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WO2023023572A1 - Molecules having certain pesticidal utilities, and intermediates, compositions, and processes related thereto - Google Patents

Molecules having certain pesticidal utilities, and intermediates, compositions, and processes related thereto Download PDF

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Publication number
WO2023023572A1
WO2023023572A1 PCT/US2022/075104 US2022075104W WO2023023572A1 WO 2023023572 A1 WO2023023572 A1 WO 2023023572A1 US 2022075104 W US2022075104 W US 2022075104W WO 2023023572 A1 WO2023023572 A1 WO 2023023572A1
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Prior art keywords
alkyl
phenyl
haloalkyl
triazol
cycloalkyl
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PCT/US2022/075104
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French (fr)
Inventor
Erich W. Baum
Gary Crouse
David A. Demeter
Natalie C. GIAMPIETRO
Lindsey G. HORTY
Jeffrey Petkus
Thomas C. Sparks
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Corteva Agriscience Llc
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Publication of WO2023023572A1 publication Critical patent/WO2023023572A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
    • A01N47/30—Derivatives containing the group >N—CO—N aryl or >N—CS—N—aryl
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
    • A01N47/36—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N< containing the group >N—CO—N< directly attached to at least one heterocyclic ring; Thio analogues thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P7/00—Arthropodicides
    • A01P7/02—Acaricides
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P7/00—Arthropodicides
    • A01P7/04—Insecticides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This disclosure relates to the field of molecules having pesticidal utility against pests in Phyla Arthropoda, Mollusca, and Nematoda, processes to produce such molecules, intermediates used in such processes, and processes of using such pesticidal compositions against such pests.
  • These pesticidal compositions may be used, for example, as acaricides, insecticides, miticides, molluscicides, and nematicides.
  • Vector-borne diseases are responsible for about 17% of the global parasitic and infectious diseases. Malaria alone causes over 800,000 deaths a year, 85% of which occur in children under five years of age. Each year there are about 50 to about 100 million cases of dengue fever. A further 250,000 to 500,000 cases of dengue hemorrhagic fever occur each year (Matthews., Integrated Vector Management: Controlling Vectors of Malaria and Other Insect Vector Borne Diseases, Ch. 1, p. 1, 2011). Vector control plays a critical role in the prevention and control of infectious diseases. However, insecticide resistance, including resistance to multiple insecticides, has arisen in all insect species that are major vectors of human diseases (Rivero et al.).
  • arthropod species have developed resistance to at least one pesticide (Whalon et al., Analysis of Global Pesticide Resistance in Arthropods, Global Pesticide Resistance in Arthropods, Ch. 1, p. 5-33, 2008). Furthermore, the cases of insect resistance continue to exceed by far the number of cases of herbicide and fungicide resistance (Sparks et al., IRAC: Mode of action classification and insecticide resistance management, Pesticide Biochemistry and Physiology (2014) available online 4 December 2014).
  • Plant parasitic nematodes are among the most widespread pests, and are frequently one of the most insidious and costly. It has been estimated that losses attributable to nematodes are from about 9% in developed countries to about 15% in undeveloped countries. However, in the United States of America a survey of 35 States on various crops indicated nematode-derived losses of up to 25% (Nicol et al., Current Nematode Threats to World Agriculture, Genomic and Molecular Genetics of Plant - Nematode Interactions, p. 21-43, 2011).
  • gastropods are pests of less economic importance than other arthropods or nematodes, but in certain places, they may reduce yields substantially, severely affecting the quality of harvested products, as well as, transmitting human, animal, and plant diseases. While only a few dozen species of gastropods are serious regional pests, a handful of species are important pests on a worldwide scale. In particular, gastropods affect a wide variety of agricultural and horticultural crops, such as, arable, scenic, and fiber crops; vegetables; bush and tree fruits; herbs; and ornamentals (Speiser, B., Molluscicides, Encyclopedia of Pest Management, Ch. 219, p. 506-508, 2002).
  • Termites cause damage to all types of private and public structures, as well as to agricultural and forestry resources. In 2005, it was estimated that termites cause over USS50 billion in damage worldwide each year (Korb, J., Termites, Current Biology, Vol. 17, No. 23, 2007).
  • alkenyl means an acyclic, unsaturated (at least one carbon-carbon double bond), branched or unbranched, substituent consisting of carbon and hydrogen, for example, vinyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, and decenyl.
  • alkoxy means an alkyl further consisting of a carbon-oxygen single bond, for example, methoxy, ethoxy, propoxy, isopropoxy, 1 -butoxy, 2-butoxy, isobutoxy, tert-butoxy, pentoxy, 2-methylbutoxy, 1,1- dimethylpropoxy, hexoxy, heptoxy, octoxy, nonoxy, and decoxy.
  • alkyl means an acyclic, saturated, branched or unbranched, substituent consisting of carbon and hydrogen, for example, methyl, ethyl, propyl, isopropyl, 1 -butyl, 2 -butyl, isobutyl, tert-butyl, pentyl, 2-methylbutyl, 1,1 -dimethylpropyl, hexyl, heptyl, octyl, nonyl, and decyl.
  • alkynyl means an acyclic, unsaturated (at least one carbon-carbon triple bond, and any double bonds), branched or unbranched, substituent consisting of carbon and hydrogen, for example, ethynyl, propargyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, and decynyl.
  • aryl means a cyclic, aromatic substituent consisting of hydrogen and carbon, for example, phenyl, naphthyl, and biphenyl.
  • cycloalkenyl means a monocyclic or polycyclic, unsaturated (at least one carbon-carbon double bond) substituent consisting of carbon and hydrogen, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclodecenyl, norbomenyl, bicyclo[2.2.2]octenyl, tetrahydronaphthyl, hexahydronaphthyl, and octahydronaphthyl.
  • cycloalkyl means a monocyclic or polycyclic, saturated substituent consisting of carbon and hydrogen, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, norbomyl, bicyclo[2.2.2]octyl, and decahydronaphthyl.
  • cycloalkoxy means a cycloalkyl further consisting of a carbon-oxy gen single bond, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, cyclodecyloxy, norbomyloxy, andbicyclo[2.2.2]octyloxy.
  • halo means fluoro, chloro, bromo, and iodo.
  • haloalkyl means an alkyl further consisting of, from one to the maximum possible number of, identical or different, halos, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoromethyl, 2- fluoroethyl, 2,2,2-trifluoroethyl, chloromethyl, trichloromethyl, and 1,1,2,2-tetrafluoroethyl.
  • heterocyclyl means a cyclic substituent that may be fully saturated, partially unsaturated, or fully unsaturated, where the cyclic structure contains at least one carbon and at least one heteroatom, where said heteroatom is nitrogen, sulfitr, or oxygen. Examples are:
  • aromatic heterocyclyl substituents include, but are not limited to, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl, benzoxazolyl, benzothienyl, benzothiazolyl, cinnolinyl, furanyl, indazolyl, indolyl, imidazolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, 1,3,4-oxadiazolyl, oxazolinyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, 1,2,3,4-tetrazolyl, thiazolinyl, thiazolyl, thi
  • (2) fully saturated heterocyclyl substituents include, but are not limited to, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, and tetrahydropyranyl;
  • (3) partially or fully unsaturated heterocyclyl substituents include, but are not limited to, 4,5-dihydro- isoxazolyl, 4,5-dihydro-oxazolyl, 4, 5-dihydro- 1 //-pyrazolyl. 2,3-dihydro-[l,3,4]-oxadiazolyl, and 1,2,3,4-tetrahydro-quinolinyl; and
  • heterocyclyls include the following: thietanyl thietanyl-oxide and thietanyl-dioxide.
  • ambient pressure refers to pressures from about 80 kilopascals (kPa) to about 105 kPa.
  • the term “ambient temperature” or “room temperature” refers to temperatures ranging from about 20 °C to about 24 °C.
  • locus means a habitat, breeding ground, plant, seed, soil, material, or environment, m which a pest is growing, may grow, or may traverse.
  • a locus may be where crops, trees, fruits, cereals, fodder species, vines, turf, and/or ornamental plants, are growing; where domesticated animals are residing; the interior or exterior surfaces of buildings (such as places where grains are stored); the materials of construction used in buildings (such as impregnated wood); and the soil around buildings.
  • substituted furanyl, substituted phenyl, substituted pyridazinyl, substituted pyridyl, substituted pyrimidinyl, or substituted thienyl wherein said substituted furanyl, substituted phenyl, substituted pyridazinyl, substituted pyridyl, substituted pyrimidinyl, and substituted thienyl have one or more substituents independently selected from H, F, Cl, Br, I, CN, OH, SH, NO2, oxo, thioxo, NR x R y , Ci-Cg alkyl, Ci-Cg haloalkyl, Cs-Cg cycloalkyl, Ci-Cx halocycloalkyl, C’.-Cx cycloalkoxy, C 3 -C 8 halocycloalkoxy, Ci-C 8 alkoxy, Ci-C 8 haloalkoxy, CL-Cs alkenyl,
  • each alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkenyl, cycloalkenyl, haloalkenyl, alkynyl, phenyl, phenoxy, and (Het-1) substituent may be optionally substituted with one or more substituents independently selected from H, F, Cl, Br, I, CN, OH, SH, NO2, oxo, thioxo, NR*R y , Ci-C 8 alkyl, Ci-Cg haloalkyl, C 3 -Cg cycloalkyl, Ci-Cg halocycloalkyl, C 3 -C 8 cycloalkoxy, C 3 -C 8 halocycloalkoxy, Ci-Cs alkoxy, Ci-Cg haloalkoxy,
  • Het is a 5- or 6-membered, saturated or unsaturated, heterocyclic ring, containing one or more heteroatoms independently selected from nitrogen, sulfur, or oxygen, and where said heterocyclic ring may also be substituted with one or more substituents independently selected from H, F, Cl, Br, I, CN, OH, SH, NO 2 , oxo, thioxo, NR x R y , Ci-C 8 alkyl, Ci-Cg haloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 halocycloalkyl, C 3 -Cg cycloalkoxy, C 3 -C 8 halocycloalkoxy, Ci-Cg alkoxy, Ci-Cg haloalkoxy, C 2 -C 8 alkenyl, C 3 -Cg cycloalkenyl, C 2 -Cg haloalkenyl, C 2 -Cg alkynyl,
  • a 6-membered non-aromatic carbocyclic ring optionally substituted with one or more substituents independently selected fromH, Cl, Br, F, I, CN, oxo, Ci-Ce alkyl, Ci-Cs -haloalkyl, Ci-Cs alkoxy, Ci-Cs haloalkoxy, Ci-Ce alkylthio, Ci-Ce haloalkylthio, Cz-Cs alkenyl, C2-C6 haloalkenyl, and C2-C6 haloalkenyl;
  • (D) L is a linker selected from
  • each of R a , R b , R c , R d , R e , and R f is selected from H, F, Cl, Br, I, CN, OH, SH, NO2, oxo, thioxo,
  • each of Q 1 and Q 2 is independently selected from O or S;
  • R 2 and R 4 together may optionally form a 1- to 4-membered saturated or unsaturated, hydrocarbyl link, which may contain one or more heteroatoms selected from nitrogen, sulfur, and oxygen, and together with (Q 2 )(C)(N) forms a 4- to 7-membered cyclic structure, wherein said hydrocarbyl link may optionally be substituted with one or more substituents independently selected from H, F, Cl, Br, I, CN, OH, SH, NO 2 , oxo, thioxo, NR x R y , Ci-C 8 alkyl, Ci-C 8 haloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 halocycloalkyl, C 3 -C 8 cycloalkoxy, C 3 -C 8 halocycloalkoxy, Ci-C 8 alkoxy, Ci-C 8 haloalkoxy, C 2 -C 8 alkenyl, C 3 --
  • (L) (Het-1) is a 5- or 6-membered, saturated or unsaturated, heterocyclic ring, containing one or more heteroatoms independently selected from nitrogen, sulfur or oxygen, wherein said heterocyclic ring may also be substituted with one or more substituents independently selected from H, F, Cl, Br, I, CN, OH, SH, NO 2 , oxo, thioxo, NR x R y , Ci-C 8 alkyl, Ci-C 8 haloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 halocycloalkyl, C 3 -C 8 cycloalkoxy, C 3 -C 8 halocycloalkoxy, Ci-C 8 alkoxy, Ci-C 8 haloalkoxy, C 2 -C 8 alkenyl, C 3 -C 8 cycloalkenyl, C 2 -C 8 haloalkenyl, C 2 -C 8 alkyn
  • each alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, phenyl, and phenoxy may be optionally substituted with one or more substituents independently selected from H, F, Cl, Br, I, CN, OH, SH, NOz, oxo, thioxo, ⁇ R'R y .
  • Ar 1 is a phenyl or a substituted phenyl having one or more substituents independently selected from Ci-Cs alkyl, Ci-Ce haloalkyl, and Ci-Cg haloalkoxy;
  • Het is a triazolyl, imidazolyl, pyrrolyl, or pyrazolyl;
  • a 6-membered non-aromatic carbocyclic ring optionally substituted with one or more substituents independently selected fromH, Cl, Br, F, I, CN, oxo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylthio, Ci-Ce haloalkylthio, G-G, alkenyl, and G-G, haloalkenyl;
  • each of R 1 , R 4 , and R 5 is independently selected from H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or phenyl;
  • R 2 is selected from H, Ci-Ce alkyl, or (i);
  • R 2 and R 4 together may form a 1- to 4-membered saturated or unsaturated, hydrocarbyl link, which may contain one or more heteroatoms selected from nitrogen, sulfur, and oxygen, and together with (Q 2 )(C)(N) forms a 4- to 7-membered cyclic structure, wherein said hydrocarbyl link, wherein said hydrocarbyl link may optionally be substituted with one or more R 6 , wherein each R 6 is independently selected fromH, F, Cl, Br, I, CN, Ci-Ce alkyl, oxo, thioxo, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, phenyl, and phenoxy;
  • R 3 is selected from phenyl, (Ci-Ce alkyl)phenyl, or (Ci-Ce alkyl)-O-phenyl, wherein each alkyl and phenyl is optionally substituted with one or more substituents independently selected from F, Cl, Br, I, CN, NO2, oxo, thioxo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Cg alkoxy, Ci-Cg haloalkoxy, phenyl, or phenoxy.
  • Ar 1 is a phenyl. In another embodiment, Ar 1 is a substituted phenyl having one or more substituents independently selected from OCF 3 , OCF 2 CF 3 , and CF 3 . In another embodiment, Het is 1,2,4-triazolyl. In another embodiment, A is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or tetrahydropyridinyl. In another embodiment, A is substituted azetidinyl, substituted pyrrolidinyl, substituted piperidinyl, substituted piperazinyl, or substituted tetrahydropyridinyl.
  • A is piperidinyl, substituted piperidinyl, piperazinyl, substituted piperazinyl, tetrahydropyridinyl, or substituted tetrahydropyridinyl.
  • A is substituted piperidinyl, substituted piperazinyl, or substituted tetrahydropyridinyl having one or more substituents independently selected fromH, Cl, Br, F, I, oxo, Ci-Ce alkyl, Ci-Cg -haloalkyl, Ci-Ce alkoxy, and Ci-Ce haloalkoxy.
  • A is a cyclohexyl, cyclohexenyl, cyclohexadienyl, substituted cyclohexyl, substituted cyclohexenyl, or substituted cyclohexadienyl.
  • A is a substituted cyclohexyl, substituted cyclohexenyl, or substituted cyclohexadienyl having one or more substituents independently selected from H, Cl, Br, F, I, oxo, Ci-Cs alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, and Ci-Cg haloalkoxy.
  • L is a bond, -CH2-, or -CH2CH2-.
  • each of R 1 , R 4 and R 5 is independently H or Ci-Ce alkyl.
  • R 1 is H or Ci-Ce alkyl.
  • R 2 is H or Ci-Ce alkyl.
  • R 4 is H or Ci-Ce alkyl.
  • R 5 is H or Ci-Ce alkyl.
  • R 3 is a substituted phenyl having one or more substituents independently selected from F, Cl, Br, I, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, and Ci-Ce haloalkoxy.
  • the compound has a structure listed in Table 1A or Table IB.
  • the compound has the structure of Formula Three or Formula Four: wherein
  • A is a (1) 4-, 5- or 6- membered nitrogen-containing non-aromatic ring containing between 0 and 1 additional nitrogen atoms optionally substituted with one or more substituents independently selected from H, Cl, Br, F, I, CN, oxo, Ci-Ce alkyl, Ci-Cg -haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylthio, Ci-Ce haloalkylthio, C 2 -Ce alkenyl, and C 2 -Ce haloalkenyl; or
  • a 6-membered non-aromatic carbocyclic ring optionally substituted with one or more substituents independently selected fromH, Cl, Br, F, I, CN, oxo, Ci-Cg alkyl, Ci-Ce -haloalkyl, Ci-Cs alkoxy, Ci-Cs haloalkoxy, Ci-Ce alkylthio, Ci-Ce haloalkylthio, C 2 -Cs alkenyl, and C 2 -Cs haloalkenyl;
  • L is a bond, -CR a R b -, -CR a R b -CR c R d -, or -CR a R b -CR c R d -CR e R f -; wherein each R a , R b , R c , R d , R e , and R f is selected from H, F, Cl, Br, I, OH, CN, NO 2 , Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and phenyl;
  • R 3 is a substituted phenyl with 1, 2, 3, 4, or 5 substituents R 7 independently selected from F, Cl, Br, I, Ci- G, alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, and Ci-Ce haloalkoxy; and
  • R 8 is selected from Ci-Cg alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, and Ci-Cc haloalkoxy.
  • A is selected from the following:
  • L is abend, -CH 2 -, -CH 2 CH 2 -, -CHFCH 2 -, or -CH 2 CH(CH 3 )-.
  • R 7 represents one, two, or three substituents independently selected from F, Cl, Ci-Ce alkyl, Ci-Ce haloalkoxy and Ci-Ce alkoxy.
  • R 8 is selected from OCF 3 , OC FiCF .. and CF3.
  • a process comprising applying a compound provided herein, to an area to control a pest, in an amount sufficient to control such pest.
  • the pest is beet armyworm (B AW), cabbage looper (CL), or green peach aphid (GPA).
  • a compound that is a pesticidally acceptable acid addition salt, a salt derivative, a solvate, or an ester derivative, of a compound provided herein in another aspect, provided is a compound provided herein wherein at least one H is 2 H or at least one C is 14 C. In another aspect, provided is a composition comprising a compound provided herein and a seed.
  • a process comprising applying a compound provided herein to a genetically modified plant, or genetically -modified seed, which has been genetically modified to express one or more specialized traits.
  • a process comprising: orally administering; or topically applying; a compound provided herein, to a non-human animal, to control endoparasites, ectoparasites, or both.
  • the compounds are selected from the structures listed in Tables 1 A and IB, wherein said compound is selected from the group consisting of Al, A2, A3, A4, A5, A6, A7, A9, A10, All, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A27, A28, A29, Bl, B2, B3, B4, B5, and B6.
  • Thiobiurets disclosed herein are prepared from the corresponding isocyanate, Ar'-Hci-A-L-NCO (1-2). Usually, these isocyanates are not isolated, but are instead generated in situ from a suitable precursor and used directly in the preparation of a thiobiuret.
  • One such suitable precursor is an amine (1-1) which can be converted into an isocyanate by using one of several common reagents such as phosgene, diphosgene, triphosgene, or carbonyldiimidazole (Scheme 1, step a), in a mixed solvent system such as dichloromethane and water or diethyl ether and water, in the presence of a base such as sodium bicarbonate or triethylamine, at temperatures from about - 10 °C to about 50 °C.
  • phosgene diphosgene
  • triphosgene triphosgene
  • carbonyldiimidazole Scheme 1, step a
  • a mixed solvent system such as dichloromethane and water or diethyl ether and water
  • a base such as sodium bicarbonate or triethylamine
  • Formation of an acyl azide (Scheme 1, step b) occurs either by treatment of the acid with ethyl chloroformate and sodium azide in the presence of an amine base such as triethylamine, or with diphenylphosphoryl azide in the presence of an amine base such as triethylamine.
  • the acyl azide is then made to undergo a Curtins rearrangement leading to the corresponding isocyanate (1-2).
  • this rearrangement may occur spontaneously at ambient temperature, or it may require heating from about 40 °C to about 100 °C in a suitable solvent, such as toluene, acetonitrile, or an ethereal solvent such as dioxane or tetrahydrofuran.
  • a suitable solvent such as toluene, acetonitrile, or an ethereal solvent such as dioxane or tetrahydrofuran.
  • Azides of arylacetic acids are known, though due to their reactivity, are often not isolated as pure solids. Accordingly, the acyl azide intermediate is not always fully characterized, but may simply be heated directly without characterization, to generate the isocyanate.
  • An isocyanate, Ar'-Hei-A-L-NCO (1-2), can be treated directly with an V-ary 1 thiourea (2-1) in the presence of about 0.1 to about 2 equivalents of an inorganic base such as cesium carbonate or sodium hydride, resulting in the formation of a thiobiuret (2-2, Scheme 2).
  • an inorganic base such as cesium carbonate or sodium hydride
  • the reaction can be performed at temperatures from about 0 °C to about 100 °C, preferably from about 20 °C to about 80 °C, in an aprotic solvent or solvent mixture chosen from acetonitrile, acetone, toluene, tetrahydrofuran, 1,2-dichloroethane, dichloromethane, or mixtures thereof, but use of acetonitrile is preferred.
  • an aprotic solvent or solvent mixture chosen from acetonitrile, acetone, toluene, tetrahydrofuran, 1,2-dichloroethane, dichloromethane, or mixtures thereof, but use of acetonitrile is preferred.
  • Thiobiurets (2-2) generated in situ can be converted directly without purification into cyclized analogs (Scheme 3), or they can be isolated from the reaction medium prior to cyclization. Cyclization can be achieved by treatment with an oc-halo ester such as methyl bromoacetate to form 2-imino l,3-thiazolin-4-ones (3-1, step a) unsubstituted or mono- or di-substituted with R 5 .
  • a protic solvent such as ethanol or methanol
  • the reaction can be performed at temperatures from about 0 °C to about 100 °C, preferably from about 20 °C to about 80 °C, in an aprotic solvent or solvent mixture chosen from acetonitrile, acetone, toluene, tetrahydrofuran, 1,2-dichloroethane, dichloromethane, or mixtures thereof, but use of acetonitrile is preferred.
  • an aprotic solvent or solvent mixture chosen from acetonitrile, acetone, toluene, tetrahydrofuran, 1,2-dichloroethane, dichloromethane, or mixtures thereof, but use of acetonitrile is preferred.
  • the 4-imino-3-arylthiazolidinone-2-one (3-la) may be reacted with 4-nitrophenyl chloroformate (step b), forming a 4-nitrophenyl carbamate intermediate (3-2a).
  • This reaction is conducted with equimolar quantities of the imine and the chloroformate, in a polar aprotic solvent such as tetrahydrofuran or dioxane, and in the presence of from about 0.1 to about 2 equivalents of an inorganic base such as cesium carbonate or potassium carbonate, preferably at room temperature.
  • the intermediate (3-2a) may be isolated by filtration from inorganic salts and evaporation of solvent, or it can be used directly in step c.
  • step c treatment of 3 -2a with a primary or secondary alkyl amine Ari-Het-A-L-NHR 1 (3-3a), wherein R 1 is H or alkyl, respectively, may generate cyclized thiobiuret (3-1).
  • Step c may also be conducted in the presence of an inorganic base such as cesium carbonate or potassium carbonate, from about 0.1 to about 2 equivalents, preferably about 1 to about 1.2 equivalents; it is also most conveniently undertaken at room temperature, although it may be undertaken at temperatures from about 0 °C to about 100 °C.
  • an inorganic base such as cesium carbonate or potassium carbonate
  • Compounds of Formula One, Two, Three, Four, and/or Five can be prepared by making a three-ring intermediate, Ar'-Hei-A. and then linking it to an appropriate intermediate to form a desired compound.
  • a wide variety of three-ring intermediates can be used to prepare compounds of Formula One, Two, Three, Four, and/or Five, provided that such three-ring intermediates contain a suitable functional group on A and/or L to which the rest of the desired functional group can be attached.
  • Suitable functional groups include an amino, amino via nitro, isocyanate, carboxyl, or a halogen (preferably bromo or iodo).
  • the alcohol (OH) can be oxidized to the corresponding aldehyde 4-3, wherein Ar 1 , Het, and A are as previously disclosed, using pyridine-sulfur trioxide in the presence of dimethylsulfoxide, and a base, such as triethylamine, and in a solvent, such as dichloro methane, at a temperature from about 0 °C to about ambient temperature as in step b of Scheme 4.
  • a in 4-2 contains a -NHC(O)OC(CH 3 )3 group
  • the protecting group (C(O)OC(CH 3 )3) can be removed to provide the corresponding amine 4-4, wherein Ar 1 , Het, and A are as previously disclosed, using either trifluoroacetic acid or 4 molar (M) hydrogen chloride in dioxane in a solvent such as dichloromethane at a temperature from about 0 °C to about ambient temperature as in step c of Scheme 4.
  • the aldehyde 4-3 and amine 4- 4 can be further functionalized to arrive at the compounds of Formula One, Two, Three, Four, and/or Five.
  • a in 5-2 contains both an alkene and an ester such as -C(O)OCH2CH3
  • the alkene can first be reduced using hydrogen gas at about 480 kilopascal (kPa) / 70 pounds per square inch (psi) and a palladium catalyst such as 10% palladium on carbon to provide the alkane, and the ester can be reduced to the corresponding alcohol 5-3, wherein Ar 1 , Het, and A are as previously disclosed, using a reducing agent such as lithium aluminum hydride in a polar aprotic solvent such as tetrahydrofuran at a temperature from about 0 °C to about ambient temperature as in steps b and c of Scheme 5.
  • a reducing agent such as lithium aluminum hydride in a polar aprotic solvent such as tetrahydrofuran at a temperature from about 0 °C to about ambient temperature as in steps b and c of Scheme 5.
  • a in 5-2 contains an ester such as -C(O)OCH2CHa
  • the ester can be reduced to the corresponding alcohol 5-3, wherein Ar 1 , Het, and A are as previously disclosed, using a reducing agent such as lithium aluminum hydride in a polar aprotic solvent such as tetrahydrofuran at a temperature from about 0 °C to about ambient temperature as in step c of Scheme 5.
  • a reducing agent such as lithium aluminum hydride in a polar aprotic solvent such as tetrahydrofuran at a temperature from about 0 °C to about ambient temperature as in step c of Scheme 5.
  • a in 5-2 contains an ester such as -C(O)OCH2CH3
  • the ester can be saponified to the corresponding carboxylic acid 5-4, wherein Ar 1 , Het, and A are as previously disclosed, with a base such a 2 normal (N) sodium hydroxide in a polar solvent such as methanol at about ambient temperature as in step d of Scheme 5.
