Figure US20120010075A1-20120112-C00618
wherein A is oxygen or sulfur;
Z is H or C1-C4 alkyl;
W is —CHR1-;
n is 0, 1, or 2;
R is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl C2-C6 haloalkynyl, or C3-C6 halocycloalkyl;
R1 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl C2-C6 haloalkynyl, C3-C6 halocycloalkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, or unsubstituted heteroaryl;
X3, X4, X5, and X6 are each independently selected from the group consisting of H, halogen, nitro, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkylthio, C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C4 haloalkenyl, C2-C4 haloalkynyl, C1-C4 haloalkylthio, —SO2R1, SONR1R1, —CR1=NOR1, —CONR1R1, NR1COOR1, —COOR1, substituted aryl, substituted heteroaryl, unsubstituted aryl, and unsubstituted heteroaryl; and
Y2, Y3, Y4, Y5, and Y6 are each independently selected from the group consisting of H, halogen, nitro, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkylthio, C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C4 haloalkenyl, C2-C4 haloalkynyl, C1-C4 haloalkylthio, —SO2R1, SONR1R1, —R1=NOR1, —CONR1R1, NR1COOR1, —COOR1, NR1R1, substituted aryl, substituted heteroaryl, unsubstituted aryl, unsubstituted heteroaryl, and phenoxy;
with the proviso that X3 and X4, X4 and X5, X5 and X6, Y2 and Y3, or Y3 and Y4 may form a 5 or 6 membered fused ring which may contain up to two heteroatoms selected from the group consisting of O, N, and S.
2. Use of the synergistic mixture of claim 1 for controlling the growth of fungal pathogens of plants.
3. Use of the synergistic mixture of claim 1 for controlling the growth of fungal of mammals.
4. Use of the synergistic mixture of claim 1 for controlling the growth of fungi on inert substrates selected from the group consisting essentially of wood, metal, and plastic.
5. Use of the synergistic mixture of claim 1 for controlling the growth of fungi belonging to at least one of Ascomycete, Basidiomycete, Oomycete, and Deuteromycete classes of fungi.
6. The synergistic mixture of claim 1 wherein the fungi is selected from the group consisting of Phytophthora species, Plasmopara viticola, Pseudoperonospora cubensis, Pythium species, Pyricularia oryzae, Colletotrichum species, Helminthosporium species, Alternaria species, Septoria nodorum, Leptosphaeria nodorum, Ustilago maydis, Erysiphe graminis, Puccinia species, Sclerotinia species, Sphaerotheca fuliginea, Cercospora species, Rhizoctonia species, Uncinula necator and Podosphaera leucotricha.
7. The synergistic mixture of claim 1, wherein a growth inhibiting amount of the hydrazone compound of Formula I in mixture with copper is provided as a mixture in which the total molar ratio of copper to the hydrazone compound of Formula 1 exceeds 1:1.
8. The synergistic mixture of claim 1, wherein a growth inhibiting amount of the hydrazone compound of Formula I is provided as an isolated hydrazone-copper complex in which the molar ratio of the copper to the hydrazone compound of Formula 1 is one of 1:1 and 1:2.
9. The synergistic mixture of claim 1, wherein the hydrazone compound of Formula 1 to be combined with copper is complexed with a metal.
10. The synergistic mixture of claim 8, wherein the metal complexed with the hydrazone compound of Formula 1 is selected from the group consisting essentially of Cu+, Cu2+, Fe2+, Fe3+, Zn2+, and Mn2+.
11. The synergistic mixture of claim 1, wherein the copper is provided as at least one of the group consisting of copper oxychloride, copper octanoate, copper ammonium carbonate, copper arsenate, copper oxysulfate, copper formate, copper propionate, copper oxyacetate, copper citrate, copper chloride, copper diammonium chloride, copper nitrate, copper carbonate, copper phosphate, copper pyrophosphate, copper disodium EDTA, copper diammonium EDTA, copper oxalate, copper tartrate, copper gluconate, copper glycinate, copper glutamate, copper aspartate, copper adipate, copper palmitate, copper stearate, copper caprylate, copper decanoate, copper undecylenate, copper neodecanoate, copper linoleate, copper oleate, copper borate, copper methanesulfonate, copper sulfamate, copper acetate, copper hydroxide, copper oxide, copper oxychloride-sulfate, copper sulfate, basic copper sulfate, copper-oxine, copper 3-phenylsalicylate, copper chloride hydroxide, copper dimethyldithiocarbamate, ammonium copper sulfate, copper magnesium sulfate, coppernaphthenate, copper ethanolamine, chromated copper arsenate, ammoniacal copper arsenate, ammoniacal copper zinc arsenate, ammoniacal copper borate, Bordeaux mixture, copper zinc chromate, cufraneb, cupric hydrazinium sulfate, cuprobam, nano-copper materials, and copper didecyldimethylammonium chloride.
12. The synergistic mixture of claim 1, wherein
W is —CHR— or —CH(R)O—;
n is 0 or 1;
A is O or S;
R is H, C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl;
R1 is H, C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, substituted aryl, or unsubstituted aryl;
Z is H or —C(CH3)3;
X3, X4, X5, and X6 are each independently selected from the group consisting of H, halogen, nitro, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C2-C4 alkenyl, and C1-C4 alkylthio; and
Y2, Y3, Y4, Y5, and Y6 are each independently selected from the group consisting of H, halogen, nitro, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy C1-C4 alkylthio, —NR1R1, substituted aryl, unsubstituted aryl, and phenoxy;
with the proviso that X3 and X4, X5 and X6, or Y3 and Y4 may form a 5 or 6 membered fused ring which may contain up to two heteroatoms selected from the group consisting of O and N.
13. The synergistic mixture of claim 12, wherein
W is —CH2—;
n is 0 or 1;
A is O or S;
R is H, C1-C4 alkyl, or C3-C6 cycloalkyl;
Z is H;
X3, X4, X5, and X6 are each independently selected from the group consisting of H, halogen, nitro, C1-C2 alkyl, C1-C2 haloalkyl, and C1-C2 alkoxy; and
Y2, Y3, Y4, Y5, and Y6 are each independently selected from the group consisting of H, halogen, nitro, hydroxyl, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy;
with the proviso that Y3 and Y4 may form a 5 or 6 membered fused ring which may contain up to two heteroatoms selected from the group consisting of O and N.
14. The synergistic mixture of claim 13, wherein
n is 0;
A is 0;
R is H, C1-C4 alkyl, or cyclopropyl;
Z is H;
X3, X4, X5, and X6 are each independently selected from the group consisting of H, halogen, nitro, methyl, trifluoromethyl, and methoxy;
Y2, Y3, Y4, Y5, and Y6 are each independently selected from the group consisting of H, halogen, nitro, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
with the proviso that Y3 and Y4 may form a 5 or 6 membered fused ring which may contain up to two oxygen atoms.
15. The synergistic mixture of claim 1, wherein a ratio of the hydrazone to the copper is from 1:0.1 to 1:10,000.
16. An agriculturally active composition including the synergistic mixture of claim 1 and at least one of a herbicide, an insecticide, a bacteriocide, a nematocide, a miticide, a biocide, a termiticide, a rodenticide, a molluscide, a arthropodicide, a fertilizer, a growth regulator, and a pheromone.
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