  • the alcohol 5-3 wherein Ar 1 , Het, and A are as previously disclosed, can be oxidized to the corresponding aldehyde 4-3 with an oxidizing agent such as Dess-Martin periodinane in a solvent such as dichloromethane at ambient temperature as in step e of Scheme 5.
  • the acid 5-4 and aldehyde 5-5 can be further functionalized to arrive at the compounds of Formula One, Two, Three, Four, and/or Five.
  • the alkene can be reduced using hydrogen gas (balloon) and a palladium catalyst such as 10% palladium on carbon in a polar aprotic solvent such as ethyl acetate to provide the saturated ester 6-2 (step b).
  • Saponification of the resultant ester may be achieved by using a strong base such as sodium hydroxide in ethyl acetate to furnish the carboxylic acid (6-3, step c).
  • the acid 6-3 can be further functionalized (e.g., as in Schemes 1, 2, 3, and 3a) to arrive at the compounds of Formula One, Two, Three, Four, and/or Five.
  • Carbinols 7-1 can be treated with phthalimide under Mitsunobu conditions to generate V-phthalimido intermediates 7-2 (step a).
  • Deprotection using hydrazine and methanol or other suitable solvent can furnish the amines 7-3 (step b).
  • Aldehyde 4-3 can be converted to the corresponding cyanohydrin 8-1, wherein Ar 1 , Het, and A are as previously disclosed, by treatment with zinc iodide and trimethylsilyl cyanide in a solvent such as dichloromethane at ambient temperature as in step a of Scheme 8.
  • the cyanohydrin 8-1 can be reacted with borane tetrahydrofuran complex in a solvent such as dichloromethane at a temperature from about 0 °C to about ambient temperature, followed by acid workup, to furnish the amine hydrochloride 8-2, wherein Ar 1 , Het, and A are as previously disclosed, as in step b of Scheme 8.
  • the amine functionality on 8-2 can be protected using di-tert-butyl dicarbonate in the presence of a base such as triethylamine and in a solvent such as dichloromethane at ambient temperature to provide 8-3, wherein Ar 1 , Het, and A are as previously disclosed, as in step c of Scheme 8.
  • Reaction of 8-3 with a fluorinating reagent such as (diethylamino)sulfur trifluoride in the presence of abase such as triethylamine and in a solvent such as dichloromethane at a temperature from about 0 °C to about ambient temperature can afford 8-4, wherein Ar 1 , Het, and A are as previously disclosed, as in step d of Scheme 8.
  • amine hydrochloride 8-6 Deprotection using 4 molar (M) hydrogen chloride in 1,4-dioxane or other suitable solvent at a temperature of about 0 °C to about ambient temperature can furnish the amine hydrochloride 8-6 (step /).
  • the amine hydrochloride 8-6 can be further functionalized (e.g., as in Schemes 1, 2, 3, 3a, and 3a’) to arrive at the compounds of Formula One, Two, Three, Four, and/or Five.
  • the cyanohydrin 8-1 can be reacted with a fluorinating reagent such as (diethylamino)sulfur trifluoride in the presence of a base such as triethylamine and in a solvent such as dichloromethane at temperature from about 0 °C to about ambient temperature can afford 8-5, wherein Ar 1 , Het, and A are as previously disclosed, as in step d of Scheme 8.
  • the cyano moiety on 8-5 can be reduced in the presence of a reducing agent such as borane tetrahydrofuran complex in a solvent such as tetrahydrofuran at a temperature from about 0 °C to about ambient temperature.
  • Incomplete reaction may require a different reducing agent such as lithium aluminum hydride to furnish the amine 8-6, wherein Ar 1 , Het, and A are as previously disclosed, as in step f of Scheme 8.
  • the amine 8-6 can be further functionalized (e.g., as in Schemes 1, 2, 3, 3a, and 3a’) to arrive at the compounds of Formula One, Two, Three, Four, and/or Five.
  • Method A A 25 mL vial under an atmosphere of nitrogen and equipped with a stir bar was charged with 3- bromo-l-(4-(trifluoromethoxy)phenyl)-177-l,2,4-triazole (Cl, 1 g, 3.25 mmol) and piperidin-4-ylmethanol (2.13 g, 18.5 mmol). The reaction mixture was heated to 120 °C. The reaction mixture was poured into ice water (250 mL). The solid was filtered, washed with water, and dried under vacuum (25 mm Hg) at 50 °C overnight.
  • Method B A mixture of 3-bromo-l-(4-(trifluoromethoxy)phenyl)-17f-l,2,4-triazole (Cl, 2 g, 6.49 mmol) and piperidin-4-ylmethanol (1.8 g, 16.22 mmol) in dimethyl sulfoxide (10 mL) was heated at 130 °C for 4 days in a sealed tube. The reaction mixture was cooled to room temperature, poured into ice water (100 mL), stirred for 1 hour.
  • reaction mixture was diluted with ethyl acetate and washed with water.
  • the aqueous layer was extracted with ethyl acetate.
  • the combined organic layers were washed with water (5x), dried over sodium sulfate, filtered, and concentrated.
  • reaction mixture was diluted with ethyl acetate and was washed with water.
  • the aqueous layer was extracted with ethyl acetate (2x).
  • the combined organic layers were washed with water (4x), dried over sodium sulfate, filtered, and concentrated.
  • the solid was dissolved in dichloromethane and washed with saturated sodium bicarbonate. The aqueous layer was extracted with dichloro methane (2x). The combined organic layers were washed with saturated sodium bicarbonate. The organic layers were poured through a phase separator and concentrated. The solid was dried overnight at 50 °C and ⁇ 25 mm Hg.
  • Example 17 Preparation of tert-butyl (l-(4-(l-(4-(trifhioromethoxv)phenvl)-l//-l,2,4-triazol-3-yl)-3,6- dihydropyridin-1(2//)-yl)propari-2-yl)carbamate (C21)
  • the reaction mixture was diluted with ethyl acetate and water.
  • the organic layer was pipetted off and filtered through a sodium sulfate cartridge directly onto a Celite® cartridge, rinsing with ethyl acetate.
  • the cartridge was dried in the vacuum oven. Purification by flash chromatography (0 - 100% ethyl acetate-hexanes) provided the title compound as a yellow oil (21 mg, 31%), which was used in the next step without purification: ESIMS m/z 468 ([M+H] + ).
  • Example 18 Preparation of l-(4-(l-(4-(trifluoromethoxy)phenyl)-l//-l,2,4-triazol-3-yl)-3,6-dihydropyridin- l(2Zf)-yl)propan-2-amine (
  • Example 19 Preparation of 2-(2-(4-(l-(4-(trifluoromethoxy)phenyl)-lZZ-l,2,4-triazol-3-yl)piperazin-l- yl)ethyl)isoindoline-l, 3-dione (C23) l-(l-(4-(Trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3-yl)piperazine (C19, 193 mg, 0.616 mmol), 2-(2- bromoethyl)isoindo line- 1,3 -dione (235 mg, 0.924 mmol), and potassium carbonate (255 mg, 1.848 mmol) in ⁇ ' ⁇ - dimethylformamide (DMF, 1540 ji L) were heated in a Biotage microwave reactor at 120 °C for 1 hour.
  • DMF ⁇ ' ⁇ - dimethylformamide
  • reaction mixture was diluted with water and extracted with dichloromethane.
  • the organic layers were filtered through a phase separator directly onto a Celite® cartridge. Purification by flash chromatography (0 - 100% ethyl acetatehexanes) provided 65 mg of the title compound as a white solid. Recovery was low so the aqueous layer was extracted with ethyl acetate.
  • the reaction mixture was stirred at 120 °C for 16 hours.
  • the reaction mixture was cooled to room temperature, filtered through a pad of Celite®, washed with ethyl acetate (50 mL), and the filtrate was concentrated under reduced pressure.
  • the title compound was synthesized from 3-bromo-l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazole (Cl) and tert-butyl 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-y l)-3,6-dihydropy ridine-l(2f/)-carboxy late and was isolated as an off-white solid (6.5 g) that was used without purification: ESIMS m/z 411 ([M+H] + ).
  • the reaction mixture was heated to 140 °C for 30 minutes in a Biotage Initiator microwave synthesizer.
  • the reaction mixture was diluted with ethyl acetate and washed with water.
  • the aqueous layer was extracted with ethyl acetate.
  • the combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated.
  • Example 25 Preparation of ethyl 4-(l-(4-(tritluoromethoxy)phenyl)-l/f-l,2,4-triazol-3-yl)cyclohexane-1- carboxylate (C30)
  • the title compound was prepared from (4-(l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3- yl)cyclohexyl)methanol (C34) and isolated as a pale yellow sticky solid, which was used in the next step without any purification and analysis (3.8 g).
  • the title compound was prepared from 1 -( 1 -(4-(trifluoromethoxy)phenyl)-l H- 1 ,2,4-triazol-3-yl)piperidin- 4-yl)methanol (C2) and was isolated as a pale yellow sticky solid, which was used in the next step without purification and analysis (5.5 g).
  • reaction mixture was quenched with saturated sodium bicarbonate (10 mL) and was extracted with dichloro methane (3 x 20 mL). The organic layers were washed with water (10 mL) followed by brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the reaction mixture was stirred at room temperature for 12 hours.
  • the mixture was quenched with saturated ammonium chloride solution (80 mL) and extracted with ethyl acetate (2 x 150 mL).
  • the organic layer was washed with water (100 mL) followed by brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound as a pale yellow sticky liquid (14.2 g), which was used in the next step without further purification.
  • Example 40 Preparation of l-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[2-[l-[l-[4- (trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4-piperidyl]ethyl]urea (A2)
  • Method A 4-(2-Isocyanatoethyl)-l-(l-(4-(trifluoromethoxy)phenyl)-l./7-l,2,4-triazol-3-yl)piperidine (C7 used as is; 239 mg, 0.627 mmol) was diluted with acetonitrile (4.0 mL), and the mixture was warmed in a heating block preheated to 80 °C for 60 minutes. The reaction mixture was cooled and l-(2-isopropyl-5- methylphenyl)thiourea (144 mg, 0.689 mmol), and cesium carbonate (245 mg, 0.752 mmol) were added. The reaction mixture was allowed to stir overnight at room temperature.
  • reaction mixture was diluted with water and dichloromethane and passed through a phase separator.
  • the organic filtrate was concentrated. Purification of the resulting residue by reverse phase chromatography (Cis silica gel; 10 - 100% acetonitrile in water) provided the title compound as an orange solid (18 mg, 5%).
  • Method B To a biphasic solution of bis(trichloro methyl) carbonate (0.638 grams (g), 2.15 mmol) and sodium bicaibonate (1.36 g, 16.1 mmol)) in dichloromethane (20 mL) and water (10 mL) was added a suspension of 2-(l-(l-(4-(trifluoromethoxy)phenyl)-lZ7-l,2,4-triazol-3-yl)piperidin-4-yl)ethanamine (C9, 1.91 g, 5.37 mmol) in dichloromethane (40 mL). The reaction mixture was allowed to stir at room temperature for 4 hours.
  • the reaction mixture was diluted with dichloromethane and passed through a phase separator and the filtrate was concentrated.
  • the resulting residue was suspended in acetonitrile (36 mL).
  • a total of 4.0 mL [l/9th of the volume (0.594 mmol)] of this suspension was transferred to a vial containing l-(2-isopropyl-5-methylphenyl)thiourea (0.136 g, 0.653 mmol) and cesium carbonate (0.387 g, 1.188 mmol).
  • the reaction mixture was allowed to stir at room temperature overnight.
  • the reaction mixture was concentrated onto Celite®. Purification by silica gel flash chromatography (0 - 60% ethyl acetate in hexanes) provided the title compound as a white solid (157 mg, 44%).
  • the title compound was synthesized from l-( 1 -(4-(trifluoromethoxy)phenyl)-l H-l ,2,4-triazol-3- yl)piperidin-3 -amine (C16) and l-(5-chloro-2-isopropylphenyl)thiourea and was isolated as a white solid (86 mg, 40%).
  • the vial was capped and the reaction mixture was stirred in a heating block that was warmed to 70 °C overnight.
  • the reaction mixture was concentrated onto Celite®. Purification by silica gel flash chromatography (10 - 70% ethyl acetate in hexanes) afforded the title compound as a light yellow solid (88 mg, 71%).
  • the title compound was synthesized from l-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[l-[l-[4- (trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4-piperidyl]urea (A3) and was isolated as a white solid (0.033 g, 65%).
  • the title compound was synthesized from l-(o-tolylcarbamothioyl)-3-[2-[l-[l-[4- (trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4-piperidyl]ethyl]urea (A5) and was isolated as an off-white solid (82 mg, 81%).
  • the title compound was synthesized from l-[(4-methoxy-2-methyl-phenyl)carbamothioyl]-3-[2-[l-[l-[4- (trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4-piperidyl]ethyl]urea (A6) and was isolated as an orange solid (104 mg, 74%).
  • the title compound was synthesized from l-[(2-ethylphenyl)carbamothioyl]-3-[2-[l-[l-[4- (trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4-piperidyl]ethyl]urea (A7) and was isolated as a light yellow solid (79 mg, 72%).
  • the title compound was synthesized from l-[(2-ethyl-6-methyl-phenyl)caibamothioyl]-3-[2-[l-[l-[4- (trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4-piperidyl]ethyl]urea (A8) and was isolated as a white solid (9 mg, 45%).
  • the title compound was synthesized from l-[(2-isopropyl-4-methyl-phenyl)carbamothioyl]-3-[2-[l-[l-[4- (trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4-piperidyl]ethyl]urea (A10) and was isolated as a light yellow solid (105 mg, 77%).
  • the title compound was synthesized from l-[(4-fluoro-2-isopropyl-phenyl)caibamothioyl]-3-[2-[l-[l-[4- (trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4-piperidyl]ethyl]urea (All) and was isolated as a light yellow solid (90 mg, 77%).
  • the title compound was synthesized from l-[(5-chloro-2-isopropyl-phenyl)carbamothioyl]-3-[2-[l-[l-[4- (trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4-piperidyl]ethyl]urea (A12) and was isolated as a light orange solid (83 mg, 66%).
  • the title compound was synthesized from l-[(5-chloro-2-isopropyl-phenyl)carbamothioyl]-3-[l-[l-[4- (trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-3-piperidyl]urea (A24) and was isolated as an off-white solid (38 mg, 47%).
  • the title compound was synthesized from l-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[4-[l-[4- (trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]cyclohex-3-en-l-yl]urea (Bl) and was isolated as a white solid (0.094 g, 63%) after ethyl acetate-water workup and drying at 50 °C at ⁇ 25 mm Hg.
  • the title compound was synthesized from 2-(4-(l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3- yl)piperazin-l-yl)ethan-l -amine (C24) and (Z)-4-nitrophenyl (3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2- ylidene)carbamate and was isolated as a yellow foam (65 mg, 73%).
  • the title compound was synthesized from 2-(4-(l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3-yl)-3,6- dihydropyridin- 1 (2//)-y I )elhan- 1 -amine (C26) and (Z) -4 -nitrophenyl (3 -(2-isopropyl-5-methylphenyl)-4- oxothiazolidin-2-ylidene)carbamate and was isolated as a yellow foam (20 mg, 19%).
  • Example 43 Preparation of (Z)-l-(2-fluoro-2-(l-(l-(4-(trifluoromethoxy)phenyl)-1//-1,2,4-triazol-3- yl)piperidin-4-yl)ethyl)-3-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)urea (A27)
  • the title compound was synthesized from 2-fluoro-2-( l-( 1 -(4-(trifluoroincthoxy)phenyl)-l//-l ,2,4-triazol- 3-yl)piperidin-4-yl)ethan-l-amine hydrochloride (C18) and 2-imino-3-(5-methyl-2 -(2,2,2- trifluoroethoxy)phenyl)thiazolidin-4-one and was isolated as a yellow oil (20 mg, 32%).
  • the title compound was synthesized from 2-(4-( 1 -(4-(trifluoromethoxy)phenyl)-l H-l ,2,4-triazol-3- y l)piperazin- 1 -y l)ethan- 1 -amine (C24) and JV-(5 -methy 1-2 -(3 ,3 , 3 -trifluoropropoxy )pheny l)-2-thiocy anatoacetamide (C49) and was isolated as a clear oil (24 mg, 22%).
  • the title compound was synthesized from 2-fluoro-2-(4-(l-(4-(trifluoromethoxy)phenyl)-177-l,2,4-triazol- 3-yl)cyclohexyl)ethan-l-amine (C43) and 2-imino-3-(2-isopropyl-5-methylphenyl)thiazolidin-4-one and was isolated as a clear oil (20 mg, 43%).
  • the title compound was synthesized from 2-fluoro-2-(4-(l-(4-(trifluoromethoxy)phenyl)-l//-l,2,4-triazol- 3 -yl)cyclo hex-3 -en-l-yl)ethan-l -amine (C42) and 2-imino-3-(2-isopropyl-5-methylphenyl)thiazolidin-4-one and was isolated as a pale yellow oil (35 mg, 62%).
  • the title compound was synthesized from 2-fluoro-2-(4-( I -(4-(trifluoromctho. ⁇ y)phcnyl)-l//-l ,2.4-triazol- 3-yl)cyclohexyl)ethan-l-amine (C43) and jV-(5-methyl-2-(3,3,3-trifluoropropoxy)phenyl)-2-thiocyanatoacetamide (C49) and was isolated as a single diastereomer (B5) as a white foam (38 mg) and as a mixture of diastereomers (B6) as a clear oil (172 mg). Total yield (210 mg, 37%).
  • the title compound was synthesized from l-(4-(l-(4-(trifluoromethoxy)phenyl)-lW-l,2,4-triazol-3-yl)-3,6- dihydropyridin-l (2//)-yl)propan-2-aminc (C22) and 2-imino-3-(2-isopropyl-5-methylphenyl)thiazolidin-4-one and was isolated as a yellow oil (5 mg, 17%).
  • the title compound was prepared from 4-(l-(4-(trifluoromethoxy)phenyl)-lW-l,2,4-triazol-3-yl)cyclohex- 3 -ene-1 -carbonyl azide (C47) by methods disclosed herein and known in the art and was isolated as a white solid (0.189 g).
  • bioassays against beet armyworm Spodoptera exigua
  • cabbage looper Trichoplusia nt
  • yellow fever mosquito Aedes aegypti
  • beet armyworm and cabbage looper are two good indicator species for a broad range of chewing pests.
  • Beet army worm is a serious pest of economic concern for alfalfa, asparagus, beets, citrus, com, cotton, onions, peas, peppers, potatoes, soybeans, sugar beets, sunflowers, tobacco, and tomatoes, among other crops. It is native to Southeast Asia but is now found in Africa, Australia, Japan, North America, and Southern Europe. The larvae may feed in large swarms causing devastating crop losses. It is known to be resistant to several pesticides.
  • Bioassays on beet armyworm were conducted using a 128-well diet tray assay.
  • One to five second instar BAW larvae were placed in each well (3 mL) of the diet tray that had been previously filled with 1 mL of artificial diet to which 50 pg/cm 2 of the test compound (dissolved in 50 pl. of 90:10 acetone-water mixture) had been applied (to each of eight wells) and then allowed to dry.
  • Trays were covered with a clear self-adhesive cover, vented to allow gas exchange, and held at 25 °C, 14:10 hght-dark for five to seven days. Percent mortality was recorded for the larvae in each well; activity in the eight wells was then averaged.
  • Cabbage looper is a serious pest found throughout the world. It attacks alfalfa, beans, beets, broccoli, Brussel sprouts, cabbage, cantaloupe, cauliflower, celery, collards, cotton, cucumbers, eggplant, kale, lettuce, melons, mustard, parsley, peas, peppers, potatoes, soybeans, spinach, squash, tomatoes, turnips, and watermelons, among other crops. This species is very destructive to plants due to its voracious appetite. The larvae consume three times their weight in food daily. The feeding sites are marked by large accumulations of sticky, wet, fecal material, which may contribute to higher disease pressure thereby causing secondary problems on the plants in the site. It is known to be resistant to several pesticides.
  • Bioassays on cabbage looper were conducted using a 128-well diet tray assay.
  • CL Tricholoplusia ni: Lepidoptera
  • One to five second instar CL larvae were placed in each well (3 mL) of the diet tray that had been previously filled with 1 mL of artificial diet to which 50 pg/cm 2 of the test compound (dissolved in 50 pL of 90: 10 acetonewater mixture) had been applied (to each of eight wells) and then allowed to dry. Trays were covered with a clear self-adhesive cover, vented to allow gas exchange, and held at 25 °C, 14:10 light-dark for five to seven days. Percent mortality was recorded for the larvae in each well; activity in the eight wells is then averaged.
  • GPA is the most significant aphid pest of peach trees, causing decreased growth, shriveling of the leaves, and the death of various tissues. It is also hazardous because it acts as a vector for the transport of plant viruses, such as potato virus Y and potato leafroll virus to members of the nightshade/potato family Solanaceae, and various mosaic viruses to many other food crops.
  • GPA attacks such plants as broccoli, burdock, cabbage, carrot, cauliflower, daikon, eggplant, green beans, lettuce, macadamia, papaya, peppers, sweet potatoes, tomatoes, watercress, and zucchini, among other crops. GPA also attacks many ornamental crops such as carnation, chrysanthemum, flowering white cabbage, poinsettia, and roses.
  • GPA has developed resistance to many pesticides. Currently, it is a pest that has the third largest number of reported cases of insect resistance (Sparks et aL). Consequently, because of the above factors control of this pest is important. Furthermore, molecules that control this pest (GPA), which is known as a sap-feeding pest, are useful in controlling other pests that feed on the sap from plants.
  • the seedlings were infested with 20-50 GPA (wingless adult and nymph stages) one day prior to chemical application.
  • Test molecules (2 mg) were dissolved in 2 mL of acetone/methanol (1:1) solvent, forming stock soludons of 1000 ppm test molecule.
  • the stock solutions were diluted 5X with 0.025% Tween 20 in water to obtain the solution at 200 ppm test molecule.
  • a hand-held aspirator-type sprayer was used for spraying a solution to both sides of cabbage leaves until runoff.
  • YFM prefers to feed on humans during the daytime and is most frequently found in or near human habitations.
  • YFM is a vector for transmitting several diseases. It is a mosquito that can spread the dengue fever and yellow fever viruses. Yellow fever is the second most dangerous mosquito-borne disease after malaria. Yellow fever is an acute viral hemorrhagic disease and up to 50% of severely affected persons without treatment will die from yellow fever. There are an estimated 200,000 cases of yellow fever, causing 30,000 deaths worldwide each year. Dengue fever is a nasty, viral disease; it is sometimes called "breakbone fever” or "break-heart fever” because of the intense pain it can produce. Dengue fever kills about 20,000 people annually.
  • DMSO dimethyl sulfoxide
  • a master plate of assembled compounds contained 15 pL per well. To this plate, 135 pL of a 90:10 water/acetone mixture was added to each well.
  • a robot Biomek® NXP Laboratory Automation Workstation
  • mosquito eggs were placed in Millipore water containing liver powder to begin hatching (4 g into 400 mL). After the “daughter” plates were created using the robot, they were infested with 220 pL of the liver powder/larval mosquito mixture (about 1 day-old larvae). After plates were infested with mosquito larvae, a non-evaporative lid was used to cover the plate to reduce drying. Plates were held at room temperature for 3 days prior to grading. After 3 days, each well was observed and scored based on mortality.
  • the compounds disclosed herein can be in the form of pesticidally acceptable acid addition salts.
  • an amine function can form salts with hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, benzoic, citric, malonic, salicylic, malic, fumaric, oxalic, succinic, tartaric, lactic, gluconic, ascorbic, maleic, aspartic, benzenesulfonic, methanesulfonic, ethanesulfonic, hydroxymethanesulfonic, and hydroxyethanesulfonic acids.
  • an acid function can form salts including those derived from alkali or alkaline earth metals and those derived from ammonia and amines.
  • preferred cations include sodium, potassium, magnesium, and aminium cations.
  • the salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt.
  • the free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia, and sodium bicarbonate.
  • a pesticide is modified to a more water soluble form e g., 2,4-dichlorophenoxy acetic acid dimethyl amine salt is a more water soluble form of 2,4-dichlorophenoxy acetic acid, a well-known herbicide.
  • the compounds disclosed herein can also form stable complexes with solvent molecules that remain intact after the non-complexed solvent molecules are removed from the compounds. These complexes are often referred to as "solvates.”
  • Certain compounds disclosed in this document can exist as one or more stereoisomers.
  • the various stereoisomers include geometric isomers, diastereomers, and enantiomers.
  • the compounds disclosed herein include racemic mixtures, individual stereoisomers, and optically active mixtures. It will be appreciated by those skilled in the art that one stereoisomer may be more active than the others.
  • Individual stereoisomers and optically active mixtures may be obtained by selective synthetic procedures, by conventional synthetic procedures using resolved starting materials, or by conventional resolution procedures.
  • pesticides are formulated into, for example, baits, concentrated emulsions, dusts, emulsifiable concentrates, iumigants, gels, granules, microencapsulations, seed treatments, suspension concentrates, suspoemulsions, tablets, water soluble liquids, water dispersible granules or dry flowables, wettable powders, and ultra-low volume solutions.
  • Pesticides are applied most often as aqueous suspensions or emulsions prepared from concentrated formulations of such pesticides.
  • Such water-soluble, water-suspendable, or emulsifiable formulations are either solids, usually known as wettable powders, or water dispersible granules, or liquids usually known as emulsifiable concentrates, or aqueous suspensions.
  • Wettable powders which may be compacted to form water dispersible granules, comprise an intimate mixture of the pesticide, a carrier, and surfactants.
  • the concentration of the pesticide is usually from about 10% to about 90% by weight.
  • the carrier is usually chosen from among the attapulgite clays, the montmorillonite clays, the diatomaceous earths, or the purified silicates.
  • Effective surfactants comprising from about 0.5% to about 10% of the wettable powder, are found among sulfonated lignins, condensed naphthalenesulfonates, naphthalenesulfonates, alkylbenzenesulfonates, alkyl sulfates, and nonionic surfactants such as ethylene oxide adducts of alkyl phenols.
  • Emulsifiable concentrates of pesticides comprise a convenient concentration of a pesticide, such as from about 50 to about 500 grams per liter of liquid dissolved in a carrier that is either a water miscible solvent or a mixture of water-immiscible organic solvent and emulsifiers.
  • Useful organic solvents include aromatics, especially xylenes and petroleum fractions, especially the high-boiling naphthalenic and olefinic portions of petroleum such as heavy aromatic naphtha.
  • Other organic solvents may also be used, such as the terpenic solvents including rosin derivatives, aliphatic ketones such as cyclohexanone, and complex alcohols such as 2-ethoxyethanol.
  • Suitable emulsifiers for emulsifiable concentrates are chosen from conventional anionic and nonionic surfactants.
  • Aqueous suspensions comprise suspensions of water-insoluble pesticides dispersed in an aqueous carrier at a concentration in the range from about 5% to about 50% by weight.
  • Suspensions are prepared by finely grinding the pesticide and vigorously mixing it into a carrier comprised of water and surfactants. Ingredients, such as inorganic salts and synthetic or natural gums, may also be added, to increase the density and viscosity of the aqueous carrier. It is often most effective to grind and mix the pesticide 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.
  • Pesticides may also be applied as granular compositions that are particularly useful for applications to the soil.
  • Granular compositions usually contain from about 0.5% to about 10% by weight of the pesticide, dispersed in a carrier that comprises clay or a similar substance.
  • Such compositions are usually prepared by dissolving the pesticide in a suitable solvent and applying it to a granular carrier which has been pre-formed to the appropriate particle size, in the range of from about 0.5 to about 3 mm.
  • Such compositions may also be formulated by making a dough or paste of the carrier and compound and crashing and drying to obtain the desired granular particle size.
  • Dusts containing a pesticide are prepared by intimately mixing the pesticide in powdered form with a suitable dusty agricultural carrier, such as kaolin clay, ground volcanic rock, and the like. Dusts can suitably contain from about 1% to about 10% of the pesticide. They can be applied as a seed dressing or as a foliage application with a dust blower machine.
  • a suitable dusty agricultural carrier such as kaolin clay, ground volcanic rock, and the like. Dusts can suitably contain from about 1% to about 10% of the pesticide. They can be applied as a seed dressing or as a foliage application with a dust blower machine.
  • a pesticide in the form of a solution in an appropriate organic solvent, usually petroleum oil, such as the spray oils, which are widely used in agricultural chemistry.
  • Pesticides can also be applied in the form of an aerosol composition.
  • the pesticide is dissolved or dispersed in a carrier, which is a pressure-generating propellant mixture.
  • the aerosol composition is packaged in a container from which the mixture is dispensed through an atomizing valve.
  • Pesticide baits are formed when the pesticide is mixed with food or an attractant or both. When the pests eat the bait, they also consume the pesticide. Baits may take the form of granules, gels, flowable powders, liquids, or solids. They are used in pest harborages.
  • Fumigants are pesticides that have a relatively high vapor pressure and hence can exist as a gas in sufficient concentrations to kill pests in soil or enclosed spaces.
  • the toxicity of the fumigant is proportional to its concentration and the exposure time. They are characterized by a good capacity for diffusion and act by penetrating the pest’s respiratoiy system or being absorbed through the pest’s cuticle. Fumigants are applied to control stored product pests under gas proof sheets, in gas sealed rooms or buildings or in special chambers. Pesticides can be microencapsulated by suspending the pesticide particles or droplets in plastic polymers of various types.
  • microcapsules By altering the chemistry of the polymer or by changing factors in the processing, microcapsules can be formed of various sizes, solubility, wall thicknesses, and degrees of penetrability. These factors govern the speed with which the active ingredient within is released, which in turn, affects the residual performance, speed of action, and odor of the product.
  • Oil solution concentrates are made by dissolving pesticide in a solvent that will hold the pesticide in solution.
  • Oil solutions of a pesticide usually provide faster knockdown and kill of pests than other formulations due to the solvents themselves having pesticidal action and the dissolution of the waxy covering of the integument increasing the speed of uptake of the pesticide.
  • Other advantages of oil solutions include better storage stability, better penetration of crevices, and better adhesion to greasy surfaces.
  • Another embodiment is an oil-in-water emulsion, wherein the emulsion comprises oily globules which are each provided with a lamellar liquid crystal coating and are dispersed in an aqueous phase, wherein each oily globule comprises at least one compound which is agriculturally active, and is individually coated with a monolameliar or oligolamellar layer comprising: (1) at least one nonionic lipophilic surface-active agent, (2) at least one nonionic hydrophilic surface-active agent and (3) at least one ionic surface-active agent, wherein the globules having a mean particle diameter of less than 800 nanometers.
  • a monolameliar or oligolamellar layer comprising: (1) at least one nonionic lipophilic surface-active agent, (2) at least one nonionic hydrophilic surface-active agent and (3) at least one ionic surface-active agent, wherein the globules having a mean particle diameter of less than 800 nanometers.
  • the compounds disclosed herein when used in a formulation can also contain other components.
  • these components include, but are not limited to, (this is a non-exhaustive and non-mutually exclusive list) wetters, spreaders, stickers, penetrants, buffers, sequestering agents, drift reduction agents, compatibility agents, anti-foam agents, cleaning agents, and emulsifiers. A few components are described forthwith.
  • a wetting agent is a substance that when added to a liquid increases the spreading or penetration power of the liquid by reducing the interfacial tension between the liquid and the surface on which it is spreading.
  • Wetting agents are used for two main lunctions in agrochemical formulations: during processing and manufacture to increase the rate of wetting of powders in water to make concentrates for soluble liquids or suspension concentrates; and during mixing of a product with water in a spray tank to reduce the wetting time of wettable powders and to improve the penetration of water into water-dispersible granules.
  • wetting agents used in wettable powder, suspension concentrate, and water-dispersible granule formulations are: sodium lauiyl sulfate; sodium dioctyl sulfosuccinate; alkyl phenol ethoxylates; and aliphatic alcohol ethoxylates.
  • a dispersing agent is a substance which adsorbs onto the surface of a particles and helps to preserve the state of dispersion of the particles and prevents them from reaggregating.
  • Dispersing agents are added to agrochemical formulations to facilitate dispersion and suspension during manufacture, and to ensure the particles redisperse into water in a spray tank. They are widely used in wettable powders, suspension concentrates and water- dispersible granules.
  • Surfactants that are used as dispersing agents have the ability to adsorb strongly onto a particle surface and provide a charged or steric barrier to reaggregation of particles. The most commonly used surfactants are anionic, nonionic, or mixtures of the two types.
  • dispersing agents For wettable powder formulations, the most common dispersing agents are sodium lignosulfonates. For suspension concentrates, very good adsorption and stabilization are obtained using polyelectrolytes, such as sodium naphthalene sulfonate formaldehyde condensates. Tristyrylphenol ethoxylate phosphate esters are also used. Nonionics such as alkylarylethylene oxide condensates and EO-PO block copolymers are sometimes combined with anionics as dispersing agents for suspension concentrates. In recent years, new types of veiy high molecular weight polymeric surfactants have been developed as dispersing agents.
  • hydrophobic backbones and a large number of ethylene oxide chains forming the ‘teeth’ of a ‘comb’ surfactant.
  • These high molecular weight polymers can give very good long-term stability to suspension concentrates because the hydrophobic backbones have many anchoring points onto the particle surfaces.
  • dispersing agents used in agrochemical formulations are: sodium lignosulfonates; sodium naphthalene sulfonate formaldehyde condensates; tristyrylphenol ethoxylate phosphate esters; aliphatic alcohol ethoxylates; alkyl ethoxylates; EO-PO block copolymers; and graft copolymers.
  • An emulsifying agent is a substance which stabilizes a suspension of droplets of one liquid phase in another liquid phase. Without the emulsifying agent the two liquids would separate into two immiscible liquid phases.
  • the most commonly used emulsifier blends contain alkylphenol or aliphatic alcohol with twelve or more ethylene oxide units and the oil-soluble calcium salt of dodecylbenzenesulfonic acid.
  • a range of hydrophile-lipophile balance (“HLB”) values from 8 to 18 will normally provide good stable emulsions. Emulsion stability can sometimes be improved by the addition of a small amount of an EO-PO block copolymer surfactant.
  • a solubilizing agent is a surfactant which will form micelles in water at concentrations above the critical micelle concentration. The micelles are then able to dissolve or solubilize water-insoluble materials inside the hydrophobic part of the micelle.
  • the type of surfactants usually used for solubilization are nonionics: sorbitan monooleates; sorbitan monooleate ethoxylates; and methyl oleate esters.
  • Surfactants are sometimes used, either alone or with other additives such as mineral or vegetable oils as adjuvants to spray -tank mixes to improve the biological performance of the pesticide on the target.
  • the types of surfactants used for bioenhancement depend generally on the nature and mode of action of the pesticide. However, they are often nonionics such as: alkyl ethoxylates; linear aliphatic alcohol ethoxylates; aliphatic amine ethoxylates.
  • a carrier or diluent in an agricultural formulation is a material added to the pesticide to give a product of the required strength.
  • Carriers are usually materials with high absorptive capacities, while diluents are usually materials with low absorptive capacities. Carriers and diluents are used in the formulation of dusts, wettable powders, granules, and water-dispersible granules.
  • Organic solvents are used mainly in the formulation of emulsifiable concentrates, ULV (ultra-low volume) formulations, and to a lesser extent granular formulations. Sometimes mixtures of solvents are used.
  • the first main groups of solvents are aliphatic paraffinic oils such as kerosene or refined paraffins.
  • the second main group and the most common comprises the aromatic solvents such as xylene and higher molecular weight fractions of C9 and CIO aromatic solvents.
  • Chlorinated hydrocarbons are useful as cosolvents to prevent ciystallization of pesticides when the formulation is emulsified into water. Alcohols are sometimes used as cosolvents to increase solvent power.
  • Thickeners or gelling agents are used mainly in the formulation of suspension concentrates, emulsions and suspoemulsions to modify the rheology or flow properties of the liquid and to prevent separation and settling of the dispersed particles or droplets.
  • Thickening, gelling, and anti-settling agents generally fall into two categories, namely water-insoluble particulates, and water-soluble polymers. It is possible to produce suspension concentrate formulations using clays and silicas. Examples of these types of materials, include, but are limited to, montmorillonite, e g., bentonite; magnesium aluminum silicate; and attapulgite. Water-soluble polysaccharides have been used as thickening-gelling agents for many years.
  • polysaccharides most commonly used are natural extracts of seeds and seaweeds or are synthetic derivatives of cellulose. Examples of these types of materials include, but are not limited to, guar gum; locust bean gum; carrageenam; alginates; methyl cellulose; sodium carboxymethyl cellulose (SCMC); hydroxyethyl cellulose (HEC).
  • SCMC carboxymethyl cellulose
  • HEC hydroxyethyl cellulose
  • Other types of anti-settling agents are based on modified starches, polyacrylates, polyvinyl alcohol and polyethylene oxide. Another good anti-settling agent is xanthan gum.
  • preservation agents are used to eliminate or reduce their effect.
  • examples of such agents include, but are not limited to: propionic acid and its sodium salt; sorbic acid and its sodium or potassium salts; benzoic acid and its sodium salt; p-hydroxybcnzoic acid sodium salt; methyl p-hydroxybenzoate: and l,2-benzisothiazalin-3-one (BIT).
  • anti-foam agents are often added either during the production stage or before filling into bottles.
  • silicones are usually aqueous emulsions of dimethyl polysiloxane while the non-silicone anti-foam agents are water-insoluble oils, such as octanol and nonanol, or silica.
  • the function of the anti-foam agent is to displace the surfactant from the air-water interface.
  • Green agents can reduce the overall environmental footprint of crop protection formulations.
  • Green agents are biodegradable and generally derived from natural and/or sustainable sources, e.g., plant and animal sources. Specific examples are vegetable oils, seed oils, and esters thereof, also alkoxylated alkyl poly glucosides.
  • the compounds disclosed herein can be used to control pests.
  • the compounds disclosed herein can be used to control pests of the Phylum Nematoda.
  • the compounds disclosed herein can be used to control pests of the Phylum Arthropoda. In another embodiment, the compounds disclosed herein can be used to control pests of the Subphylum Chelicerata.
  • the compounds disclosed herein can be used to control pests of the Class Arachnida.
  • the compounds disclosed herein can be used to control pests of the Subphylum Myriapoda.
  • the compounds disclosed herein can be used to control pests of the Class Symphyla.
  • the compounds disclosed herein can be used to control pests of the Subphylum Hexapoda.
  • the compounds disclosed herein can be used to control pests of the Class Insecta.
  • the compounds disclosed herein can be used to control Coleoptera (beetles).
  • the compounds disclosed herein can be used to control Dermaptera (earwigs).
  • the compounds disclosed herein can be used to control Dictyoptera (cockroaches).
  • the compounds disclosed herein can be used to control Diptera (true flies).
  • the compounds disclosed herein can be used to control Hemiptera (true bugs).
  • the compounds disclosed herein can be used to control Homoptera (aphids, scales, whiteflies, leafhoppers).
  • the compounds disclosed herein can be used to control Hymenoptera (ants and wasps).
  • the compounds disclosed herein can be used to control Isoptera (termites).
  • the compounds disclosed herein can be used to control Lepidoptera (moths and butterflies).
  • the compounds disclosed herein can be used to control Mallophaga (chewing lice).
  • the compounds disclosed herein can be used to control Orthoptera (grasshoppers, locusts, and crickets).
  • the compounds disclosed herein can be used to control Phthiraptera (sucking lice).
  • the compounds disclosed herein can be used to control Siphonaptera (fleas).
  • the compounds disclosed herein can be used to control Thysanoptera (thrips).
  • the compounds disclosed herein can be used to control Thysanura (bristletails).
  • the compounds disclosed herein can be used to control Acarina (mites and ticks).
  • the compounds disclosed herein can be used to control Nematoda (nematodes).
  • the compounds disclosed herein can be used to control Symphyla (symphylans).
  • Controlling pests of Phyla Nematoda, Arthropoda, and/or Mollusca generally means that pest populations, pest activity, or both, are reduced in a locus. This can come about when:
  • pests are exterminated in, or around, a locus.
  • pest populations, activity, or both are desirably reduced more than fifty percent, preferably more than 90 percent, and most preferably more than 98 percent.
  • the locus is not in, or on, a human; consequently, the locus is generally a non-human locus.
  • the locus to which a molecule of Formula One is applied can be any locus that is inhabited, or that may become inhabited, or that may be traversed, by a pest of Phyla Nematoda, Arthropoda, and/or Mollusca.
  • the locus can be:
  • Particular crop areas to use a molecule of Formula One include areas where apples, com, sunflowers, cotton, soybeans, canola, wheat, rice, sorghum, barley, oats, potatoes, oranges, alfalfa, lettuce, strawberries, tomatoes, peppers, crucifers, pears, tobacco, almonds, sugar beets, beans and other valuable crops are growing or the seeds thereof are going to be planted. It is also advantageous to use ammonium sulfate with a molecule of Formula One when growing various plants.
  • the actual amount of pesticide to be applied to loci of pests is generally not critical and can readily be determined by those skilled in the art. In general, concentrations from about 0.01 grams of pesticide per hectare to about 5000 grams of pesticide per hectare are expected to provide good control.
  • the locus to which a pesticide is applied can be any locus inhabited by an pest, for example, vegetable crops, fruit and nut trees, grape vines, ornamental plants, domesticated animals, the interior or exterior surfaces of buildings, and the soil around buildings.
  • Controlling pests generally means that pest populations, activity, or both, are reduced in a locus. This can come about when: pest populations are repulsed from a locus; when pests are incapacitated in or around a locus; or pests are exterminated, in whole or in part, in or around a locus. Of course, a combination of these results can occur.
  • pest populations, activity, or both are desirably reduced more than fifty percent, preferably more than 90 percent.
  • Baits are placed in the ground where, for example, termites can come into contact with the bait. Baits can also be applied to a surface of a building, (horizontal, vertical, or slant surface) where, for example, ants, termites, cockroaches, and flies, can come into contact with the bait.
  • Systemic movement of pesticides in plants may be utilized to control pests on one portion of the plant by applying the pesticides to a different portion of the plant.
  • control of foliar-feeding insects can be controlled by drip irrigation or furrow application, or by treating the seed before planting.
  • Seed treatment can be applied to all types of seeds, including those from which plants genetically transformed to express specialized traits will germinate. Representative examples include those expressing proteins toxic to invertebrate pests, such as Bacillus thuringiensis or other insecticidal toxins, those expressing herbicide resistance, such as “Roundup Ready” seed, or those with “stacked” foreign genes expressing insecticidal toxins, herbicide resistance, nutritionenhancement, or any other beneficial traits.
  • seed treatments with the compounds disclosed herein can further enhance the ability of a plant to better withstand stressful growing conditions. This results in a healthier, more vigorous plant, which can lead to higher yields at harvest time.
  • the compounds disclosed herein can be used with plants genetically transformed to express specialized traits, such as Bacillus thuringiensis or other insecticidal toxins, or those expressing herbicide resistance, or those with “stacked” foreign genes expressing insecticidal toxins, herbicide resistance, nutrition-enhancement, or any other beneficial traits.
  • specialized traits such as Bacillus thuringiensis or other insecticidal toxins, or those expressing herbicide resistance, or those with “stacked” foreign genes expressing insecticidal toxins, herbicide resistance, nutrition-enhancement, or any other beneficial traits.
  • Table 3 Biological Data for Compounds in Tables 1 A and IB A25 A A C c
  • substituted furanyl, substituted phenyl, substituted pyridazinyl, substituted pyridyl, substituted pyrimidinyl, or substituted thienyl wherein said substituted furanyl, substituted phenyl, substituted pyridazinyl, substituted pyridyl, substituted pyrimidinyl, and substituted thienyl have one or more substituents independently selected from H, F, Cl, Br, I, CN, OH, SH, NOz, oxo, thioxo, NR’R 5 ', Ci-Cg alkyl, Ci-Cs haloalkyl, Cj-Cg cycloalkyl, Cs-Cg halocycloalkyl, Cs-Cs cycloalkoxy, Ch-Cg halocycloalkoxy, Ci-C 8 alkoxy, Ci-Q haloalkoxy, Ch-Cg alkenyl, Ch-C
  • Het is a 5- or 6-membered, saturated or unsaturated, heterocyclic ring, containing one or more heteroatoms independently selected from nitrogen, sulfur, or oxygen, and where said heterocyclic ring may also be substituted with one or more substituents independently selected from H, F, Cl, Br, I, CN, OH, SH, NO2, oxo, thioxo, NR x R y , Ci-C 8 alkyl, Ci-C 8 haloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 halocycloalkyl, C 3 -C 8 cycloalkoxy, C 3 -C 8 halocycloalkoxy, Ci-C 8 alkoxy, Ci-C 8 haloalkoxy, C 3 -C 8 alkenyl, C 3 -C 8 cycloalkenyl, C 3 -C 8 haloalkenyl, C 3 -C 8 alkynyl, S(
  • a 6-membered saturated or partially unsaturated carbocyclic ring optionally substituted with one or more substituents independently selected from H, Cl, Br, F, I, CN, oxo, Ci-Ce alkyl, Ci-Ce -haloalkyl, Ci-Ce alkoxy, Ci-Cg haloalkoxy, Ci-Ce alkylthio, Ci-Cs haloalkylthio, C2-C6 alkenyl, C 2 -Ce haloalkenyl, and C 2 -Ce haloalkenyl;
  • (D) L is a linker selected from
  • each of R a , R b , R c , R d , R e , and R f is selected from H, F, Cl, Br, I, CN, OH, SH, NO 2 , oxo, thioxo,
  • each of Q 1 and Q 2 is independently selected from O or S;
  • R 3 is selected from C 3 -C 8 cycloalkyl, phenyl, (Ci-C 8 alkyl)phenyl, (Ci-C 8 alkyl)-O-phenyl, (C 2 -C 8 alkenyl)- O-phenyl, (Het-1), (Ci-C 8 alkyl)(Het-l), (Ci-C 8 alkyl)O(Het-l), wherein the C 3 -C 8 cycloalkyl, phenyl, (Ci-C 8 alkyl)phenyl, (Ci-C 8 alkyl)-O-phenyl, (C 2 -C 8 alkenyl)-O- phenyl, (Het-1), (Ci-C 8 alkyl)(Het-l), or (Ci-C 8 alkyl)O(Het-l) may be optionally substituted with one or more substituents independently selected from H, F, Cl, Br, I, CN,
  • R 2 and R 4 together may optionally form a 1- to 4-membered saturated or unsaturated, hydrocarbyl link, which may contain one or more heteroatoms selected from nitrogen, sulfur, and oxygen, and together with (Q 2 )(C)(N) forms a 4- to 7-membered cyclic structure, wherein said hydrocarbyl link may optionally be substituted with one or more substituents independently selected from H, F, Cl, Br, I, CN, OH, SH, NO 2 , oxo, thioxo, NR x R y , Ci-C 8 alkyl, Ci-C 8 haloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 halocycloalkyl, C 3 -C 8 cycloalkoxy, C 3 -C 8 halocycloalkoxy, Ci-Cs alkoxy, Ci-C 8 haloalkoxy, C 2 -C 8 alkenyl, C 3 -
  • Ar 1 is a phenyl or a substituted phenyl having one or more substituents independently selected from Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy;
  • Het is a triazolyl, imidazolyl, pyrrolyl, or pyrazolyl;
  • a 6-membered non-aromatic carbocyclic ring optionally substituted with one or more substituents independently selected fromH, Cl, Br, F, I, CN, oxo, Ci-Ce alkyl, Ci-Ce -haloalkyl, Ci-Cs alkoxy, Ci-Cs haloalkoxy, Ci-Ce alkylthio, Ci-Ce haloalkylthio, G-G, alkenyl, and G-G, haloalkenyl;
  • L is a linker selected from a bond or -CR a R b -CR c R d , wherein each of R a , R b , R c , and R d is selected from H, F, Cl, Br, I, CN, OH, SH, NOz, oxo, thioxo, NR'R' .
  • Ci-Cs alkyl Ci-Cg haloalkyl, Ci-Cs alkoxy, and Ci-Cs haloalkoxy
  • each of R 1 , R 4 , and R 5 is independently selected from H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or phenyl;
  • R 2 is selected from H, Ci-Ce alkyl, or (i);
  • R 2 and R 4 together may form a 1- to 4-membered saturated or unsaturated, hydrocarbyl link, which may contain one or more heteroatoms selected from nitrogen, sulfur, and oxygen, and together with (Q 2 )(C)(N) forms a 4- to 7-membered cyclic structure, wherein said hydrocarbyl link, wherein said hydrocarbyl link group may optionally be substituted with one or more R 6 , wherein each R 6 is independently selected fromH, F, Cl, Br, I, CN, Ci-Cg alkyl, oxo, thioxo, Ci-Cg haloalkyl, Ci-Cg alkoxy, Ci-Ce haloalkoxy, phenyl, and phenoxy;
  • R 3 is selected from phenyl, Ci-Ce alkyl-phenyl, or Ci-Cg alkyl-O-phenyl, wherein each alkyl and phenyl is optionally substituted with one or more substituents independently selected from F, Cl, Br, I, CN, NO2, oxo, thioxo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, phenyl, or phenoxy.
  • A is azetidinyl, cyclo hexyl, cyclohexenyl, cyclohexadienyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, substituted cyclohexyl, substituted cyclohexenyl, substituted cyclohexadienyl, substituted pyrrolidinyl, substituted piperidinyl, substituted tetrahydropyridinyl, or substituted piperazinyl.
  • A is a substituted piperidinyl, substituted tetrahydropyridinyl, or substituted piperazinyl having one or more substituents independently selected from H, Cl, Br, F, I, oxo, Ci-Cg alkyl, Ci-Ce -haloalkyl, Ci-Ce alkoxy, and Ci-Ce haloalkoxy.
  • R 3 is a substituted phenyl having one or more substituents independently selected from F, Cl, Br, I, Ci-Ce alkyl, Ci-Cs haloalkyl, Ci-Cs alkoxy, and Ci-Cg haloalkoxy.
  • A is selected from the group consisting of
  • L is a bond, -CR a R b -, -CR a R b -CR c R d -, or -CR a R b -CR c R d -CR e R f , wherein each of R a , R b , R c , R d , R e , and R f is selected from the group consisting of H, F, Cl, and C1-C3 alkyl; each of Q 1 and Q 2 is independently selected from O or S;
  • R 1 , R 2 , and R 5 are each independently selected from the group consisting of H and CH ,: R 3 is a substituted phenyl with 1, 2, 3, 4, or 5 substituents R 7 independently selected from the group consisting of F, Cl, Br, I, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; and
  • R 8 is selected from the group consisting of C1-C4 haloalkyl and C1-C4 haloalkoxy.
  • composition comprising a compound according to any of the previous details and a carrier.
  • a process comprising applying (a) a compound according to any of the previous details Id through 19d inclusive, or (b) a composition according to 20d, to an area to control a pest, in an amount sufficient to control such pest.
  • a process comprising applying (a) a compound according to any of the previous details Id through 19d inclusive, or (b) a composition according to 20d, to a genetically modified plant, or genetically -modified seed, which has been genetically modified to express one or more specialized traits.
  • 24d A process comprising: orally administering or topically applying (a) a compound according to any of the previous details Id through 19d inclusive, or (b) a composition according to 20d, to a non-human animal, to control endoparasites, ectoparasites, or both.
  • a composition comprising a compound according to any of the previous details Id through 19d inclusive and a seed.

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Abstract

Provided are compounds having the structure of Formula One or Formula Two: Formula One, or Formula Two. Pesticidal compositions and their uses are disclosed. Also disclosed are methods of synthesis for compounds disclosed herein.

Description

MOLECULES HAVING CERTAIN PESTICIDAL UTILITIES, AND INTERMEDIATES, COMPOSITIONS, AND PROCESSES RELATED THERETO
CROSS REFERENCE TO RELATED APPLICATIONS
This Application claims the benefit of and priority from U.S. provisional application serial number 63/234726, which was filed on August 19, 2021. The entire contents of the above-identified application is hereby incorporated by reference into this Application.
BACKGROUND
This disclosure relates to the field of molecules having pesticidal utility against pests in Phyla Arthropoda, Mollusca, and Nematoda, processes to produce such molecules, intermediates used in such processes, and processes of using such pesticidal compositions against such pests. These pesticidal compositions may be used, for example, as acaricides, insecticides, miticides, molluscicides, and nematicides.
“Many of the most dangerous human diseases are transmitted by insect vectors” (Rivero et al., Insect Control of Vector-Borne Diseases: When is Insect Resistance a Problem? Public Library of Science Pathogens, Vol. 6, No. 8, p. 1-9, 2010). “Historically, malaria, dengue, yellow fever, plague, filariasis, louse-borne typhus, trypanosomiasis, leishmaniasis, and other vector borne diseases were responsible for more human disease and death in the 17th through the early 20th centuries than all other causes combined” (Gubler, D., Resurgent Vector-Bome Diseases as a Global Health Problem, Emerging Infectious Diseases, Vol. 4, No. 3, p. 442-450, 1998). Vector-borne diseases are responsible for about 17% of the global parasitic and infectious diseases. Malaria alone causes over 800,000 deaths a year, 85% of which occur in children under five years of age. Each year there are about 50 to about 100 million cases of dengue fever. A further 250,000 to 500,000 cases of dengue hemorrhagic fever occur each year (Matthews., Integrated Vector Management: Controlling Vectors of Malaria and Other Insect Vector Borne Diseases, Ch. 1, p. 1, 2011). Vector control plays a critical role in the prevention and control of infectious diseases. However, insecticide resistance, including resistance to multiple insecticides, has arisen in all insect species that are major vectors of human diseases (Rivero et al.). Recently, more than 550 arthropod species have developed resistance to at least one pesticide (Whalon et al., Analysis of Global Pesticide Resistance in Arthropods, Global Pesticide Resistance in Arthropods, Ch. 1, p. 5-33, 2008). Furthermore, the cases of insect resistance continue to exceed by far the number of cases of herbicide and fungicide resistance (Sparks et al., IRAC: Mode of action classification and insecticide resistance management, Pesticide Biochemistry and Physiology (2014) available online 4 December 2014).
Each year insects, plant pathogens, and weeds, destroy more than 40% of all food production. This loss occurs despite the application of pesticides and the use of a wide array of non-chemical controls, such as, crop rotations, and biological controls. If just some of this food could be saved, it could be used to feed the more than three billion people in the world who are malnourished (Pimental, D., Pest Control in World Agriculture, Agricultural Sciences - Vol. II, 2009).
Plant parasitic nematodes are among the most widespread pests, and are frequently one of the most insidious and costly. It has been estimated that losses attributable to nematodes are from about 9% in developed countries to about 15% in undeveloped countries. However, in the United States of America a survey of 35 States on various crops indicated nematode-derived losses of up to 25% (Nicol et al., Current Nematode Threats to World Agriculture, Genomic and Molecular Genetics of Plant - Nematode Interactions, p. 21-43, 2011).
It is noted that gastropods (slugs and snails) are pests of less economic importance than other arthropods or nematodes, but in certain places, they may reduce yields substantially, severely affecting the quality of harvested products, as well as, transmitting human, animal, and plant diseases. While only a few dozen species of gastropods are serious regional pests, a handful of species are important pests on a worldwide scale. In particular, gastropods affect a wide variety of agricultural and horticultural crops, such as, arable, pastoral, and fiber crops; vegetables; bush and tree fruits; herbs; and ornamentals (Speiser, B., Molluscicides, Encyclopedia of Pest Management, Ch. 219, p. 506-508, 2002).
Termites cause damage to all types of private and public structures, as well as to agricultural and forestry resources. In 2005, it was estimated that termites cause over USS50 billion in damage worldwide each year (Korb, J., Termites, Current Biology, Vol. 17, No. 23, 2007).
Consequently, for many reasons, including those mentioned above, there is an on-going need for the costly (estimated to be about US$286 million per pesticide in 2014), time-consuming (on average about 11.3 years per pesticide), and difficult, development of new pesticides (Phillips McDougall, The Cost of New Agrochemical Product Discovery, Development and Registration in 1995, 2000, 2005-8 and 2010-2014. R&D expenditure in 2014 and expectations for 2019, 2016).
DEFINITIONS FOR THIS DISCLOSURE
Examples provided herein are not exhaustive and should not be construed as limiting. It is understood that a substituent should comply with chemical bonding rules and steric compatibility constraints in relation to the particular molecule to which it is attached. These definitions are only to be used for the purposes of this disclosure.
The term “alkenyl” means an acyclic, unsaturated (at least one carbon-carbon double bond), branched or unbranched, substituent consisting of carbon and hydrogen, for example, vinyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, and decenyl.
The term “alkoxy” means an alkyl further consisting of a carbon-oxygen single bond, for example, methoxy, ethoxy, propoxy, isopropoxy, 1 -butoxy, 2-butoxy, isobutoxy, tert-butoxy, pentoxy, 2-methylbutoxy, 1,1- dimethylpropoxy, hexoxy, heptoxy, octoxy, nonoxy, and decoxy.
The term “alkyl” means an acyclic, saturated, branched or unbranched, substituent consisting of carbon and hydrogen, for example, methyl, ethyl, propyl, isopropyl, 1 -butyl, 2 -butyl, isobutyl, tert-butyl, pentyl, 2-methylbutyl, 1,1 -dimethylpropyl, hexyl, heptyl, octyl, nonyl, and decyl.
The term “alkynyl” means an acyclic, unsaturated (at least one carbon-carbon triple bond, and any double bonds), branched or unbranched, substituent consisting of carbon and hydrogen, for example, ethynyl, propargyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, and decynyl.
The term “aryl” means a cyclic, aromatic substituent consisting of hydrogen and carbon, for example, phenyl, naphthyl, and biphenyl. The term “cycloalkenyl” means a monocyclic or polycyclic, unsaturated (at least one carbon-carbon double bond) substituent consisting of carbon and hydrogen, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclodecenyl, norbomenyl, bicyclo[2.2.2]octenyl, tetrahydronaphthyl, hexahydronaphthyl, and octahydronaphthyl.
The term “cycloalkyl” means a monocyclic or polycyclic, saturated substituent consisting of carbon and hydrogen, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, norbomyl, bicyclo[2.2.2]octyl, and decahydronaphthyl.
The term “cycloalkoxy” means a cycloalkyl further consisting of a carbon-oxy gen single bond, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, cyclodecyloxy, norbomyloxy, andbicyclo[2.2.2]octyloxy.
The term “halo” means fluoro, chloro, bromo, and iodo.
The term “haloalkyl” means an alkyl further consisting of, from one to the maximum possible number of, identical or different, halos, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoromethyl, 2- fluoroethyl, 2,2,2-trifluoroethyl, chloromethyl, trichloromethyl, and 1,1,2,2-tetrafluoroethyl.
The term “heterocyclyl” means a cyclic substituent that may be fully saturated, partially unsaturated, or fully unsaturated, where the cyclic structure contains at least one carbon and at least one heteroatom, where said heteroatom is nitrogen, sulfitr, or oxygen. Examples are:
(1) aromatic heterocyclyl substituents include, but are not limited to, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl, benzoxazolyl, benzothienyl, benzothiazolyl, cinnolinyl, furanyl, indazolyl, indolyl, imidazolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, 1,3,4-oxadiazolyl, oxazolinyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, 1,2,3,4-tetrazolyl, thiazolinyl, thiazolyl, thienyl, 1,2,3 -triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, and 1,2,4-triazolyl;
(2) fully saturated heterocyclyl substituents include, but are not limited to, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, and tetrahydropyranyl;
(3) partially or fully unsaturated heterocyclyl substituents include, but are not limited to, 4,5-dihydro- isoxazolyl, 4,5-dihydro-oxazolyl, 4, 5-dihydro- 1 //-pyrazolyl. 2,3-dihydro-[l,3,4]-oxadiazolyl, and 1,2,3,4-tetrahydro-quinolinyl; and
(4) Additional examples of heterocyclyls include the following:
Figure imgf000004_0001
thietanyl thietanyl-oxide and thietanyl-dioxide.
The term “ambient pressure” refers to pressures from about 80 kilopascals (kPa) to about 105 kPa.
The term “ambient temperature” or “room temperature” refers to temperatures ranging from about 20 °C to about 24 °C. The term locus means a habitat, breeding ground, plant, seed, soil, material, or environment, m which a pest is growing, may grow, or may traverse. For example, a locus may be where crops, trees, fruits, cereals, fodder species, vines, turf, and/or ornamental plants, are growing; where domesticated animals are residing; the interior or exterior surfaces of buildings (such as places where grains are stored); the materials of construction used in buildings (such as impregnated wood); and the soil around buildings.
In this disclosure the terms “molecule” and “compound” may be used interchangeably.
DETAILED DESCRIPTION
In one aspect, provided are compounds having the structure of Formula One or Formula Two: wherein:
Figure imgf000005_0001
(A) Ar1 is selected from
(1) furanyl, phenyl, pyridazinyl, pyridyl, pyrimidinyl, thienyl, or
(2) substituted furanyl, substituted phenyl, substituted pyridazinyl, substituted pyridyl, substituted pyrimidinyl, or substituted thienyl, wherein said substituted furanyl, substituted phenyl, substituted pyridazinyl, substituted pyridyl, substituted pyrimidinyl, and substituted thienyl have one or more substituents independently selected from H, F, Cl, Br, I, CN, OH, SH, NO2, oxo, thioxo, NRxRy, Ci-Cg alkyl, Ci-Cg haloalkyl, Cs-Cg cycloalkyl, Ci-Cx halocycloalkyl, C’.-Cx cycloalkoxy, C3-C8 halocycloalkoxy, Ci-C8 alkoxy, Ci-C8 haloalkoxy, CL-Cs alkenyl, C.-Cx cycloalkenyl, C2- C8 haloalkenyl, Ci-Cg alkynyl, S(=O)n(C3-C8 cycloalkyl), S(=O)n(C’.-C« halocycloalkyl), S(=O)n(Ci-C8 alkyl), S(=O)n(Ci-C8 haloalkyl), OSO2(Ci-C8 alkyl), OSO2(Ci-C8 haloalkyl), C(=O)NRxRy, (Ci-C8 alkyl)NRxRy, C(=O)C(=O)(Ci-C8 alkyl), C(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 haloalkyl), C(=O)O(Ci-C8 haloalkyl), C(=O)(C3-C8 cycloalkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(C2-C8 alkenyl), C(=O)O(C2-C8 alkenyl), (Ci-C8 alkyl)O(Ci-C8 alkyl), (Ci-C8 alkyl)S(=O)n(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)O(Ci-C8 alkyl), C(=O)(C1-C8 alkyl)C(=O)O(Ci-Cg alkyl), (Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)(Ci-C8 alkyl), (Ci- C8 alkyl)phenyl, (Ci-C8 alkyl)-O-phenyl, phenyl, phenoxy, Si(Ci-C8 alky 1 b. or S(=O)nNRxRy, or (Het-1), wherein each alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkenyl, cycloalkenyl, haloalkenyl, alkynyl, phenyl, phenoxy, and (Het-1) substituent may be optionally substituted with one or more substituents independently selected from H, F, Cl, Br, I, CN, OH, SH, NO2, oxo, thioxo, NR*Ry, Ci-C8 alkyl, Ci-Cg haloalkyl, C3-Cg cycloalkyl, Ci-Cg halocycloalkyl, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, Ci-Cs alkoxy, Ci-Cg haloalkoxy, C2-Cg alkenyl, C -Cs cycloalkenyl, C2-Cg haloalkenyl, Ci-Cs alkynyl, S(=O)n(C3-Cg cycloalkyl), S(=O)n(C3-Cg halocycloalkyl), S(=O)n(Ci-Cg alkyl), S(=O)n(Ci-Cg haloalkyl), OSOgfC'i-Cg alkyl), OSO2(Ci-C8 haloalkyl), C(=O)NRxRy, (Ci-Cg alkyl)NRxRy, C(=O)(Ci-Cg alkyl), C(=O)O(Ci-Cg alkyl), C(=O)(Ci-C8 haloalkyl), C(=O)O(Ci-Cg haloalkyl), C(=O)(C3-Cg cycloalkyl), C(=O)O(C3-Cg cycloalkyl), C(=O)(C2-Cg alkenyl), C(=O)O(C2-C8 alkenyl), (Ci-Cg alkyl)O(Ci-Cg alkyl), (Ci-Cg alkyl)S(=O)„(Ci-C8 alkyl), (Ci-Cg alkyl)OC(=O)(Ci-Cg alkyl), (Ci-Cg alkyl)OC(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 alkyl)C(=O)O(Ci-Cg alkyl), (Ci-Cg alkyl)C(=O)O(Ci-C8 alkyl), (Ci-Cg alkyl)C(=O)(Ci-C8 alkyl), (Ci-Cg alkyl)phenyl, (Ci-Cg alkyl)-O-phenyl, phenyl, phenoxy, Si(Ci-Cg alkyl)3, S(=O)„NRxRy, or (Het-1);
(B) Het is a 5- or 6-membered, saturated or unsaturated, heterocyclic ring, containing one or more heteroatoms independently selected from nitrogen, sulfur, or oxygen, and where said heterocyclic ring may also be substituted with one or more substituents independently selected from H, F, Cl, Br, I, CN, OH, SH, NO2, oxo, thioxo, NRxRy, Ci-C8 alkyl, Ci-Cg haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C3-Cg cycloalkoxy, C3-C8 halocycloalkoxy, Ci-Cg alkoxy, Ci-Cg haloalkoxy, C2-C8 alkenyl, C3-Cg cycloalkenyl, C2-Cg haloalkenyl, C2-Cg alkynyl, S(=O)n(C3-Cg cycloalkyl), S(=O)n(C3-Cg halocycloalkyl), S(=O)n(Ci-Cg alkyl), S(=O)n(Ci-C8 haloalkyl), OSO2(Ci-Cg alkyl), OSO2(Ci-C8 haloalkyl), C(=O)NRxRy, (Ci-Cg alkyl)NRxRy, C(=O)(Ci-Cg alkyl), C(=O)O(Ci-Cg alkyl), C(=O)(Ci-C8 haloalkyl), C(=O)O(Ci-Cg haloalkyl), C(=O)(C3-Cg cycloalkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(C2-C8 alkenyl), C(~O)O(C2-C8 alkenyl), (Ci-Cg alkyl)O(Ci-C8 alkyl), (Ci-Cg alkyl)S(=O)n(Ci-C8 alkyl), (Ci-Cg alkyl)OC(=O)(Ci-C8 alkyl), (Ci-Cg alkyl)OC(=O)O(Ci-C8 alkyl), C(=O)(Ci-Cg alkyl)C(=O)O(Ci-Cg alkyl), (Ci-Cg alkyl)C(=O)O(Ci-C8 alkyl), (Ci-Cg alkyl)C(=O)(Ci-Cg alkyl), (Ci-Cg alkyl)phenyl, (Ci-Cg alkyl)-O-phenyl, phenyl, phenoxy, Si(Ci-Cg alkyl)3, or S(=O)nNRxRy, wherein each alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkenyl, cycloalkenyl, haloalkenyl, alkynyl, phenyl, and phenoxy substituent may be optionally substituted with one or more substituents independently selected fromH, F, Cl, Br, I, CN, OH, SH, NO2, oxo, thioxo, NRxRy, Ci-Cg alkyl, Ci-Cg haloalkyl, C3-Cg cycloalkyl, Ci-Cs halocycloalkyl, C3-Cg cycloalkoxy, C3-Cg halocycloalkoxy, Ci-Cg alkoxy. Ci-Cg haloalkoxy, C2-Cg alkenyl, C3-C8 cycloalkenyl, C2-C8 haloalkenyl, C2-C8 alkynyl, S(=O)n(C3-Cg cycloalkyl), S(=O)n(C3-Cg halocycloalkyl), S(=O)n(Ci-C8 alkyl), S(=O)„(Ci-C8 haloalkyl), OSO2(Ci-C8 alkyl), OSO2(Ci-C8 haloalkyl), C(=O)NRxRy, (Ci-Cg alkyl)NRxRy, C(=O)(Ci-Cg alkyl), C(=O)O(Ci-C8 alkyl), C(=O)(Ci-Cg haloalkyl), C(=O)O(Ci-C8 haloalkyl), C(=O)(C3-C8 cycloalkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(C2-C8 alkenyl), C(=O)O(C2-C8 alkenyl), (Ci-Cg alkyl)O(Ci-C8 alkyl), (Ci-Cg alkyl)S(=O)n(Ci-C8 alkyl), (Ci-Cg alkyl)OC(=O)(Ci-C8 alkyl), (Ci-Cg alkyl)OC(=O)O(Ci-C8 alkyl), C(=O)(Ci-Cg alkyl)C(=O)O(Ci-Cg alkyl), (Ci-Cg alkyl)C(=O)O(Ci-C8 alkyl), (Ci-Cg alkyl)C(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)phenyl, (Ci-C8 alkyl)-O-phenyl, phenyl, phenoxy, Si(Ci-C8 alkyl)3, or S(=O)nNRxRy;
(C) A is a
(1) 3-, 4-, 5-, 6-, or 7-membered nitrogen containing non-aromatic ring containing between 0 and 1 additional nitrogen atoms optionally substituted with one or more substituents independently selected from H, Cl, Br, F, I, CN, oxo, Ci-Cs alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylthio, Ci-Cs haloalkylthio, CS-Cr alkenyl, and Cz-Cs haloalkenyl; or
(2) a 6-membered non-aromatic carbocyclic ring optionally substituted with one or more substituents independently selected fromH, Cl, Br, F, I, CN, oxo, Ci-Ce alkyl, Ci-Cs -haloalkyl, Ci-Cs alkoxy, Ci-Cs haloalkoxy, Ci-Ce alkylthio, Ci-Ce haloalkylthio, Cz-Cs alkenyl, C2-C6 haloalkenyl, and C2-C6 haloalkenyl;
(D) L is a linker selected from
(1) a bond,
(2) -CRaRb-, -CRaRb-CRcRd-, or -CRaRb-CRcRd-CReRf-; or
(3) -CRa=CRb-, wherein each of Ra, Rb, Rc, Rd, Re, and Rf is selected from H, F, Cl, Br, I, CN, OH, SH, NO2, oxo, thioxo,
NR’R’', Ci-Cs alkyl, Ci-C8 haloalkyl, Ci-Cs alkoxy, Ci-Cs haloalkoxy, Cz-C8 alkenyl, Cz-Cs haloalkenyl, Cz-C8 alkynyl, Cz-Cs haloalkynyl, Cz-C8 cycloalkyl, Cz-C8 halocycloalkyl, Cz-Cg cycloalkoxy, Cz-Cs halocycloalkoxy, Cz- Cs cycloalkenyl, Cz-Cs halocycloalkenyl, C(_O)( C i-Cf alkyl), C(=O)O(Ci-Cs alkyl), C(=O)(C3-Cs cycloalkyl), C(=O)O(C3-C6 cycloalkyl), C(=O)(C2-C6 alkenyl), C(=O)O(C2-C6 alkenyl), (Ci-C6 alkyl)O(Ci-C6 alkyl), (Ci-C6 alkyl)S(=O)n(Ci-C6 alkyl), C(=O)(Ci-C6 alkyl)C(=O)O(Ci-C6 alkyl), S(=O)n(Ci-C8 alkyl), S(=O)„(C3-C8 cycloalkyl), S(=O)n(Ci-C8 haloalkyl), S(=O)n(Cz-Cg halocycloalkyl), phenyl, or phenoxy;
(E) Ra and Rc together can optionally form a 3- to 7-membered saturated or unsaturated ring which may contain C=O, C=S, N, S or O, and is optionally substituted with H, OH, F, Cl, Br, I, CN, NOz, NRxRy, Ci-Cs alkyl, Ci-Cg haloalkyl, Ci-Ce hydroxyalkyl, Cz-Cs cycloalkyl, Cz-Cs halocycloalkyl, Cz-Cs hydroxycycloalkyl, Cz-Cs cycloalkoxy, Cz-Cs halocycloalkoxy, Cz-Cs hydroxycycloalkoxy, Ci-Cs alkoxy, Ci-Cs haloalkoxy, Cz-Cs alkenyl, Cz-Cs cycloalkenyl, Cz-Cs alkynyl, Cz-Cs cycloalkynyl, S(=O)n(Ci-Cs alkyl), S(=O)n(Ci-Cs haloalkyl), OSOz(Ci-Cs alkyl), OSOz(Ci-Cs haloalkyl), C(=O)H, C(=O)OH, C(=O)NRxRy, (Ci-Cs alkyl)NRxRy, C(=O)(Ci-Cs alkyl), C(=O)O(Ci-C6 alkyl), C(=O)(Ci-C6 haloalkyl), C(=O)O(Ci-Cs haloalkyl), C(=O)(C3-C6 cycloalkyl), C(=O)O(C3-C6 cycloalkyl), C(=O)(C2-C6 alkenyl), C(=O)O(C2-Cs alkenyl), (Ci-Cs alkyl)O(Ci-C6 alkyl), (Ci-C6 alkyl)S(=O)„(Ci-C6 alkyl), C(=O)(Ci-Cs alkyl)C(=O)O(Ci-Cs alkyl), phenyl, phenoxy, and Het-1;
(F) each of Q1 and Q2 is independently selected from O or S;
(G) each of R1, R4, and R5 is independently selected from H, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cg alkoxy, Ci-Cg haloalkoxy, phenyl, C3-Cs cycloalkyl, Cz-Cs alkenyl, Cz-Cs alkynyl, C(=O)(Ci-Cs alkyl), (Ci-Cs alkyl)O(Ci-Cs alkyl), (Ci-Cs alkyl)S(=O)n(Ci-C8 alkyl), (Ci-Cg alkyl)phenyl, (Ci-Cs alkyl)-O-phenyl, C(=O)(Het-l), (Het-1), (Ci- Cg alkyl)(Het-l), (Ci-Cg alkyl)C(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)O(Ci-C8 alkyl), (Ci-Cs alkyl)OC(=O)NRxRy, (Ci-C8alkyl)C(=O)N(Rx)(Ci-C8 alkyl)(Het-l), (Ci-C8alkyl)C(=O)(Het-l), (Ci- C8 alkyl)C(=O)N(Rx)(Ci-Cg alkyl)N(Ry)C(=O)OH, (Ci-C8alkyl)C(=O)N(Rx)(Ci-C8 alkyl)N(Rx)(Ry), (Ci-Cg alkyl)C(=O)N(Rx)(Ci-Cs alkyl)N(Ry)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)N(Rx)(Ci-C8 alkyl)(N(Ry)C(=O)O(Ci-Cs alkyl)C(=O)OH, (Ci-C8alkyl)C(=O)(Het-l)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)(C3-C8 cycloalkyl), (Ci-C8 alkyl)OC(=O)(Het-l), (Ci-C8alkyl)OC(=O)(Ci-C8 alkyl)N(Rx)C(=O)O(Ci- C8 alkyl), (Ci-Cs alkyl)-NR*Ry, (Ci-C8 alkyl)S(Het-l), (Ci-C8 alkyl)S(=O)n(Het-l), or (Ci-C8 alkyl)O(Het-l), wherein each alkyl, cycloalkyl, phenyl, and (Het-1) are optionally substituted with one or more substituents independently selected fromH, F, Cl, Br, I, CN, OH, SH, NO2, oxo, thioxo, NR'R'. Ci-Cg alkyl, Ci-Cg haloalkyl, C3-C8 cycloalkyl, C.-Cx halocycloalkyl, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, Ci-Cg alkoxy, Ci-Cg haloalkoxy, C2-Cg alkenyl, C3-C8 cycloalkenyl, C2-C8 haloalkenyl, C2-C8 alkynyl, S(=O)n(C3-Cg cycloalkyl), S(=O)n(C3-Cg halocycloalkyl), S(=O)n(Ci-Cg alkyl), S(=O)n(Ci-C8 haloalkyl), OSO2(Ci-C8 alkyl), OSO2(Ci-Cg haloalkyl), C(=O)H, C(=O)OH, C(=O)\R R'. (Ci-Cg alkyONRW, C(=O)(Ci-Cg alkyl), C(=O)O(Ci-Cg alkyl), C(=O)(Ci-C8 haloalkyl), C(=O)O(Ci-Cg haloalkyl), C(=O)(C3-C8 cycloalkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(C2-C8 alkenyl), C(=O)O(C2-C8 alkenyl), (Ci-Cg alkyl)O(Ci-C8 alkyl), (Ci-C8 alkyl)S(=O)n(Ci-C8 alkyl), (Ci- C8 alkyl)OC(=O)(Ci-C8 alkyl), (Ci-Cg alkyl)OC(=O)O(Ci-Cg alkyl), C(=O)(Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci- C8 alkyl)C(=O)O(Ci-Cg alkyl), (Ci-Cg alkyl)C(=O)(Ci-C8 alkyl), (Ci-Cg alkyl)phenyl, (Ci-Cg alkyl)-O-phenyl, phenyl, phenoxy, Si(Ci-Cg alkyl)3, S(=O)nNRxR5', or (Het-1);
(H) R2 is selected from H, OH, SH, Ci-Cg alkyl, Ci-Cg haloalkyl, C3-Cg cycloalkyl, C3-Cg halocycloalkyl, C3-Cg cycloalkoxy, C3-Cg halocycloalkoxy, Ci-C8 alkoxy, Ci-Cg haloalkoxy, C2-Cg alkenyl, C3-Cg cycloalkenyl, C2-Cg haloalkenyl, C2-Cg alkynyl, S(=O)n(C3-Cg cycloalkyl), S(=O)n(C3-Cg halocycloalkyl), S(=O)n(Ci-Cg alkyl), S(=O)n(Ci-Cg haloalkyl), OSO2(Ci-Cg alkyl), OSO2(Ci-Cg haloalkyl), C(=O)H, C(=O)(Ci-C8 alkyl), C(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 haloalkyl), C(=O)O(Ci-Cg haloalkyl), C(=O)(C3-Cg cycloalkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(C2-C8 alkenyl), C(=O)O(C2-C8 alkenyl), (Ci-Cg alkyl)O(Ci-Cg alkyl), (Ci-Cg alkyl)S(=O)n(Ci-Cg alkyl), (Ci- C8 alkyl)OC(=O)(Ci-C8 alkyl), (Ci-Cg alkyl)OC(=O)O(Ci-C8 alkyl), C(=O)(Ci-Cg alkyl)C(=O)O(Ci-Cg alkyl), (Ci- C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-Cg alkyl)C(=O)(Ci-C8 alkyl), (Ci-Cg alkyl)phenyl, (Ci-Cg alkyl)-O-phenyl, phenyl, C(=O)(Het-l), (Het-1), (Ci-C8 alkyl)(Het-l), (Ci-C8 alkyl)OC(=O)NRxR>', (Ci-Cg alkyl)C(=O)N(Rx)(Ci-Cg alkyl)(Het-l), (Ci-C8alkyl)C(=O)(Het-l), (Ci-C8 alkyl)C(=O)N(Rx)(Ci-C8 alkyl)\(Rv)C(=O)OH. (Ci-Cg alkyl)C(=O)N(Rx)(Ci-Cg alkyl )N(RX)(R?), (Ci-Cg alkyl)C(=O)N(Rx)(Ci-Cg alkyl)N(R0C(=O)O(Ci-Cg alkyl), (Ci-Cg alkyl)C(=O)N(Rx)(Ci-Cg alkyl)N(Ry)C(=O)O(Ci-Cg alkyl)C(=O)OH, (Ci-C8alkyl)C(=O)(Het-l)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)(C3-Cg cycloalkyl), (Ci-C8alkyl)OC(=O)(Het-l), (Ci-Cg alkyl)OC(=O)(Ci-Cg alkyl)N(Rx)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)NR‘R'. (Ci-Cg alkyl)S(Het-l), (Ci-C8 alkyl)S(=O)n(Het-l), or (Ci-Cg alkyl)O(Het-l), wherein each alkyl, haloalkyl, cycloalkyl, halocycloalkyl, cycloalkoxy, halocycloalkoxy, alkoxy, haloalkoxy, alkenyl, cycloalkenyl, haloalkenyl, alkynyl, phenyl, and (Het-1), are optionally substituted with one or more substituents independently selected from H, F, Cl, Br, I, CN, OH, SH, NO2, oxo, thioxo, Ci-Cg alkyl, Ci-C8 haloalkyl, C3-Cg cycloalkyl, C3-Cg halocycloalkyl, C3-Cg cycloalkoxy, C3-C8 halocycloalkoxy, Ci-C8 alkoxy, Ci-C8 haloalkoxy, C2-Cg alkenyl, C3-C8 cycloalkenyl, C2-C8 haloalkenyl, C2-C8 alkynyl, S(=O)n(C3-C8 cycloalkyl), S(=O)n(C3-Cg halocycloalkyl), S(=O)n(Ci-Cg alkyl), S(=O)„(Ci-C8 haloalkyl), OSO2(Ci-C8 alkyl), OSO2(Ci-C8 haloalkyl), C(=O)H, C(=O)OH, C(=O)(Ci-C8 alkyl), C(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 haloalkyl), C(=O)O(Ci-C8 haloalkyl), C(=O)(C3-C8 cycloalkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(C2-C8 alkenyl), C(=O)O(C2-C8 alkenyl), (Ci-Cg alkyl)O(Ci-C8 alkyl), (Ci-C8 alkyl)S(=O)n(Ci-Cg alkyl), (Ci-Cg alkyl)OC(=O)(Ci-Cg alkyl), (Ci-Cg alkyl)OC(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-Cg alkyl)C(=O)(Ci-C8 alkyl), (Ci-Cg alkyl)phenyl, (Ci-Cg alkyl)-O-phenyl, phenyl, halophenyl, phenoxy, and (Het-1); (I) R3 is selected from C3-C8 cycloalkyl, phenyl, (Ci-Cg alkyl)phenyl, (Ci-Cs alkyl)-O-phenyl, (C2-C8 alkenyl)- O-phenyl, (Het-1), (Ci-Cs alkyl)(Het-l), (Ci-Cs alkyl)O(Het-l), wherein the C3-C8 cycloalkyl, phenyl, (Ci-Cs alkyl)phenyl, (Ci-Cs alkyl)-O-phenyl, (C2-C8 alkenyl)-O- phenyl, (Het-1), (Ci-Cg alkyl)(Het-l), or (Ci-Cg alkyl)O(Het-l) may be optionally substituted with one or more substituents independently selected from H, F, Cl, Br, I, CN, OH, SH, NO2, oxo, thioxo, NRxRy, Ci-C8 alkyl, Ci-C8 haloalkyl, C3-C8 cycloalkyl, C -Cx halocycloalkyl, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, Ci-C8 alkoxy, Ci-Cg haloalkoxy, C2-C8 alkenyl, C3-C8 cycloalkenyl, Ca-Cs haloalkenyl, Ca-Cs alkynyl, S(=O)n(C3-C8 cycloalkyl), S(=O)n(Ca-C8 halocycloalkyl), S(=O)n(Ci-C8 alkyl), S(=O)n(Ci-C8 haloalkyl), OSO2(Ci-C8 alkyl), OSO2(Ci-C8 haloalkyl), C(=O)(Ci-C8 alkyl), C(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 haloalkyl), C(=O)O(Ci-C8 haloalkyl), C(=O)(C3-C8 cycloalkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(C2-C8 alkenyl), C(=O)O(C2-C8 alkenyl), (Ci-C8 alkyl)O(Ci-C8 alkyl), (Ci-C8 alkyl)O(Ci-C8 haloalkyl), (Ci-C8 alkyl)S(=O)„(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)(Ci- C8 alkyl), (Ci-C8 alkyl)OC(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)O(Ci- C8 alkyl), (Ci-C8 alkyl)C(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)phenyl, (Ci-C8 alkyl)-O-phenyl, phenyl, phenoxy, Si(Ci-C8 alkyl)3, S(=O)nNRxRy, or (Het-1) or wherein two adjacent substituents form a 5- or 6-membered saturated or unsaturated, hydrocarbyl link, which may contain one or more heteroatoms selected from nitrogen, sulfur, and oxygen, and wherein said hydrocarbyl link may optionally be substituted with one or more substituents independently selected fromH, F, Cl, Br, I, CN, OH, SH, NO2, NRxRy, Ci-Ce alkyl, Ci-Cs haloalkyl, Ci-Cs alkoxy, Ci-Ce haloalkoxy, S(=O)n(Ci-C6 alkyl), S(=O)n(Ci-C6 haloalkyl), phenyl, and oxo;
(J) R2 and R4 together may optionally form a 1- to 4-membered saturated or unsaturated, hydrocarbyl link, which may contain one or more heteroatoms selected from nitrogen, sulfur, and oxygen, and together with (Q2)(C)(N) forms a 4- to 7-membered cyclic structure, wherein said hydrocarbyl link may optionally be substituted with one or more substituents independently selected from H, F, Cl, Br, I, CN, OH, SH, NO2, oxo, thioxo, NRxRy, Ci-C8 alkyl, Ci-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, Ci-C8 alkoxy, Ci-C8 haloalkoxy, C2-C8 alkenyl, C3-C8 cycloalkenyl, C2-C8 haloalkenyl, C2-C8 alkynyl, S(=O)n(C3-C8 cycloalkyl), S(=O)n(C3-C8 halocycloalkyl), S(=O)n(Ci-C8 alkyl), S(=O)n(Ci-C8 haloalkyl), OSO2(Ci-C8 alkyl), OSO2(Ci-C8 haloalkyl), C(=O)H, C(=O)(Ci-C8 alkyl), C(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 haloalkyl), C(=O)O(Ci- C8 haloalkyl), C(=O)(C3-C8 cycloalkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(C2-C8 alkenyl), C(=O)O(C2-C8 alkenyl), (Ci-C8 alkyl)O(Ci-C8 alkyl), (Ci-C8 alkyl)S(=O)n(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)(Ci-C8 alkyl), (Ci-C8 alkyljphenyl, (Ci-C8 alkyl)-O-phenyl, phenyl, substituted phenyl, phenoxy, or (Het-1);
(K) Rx and Ry are independently selected from H, OH, SH, Ci-C8 alkyl, Ci-C8 haloalkyl, C3-C8 cycloalkyl, C3- C8 halocycloalkyl, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, Ci-C8 alkoxy, Ci-C8 haloalkoxy, C2-C8 alkenyl, C3- C8 cycloalkenyl, C2-C8 haloalkenyl, C2-C8 alkynyl, S(=O)n(C3-C8 cycloalkyl), S(=O)n(C3-C8 halocycloalkyl), S(=O)n(Ci-C8 alkyl), S(=O)„(Ci-C8 haloalkyl), OSO2(Ci-C8 alkyl), OSO2(Ci-C8 haloalkyl), C(=O)H, C(=O)(Ci-C8 alkyl), C(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 haloalkyl), C(=O)O(Ci-C8 haloalkyl), C(=O)(C3-C8 cycloalkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(C2-C8 alkenyl), C(=O)O(C2-C8 alkenyl), (Ci-C8 alkyl)O(Ci-C8 alkyl), (Ci-C8 alkyl)S(=O)„(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)phenyl, (Ci-C8 alkyl)-O-phenyl, phenyl, C(=O)(Het-l), (Het-1), (Ci-C8 alkyl)(Het-l), (Ci-C8 alkyl)C(=O)(Het- 1), (Ci-C8alkyl)C(=O)(Het-l)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)(C3-C8 cycloalkyl), (Ci-C8 alkyl)OC(=O)(Het-l), (Ci-C8 alkyl)S(Het-l), (Ci-C8 alkyl)S(=O)n(Het-l), or (Ci-C8 alkyl)O(Het-l), wherein each alkyl, haloalkyl, cycloalkyl, halocycloalkyl, cycloalkoxy, halocycloalkoxy, alkoxy, haloalkoxy, alkenyl, cycloalkenyl, haloalkenyl, alkynyl, phenyl, and (Het-1), are optionally substituted with one or more substituents independently selected from H, F, Cl, Br, I, CN, OH, SH, NO2, oxo, thioxo, Ci-C8 alkyl, Ci-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, Ci-C8 alkoxy, Ci-C8 haloalkoxy, C2-C8 alkenyl, C3-C8 cycloalkenyl, C2-C8 haloalkenyl, Cb-Cx alkynyl, S(=O)n(C3-C8 cycloalkyl), S(=O)n(C3-C8 halocycloalkyl), S(=O)n(Ci-C8 alkyl), S(=O)„(Ci-C8 haloalkyl), OSO2(Ci-C8 alkyl), OSO2(Ci-C8 haloalkyl), C(=O)H, C(=O)OH, C(=O)(Ci-C8 alkyl), C(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 haloalkyl), C(=O)O(Ci-C8 haloalkyl), C(=O)(C3-C8 cycloalkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(C2-C8 alkenyl), C(=O)O(C2-C8 alkenyl), (Ci-C8 alkyl)O(Ci-C8 alkyl), (Ci-C8 alkyl)S(=O)n(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)phenyl, (Ci-C8 alkyl)-O-phenyl, phenyl, halophenyl, phenoxy, and (Het-1), or Rx and Ry together can optionally form a 5- to 7-membered saturated or unsaturated cyclic group which may contain one or more heteroatoms selected from nitrogen, sulfur, and oxygen, and where said cyclic group may be substituted with H, F, Cl, Br, I, CN, OH, SH, NO2, oxo, thioxo, Ci-C8 alkyl, Ci-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, Ci-C8 alkoxy, Ci-C8 haloalkoxy, C2-C8 alkenyl, C3-C8 cycloalkenyl, C2-C8 haloalkenyl, C2-C8 alkynyl, S(=O)n(C3-C8 cycloalkyl), S(=O)n(C3-C8 halocycloalkyl), S(=O)n(Ci-C8 alkyl), S(=O)„(Ci-C8 haloalkyl), OSO2(Ci-C8 alkyl), OSO2(Ci-C8 haloalkyl), C(=O)(Ci-C8 alkyl), C(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 haloalkyl), C(=O)O(Ci-C8 haloalkyl), C(=O)(C3-C8 cycloalkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(C2-C8 alkenyl), C(=O)O(C2-C8 alkenyl), (Ci-C8 alkyl)O(Ci-C8 alkyl), (Ci-C8 alkyl)S(=O)n(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)phenyl, (Ci-C8 alkyl)-O- phenyl, phenyl, substituted phenyl, phenoxy, and (Het-1);
(L) (Het-1) is a 5- or 6-membered, saturated or unsaturated, heterocyclic ring, containing one or more heteroatoms independently selected from nitrogen, sulfur or oxygen, wherein said heterocyclic ring may also be substituted with one or more substituents independently selected from H, F, Cl, Br, I, CN, OH, SH, NO2, oxo, thioxo, NRxRy, Ci-C8 alkyl, Ci-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, Ci-C8 alkoxy, Ci-C8 haloalkoxy, C2-C8 alkenyl, C3-C8 cycloalkenyl, C2-C8 haloalkenyl, C2-C8 alkynyl, S(=O)n(C3-C8 cycloalkyl), S(=O)n(C3-C8 halocycloalkyl), S(=O)n(Ci-C8 alkyl), S(=O)n(Ci-C8 haloalkyl), OSO2(Ci-C8 alkyl), OSO2(Ci-C8 haloalkyl), C(=O)NRxRy, (Ci-C8 alkyl)NRxRy, C(=O)(Ci-C8 alkyl), C(=O)O(Ci-C8 alkyl), C(=O)(Ci-Cs haloalkyl), C(=O)O(Ci-C8 haloalkyl), C(=O)(C3-C8 cycloalkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(C2-C8 alkenyl), C(=O)O(C2-C8 alkenyl), (Ci-C8 alkyl)O(Ci-C8 alkyl), (Ci-C8 alkyl)O(Ci-C8 haloalkyl), (Ci- C8 alkyl)S(=O)„(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)pheny 1, (Ci-C8 alkyl)-O-phenyl, phenyl, and phcnoxy. wherein each alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, phenyl, and phenoxy may be optionally substituted with one or more substituents independently selected from H, F, Cl, Br, I, CN, OH, SH, NOz, oxo, thioxo, \R'Ry. Ci-C8 alkyl, Ci-C8 haloalkyl, Ci-C« cycloalkyl, C3-C8 halocycloalkyl, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, Ci-C8 alkoxy, Ci-C8 haloalkoxy, C2-C8 alkenyl, Ca-C8 cycloalkenyl, Cz-Cs haloalkenyl, Cz-C8 alkynyl, S(=O)n(Ca-C8 cycloalkyl), S(=O)n(Ca-C8 halocycloalkyl), S(=O)n(Ci-C8 alkyl), S(=O)n(Ci-C8 haloalkyl), OSO2(Ci-C8 alkyl), OSO2(Ci-C8 haloalkyl), C(=O)H, G=O)NR'R'. (Ci-C8 alkyl)NRxRy, C(=O)(Ci-C8 alkyl), C(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 haloalkyl), C(=O)O(Ci-C8 haloalkyl), C(=O)(C3-C8 cycloalkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(C2-C8 alkenyl), C(=O)O(C2-C8 alkenyl), (Ci-C8 alkyl)O(Ci-C8 alkyl), (Ci-C8 alkyl)S(=O)n(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)phenyl, (Ci-C8 alkyl)-O- phenyl, phenyl, and phenoxy; and (M) n is each individually 0, 1, or 2.
In another aspect, provided are compounds of Formula One or Formula Two, wherein
(a) Ar1 is a phenyl or a substituted phenyl having one or more substituents independently selected from Ci-Cs alkyl, Ci-Ce haloalkyl, and Ci-Cg haloalkoxy;
(b) Het is a triazolyl, imidazolyl, pyrrolyl, or pyrazolyl;
(c) A is a
(1) 3-, 4-, 5-, 6-, or 7-membered nitrogen containing non-aromatic ring containing between 0 and 1 additional nitrogen atoms optionally substituted with one or more substituents independently selected from H, Cl, Br, F, I, CN, oxo, Ci-Ce alkyl, Ci-Cg haloalkyl, Ci-Cg alkoxy, Ci-Cg haloalkoxy, Ci-Ce alkylthio, Ci-Ce haloalkylthio, G-G alkenyl, and G-G. haloalkenyl; or
(2) a 6-membered non-aromatic carbocyclic ring optionally substituted with one or more substituents independently selected fromH, Cl, Br, F, I, CN, oxo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylthio, Ci-Ce haloalkylthio, G-G, alkenyl, and G-G, haloalkenyl;
(d) L is a bond;
(e) Q1 is O and Q2 is S;
(f) each of R1, R4, and R5 is independently selected from H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or phenyl;
(g) R2 is selected from H, Ci-Ce alkyl, or (i); and
(i) in the case of Formula One, optionally R2 and R4 together may form a 1- to 4-membered saturated or unsaturated, hydrocarbyl link, which may contain one or more heteroatoms selected from nitrogen, sulfur, and oxygen, and together with (Q2)(C)(N) forms a 4- to 7-membered cyclic structure, wherein said hydrocarbyl link, wherein said hydrocarbyl link may optionally be substituted with one or more R6, wherein each R6 is independently selected fromH, F, Cl, Br, I, CN, Ci-Ce alkyl, oxo, thioxo, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, phenyl, and phenoxy;
(h) R3 is selected from phenyl, (Ci-Ce alkyl)phenyl, or (Ci-Ce alkyl)-O-phenyl, wherein each alkyl and phenyl is optionally substituted with one or more substituents independently selected from F, Cl, Br, I, CN, NO2, oxo, thioxo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Cg alkoxy, Ci-Cg haloalkoxy, phenyl, or phenoxy.
In one embodiment, Ar1 is a phenyl. In another embodiment, Ar1 is a substituted phenyl having one or more substituents independently selected from OCF3, OCF2CF3, and CF3. In another embodiment, Het is 1,2,4-triazolyl. In another embodiment, A is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or tetrahydropyridinyl. In another embodiment, A is substituted azetidinyl, substituted pyrrolidinyl, substituted piperidinyl, substituted piperazinyl, or substituted tetrahydropyridinyl. In another embodiment, A is piperidinyl, substituted piperidinyl, piperazinyl, substituted piperazinyl, tetrahydropyridinyl, or substituted tetrahydropyridinyl. In another embodiment, A is substituted piperidinyl, substituted piperazinyl, or substituted tetrahydropyridinyl having one or more substituents independently selected fromH, Cl, Br, F, I, oxo, Ci-Ce alkyl, Ci-Cg -haloalkyl, Ci-Ce alkoxy, and Ci-Ce haloalkoxy. In another embodiment, A is a cyclohexyl, cyclohexenyl, cyclohexadienyl, substituted cyclohexyl, substituted cyclohexenyl, or substituted cyclohexadienyl. In another embodiment, A is a substituted cyclohexyl, substituted cyclohexenyl, or substituted cyclohexadienyl having one or more substituents independently selected from H, Cl, Br, F, I, oxo, Ci-Cs alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, and Ci-Cg haloalkoxy.
In another embodiment, L is a bond, -CH2-, or -CH2CH2-. In another embodiment, each of R1, R4 and R5 is independently H or Ci-Ce alkyl. In another embodiment, R1 is H or Ci-Ce alkyl. In another embodiment, R2 is H or Ci-Ce alkyl. In another embodiment, R4 is H or Ci-Ce alkyl. In another embodiment, R5 is H or Ci-Ce alkyl. In another embodiment, R3 is a substituted phenyl having one or more substituents independently selected from F, Cl, Br, I, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, and Ci-Ce haloalkoxy. In another embodiment, the compound has a structure listed in Table 1A or Table IB. In another embodiment, the compound has the structure of Formula Three or Formula Four:
Figure imgf000012_0001
wherein
(a) A is a (1) 4-, 5- or 6- membered nitrogen-containing non-aromatic ring containing between 0 and 1 additional nitrogen atoms optionally substituted with one or more substituents independently selected from H, Cl, Br, F, I, CN, oxo, Ci-Ce alkyl, Ci-Cg -haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylthio, Ci-Ce haloalkylthio, C2-Ce alkenyl, and C2-Ce haloalkenyl; or
(2) a 6-membered non-aromatic carbocyclic ring optionally substituted with one or more substituents independently selected fromH, Cl, Br, F, I, CN, oxo, Ci-Cg alkyl, Ci-Ce -haloalkyl, Ci-Cs alkoxy, Ci-Cs haloalkoxy, Ci-Ce alkylthio, Ci-Ce haloalkylthio, C2-Cs alkenyl, and C2-Cs haloalkenyl;
L is a bond, -CRaRb-, -CRaRb-CRcRd-, or -CRaRb-CRcRd-CReRf-; wherein each Ra, Rb, Rc, Rd, Re, and Rf is selected from H, F, Cl, Br, I, OH, CN, NO2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and phenyl;
R3 is a substituted phenyl with 1, 2, 3, 4, or 5 substituents R7 independently selected from F, Cl, Br, I, Ci- G, alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, and Ci-Ce haloalkoxy; and
R8 is selected from Ci-Cg alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, and Ci-Cc haloalkoxy.
In one embodiment, A is selected from the following:
Figure imgf000013_0001
A4 A5 J A6
; ; and
In one embodiment, L is abend, -CH2-, -CH2CH2-, -CHFCH2-, or -CH2CH(CH3)-.
In one embodiment, R7 represents one, two, or three substituents independently selected from F, Cl, Ci-Ce alkyl, Ci-Ce haloalkoxy and Ci-Ce alkoxy.
In another embodiment, R8 is selected from OCF3, OC FiCF .. and CF3.
In another aspect, provided is a process comprising applying a compound provided herein, to an area to control a pest, in an amount sufficient to control such pest. In one embodiment, the pest is beet armyworm (B AW), cabbage looper (CL), or green peach aphid (GPA).
In another aspect, provided is a compound that is a pesticidally acceptable acid addition salt, a salt derivative, a solvate, or an ester derivative, of a compound provided herein. In another aspect, provided is a compound provided herein wherein at least one H is 2H or at least one C is 14C. In another aspect, provided is a composition comprising a compound provided herein and a seed.
In another aspect, provided is a process comprising applying a compound provided herein to a genetically modified plant, or genetically -modified seed, which has been genetically modified to express one or more specialized traits. In another aspect, provided is a process comprising: orally administering; or topically applying; a compound provided herein, to a non-human animal, to control endoparasites, ectoparasites, or both.
In some embodiments, the compounds are selected from the structures listed in Tables 1 A and IB, wherein said compound is selected from the group consisting of Al, A2, A3, A4, A5, A6, A7, A9, A10, All, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A27, A28, A29, Bl, B2, B3, B4, B5, and B6.
PREPARATION OF COMPOUNDS IN THIS DISCLOSURE
PREPARATION OF THIOBIURETS
Thiobiurets disclosed herein are prepared from the corresponding isocyanate, Ar'-Hci-A-L-NCO (1-2). Usually, these isocyanates are not isolated, but are instead generated in situ from a suitable precursor and used directly in the preparation of a thiobiuret. One such suitable precursor is an amine (1-1) which can be converted into an isocyanate by using one of several common reagents such as phosgene, diphosgene, triphosgene, or carbonyldiimidazole (Scheme 1, step a), in a mixed solvent system such as dichloromethane and water or diethyl ether and water, in the presence of a base such as sodium bicarbonate or triethylamine, at temperatures from about - 10 °C to about 50 °C.
Scheme 1
Het L a Het L
Ar1x vAZ NH2 Af1^ xAZ \NCO „ 1- .1 1-2
Figure imgf000014_0001
Alternatively, the isocyanates may be generated via a Curtins rearrangement of an acyl azide, AH-Het-A-L- C(=O)Ns (1-4), which is prepared from the corresponding carboxylic acid precursor, Ar'-Hct-A-L-COrH (1-3). Formation of an acyl azide (Scheme 1, step b) occurs either by treatment of the acid with ethyl chloroformate and sodium azide in the presence of an amine base such as triethylamine, or with diphenylphosphoryl azide in the presence of an amine base such as triethylamine. The acyl azide is then made to undergo a Curtins rearrangement leading to the corresponding isocyanate (1-2). Depending on the nature of the particular acyl azide, this rearrangement may occur spontaneously at ambient temperature, or it may require heating from about 40 °C to about 100 °C in a suitable solvent, such as toluene, acetonitrile, or an ethereal solvent such as dioxane or tetrahydrofuran. Azides of arylacetic acids are known, though due to their reactivity, are often not isolated as pure solids. Accordingly, the acyl azide intermediate is not always fully characterized, but may simply be heated directly without characterization, to generate the isocyanate. An isocyanate, Ar'-Hei-A-L-NCO (1-2), can be treated directly with an V-ary 1 thiourea (2-1) in the presence of about 0.1 to about 2 equivalents of an inorganic base such as cesium carbonate or sodium hydride, resulting in the formation of a thiobiuret (2-2, Scheme 2). The reaction can be performed at temperatures from about 0 °C to about 100 °C, preferably from about 20 °C to about 80 °C, in an aprotic solvent or solvent mixture chosen from acetonitrile, acetone, toluene, tetrahydrofuran, 1,2-dichloroethane, dichloromethane, or mixtures thereof, but use of acetonitrile is preferred.
Figure imgf000015_0002
Thiobiurets (2-2) generated in situ can be converted directly without purification into cyclized analogs (Scheme 3), or they can be isolated from the reaction medium prior to cyclization. Cyclization can be achieved by treatment with an oc-halo ester such as methyl bromoacetate to form 2-imino l,3-thiazolin-4-ones (3-1, step a) unsubstituted or mono- or di-substituted with R5. In step a, use of sodium acetate in a protic solvent such as ethanol or methanol, at temperatures ranging from about 20 °C to about 70 °C is preferred.
Scheme 3
Figure imgf000015_0001
An alternative method for preparing analogs having the general structure 3-1 is described in Scheme 3a. Intermediate 4-imino-3-arylthiazolidinone-2-one (3-la, step a) is reacted directly with an isocyanate (1-2), in the presence of about 0.1 to about 2 equivalents of an inorganic base such as cesium carbonate or sodium hydride to form cyclized thiobiuret (3-1). The reaction can be performed at temperatures from about 0 °C to about 100 °C, preferably from about 20 °C to about 80 °C, in an aprotic solvent or solvent mixture chosen from acetonitrile, acetone, toluene, tetrahydrofuran, 1,2-dichloroethane, dichloromethane, or mixtures thereof, but use of acetonitrile is preferred.
Alternatively, the 4-imino-3-arylthiazolidinone-2-one (3-la) may be reacted with 4-nitrophenyl chloroformate (step b), forming a 4-nitrophenyl carbamate intermediate (3-2a). This reaction is conducted with equimolar quantities of the imine and the chloroformate, in a polar aprotic solvent such as tetrahydrofuran or dioxane, and in the presence of from about 0.1 to about 2 equivalents of an inorganic base such as cesium carbonate or potassium carbonate, preferably at room temperature. The intermediate (3-2a) may be isolated by filtration from inorganic salts and evaporation of solvent, or it can be used directly in step c. In step c, treatment of 3 -2a with a primary or secondary alkyl amine Ari-Het-A-L-NHR1 (3-3a), wherein R1 is H or alkyl, respectively, may generate cyclized thiobiuret (3-1). Step c may also be conducted in the presence of an inorganic base such as cesium carbonate or potassium carbonate, from about 0.1 to about 2 equivalents, preferably about 1 to about 1.2 equivalents; it is also most conveniently undertaken at room temperature, although it may be undertaken at temperatures from about 0 °C to about 100 °C.
Scheme 3 a
Figure imgf000016_0001
Figure imgf000016_0002
3-1 a
Figure imgf000016_0004
Alternatively, treatment of a primary or secondary alkyl amine Ar'-Hct-A-L-NHR (3 -3a), wherein R1 is H or alkyl, respectively, with an activating agent such bis(2,5-dioxopyrrolidin-l-yl) carbonate in the presence of an organic base such as pyridine, preferably from about 1 to about 1.2 equivalents, triphosgene in the presence of an organic base such as N, V-diisopropy lethy lami ne. or 4-nitrophenyl carbonochloridate in an aprotic solvent such as dichloromethane may generate in situ an activated amine (not shown), which is reacted with a 4-imino-3- arylthiazolidinone-2-one (3-la) with or without an organic base such as \ V-diisopropy lethy lamine to afford the cyclized thiobiuret (3-1) as in step a, Scheme 3a’.
Scheme 3a’
Figure imgf000016_0003
PREPARATION OF THREE RING-INTERMEDIATES
Compounds of Formula One, Two, Three, Four, and/or Five can be prepared by making a three-ring intermediate, Ar'-Hei-A. and then linking it to an appropriate intermediate to form a desired compound. A wide variety of three-ring intermediates can be used to prepare compounds of Formula One, Two, Three, Four, and/or Five, provided that such three-ring intermediates contain a suitable functional group on A and/or L to which the rest of the desired functional group can be attached. Suitable functional groups include an amino, amino via nitro, isocyanate, carboxyl, or a halogen (preferably bromo or iodo).
Intermediate 4-2, wherein Ar1, Het, and A are as previously disclosed and wherein A is bound to Het via a nitrogen (N) atom, can be prepared in a number of ways, including via nucleophilic displacement of the halide on 4- 1 with A in the presence or absence of a solvent such as dimethyl sulfoxide or toluene at a temperature from about 100 °C to about 150 °C or via an Ullmann-type coupling of the bromide and A, in presence of copper(I) iodide and L-proline, in the presence or absence of a polar, aprotic solvent such as dimethyl sulfoxide at a temperature from about 80 °C to about 100 °C as in step a of Scheme 4. When A in 4-2 contains a -CH2OH group, the alcohol (OH) can be oxidized to the corresponding aldehyde 4-3, wherein Ar1, Het, and A are as previously disclosed, using pyridine-sulfur trioxide in the presence of dimethylsulfoxide, and a base, such as triethylamine, and in a solvent, such as dichloro methane, at a temperature from about 0 °C to about ambient temperature as in step b of Scheme 4. When A in 4-2 contains a -NHC(O)OC(CH3)3 group, the protecting group (C(O)OC(CH3)3) can be removed to provide the corresponding amine 4-4, wherein Ar1, Het, and A are as previously disclosed, using either trifluoroacetic acid or 4 molar (M) hydrogen chloride in dioxane in a solvent such as dichloromethane at a temperature from about 0 °C to about ambient temperature as in step c of Scheme 4. The aldehyde 4-3 and amine 4- 4 can be further functionalized to arrive at the compounds of Formula One, Two, Three, Four, and/or Five.
Figure imgf000017_0001
Intermediate 5-2, wherein Ar1, Het, and A are as previously disclosed and wherein A is bound to Het via a carbon (C) atom, can be prepared via Suzuki coupling of the bromide 4-1 with A in the presence of a polar aprotic solvent such as 1 ,4-dioxane, an aqueous base such as 3 molar (M) sodium carbonate, a boronic acid or boronate 5- 1 , and palladium catalyst such as tetrakis(triphenylphosphine)palladium(0), at a temperature from about 100 °C to about 150 °C under thermal or microwave conditions as in step a of Scheme 5. When A in 5-2 contains both an alkene and an ester such as -C(O)OCH2CH3, the alkene can first be reduced using hydrogen gas at about 480 kilopascal (kPa) / 70 pounds per square inch (psi) and a palladium catalyst such as 10% palladium on carbon to provide the alkane, and the ester can be reduced to the corresponding alcohol 5-3, wherein Ar1, Het, and A are as previously disclosed, using a reducing agent such as lithium aluminum hydride in a polar aprotic solvent such as tetrahydrofuran at a temperature from about 0 °C to about ambient temperature as in steps b and c of Scheme 5. When A in 5-2 contains an ester such as -C(O)OCH2CHa, the ester can be reduced to the corresponding alcohol 5-3, wherein Ar1, Het, and A are as previously disclosed, using a reducing agent such as lithium aluminum hydride in a polar aprotic solvent such as tetrahydrofuran at a temperature from about 0 °C to about ambient temperature as in step c of Scheme 5. When A in 5-2 contains an ester such as -C(O)OCH2CH3, the ester can be saponified to the corresponding carboxylic acid 5-4, wherein Ar1, Het, and A are as previously disclosed, with a base such a 2 normal (N) sodium hydroxide in a polar solvent such as methanol at about ambient temperature as in step d of Scheme 5. The alcohol 5-3, wherein Ar1, Het, and A are as previously disclosed, can be oxidized to the corresponding aldehyde 4-3 with an oxidizing agent such as Dess-Martin periodinane in a solvent such as dichloromethane at ambient temperature as in step e of Scheme 5. The acid 5-4 and aldehyde 5-5 can be further functionalized to arrive at the compounds of Formula One, Two, Three, Four, and/or Five.
Scheme 5
Figure imgf000018_0002
Figure imgf000018_0001
PREPARATION OF ETHYL LINKED INTERMEDIATES
Preparation of compounds wherein L is a two-atom group is described in Schemes 6 to Schemes 8. Condensation of the aldehyde 4-3, wherein Ar1, Het, and A are as previously disclosed, with a reagent such as triethyl phosphonoacetate in the presence of a suitable base such as sodium hydride in aprotic solvents such as tetrahydrofuran or diethyl ether at temperatures from about -10 °C to about 20 °C can be used to prepare acrylic esters (6-1, step a) unsubstituted or mono-substituted with Ra and Rc. The alkene can be reduced using hydrogen gas (balloon) and a palladium catalyst such as 10% palladium on carbon in a polar aprotic solvent such as ethyl acetate to provide the saturated ester 6-2 (step b). Saponification of the resultant ester may be achieved by using a strong base such as sodium hydroxide in ethyl acetate to furnish the carboxylic acid (6-3, step c). The acid 6-3 can be further functionalized (e.g., as in Schemes 1, 2, 3, and 3a) to arrive at the compounds of Formula One, Two, Three, Four, and/or Five.
Scheme 6
Figure imgf000019_0001
6-3
Carbinols 7-1 can be treated with phthalimide under Mitsunobu conditions to generate V-phthalimido intermediates 7-2 (step a). Deprotection using hydrazine and methanol or other suitable solvent can furnish the amines 7-3 (step b).
Scheme 7
Figure imgf000019_0002
Aldehyde 4-3 can be converted to the corresponding cyanohydrin 8-1, wherein Ar1, Het, and A are as previously disclosed, by treatment with zinc iodide and trimethylsilyl cyanide in a solvent such as dichloromethane at ambient temperature as in step a of Scheme 8. The cyanohydrin 8-1 can be reacted with borane tetrahydrofuran complex in a solvent such as dichloromethane at a temperature from about 0 °C to about ambient temperature, followed by acid workup, to furnish the amine hydrochloride 8-2, wherein Ar1, Het, and A are as previously disclosed, as in step b of Scheme 8. The amine functionality on 8-2 can be protected using di-tert-butyl dicarbonate in the presence of a base such as triethylamine and in a solvent such as dichloromethane at ambient temperature to provide 8-3, wherein Ar1, Het, and A are as previously disclosed, as in step c of Scheme 8. Reaction of 8-3 with a fluorinating reagent such as (diethylamino)sulfur trifluoride in the presence of abase such as triethylamine and in a solvent such as dichloromethane at a temperature from about 0 °C to about ambient temperature can afford 8-4, wherein Ar1, Het, and A are as previously disclosed, as in step d of Scheme 8. Deprotection using 4 molar (M) hydrogen chloride in 1,4-dioxane or other suitable solvent at a temperature of about 0 °C to about ambient temperature can furnish the amine hydrochloride 8-6 (step /).The amine hydrochloride 8-6 can be further functionalized (e.g., as in Schemes 1, 2, 3, 3a, and 3a’) to arrive at the compounds of Formula One, Two, Three, Four, and/or Five.
The cyanohydrin 8-1 can be reacted with a fluorinating reagent such as (diethylamino)sulfur trifluoride in the presence of a base such as triethylamine and in a solvent such as dichloromethane at temperature from about 0 °C to about ambient temperature can afford 8-5, wherein Ar1, Het, and A are as previously disclosed, as in step d of Scheme 8. The cyano moiety on 8-5 can be reduced in the presence of a reducing agent such as borane tetrahydrofuran complex in a solvent such as tetrahydrofuran at a temperature from about 0 °C to about ambient temperature. Incomplete reaction may require a different reducing agent such as lithium aluminum hydride to furnish the amine 8-6, wherein Ar1, Het, and A are as previously disclosed, as in step f of Scheme 8. The amine 8-6 can be further functionalized (e.g., as in Schemes 1, 2, 3, 3a, and 3a’) to arrive at the compounds of Formula One, Two, Three, Four, and/or Five.
Scheme 8
Figure imgf000020_0001
EXAMPLES
Starting materials, reagents and solvents which are obtained from commercial sources are used without further purification. Anhydrous solvents are purchased as Sure/Seal™ from Sigma- Aldrich and are used as received. Melting points are obtained on a Thomas Hoover Unimelt capillary melting point apparatus or an OptiMelt Automated Melting Point System from Stanford Research Systems and are uncorrected. Molecules are given their known names, named according to the naming program within ChemDraw (version 17.1.0.105 (19)). If such a program is unable to name a molecule, such molecule is named using conventional naming rules. 1 H NMR spectral data are in ppm (5) and were recorded at 400 MHz; 13C NMR spectral data are in ppm (5) and were recorded at 101 MHz; and 19F NMR spectral data are in ppm (8) and were recorded at 376 MHz, unless otherwise stated.
Example 1: Preparation of 3-bromo-l-(4-(trifluoromethoxy)phenyl)-l//-l,2,4-triazole (Cl)
Figure imgf000021_0001
To a solution of 3-bromo-l H-i ,2,4-triazole (25 g, 169 mmol) in dry dimethyl sulfoxide (200 mL) were added l-iodo-4-(trifluoromethoxy (benzene (61 g, 211 mmol), cesium carbonate (83 g, 253 mmol), and copper(I) iodide (6.4 g, 33.8 mmol). The reaction mixture was stirred at 100 °C for 36 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (250 mL), filtered through a pad of Celite®, and washed with ethyl acetate (250 mL). The filtrate was washed with water (400 mL) followed by brine (300 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product was purified by column chromatography (5 - 10% ethyl acetate-petroleum ether) to provide the title compound as an off-white solid (16.8 g, 32%): II NMR (300 MHz, DMSO-c/e) 5 9.36 (s, 1H), 7.97 (dd, J= 1.8, 7.1 Hz, 2H), 7.61 (d, J= 9.0 Hz, 2H); ESIMS m/z 308 ([M+H]+(.
Example 2: Preparation of (l-(l-(4-(trifluoromethoxy)phenyl)-lZ/-l,2,4-triazol-3-yl)piperidin-4-yl)methanol (C2)
Figure imgf000021_0002
Method A: A 25 mL vial under an atmosphere of nitrogen and equipped with a stir bar was charged with 3- bromo-l-(4-(trifluoromethoxy)phenyl)-177-l,2,4-triazole (Cl, 1 g, 3.25 mmol) and piperidin-4-ylmethanol (2.13 g, 18.5 mmol). The reaction mixture was heated to 120 °C. The reaction mixture was poured into ice water (250 mL). The solid was filtered, washed with water, and dried under vacuum (25 mm Hg) at 50 °C overnight. The title compound was isolated as a tan solid (1.02 g, 92%): H NMR (400 MHz, CDClj) 6 8.22 (s, 1H), 7.69 - 7.60 (m, 2H), 7.31 (dq, 7= 9.0, 1.0 Hz, 2H), 4.21 (dt, J= 12.9, 3.1 Hz, 2H), 3.55 (t, J= 5.5 Hz, 2H), 2.90 (td, J= 12.6, 2.8 Hz, 2H), 1.84 (dd, 7= 13.8, 3.3 Hz, 2H), 1.73 (tdd, J = 9.8, 8.7, 4.7 Hz, 1H), 1.36 (qd, J= 12.3, 4.4 Hz, 3H); 19F NMR (376 MHz, CDCI3) 5 -58.10; ESIMS m/z 343 ([M+H]+). Method B: A mixture of 3-bromo-l-(4-(trifluoromethoxy)phenyl)-17f-l,2,4-triazole (Cl, 2 g, 6.49 mmol) and piperidin-4-ylmethanol (1.8 g, 16.22 mmol) in dimethyl sulfoxide (10 mL) was heated at 130 °C for 4 days in a sealed tube. The reaction mixture was cooled to room temperature, poured into ice water (100 mL), stirred for 1 hour. The precipitate was filtered under vacuum, was washed with water (50 mL), and was dried to afford the title compound as an off-white solid (1.8 g, 81%): 'II NMR (300 MHz, DMSO-c/e) 5 8.98 (s, 1H), 7.88 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 4.49 (t, 7= 5.4 Hz, 1H), 4.07 - 4.03 (m, 2H), 3.30 - 3.28 (m, 2H), 2.84 - 2.75 (m, 2H), 1.75 - 1.69 (m, 2H), 1.57 - 1.52 (m, 1H) 1.24 - 1.11 (m, 2H); ESIMS m/z 343 ([M+H]+).
Example 3: Preparation of l-(l-(4-(trifluoromethoxy)phenyl)-12/-l,2,4-triazol-3-yl)piperidine-4-carbaldehyde (C3)
Figure imgf000022_0001
A 100 mL round-bottomed flask under an atmosphere of nitrogen and equipped with a stir bar was charged with (l-(l-(4-(trifluoromethoxy)phenyl)-177-l,2,4-triazol-3-yl)piperidin-4-yl)methanol (C2, 1.02 g, 2.98 mmol), dichloromethane (24.8 mL) and dimethyl sulfoxide (4.97 mL). The reaction mixture was cooled in an ice-water bath. Triethylamine (2.08 mL, 14.9 mmol) and pyridine-sulfur trioxide (1.90 g, 11.9 mmol) were added to the reaction mixture. The reaction mixture was allowed to warm to room temperature slowly. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water (5x), dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (0 - 100% ethyl acetate in hexanes) provided the title compound as a white solid which was dried under vacuum (25 mm Hg) at 50 °C (0.849 g, 84%): H NMR (400 MHz, CDCL) 5 9.71 (d, J = 1.0 Hz, 1H), 8.22 (s, 1H), 7.64 (d, J= 9.1 Hz, 2H), 7.37 - 7.27 (m, 2H), 4.11 (dt, J= 12.7, 3.8 Hz, 2H), 3.09 (ddd, J = 12.9, 11.0, 3.0 Hz, 2H), 2.53 - 2.42 (m, 1H), 2.10 - 1.96 (m, 2H), 1.74 (dtd, J = 13.4, 10.9, 4.2 Hz, 2H); 19F NMR (376 MHz, CDCL) 5 -58.09; ESIMS m/z 341 ([M+H]+).
Example 4: Preparation of ethyl (£')-3-(l-(l-(4-(trifluoromethoxy)phenyl)-l/f-l,2,4-triazol-3-yl)piperidin-4- yl)acrylate (C4)
Figure imgf000022_0002
To an oven-dried 100 mL round-bottomed flask equipped with a stir bar and under an atmosphere of nitrogen were added sodium hydride (60%, 0.091 g, 2.29 mmol) and tetrahydrofuran (19.1 mL). The reaction mixture was cooled with an ice-water bath. Triethyl phosphonoacetate (0.385 mL, 1.92 mmol) was added dropwise via syringe. A solution of l-(l-(4-(trifluoromethoxy)phenyl)-l/f-l,2,4-triazol-3-yl)piperidine-4-carbaldehyde (C3, 0.649 g, 1.91 mmol) in tetrahydrofuran (5 mL) was added upon cessation of hydrogen evolution. The reaction mixture was allowed to warm to room temperature, was diluted with ethyl acetate, and was washed with water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash silica gel column chromatography (0 - 60% ethyl acetate in hexanes) provided the title compound as a white solid which was dried under vacuum (25 mm Hg) overnight at 50 °C (0.564 g, 72%): H NMR (400 MHz, CDCL) S 8.22 (s, 1H), 7.70 - 7.59 (m, 2H), 7.31 (dt, J= 8.1, 1.0 Hz, 2H), 6.95 (dd, 7 = 15.8, 6.6 Hz, 1H), 5.84 (dd, J= 15.8, 1.4 Hz, 1H), 4.20 (q, 7= 7.1 Hz, 4H), 3.03 - 2.89 (m, 2H), 2.44 - 2.29 (m, 1H), 1.92 - 1.78 (m, 2H), 1.65 - 1.47 (m, 2H), 1.29 (t, 7= 7.1 Hz, 3H); 19F NMR (376 MHz, CDCL) 8 -58.09; ESIMS w/z 411 ([M+H]+).
Example 5: Preparation of ethyl 3-(l-(l-(4-(trifluoromethoxy)phenyl)-l/7-l,2,4-triazol-3-yl)piperidin-4- yl)propanoate (C5)
Figure imgf000023_0001
To ethyl (E)-3-(l-(l-(4-(trifluoromethoxy)phenyl)-177-l,2,4-triazol-3-yl)piperidin-4-yl)acrylate (C4, 0.564 g, 1.37 mmol) in a 100 mL round-bottomed flask equipped with a stir bar and rubber septum were added sequentially 10% palladium on carbon (Pd-C, 0.146 g, 0.137 mmol) and ethyl acetate (13.7 mL). The reaction mixture was evacuated and back-filled with hydrogen (balloon). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through Celite® and washed with ethyl acetate. The solvent was concentrated. The title compound was isolated as a white solid (0.563 g, 99%): 'H NMR (400 MHz, CDCL) 8 8.21 (s, 1H), 7.67 - 7.61 (m, 2H), 7.33 - 7.28 (m, 2H), 4.19 - 4.09 (m, 5H), 2.86 (td, J= 12.5, 2.7 Hz, 2H), 2.36 (dd, J= 8.3, 7.2 Hz, 2H), 1.78 (dd, 7= 13.4, 3.3 Hz, 2H), 1.69 - 1.57 (m, 2H), 1.55 - 1.40 (m, 1H), 1.37 - 1.29 (m, 1H), 1.29 - 1.21 (m, 3H); 19F NMR (376 MHz, CDCL) 8 -58.10; ESIMS m/z 413 ([M+H]+).
Example 6: Preparation of 3-(l-(l-(4-(trifluoromethoxy)phenyl)-l//-l,2,4-triazol-3-yl)piperidin-4- yl)propanoic acid (C6)
Figure imgf000023_0002
A 100 mL round-bottomed flask equipped with a stir bar was charged with ethyl 3-(l-(l-(4- (trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3-yl)piperidin-4-yl)propanoate (C5, 0.564 g, 1.37 mmol), ethyl acetate (13.7 mL), and 2 normal (N) sodium hydroxide (6.84 mL, 13.68 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated and acidified to pH 4 with 1 N hydrochloric acid. The solid was extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The title compound was isolated as a white solid after drying under vacuum (0.480 g, 91%): *H NMR (400 MHz, CDCL) 8 10.25 (br s, 1H), 8.24 (s, 1H), 7.68 - 7.60 (m, 2H), 7.33 - 7.28 (m, 2H), 4.22 - 4.06 (m, 2H), 2.87 (td, 7= 12.6, 2.6 Hz, 2H), 2.43 (t, 7= 7.7 Hz, 2H), 1.79 (d, 7= 12.6 Hz, 2H), 1.66 (q, 7= 7.3 Hz, 2H), 1.52 (ddp, 7= 14.7, 7.2, 3.5 Hz, 1H), 1.32 (qd, 7= 12.3, 4.3 Hz, 2H); 19F NMR (376 MHz, CDCL) 8 -58.09; ESIMS m/z 385 ([M+H]+). Example 7: Preparation of 4-(2-isocyanatoethyl)-l-(l-(4-(trifluoromethoxy)phenyl)-lf/-l,2,4-triazol-3- yl)piperidine (C7)
Figure imgf000024_0001
To a solution of ethyl carbonochloridate (0.131 mL, 1.37 mmol) and triethylamine (0.190 mL, 1.37 mmol) in tetrahydrofuran (2.5 mL) was added a solution of 3-(l-(l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3- yl)piperidin-4-yl)propanoic acid (C6, 0.477 g, 1.24 mmol) in tetrahydrofuran (4.68 mL) at 0 °C. The reaction mixture was allowed to stir for 1.5 hours. A solution of sodium azide (0.089 g, 1.37 mmol) in water (1.75 mL) was added dropwise at 0 °C. The reaction mixture was allowed to stir overnight. The reaction mixture was poured into brine. An attempt to remove the resulting emulsion via filtration was unsuccessful as the precipitate went through the filter paper. The resulting filtrate was extracted with ethyl acetate (3 x 75 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to a light tan solid (239 mg), which appeared to be a mixture of the starting carboxylic acid and the title compound and was used as is.
Example 8: Preparation of 2-(2-(l-(l-(4-(trifluoromethoxy)phenyl)-lZ/-l,2,4-triazol-3-yl)piperidin-4- yl)ethyl)isoindoline-l, 3-dione (C8)
Figure imgf000024_0002
To a solution of 2-(l-(l-(4-(trifluoromethoxy)phenyl)-177-l,2,4-triazol-3-yl)piperidin-4-yl)ethanol (C14, containing some triphenylphosphine oxide; 7.2 g, 20.2 mmol) in tetrahydrofuran (200 mL) was added isoindoline- 1, 3-dione (3.27 g, 22 2 mmol) and 2-(diphenylphosphino)pyridine (5 85 g, 22.2 mmol). The solution was cooled in an ice water bath, and (E)-di-tert-butyl diazene-l,2-dicarboxylate (5.12 g, 22.2 mmol) was added. The reaction mixture was allowed to stir overnight while warming to room temperature as the ice bath melted. The reaction mixture was poured into an aqueous solution of acetic acid and was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. Purification of the resulting residue by silica gel flash chromatography (0 - 50% ethyl acetate in hexanes) yielded the title compound as an off- white solid (4.74 g): 'H NMR (400 MHz, DMSCM,) 5 8.98 (s, 1H), 7.95 - 7.79 (m, 6H), 7.57 - 7.44 (m, 2H), 4.02 (dt, J= 12.9, 2.4 Hz, 2H), 3.64 (t, J= 7.1 Hz, 2H), 2.79 (td, J= 12.6, 2.7 Hz, 2H), 1.85 - 1.74 (m, 2H), 1.63 - 1.51 (m, 2H), 1.52 - 1.44 (m, 1H), 1.26 - 1.14 (m, 2H); 19F NMR (376 MHz, DMSO-rfe) 5 -57.04; ESIMS m/z 486 ([M+H]+).
Example 9: Preparation of 2-(l-(l-(4-(trifhioromethoxy)phenyl)-l//-l,2,4-triazol-3-yl)piperidin-4- yl)ethanamine (C9)
Figure imgf000025_0001
To a suspension of 2-(2-( 1 -(1 -(4-(trifluoromethoxy )phenyl)-l H- 1 ,2,4-triazol-3-yl)piperidin-4- yl)ethyl)isoindoline-l, 3-dione (C8, 7.25 g, 14.9 mmol) in methanol (150 mL) was added hydrazine hydrate (2.17 mL, 44.8 mmol). The reaction mixture was heated to reflux for 48 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane, and extracted with 1 N sodium hydroxide. The layers were separated, and the aqueous layer was extracted with dichloromethane (100 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The resulting yellow liquid showed a slight impurity. The residue was diluted with ethyl acetate and the mixture was washed with 1 N hydrochloric acid (4 x 100 mL). The combined aqueous layers were made basic with 1 N sodium hydroxide and were extracted with ethyl acetate. These combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The title compound was isolated as a pale yellow residue (4.98 g, 92%): 'H NMR (400 MHz, DMSO-</„) 6 8.98 (s, 1H), 7.95 - 7.80 (m, 2H), 7.51 (d, J= 8.6 Hz, 2H), 4.02 (ddd, J= 12.0, 5.0, 2.8 Hz, 2H), 3.39 (s, 2H), 2.90 - 2.73 (m, 2H), 2.61 (t, J= 7.1 Hz, 2H), 1.77 - 1.63 (m, 2H), 1.55 (ddd, J= 11.0, 7.2, 3.9 Hz, 1H), 1.32 (q, J= 7.0 Hz, 2H), 1.25 - 1.05 (m, 2H); 19F NMR (376 MHz, DMSO-cL) 8 -57.03; ESIMS m/z 356 ([M+H]+).
Example 10: Preparation of tert-butyl (l-(l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3-yl)piperidin-4- yl)carbamate (CIO)
Figure imgf000025_0002
To 3-bromo-l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazole (Cl, 2 g, 6.49 mmol), tert-butyl piperidin-4-ylcarbamate (1.560 g, 7.79 mmol), L-proline (0.149 g, 1.298 mmol) and copper(I) iodide (0.124 g, 0.649 mmol) in a 100 mL round-bottomed flask equipped with a stir bar and under a nitrogen atmosphere was added dimethyl sulfoxide (12.98 mL). The reaction mixture was heated to 90 °C overnight. The reaction mixture was diluted with ethyl acetate and was washed with water. The aqueous layer was extracted with ethyl acetate (2x). The combined organic layers were washed with water (4x), dried over sodium sulfate, filtered, and concentrated. Purification by silica gel flash column chromatography (5 - 40% ethyl acetate in hexanes) followed by drying at 50 °C and ~25 mm Hg overnight provided the title compound as a white solid (222 mg, 8%): 'H NMR (400 MHz, CDCls) 8 8.21 (s, 1H), 7.66 - 7.60 (m, 2H), 7.31 (dt, J= 8.1, 1.0 Hz, 2H), 4.48 (s, 1H), 4.10 (d, J= 13.3 Hz, 2H), 3.67 (s, 1H), 3.03 (ddd, J = 13.0, 11.5, 2.8 Hz, 2H), 2.04 (d,J= 12.4 Hz, 2H), 1.55 - 1.37 (m, 11H); 19F NMR (376 MHz, CDC13) S -58.09; ESIMS m/z 428 ([M+H]+).
Example 11: Preparation of tert-butyl (l-(l-(4-(trifhioromethoxy)phenyl)-l H-l,2,4-triazol-3-yl)piperidin-3- yl)carbamate (CH)
Figure imgf000026_0001
To a 25 mL vial equipped with a stir bar were added 3-bromo-l -(4-(trifluoromethoxy)pheny 1)-1 H-l, 2,4- triazole (Cl, 1 g, 3.25 mmol) and tert-butyl piperidin-3-ylcarbamate (1.95 g, 9.74 mmol). Toluene (3.246 mL) was added. The reaction mixture was heated to 120 °C for 40 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane, and transferred to a round bottom flask. The reaction mixture was concentrated onto silica. Purification via silica gel flash chromatography (ethyl acetate-hexanes) led to recovery of bromo triazole and the title compound as a white solid (600 mg, 42%): 3H NMR (400 MHz, CDOs) 3 8.22 (s, 1H), 7.64 (m, 2H), 7.31 (m, 2H), 4.87 (d, J= 8.4 Hz, 1H), 3.84 (s, 1H), 3.69 (m, 1H), 3.46 (t, J= 52 Hz, 2H), 3.32 (dd, J = 12.6, 6.7 Hz, 1H), 1.83 (tdd, J= 10.4, 7.2, 3.1 Hz, 2H), 1.69 (m, 2H), 1.45 (s, 9H); 13C NMR (101 MHz, CDCI3) 6
167.07, 155.08, 147.52, 147.50, 139.85, 135.76, 124.25, 122.28, 121.69, 120.17, 119.13, 51.67, 46.79, 45.84, 30.02, 28.44, 21.97; 19F NMR (376 MHz, CDCL) 6 -58.10; ESIMS m/z 428 ([M+H]+).
Example 12: Preparation of tert-butyl (l-(l-(4-(perfluoroethoxy)phenyl)-lZT-l,2,4-triazol-3-yl)piperidin-4- yl)carbamate (C12)
Figure imgf000026_0002
To 3-bromo-l-(4-(perfluoroethoxy)phenyl)-lH-l,2,4-triazole (prepared as in US 20140275502 Al; 1 g,
2.79 mmol) in a 25 mL vial equipped with a stir bar and under an atmosphere of nitrogen were added tert-butyl piperidin-4-ylcarbamate (1.398 g, 6.98 mmol) and then DMSO (0.698 mL). The reaction mixture was heated to 120
°C for 48 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane, and transferred to a 100 mL round bottom flask. The reaction mixture was concentrated in vacuo. Purification via silica gel flash chromatography (ethyl acetate-hexanes) yielded the title compound as a white solid (400 mg, 29%): 'H
NMR (400 MHz, CDCL) 8 8.22 (s, 1H), 7.64 (m, 2H), 7.31 (m, 2H), 4.48 (s, 1H), 4.10 (m, 2H), 3.66 (s, 1H), 3.03
(ddd, J = 13.1, 11.5, 2.8 Hz, 2H), 2.05 (m, 2H), 1.56 (s, 1H), 1.46 (s, 9H); 13C NMR (101 MHz, CDCL) 6 166.76,
155.14, 139.89, 135.92, 122.94, 120.11, 45.52, 31.84, 28.42; 19F NMR (376 MHz, CDCL) 6 -85.92, -87.86.
Example 13: Preparation of tert-butyl 4-(l-(4-(trifluoromethoxy)phenyl)-lZZ-l,2,4-triazol-3-yl)piperazine-l- carboxylate (C13)
Figure imgf000026_0003
A mixture of 3-bromo-l -(4-(trifluoromethoxy)pheny 1)-1 H-l ,2,4-triazole (Cl, 5 g, 16.2 mmol) and tertbutyl piperazine-l-carboxylate (7.56 g, 40.5 mmol) in dimethyl sulfoxide (30 mL) was stirred at 130 °C for 4 days in a sealed tube. The reaction mixture was cooled to room temperature and poured into ice cold water (80 mL). The reaction mixture was extracted with ethyl acetate (150 mL). The organic layer was washed with water (80 mL) followed by brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product was purified by column chromatography (40 - 50% ethyl acetate-petroleum ether) to provide the title compound as an off-white solid (2.9 g, 43%): ESIMS m/z 414 ([M+H]+).
Example 14: Preparation of 2-(1-(l-(4-(trifliioromethoxy)phenyl)-lf/-1,2,4-triazol-3-yl)piperidin-4-yl)ethanol (C14)
Figure imgf000027_0001
A neat suspension of 3-bromo-l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazole (Cl, 14.9 g, 48.4 mmol) in 2-(piperidin-4-yl)ethanol (25 g, 193 mmol) was stirred in a heating block that was heated to 120 °C. The reaction mixture was allowed to stir overnight and was cooled to room temperature. The resulting thick, orange syrup was warmed slightly with a heat gun so that it could be poured into ice water (600 mL), and the mixture was stirred for 1 hour. The resulting white precipitate was collected via filtration and was dried in a vacuum oven for 6 hours. The title compound was isolated as a white solid (17.4 g, 91%): :H NMR (400 MHz, DMSO-iL) 8 8.98 (s, 1H), 7.94 - 7.83 (m, 2H), 7.56 - 7.45 (m, 2H), 4.38 (t, J= 5.1 Hz, 1H), 4.02 (dt, J= 12.9, 3.3 Hz, 2H), 3.47 (td, J= 6.4, 3.9 Hz, 2H), 2.79 (td, 7 = 12.6, 2.7 Hz, 2H), 1.77 - 1.65 (m, 2H), 1.57 (dtd, J= 10.9, 7.1, 3.5 Hz, 1H), 1.39 (q, J= 6.6 Hz, 2H), 1.17 (qd, J= 12.3, 4.2 Hz, 2H); 19F NMR (376 MHz, DMSO-cfc) 5 -57.06; ESIMS m/z 357 ([M+H]+).
Example 15: Preparation of l-(l-(4-(trifluoromethoxy)phenyl)-12f-l,2,4-triazol-3-yl)piperidm-4-amine (C15)
Figure imgf000027_0002
To /er/ -buty I (l-(l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3-yl)piperidin-4-yl)carbamate (CIO, 0.222 g, 0.518 mmol) in a 25 mL vial equipped with a stir bar and under nitrogen atmosphere was added dichloromethane (5.18 mL). The reaction mixture was cooled with an ice-water bath. To the reaction mixture was added trifluoroacetic acid (0.439 mL, 5.70 mmol). The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was concentrated, taken up in hexanes, concentrated until a solid was obtained. The solid was dissolved in dichloromethane and washed with saturated sodium bicarbonate. The aqueous layer was extracted with dichloro methane (2x). The combined organic layers were washed with saturated sodium bicarbonate. The organic layers were poured through a phase separator and concentrated. The solid was dried overnight at 50 °C and ~25 mm Hg. The title compound was isolated as a white solid (0.162 g, 95%) : H NMR (400 MHz, CDCL ) 8 8.21 (s, 1H), 7.67 - 7.61 (m, 2H), 7.31 (dt, J= 8.0, 1.0 Hz, 2H), 4.13 (dt, J= 12.6, 3.2 Hz, 2H), 2.97 (ddd, J= 13.0, 11.8, 2.8 Hz, 2H), 2.88 (tt, J= 10.6, 4.0 Hz, 1H), 1.97 - 1.85 (m, 2H), 1.72 - 1.12 (m, 4H); 19F NMR (376 MHz, CDCL) 8 -58.09; ESIMS m/z 328 ([M+H]+).
The following compounds were synthesized in a manner similar to that provided in Example 15. l-(l-(4-(Trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3-yl)piperidin-3-amine (C16)
Figure imgf000028_0001
The title compound was synthesized from tert-butyl (1-(1 -(4-(trifliioronicthoxy)phcnyl)-l//-l ,2,4-triazol-3- yl)piperidin-3-yl)carbamate (Cll) and was isolated as a white sohd (468 mg, 100%): 3H NMR (400 MHz, CDCls) 8 8.21 (s, 1H), 7.64 (m, 2H), 7.30 (m, 2H), 4.03 (ddt, J= 12.2, 4.0, 1.5 Hz, 1H), 3.90 (m, 1H), 3.00 (m, 2H), 2.78 (dd, J= 12.2, 9.1 Hz, 1H), 1.98 (dd, J= 12.9, 4.5 Hz, 1H), 1.82 (dp, 7 = 12.6, 4.0 Hz, 1H), 1.67 (m, 1H), 1.42 (d, 7 = 18.7 Hz, 2H), 1.31 (m, 1H); 13C NMR (101 MHz, CDCh) 8 166.92, 147.43, 139.77, 135.82, 122.28, 120.10, 119.12, 55.12, 47.25, 46.37, 33.81, 23.24; 19F NMR (376 MHz, CDCh) 6 -58.10; ESIMS m/z 328 ([M+H]+). l-(l-(4-(Perfluoroethoxy)phenyl)-12/-l,2,4-triazol-3-yl)piperidin-4-amine (C17)
Figure imgf000028_0002
The title compound was synthesized from tert-butyl (1-(1 -(4-(perfluoroethoxy)phenyl)-l //-1.2.4-lriazol-3- yl)piperidin-4-yl)carbamate (C12) and was isolated as an off-white solid (156 mg, 49%): 'H NMR (400 MHz, CDCh) 8 8.22 (s, 1H), 7.65 (m, 2H), 7.31 (m, 3H), 4.13 (m, 2H), 2.95 (m, 3H), 1.91 (m, 2H), 1.45 (m, 4H); 13C NMR (101 MHz, CDCh) 8 166.88, 146.58, 139.86, 135.98, 122.93, 120.10, 48.80, 45.54, 34.98; 19F NMR (376 MHz, CDCh) 8 -85.93, -87.86; ESIMS m/z ([M+H]+).
Example 16: Preparation of 2-fluoro-2-(l-(l-(4-(trifluoromethoxy)phenyl)-l//-l,2,4-triazol-3-yl)piperidm-4- yl)ethan-l-amine hydrochloride (C18)
Figure imgf000028_0003
To a solution of tert-butyl (2-fluoro-2-(l-(l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3-yl)piperidin- 4-yl)ethyl)carbamate (C46, 0.12 g, 0.25 mmol) in dichloromethane (5 mL) was added 4 M hydrogen chloride in 1,4- dioxane (0.3 mL, 1.25 mmol) at 0 °C. The reaction mixture was warmed to room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting product was triturated with diethyl ether (2 mL) to provide the title compound as a white solid (0.1 g, 96%): mp 210 - 212 °C; 'H NMR (400 MHz, DMSO-cL) 8 9.00 (s, 1H), 8.24 (br s, 3H), 7.88 (dd, 7= 2.4, 7.2 Hz, 2H), 7.51 (d, J= 8.8 Hz, 2H), 4.67 - 4.65 (m, 1H), 4.11 - 4.08 (m, 2H), 3.29 - 2.98 (m, 2H), 2.87 - 2.79 (m, 2H), 1.89 - 1.79 (m, 2H), 1.68 - 1.64 (m, 1H), 1.39 - 1.29 (m, 2H); 19F NMR (376 MHz, DMSO-7,) 8 -57.03; ESIMS m/z 374 ([M+H]+).
The following compounds were synthesized in a manner similar to that provided in Example 16. l-(l-(4-(Trifluoromethoxy)phenyl)-l//-l,2,4-triazol-3-yl)piperazine hydrochloride (C19)
Figure imgf000029_0001
The title compound was prepared from tert-butyl 4-( 1 -(4-(trifluoromethoxy )pheny 1)- 1 H-i ,2,4-triazol-3- yl)piperazine-l -carboxylate (C13) and was isolated as an off-white solid (1.8 g, 76%): mp 245 - 248 °C; 'H NMR (400 MHz, DMSO-c/„ + DzO) 8 8.99 (s, 1H), 7.80 (d, J= 8.8 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 3.65 (t, J= 5.2 Hz, 4H), 3.23 (t, J= 5.2 Hz, 4H); 19F NMR (376 MHz, DMSO-t/,) 8 -57.04; ESIMS m/z 314 ([M+H]+).
4-(l-(4-(Trifluoromethoxy)phenyl)-l//-l,2,4-triazol-3-yl)-l,2,3,6-tetrahydropyridine hydrochloride (C20)
Figure imgf000029_0002
The title compound was synthesized from tert-butyl 4-(l -(4-(trifluoromethoxy)phenyl)-l H-l ,2,4-triazol-3- yl)-3,6-dihydropyridine-l(2rt)-carboxylate (C28) and was isolated as an off-white solid (4.9 g, 88%): mp 289 - 291 °C; H NMR (400 MHz, DMSO-cfc) 8 9.41 (br s, 2H), 9.33 (s, 1H), 7.80 (dd, J= 2.0, 6.8 Hz, 2H), 7.60 (d, J= 8.4 Hz, 2H), 6.75 - 6.71 (m, 1H), 3.80 - 3.79 (m, 2H), 3.31 - 3.29 (m, 2H), 2.79 - 2.72 (m, 2H); 19F NMR (376 MHz,
DMSO-de) 8 -57.01; ESIMS m/z 311 ([M+H]+).
Example 17: Preparation of tert-butyl (l-(4-(l-(4-(trifhioromethoxv)phenvl)-l//-l,2,4-triazol-3-yl)-3,6- dihydropyridin-1(2//)-yl)propari-2-yl)carbamate (C21)
Figure imgf000029_0003
A mixture of 4-(l-(4-(trifluoromethoxy)phenyl)-177-l,2,4-triazol-3-yl)-l,2,3,6-tetrahydropyridine hydrochloride (C20, 50 mg, 0.144 mmol), tert-butyl (l-bromopropan-2-yl)carbamate (63 mg, 0.26 mmol), and potassium carbonate (60 mg, 0.43 mmol) in \', \'-dimcthylformamidc (DMF, 0.5 mL) was heated at 80 °C overnight
The reaction mixture was diluted with ethyl acetate and water. The organic layer was pipetted off and filtered through a sodium sulfate cartridge directly onto a Celite® cartridge, rinsing with ethyl acetate. The cartridge was dried in the vacuum oven. Purification by flash chromatography (0 - 100% ethyl acetate-hexanes) provided the title compound as a yellow oil (21 mg, 31%), which was used in the next step without purification: ESIMS m/z 468 ([M+H]+).
Example 18: Preparation of l-(4-(l-(4-(trifluoromethoxy)phenyl)-l//-l,2,4-triazol-3-yl)-3,6-dihydropyridin- l(2Zf)-yl)propan-2-amine (
Figure imgf000029_0004
To tert-butyl (1 -(4-( 1 -(4-(trifluoromethoxy)phenyl)- 1H- 1 ,2,4-triazol-3-yl)-3 ,6-dihydropyridin- 1 (111)- yl)propan-2-yl)carbamate (C21, 21 mg, 0.045 mmol) in dichloromethane (0.2 ml) was added trifluoroacetic acid (0.14 mL, 0.180 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate and extracted with dichloro methane. The organic layer was filtered through a phase separator into a tared vial and concentrated to provide the title compound as a yellow oil (16 mg), which was used in the next step without purification.
Example 19: Preparation of 2-(2-(4-(l-(4-(trifluoromethoxy)phenyl)-lZZ-l,2,4-triazol-3-yl)piperazin-l- yl)ethyl)isoindoline-l, 3-dione (C23)
Figure imgf000030_0001
l-(l-(4-(Trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3-yl)piperazine (C19, 193 mg, 0.616 mmol), 2-(2- bromoethyl)isoindo line- 1,3 -dione (235 mg, 0.924 mmol), and potassium carbonate (255 mg, 1.848 mmol) in \' \- dimethylformamide (DMF, 1540 ji L) were heated in a Biotage microwave reactor at 120 °C for 1 hour. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layers were filtered through a phase separator directly onto a Celite® cartridge. Purification by flash chromatography (0 - 100% ethyl acetatehexanes) provided 65 mg of the title compound as a white solid. Recovery was low so the aqueous layer was extracted with ethyl acetate. The organic layers were filtered through a sodium sulfate cartridge into a tared 25 -mL vial and concentrated under nitrogen to provide another 30 mg of the title compound (95 mg total, 31%): mp 167.3- 168.3 °C; Tf NMR (300 MHz, CDC13) 5 8.21 (s, 1H), 7.88 - 7.82 (m, 2H), 7.74 - 7.68 (m, 2H), 7.65 - 7.57 (m, 2H), 7.30 (dd, J= 8.9, 1.0 Hz, 2H), 3.87 (t, J= 6.5 Hz, 2H), 3.50 - 3.41 (m, 4H), 2.74 - 2.60 (m, 6H); 19F NMR (471 MHz, CDCI3) 5 -58.10; HRMS-ESI (m/z) [M+H]+ calcd for C23H21F3N6O3, 487.1700; found, 487.1703.
Example 20: Preparation of 2-(4-(l-(4-(trifluoromethoxy)phenyl)-l//-l,2,4-triazol-3-yl)piperazin-l-yl)ethan- 1-amine (C24)
Figure imgf000030_0002
To 2-(2-(4-(l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3-yl)piperazin-l-yl)ethyl)isoindohne-l,3- dione (C23, 90 mg, 0.185 mmol) in dichloromethane (1 mL) was added hydrazine monohydrate (8.71 uL. 0.278 mmol). Additional hydrazine mo no hydrate was added and the mixture was stirred overnight. The reaction mixture was diluted with water and dichloromethane and was filtered through a phase separator into a tared vial. The organic layer was concentrated under a stream of nitrogen. The title compound was isolated as a pale yellow oil (57 mg, 85%): Tf NMR (400 MHz, CDCI3) 6 8.22 (s, 1H), 7.67 - 7.62 (m, 2H), 7.34 - 7.28 (m, 2H), 3.58 - 3.50 (m, 4H), 2.84 (t, J= 6.1 Hz, 2H), 2.63 - 2.55 (m, 4H), 2.49 (t, J= 6.1 Hz, 2H); 19F NMR (376 MHz, CDCI3) 8 -58.10; ESIMS m/z 357 ([M+H]+).
Example 21: Preparation of 2-(2-(4-(l-(4-(trifluoromethoxy)phenyl)-lZ/-l,2,4-triazol-3-yl)-3,6- dihydropyridin-l(2/f)-yl)ethyl)isoindoline-l, 3-dione (C25)
Figure imgf000031_0001
A mixture of 4-(l-(4-(trifluoromethoxy)phenyl)-17/-l,2,4-triazol-3-yl)-l,2,3,6-tetrahydropyridine hydrochloride (C20, 200 mg, 0.58 mmol), 2-(2-bromoethyl)isoindoline-l, 3-dione (220 mg, 0.86 mmol), and potassium carbonate (239 mg, 1.73 mmol) in DMF (1.4 mL) was heated in a Biotage microwave reactor at 120 °C for 1 hour. The reaction mixture was diluted with ethyl acetate and water. The organic layers were separated and filtered through a sodium sulfate cartridge directly onto a Celite® cartridge. The cartridge was dried in a vacuum oven overnight. Purification by flash chromatography (0 - 100% ethyl acetate-hexanes) provided the title compound as a yellow oil (41 mg, 50%): Tl NMR (300 MHz, CDC13) 5 8.43 (d, J= 0.4 Hz, 1H), 7.84 (dd, J= 5.5, 3.0 Hz, 2H), 7.74 - 7.66 (m, 4H), 7.35 (d, J= 8.6 Hz, 2H), 6.81 - 6.76 (m, 1H), 3.91 (t, J= 6.7 Hz, 2H), 3.31 (q, J= 2.9 Hz, 2H), 2.86 - 2.76 (m, 4H), 2.68 (s, 2H); 19F NMR (471 MHz, CDC13) 8 -58.06; HRMS-ESI (m/z) [M+H]+ calcd for C24H20F3N5O3, 484.1591; found, 484.1594.
Example 22: Preparation of 2-(4-(l-(4-(trifliioromethoxy)phenyl)-1 Jf-1,2,4-triazol-3-vl)-3,6-dihydropyridin- 1(2//)-yl)ethan-1-amine
Figure imgf000031_0002
To 2-(2-(4-(l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3-yl)-3,6-dihydropyridin-l(2Zf)- yl)ethyl)isoindoline-l, 3-dione (C25, 135 mg, 0.28 mmol) in dichloromethane (1.5 mL) was added hydrazine monohydrate (0.013 mL, 0.42 mmol). The reaction mixture was stirred at room temperature for 2 hours, was diluted with water and dichloromethane, and was filtered through a phase separator into a tared vial. The dichloromethane layer was concentrated to provide the title compound as a yellow oil (110 mg), which was used in the next step without purification: HRMS-ESI (m/z) [M+H]+ calcd for C ieH ixFiNsO. 354.1536; found, 354.1536.
Example 23: Preparation of ethyl 4-(1-(4-(trifluoromethoxy)phenyl)-1/f-l,2,4-triazol-3-yl)cyclohex-3-ene-1- carboxylate (C27)
Figure imgf000031_0003
To an argon degassed solution of 3-bromo-l -(4-(trifluoro metho xy)phenyl)-l //-1.2.4-triazolc (Cl, 4 g, 13.0 mmol) in 1,4-dioxane (60 mL) were added 3 M aqueous sodium carbonate (10.8 mL, 32.5 mmol) and ethyl 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-ene-l-carboxylate (C51, 4.5 g, 16.2 mmol), followed by tetrakis(triphenylphosphine)palladium(0) (1.5 g, 1.3 mmol). The reaction mixture was stirred at 120 °C for 16 hours. The reaction mixture was cooled to room temperature, filtered through a pad of Celite®, washed with ethyl acetate (50 mL), and the filtrate was concentrated under reduced pressure. The resulting product was purified by flash column chromatography (25 - 30% ethyl acetate-petroleum ether) to provide the title compound as an off-white solid (2.5 g, 50%): 'H NMR (400 MHz, DMSO-76) 59.24 (s, 1H), 7.97 (d, 7 = 8.7 Hz, 2H), 7.58 (d, J= 8.7 Hz, 2H), 6.84 - 6.80 (m, 1H), 4.16 - 4.05 (m, 2H), 2.68 - 2.62 (m, 2H), 2.49 - 2.32 (m, 3H), 2.11 - 2.07 (m, 1H), 1.78 - 1.64 (m, 1H), 1.21 (t, J= 7.2 Hz, 3H); ESIMS m/z 382 ([M+H]+).
The following compounds were synthesized in a manner similar to that provided in Example 23. tert-Butyl 4-(l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3-yl)-3,6-dihydropyridme-l(2/r)-carboxylate (C28)
Figure imgf000032_0001
The title compound was synthesized from 3-bromo-l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazole (Cl) and tert-butyl 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-y l)-3,6-dihydropy ridine-l(2f/)-carboxy late and was isolated as an off-white solid (6.5 g) that was used without purification: ESIMS m/z 411 ([M+H]+).
Example 24: Preparation of ethyl 4-(l-(4-(trifhioromethoxy)phenyl)-lH-l,2,4-triazol-3-yl)cyclohex-3-ene-l- carboxylate (C27)
Figure imgf000032_0002
To 3-bromo-l-(4-(trifluoromethoxy)phenyl)-17f-l,2,4-triazole (Cl, 1.277 g, 4.14 mmol), ethyl 4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-ene-l-carboxylate (C51, 1.219 g, 4.35 mmol), tetrakis(triphenylphosphine)palladium(0) (0.479 g, 0.414 mmol), and sodium bicarbonate (0.696 g, 8.29 mmol) in a 10-20 mL microwave vial equipped with a stir bar were added dioxane (12.43 mL) and water (4.14 mL). The reaction mixture was heated to 140 °C for 30 minutes in a Biotage Initiator microwave synthesizer. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by silica gel flash column chromatography (0 - 30% ethyl acetate-B, where B = 50% dichloromethanehexanes) provided the title compound as a white solid (0.803 g, 50.8%): 'H NMR (400 MHz, CDCh) 6 8.44 (s, 1H), 7.75 - 7.69 (m, 2H), 7.35 (dt, 7= 8.0, 1.0 Hz, 2H), 6.95 - 6.88 (m, 1H), 4.23 - 4.13 (m, 2H), 2.88 - 2.77 (m, 1H), 2.71 - 2.61 (m, 1H), 2.61 - 2.45 (m, 3H), 2.26 - 2.17 (m, 1H), 1.85 (dtd, 7 = 13.0, 10.7, 5.4 Hz, 1H), 1.29 (t, 7 = 7.1 Hz, 3H); 19F NMR (376 MHz, CDCI3) S -58.05; ESIMS m/z 382 ([M+H]+).
The following compounds were synthesized in a manner similar to that provided in Example 24. Ethyl 4-(l-(4-(perfluoroethoxy)phenyl)-l//-l,2,4-triazol-3-yl)cyclohex-3-ene-l-carboxylate (C29)
Figure imgf000033_0001
The title compound was synthesized from 3-bromo-l-(4-(perfluoroethoxy)phenyl)-177-l,2,4-triazole (prepared as in US 20140275502 Al) and ethyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-ene-l- carboxylate (C51) and was isolated as a white solid, which was dried at 50 °C and ~25 mm Hg (0.48 g, 80%): mp 146 - 150 °C; H NMR (400 MHz, CDCh) 5 8.45 (d, J= 0.7 Hz, 1H), 7.80 - 7.67 (m, 2H), 7.36 (dd, J= 9.0, 0.9 Hz, 2H), 6.96 - 6.86 (m, 1H), 4.26 - 4.11 (m, 2H), 2.90 - 2.76 (m, 1H), 2.66 (dddd, J= 11.7, 8.8, 5.6, 3.2 Hz, 1H), 2.61 - 2.45 (m, 3H), 2.21 (ddt, J= 12.6, 6.0, 2.9 Hz, 1H), 1.93 - 1.76 (m, 1H), 1.29 (td, J= 7.1, 0.7 Hz, 3H); 19F NMR (376 MHz, CDCL) 8 -85.91, -87.86; ESIMS m/z 432 ([M+H]+).
Example 25: Preparation of ethyl 4-(l-(4-(tritluoromethoxy)phenyl)-l/f-l,2,4-triazol-3-yl)cyclohexane-1- carboxylate (C30)
Figure imgf000033_0002
To a solution of ethyl 4-(l-(4-(trifluoromethoxy)phenyl)-17/-l,2,4-triazol-3-yl)cyclohex-3-ene-l- carboxylate (C27, 3 g, 7.9 mmol) in ethyl acetate (80 mL) was added 10% palladium on carbon (Pd/C, 600 mg). The reaction mixture was stirred under hydrogen (482.6 kilopascal (kPa), 70 pounds per square inch (psi)) in a Panshaker for 24 hours at room temperature. The reaction mixture was filtered through a pad of Celite®, washed with ethyl acetate (150 mL), and the filtrate was concentrated under reduced pressure to provide the title compound as a pale yellow sticky solid (2.5 g, 83%): 'H NMR (300 MHz, DMSO-c/6) S 9.19 (s, 1H), 7.96 (d, J= 9.3 Hz, 2H), 7.56 (d, J= 8.7 Hz, 2H), 4.11 - 4.02 (m, 2H), 2.58 - 2.56 (m, 1H), 2.11 - 1.84 (m, 6H), 1.71 - 1.51 (m, 3H), 1.23 - 1.53 (m, 3H); ESIMS m/z 384 ([M+H]+).
Example 26: Preparation of 4-(l-(4-(trifluoromethoxy)phenyl)-lZf-l,2,4-triazol-3-yl)cyclohex-3-ene-l- carboxylic acid (C31)
Figure imgf000033_0003
To ethyl 4-(l -(4-(trifhroromethoxy)phenyl)-l H-l ,2,4-triazol-3-yl)cyclohex-3-ene-l -carboxylate (C27, 0.802 g, 2.1 mmol) in a 250 mL round-bottomed flask equipped with a stir bar was added methanol (75 mL). To this was added 2 N sodium hydroxide (11 mL, 21 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated and diluted with water. The solution was acidified with 1 N hydrochloric acid. The aqueous layer was extracted with ethyl acetate (2x). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to a yellow solid. The solid was dried overnight at 50 °C at ~25 in. Hg. The title compound was isolated as a yellow solid (0.7425 g, 100%): H NMR (400 MHz, DMSO-de) 8 12.24 (s, 1H), 9.24 (s, 1H), 8.02 - 7.93 (m, 2H), 7.68 - 7.51 (m, 2H), 6.80 (ddt, J= 4.8, 3.2, 1.7 Hz, 1H), 2.70 - 2.51 (m, 2H), 2.51 - 2.32 (m, 3H), 2.08 (dq, J= 13.2, 5.2, 3.9 Hz, 1H), 1.70 (dtd, J= 12.9, 10.3, 5.5 Hz, 1H); 19F NMR (376 MHz, DMSO-de) S -56.99; ESIMS m/z 354 ([M+H]+).
The following compounds were synthesized in a manner similar to that provided in Example 26.
4-(l-(4-(Perfluoroethoxy)|)henvl)-1//-1, 2, 4-tri;izol-3-vl)cvcloliex-3-ene-1 -carboxylic acid (C32)
Figure imgf000034_0001
The title compound was synthesized from ethyl 4-(l-(4-(perfluoroethoxy)phenyl)-177-I,2,4-triazol-3- yl)cyclohex-3-ene-l -carboxylate (C29) and was isolated as a white solid (0.38 g, 93%): mp 169 - 177 °C; 'H NMR (400 MHz, DMSCWs) 8 12.24 (s, 1H), 9.25 (s, 1H), 8.04 - 7.94 (m, 2H), 7.68 - 7.51 (m, 2H), 6.81 (dt, J= 4.8, 2.2 Hz, 1H), 2.71 - 2.53 (m, 2H), 2.47 - 2.30 (m, 3H), 2.13 - 2.02 (m, 1H), 1.78 - 1.62 (m, 1H); 19F NMR (376 MHz, DMSO-de) 8 -85.20, -86.93; ESIMS m/z 404 ([M+H]+).
Example 27: Preparation of (4-(l-(4-(trifhioromethoxy)phenyl)-l/f-l,2,4-triazol-3-yl)cyclohex-3-en-l- yl)methanol (C33)
Figure imgf000034_0002
To a suspension of lithium aluminum hydride (0.31 g, 8.19 mmol) in dry tetrahydrofuran (15 mL) was added a solution of ethyl 4-(l-(4-(trifluoromethoxy)phenyl)-lW-l,2,4-triazol-3-yl)cyclohex-3-ene-l-carboxylate
(C27, 2.5 g, 6.55 mmol) in tetrahydrofuran (20 mL) dropwise at 0 °C over a period of 10 minutes. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 °C. Water (1.5 mL) was added dropwise, followed by 15% aqueous sodium hydroxide (1.5 mL) and water (4.5 mL). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through a pad of Celite® and the pad was washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure. The resultant product was purified by silica gel column chromatography (100-200 mesh, 40 - 45% ethyl acetate-petroleum ether) to provide the title compound as an off-white solid (1.8 g, 64%): H NMR (300 MHz, DMSO-cL) 5 9.22 (s, 1H),
7.97 (d, J= 9.3 Hz, 2H), 7.67 (d, J= 8.7 Hz, 2H), 6.84 - 6.79 (m, 1H), 4.52 (t, J= 5.1 Hz, 1H), 3.38 - 3.32 (m, 2H),
2.69 - 2.62 (m, 1H), 2.41 - 2.27 (m, 2H), 1.94 - 1.84 (m, 2H), 1.72 - 1.71 (m, 1H), 1.36 - 1.26 (m, 1H); ESIMS m/z 340 ([M+H]+).
The following compounds were synthesized in a manner similar to that provided in Example 27. (4-(l-(4-(Trifluoromethoxy)phenyl)-l/7-l,2,4-triazol-3-yl)cyclohexyl)methanol (C34)
Figure imgf000034_0003
The title compound was synthesized from ethyl 4-( l -(4-(trifluoromeihoxy)phcnyl)-l//-l .2.4-triazol-3- yl)cyclohexane-l -carboxylate (C30) and was isolated as an off-white solid (2.5 g, 85%): !H NMR (300 MHz, DMSO-t/e) 5 9.18 (s, 1H), 7.97 - 7.93 (m, 2H), 7.56 (d, J= 8.1 Hz, 2H), 4.43 - 4.33 (m, 1H), 3.26 (t, J= 5.7 Hz, 2H), 3.22 - 2.95 (m, 1H), 2.08 - 1.99 (m, 2H), 1.86 - 1.83 (m, 1H), 1.82 - 1.68 (m, 1H), 1.59 - 1.43 (m, 2H), 1.43 - 1.32 (m, 2H), 1.11 - 0.95 (m, 1H); ESIMS m/z 342 ([M+H]+).
Example 28: Preparation of 4-(l-(4-(trifluoromethoxy)phenyl)-l/f-l,2,4-triazol-3-yl)cyclohex-3-ene-l- carbaldehyde (C35)
Figure imgf000035_0001
To a solution of (4-(l-(4-(trifluoromethoxy)phenyl)-l/7-l,2,4-triazol-3-yl)cyclohex-3-en-l-yl)methanol (C33, 0.9 g, 2.65 mmol) in dichloromethane (20 mL) was added Dess-Martin periodinane (1.6 g, 3.31 mmol) portion wise at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated sodium bicarbonate (20 mL) and the mixture was extracted with dichloromethane (3 x 50 mL). The organic layer was washed with water (30 mL) followed by brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resultant product was triturated with 20% diethyl ether in pentane (10 mL) to afford the title compound as an off-white sticky solid, which was used in the next step without any purification and analysis (0.9 g).
The following compounds were synthesized in a manner similar to that provided in Example 28. 4-(l-(4-(Trifhioromethoxy)phenyl)-l//-l,2,4-triazol-3-yl)cyclohexane-l-carbaldehyde (C36)
Figure imgf000035_0002
The title compound was prepared from (4-(l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3- yl)cyclohexyl)methanol (C34) and isolated as a pale yellow sticky solid, which was used in the next step without any purification and analysis (3.8 g).
1-(l-(4-(Trifluoromethoxy)plienyl)-1//-l,2,4-triazol-3-yl)piperidine-4-carbaldehyde (C3)
Figure imgf000035_0003
The title compound was prepared from 1 -( 1 -(4-(trifluoromethoxy)phenyl)-l H- 1 ,2,4-triazol-3-yl)piperidin- 4-yl)methanol (C2) and was isolated as a pale yellow sticky solid, which was used in the next step without purification and analysis (5.5 g).
Example 29: Preparation of 2-hydroxy-2-(4-(l-(4-(trifluoromethoxy)phenyl)-l/7-l,2,4-triazol-3-yl)cyclohex-3- en-l-yl)acetonitrile (C37)
Figure imgf000036_0001
To a solution of 4-(l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3-yl)cyclohex-3-ene-l-carbaldehyde (C35, 1.1 g, 3.28 mmol) in dichloromethane (20 mL) was added trimethylsilyl cyanide (0.8 mL, 6.53 mmol), zinc iodide (ZnL. 1.04 g, 3.28 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated sodium bicarbonate (40 mL) and extracted with dichloromethane (3 x 50 mL). The organic layer was washed with water (30 mL) followed by brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The reaction material (1.5 g) of trimethylsilyl-protected cyanohydrin was dissolved in tetrahydrofuran (30 mL). 2 N Hydrochloric acid (2 mL) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate (20 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layer was washed with water (30 mL) followed by brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (20 - 30% ethyl acetate in petroleum ether) to provide the title compound as an off-white solid (1.1 g, 45% over two steps): mp 173 - 176 °C; H NMR (400 MHz, DMSO-rie) 5 9.22 (s, 1H), 7.97 (dd, J = 2.0, 6.8 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 6.84 - 6.78 (m, 1H), 6.46 (d, J = 6.4 Hz, 1H), 4.50 (t, J= 6.4 Hz, 1H), 2.76 - 2.71 (m, 1H), 2.51 - 2.38 (m, 2H), 2.11 - 1.96 (m, 2H), 1.47 - 1.42 (m, 1H); 19F NMR (376 MHz, DMSO-de) 5 -57.02; ESIMS m/z 365 ([M+H]+).
The following compounds were synthesized in a manner similar to that provided in Example 29. 2-Hydroxy-2-(4-(l-(4-(trifluoromethoxy)phenyl)-l//-l,2,4-triazol-3-yl)cyclohexyl)acetonitrile (C38)
Figure imgf000036_0002
The title compound was synthesized from 4-( 1 -(4-(trifhroromethoxy)phenyl)-l H-l ,2,4-triazol-3- yl)cyclohexane-l-carbaldehyde (C36) and was isolated as a pale yellow sticky liquid (1.95 g, 55% over two steps): IR 3423.27 cm’1 (OH stretching present); 'H NMR (400 MHz, DMSO-cL) 6 9.18 (s, 1H), 7.98 - 7.93 (m, 2H), 7.55 (d, J= 8.8 Hz, 2H), 6.25 (d, J= 5.6 Hz, 1H), 4.41 - 4.32 (m, 1H), 3.10 - 3.08 (m, 1H), 2.24 - 1.91 (m, 2H), 1.78 - 1.75 (m, 1H), 1.74 - 1.56 (m, 3H), 1.53 - 1.47 (m, 2H), 1.29 - 1.19 (m, 1H); 19F NMR (376 MHz, DMSO-<L) 8 - 57.02; ESIMS m/z 367 ([M+H]+).
2-Hydroxy-2-(l-(l-(4-(trifhioromethoxy)plienyl)-lH-l,2,4-triazol-3-yl)piperidin-4-yl)acetonitrile (C39)
Figure imgf000036_0003
The title compound was prepared from 1 -( 1 -(4-(trifluoromethoxy)phenyl)-l H- 1 ,2,4-triazol-3-yl)piperidine- 4-carbaldehyde (C3) and was isolated as an off-white solid (3.5 g, 59% over two steps): mp 150 - 153 °C; 'H NMR (400 MHz, DMSO-7,) 8 8.98 (s, 1H), 7.88 (dd, J= 2.4, 7.2 Hz, 2H), 7.51 (d, J= 8.8 Hz, 2H), 6.41 (d, J= 6.0 Hz, 1H), 4.42 (1, 7= 6.4 Hz, 1H), 4.12 - 4.09 (m, 2H), 2.86 - 2.83 (m, 2H), 1.85 - 1.77 (m, 3H), 1.36 - 1.32 (m, 2H); 19F NMR (376 MHz, DX4SO-7,) 8 -57.05; ESIMS m/z 368 ([M+H]+).
Example 30: Preparation of 2-fluoro-2-(4-(l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3-yl)cyclohex-3- en-l-yl)acetonitrile (C40)
Figure imgf000037_0001
To 2-hydroxy-2-(4-(l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3-yl)cyclohex-3-en-l-yl)acetonitrile (C37, 119 mg, 0.327 mmol) in dichloromethane (2178 pL) at O °C was added (diethylamino)sulfur trifluoride (47.5 pL. 0.359 mmol). The insoluble starting material immediately dissolved and the solution turned golden yellow. The reaction mixture was stirred overnight while warming to room temperature. The reaction mixture was loaded onto a Celite® cartridge. Purification by flash chromatography (0 - 60% ethyl acetate in hexanes) provided the title compound as a clear oil (104 mg, 83%): 'H NMR (400 MHz, CDC13) 8 8.46 (s, 1H), 7.76 - 7.67 (m, 2H), 7.39 - 7.32 (m, 2H), 6.92 - 6.86 (m, 1H), 5.10 (dd, 7= 46.9, 6.2 Hz, 1H), 2.87 (t, 7= 16.4 Hz, 1H), 2.68 - 2.48 (m, 2H), 2.43 - 2.22 (m, 2H), 2.19 - 2.11 (m, 1H), 1.70 (dddd, 7 = 24.0, 22.0, 11.1, 5.5 Hz, 1H); 19F NMR (376 MHz, CDC13) 6 -58.06, -192.61, -193.22; ESIMS m/z 367 ([M+H]+).
The following compounds were synthesized in a manner similar to that provided in Example 30. 2-Fluoro-2-(4-(l-(4-(trifluoromethoxy)phenyl)-lLf-l,2,4-triazol-3-yl)cyclohexyl)acetonitrile (C41)
Figure imgf000037_0002
The title compound was prepared from 2-hydroxy-2-(4-(l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3- yl)cyclohexyl)acetonitrile (C38) and isolated as a clear oil (74 mg, 48%): 'H NMR (400 MHz, CDCI3) 8 8.45 (d, 7 = 8.3 Hz, 1H), 7.74 - 7.65 (m, 2H), 7.36 (dq, 7= 8.0, 1.0 Hz, 2H), 5.07 - 4.89 (m, 1H), 3.24 (t, 7= 4.4 Hz, 1H), 2.86 (tt, 7= 12.2, 3.7 Hz, 1H), 2.42 - 2.21 (m, 3H), 2.16 - 1.95 (m, 1H), 1.90 - 1.62 (m, 3H), 1.52 - 1.35 (m, 1H); 19F NMR (376 MHz, CDCh) 5 -58.06, -192.19, -192.39; ESIMS m/z 369 ([M+H]+).
Example 31: Preparation of 2-fluoro-2-(4-(1-(4-(trifluoromethoxy)phenyl)-l//-1,2,4-triazol-3-yl)cyclohex-3- en-l-yl)ethan-l-amine (C42)
Figure imgf000037_0003
To 2-fluoro-2-(4-(l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3-yl)cyclohex-3-en-l-yl)acetonitrile (C40, 95 mg, 0.259 mmol) in tetrahydrofuran (1 mL) at 0 °C was added 1 M borane tetrahydrofuran complex solution in tetrahydrofuran (BH ,«THF. 0.78 mL, 0.780 mmol). The reaction mixture was stirred overnight while warming to room temperature. Additional BH .«THF (0.26 mL, 1 molar equivalent) was added to the reaction mixture, and the reaction mixture was stirred at room temperature overnight. 1 M Lithium aluminum hydride in tetrahydrofuran (0.571 mL, 0.571 mmol) was added, and the reaction mixture was stirred overnight. The reaction was quenched with water and aqueous Rochelle's salt and was extracted (2x) with ethyl acetate. The organic extracts were filtered through a sodium sulfate cartridge directly onto a Celite® cartridge. The cartridge was dried in the vacuum oven overnight. Purification by reverse-phase flash chromatography (0 - 100% aceto nitrile-water) provided, after drying overnight under nitrogen, the title compound as an impure mixture (32 mg) that was used without purification: ESIMS m/z 371 ([M+H]+).
The following compounds were synthesized in a manner similar to that provided in Example 31. 2-Fluoro-2-(4-(l-(4-(trifluoromethoxy)phenyl)-lZf-l,2,4-triazol-3-yl)cyclohexyl)ethan-l-amine (C43)
Figure imgf000038_0001
The title compound was prepared from 2-fluoro-2-(4-( 1 -(4-(trifluoromethoxy )phenyl)-l H- 1 ,2,4-triazol-3- yl)cyclohexyl)acetonitrile (C41) and isolated as an impure brown oil (26 mg) that was used without purification: ESIMS m/z 373 ([M+H]+).
Example 32: Preparation 2-amino-l-(l-(l-(4-(trifluoromethoxy)phenyl)-l/7-l,2,4-triazol-3-yl)piperidin-4- yl)ethan-l-ol hydrochloride (C44)
Figure imgf000038_0002
To a solution of 2-hydroxy-2-(l-(l-(4-(trifluoromethoxy)phenyl)-177-l,2,4-triazol-3-yl)piperidin-4- yl)acetonitrile (C39, 1 g, 2.71 mmol) in dichloromethane (20 mL) was added 1 M BH ,*THF (10.8 mL, 10.8 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with 3 M hydrogen chloride in methanol (20 mL) and was concentrated under reduced pressure. The resulting product was triturated with diethyl ether (10 mL) to provide the title compound as a pale yellow sticky liquid (1.25 g), which was used in the next step without purification.
Example 33: Preparation of tert-butyl (2-hydroxy-2-(l-(l-(4-(trifhioromethoxy)phenyl)-lZ7-l,2,4-triazol-3- yl)piperidin-4-yl)ethyl)carbamate (C45)
Figure imgf000038_0003
To a solution of 2-amino-l-(l-(l-(4-(trifluoromethoxy)phenyl)-lZ7-l,2,4-triazol-3-yl)piperidin-4-yl)ethan- l-ol hydrochloride (C44, 1 g, 2.69 mmol) in dichloromethane (25 mL) were added triethylamine (1.9 mL, 13.5 mmol) followed by di-fert-butyl dicarbonate (1.1 mL, 4.04 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (50 mL) and extracted with dichloromethane (2 x 80 mL). The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product was triturated with //-pentane to provide the title compound as an off-white solid (0.8 g, 62% over two steps): Tl NMR (300 MHz, DMSO-c/g) 58.98 (s, 1H), 7.88 (d, J= 8.7 Hz, 2H), 7.51 (d, J= 8.4 Hz, 2H), 6.64 - 6.61 (m, 1H), 4.58 (br s, 1H), 4.09 - 4.05 (m, 2H), 3.32 - 3.12 (m, 1H), 3.08 - 2.98 (m, 1H), 2.80 - 2.71 (m, 3H), 1.79 - 1.73 (m, 1H), 1.59 - 1.52 (m, 1H), 1.38 - 1.27 (m, 12H); ESIMS m/z 472 ([M+H]+).
Example 34: Preparation of tert-butyl (2-fluoro-2-(l-(l-(4-(trifluoromethoxy)phenyl)-lZT-l,2,4-triazol-3- yl)piperidin-4-yl)ethyl)carbamate (C46)
Figure imgf000039_0001
To a solution of tert-butyl (2-hydroxy-2-(l-(l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3- yl)piperidin-4-yl)ethyl)carbamate (C45, 0.5 g, 1.06 mmol) in dichloromethane (10 mL) were added triethylamine (0.14 mL, 1.06 mmol), followed by (diethylamino)sulfur trifluoride (0.17 mL, 1.32 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate (10 mL) and was extracted with dichloro methane (3 x 20 mL). The organic layers were washed with water (10 mL) followed by brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product was purified by preparative high performance liquid chromatography (HPLC) to provide the title compound as a white solid (0.1 g, 20%): mp 145 - 148 °C; :H NMR (400 MHz, DMSO- d6) 5 8.97 (s, 1H), 7.88 (dd, J= 2.0, 6.8 Hz, 2H), 7.50 (d, J= 8.4 Hz, 2H), 7.04 - 7.00 (m, 1H), 4.36 - 4.21 (m, 1H), 4.10 - 4.06 (m, 2H), 3.29 - 3.08 (m, 2H), 2.83 - 2.77 (m, 2H), 1.81 - 1.66 (m, 3H), 1.38 - 1.27 (m, 11H); 19F NMR (376 MHz, DMSO-t/e) 6 -57.04; ESIMS m/z 474 ([M+H]+).
Example 35: Preparation of 4-(l-(4-(trifluoromethoxy)phenyl)-17/-l,2,4-triazol-3-yl)cyclohex-3-ene-l- carbonyl azide (C47)
Figure imgf000039_0002
To 4-( l-(4-(trifluoromethoxy)pheiiyl)-l//- l.2.4-triazol-3-yl)cyclohex-3-ene- l -carboxylic acid (C31, 0.743 g, 2.102 mmol) in a 25 mL vial equipped with a stir bar and under an atmosphere of nitrogen was added toluene (10.5 mL). To this were added triethylamine (0.322 rnL, 2.312 mmol) followed by diphenyl phosphorazidate (0.468 mL, 2.102 mmol). The reaction mixture was stirred until conversion of starting material to desired product was observed by LC-MS. The reaction mixture was loaded directly onto a Celite® cartridge. Purification by silica gel flash column chromatography (0 - 30% ethyl acetate-hexanes) provided, after drying under house vacuum overnight, the title compound as a light yellow solid (0.441 g, 55%) which was used without further purification or characterization: ESIMS m/z 319 ([M+H]+).
Example 37: Preparation of/V-(5-methyl-2-(3,3,3-trifluoropropoxy)phenyl)-2-thiocyanatoacetamide (C49)
Figure imgf000040_0001
To a 250 mL round bottom flask were added 2-chloro- '\'-(5-mcthyl-2 -(3,3,3- trifluoropropoxy)phenyl)acetamide (5.60 g, 18.94 mmol), acetone (95 mL), and potassium thiocyanate (1.84 g, 18.94 mmol). The reaction mixture was stirred at 63 °C overnight. The reaction mixture was diluted with ethyl acetate and water. The mixture was extracted with ethyl acetate (2x). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (0 - 70% ethyl acetate-hexanes) afforded the title compound as a white solid (3.66 g, 58%): rH NMR (400 MHz, CDCls) 8 8.32 - 8.03 (m, 2H), 7.01 - 6.85 (m, 1H), 6.79 (d, J= 8.3 Hz, 1H), 4.28 (t, J= 6.0 Hz, 2H), 3.86 (s, 2H), 2.68 (qt, J= 10.4, 6.0 Hz, 2H), 2.31 (s, 3H); 19F NMR (376 MHz, CDCh) 6 -64.23.
Example 38: Preparation of ethyl 4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-l-carboxylate (C50)
Figure imgf000040_0002
To a solution of ethyl 4-oxocyclohexane-l-carboxylate (10 g, 58.8 mmol) in tetrahydrofuran (100 mL) was added a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (74 mL, 73.5 mmol) dropwise over 30 minutes at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour. \'-Phcnyl-bis(irifliioromcthancsulfonamidc) (26 g, 73.5 mmol) dissolved in tetrahydrofuran (100 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 12 hours. The mixture was quenched with saturated ammonium chloride solution (80 mL) and extracted with ethyl acetate (2 x 150 mL). The organic layer was washed with water (100 mL) followed by brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound as a pale yellow sticky liquid (14.2 g), which was used in the next step without further purification.
Example 39: Preparation of ethyl 4-(4,4,5,5-tetramethyl-l,3»2-dioxaborolan-2-yl)cydohex-3-ene-l-carboxylate (C51)
Figure imgf000041_0001
To an argon degassed solution of ethyl 4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-l-carboxylate (C50, 14.2 g, 47.1 mmol) in 1,4-dioxane (200 mL) were added potassium acetate (10.3 g, 106 mmol), bis(pinacolato)diboron (11.9 g, 47.1 mmol), and [l,T-bis(diphenylphosphino) ferrocene] die hloropalladium(II) dichloromethane complex (1.9 g, 2.3 mmol). The reaction mixture was stirred at 100 °C for 18 hours. The reaction mixture was cooled to room temperature, filtered through a pad of Celite®, washed with ethyl acetate (100 mL), and the filtrate was concentrated under reduced pressure. The resulting product was purified by column chromatography (5 - 10% ethyl acetate-petroleum ether) to provide the title compound as a pale yellow sticky liquid (4.5 g, 42% over two steps): ESIMS m/z 281 ([M+H]+).
Example 40: Preparation of l-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[2-[l-[l-[4- (trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4-piperidyl]ethyl]urea (A2)
Figure imgf000041_0002
Method A: 4-(2-Isocyanatoethyl)-l-(l-(4-(trifluoromethoxy)phenyl)-l./7-l,2,4-triazol-3-yl)piperidine (C7 used as is; 239 mg, 0.627 mmol) was diluted with acetonitrile (4.0 mL), and the mixture was warmed in a heating block preheated to 80 °C for 60 minutes. The reaction mixture was cooled and l-(2-isopropyl-5- methylphenyl)thiourea (144 mg, 0.689 mmol), and cesium carbonate (245 mg, 0.752 mmol) were added. The reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was diluted with water and dichloromethane and passed through a phase separator. The organic filtrate was concentrated. Purification of the resulting residue by reverse phase chromatography (Cis silica gel; 10 - 100% acetonitrile in water) provided the title compound as an orange solid (18 mg, 5%).
Method B: To a biphasic solution of bis(trichloro methyl) carbonate (0.638 grams (g), 2.15 mmol) and sodium bicaibonate (1.36 g, 16.1 mmol)) in dichloromethane (20 mL) and water (10 mL) was added a suspension of 2-(l-(l-(4-(trifluoromethoxy)phenyl)-lZ7-l,2,4-triazol-3-yl)piperidin-4-yl)ethanamine (C9, 1.91 g, 5.37 mmol) in dichloromethane (40 mL). The reaction mixture was allowed to stir at room temperature for 4 hours. The reaction mixture was diluted with dichloromethane and passed through a phase separator and the filtrate was concentrated. The resulting residue was suspended in acetonitrile (36 mL). A total of 4.0 mL [l/9th of the volume (0.594 mmol)] of this suspension was transferred to a vial containing l-(2-isopropyl-5-methylphenyl)thiourea (0.136 g, 0.653 mmol) and cesium carbonate (0.387 g, 1.188 mmol). The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was concentrated onto Celite®. Purification by silica gel flash chromatography (0 - 60% ethyl acetate in hexanes) provided the title compound as a white solid (157 mg, 44%).
The following compounds were synthesized in a manner similar to that provided in Example 40, Method B. l-[(2-Isopropyl-5-methyl-phenyl)carbamothioyl]-3-[l-[l-[4-(trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4- piperidyljurea (A3)
Figure imgf000042_0001
The title compound was synthesized from l-( 1 -(4-(trifluoromethoxy)phenyl)-l H-i ,2,4-triazol-3- yl)piperidin-4-amine (C15) and l-(2-isopropyl-5-methylphenyl)thiourea and was isolated as a white solid (0.057 g, 21%). l-(o-Tolylcarbamothioyl)-3-[2-[l-[l-[4-(trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4-piperidyl]ethyl]urea
(A5)
Figure imgf000042_0002
The title compound was synthesized from 2-(l-(l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3- yl)piperidin-4-yl)ethanamine (C9) and l-(o-tolyl)thiourea and was isolated as a white solid (117 mg, 36%). l-[(4-Methoxy-2-methyl-phenyl)carbamothioyl]-3-[2-[l-[l-[4-(trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4- piperidyl]ethyl]urea (A6)
Figure imgf000042_0003
The title compound was synthesized from 2-(l-(l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3- yl)piperidin-4-yl)ethanamine (C9) and l-(4-methoxy-2-methylphenyl)thiourea and was isolated as a white solid (154 mg, 45%). l-[(2-Ethylphenyl)carbamothioyl]-3-[2-[l-[l-[4-(trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4- piperidyl]ethyl]urea (A7)
Figure imgf000043_0001
The title compound was synthesized from 2-(l-(l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3- yl)piperidin-4-yl)ethanamine (C9) and l-(2-ethylphenyl)thiourea and was isolated as a white solid (134 mg, 39%). l-[(2-Ethyl-6-methyl-phenyl)carbamothioyl]-3-[2-[l-[l-[4-(trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4- piperidyljethyljurea (A8)
Figure imgf000043_0002
The title compound was synthesized from 2-(l-(l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3- yl)piperidin-4-yl)ethanamine (C9) and l-(2-ethyl-6-methylphenyl)thiourea and was isolated as a white solid (20 mg, 6%). l-[(2-Isopropylphenyl)carbamothioyl]-3-[2-[l-[l-[4-(trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4- piperidyl]ethyl]urea (A9)
Figure imgf000043_0003
The title compound was synthesized from 2-(l-(l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3- yl)piperidin-4-yl)ethanamine (C9) and l-(2-isopropylphenyl)thiourea and was isolated as a white solid (52 mg, 15%). l-[(2-Isopropyl-4-methyl-phenyl)carbamothioyl]-3-[2-[l-[l-[4-(trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4- piperidyljethyljurea (A10)
Figure imgf000043_0004
The title compound was synthesized from 2-( 1 -(1 -(4-(trifluoromethoxy)phenyl)-l H-l ,2,4-triazol-3- yl)piperidin-4-yl)ethanamine (C9) and l-(2-isopropyl-4-methylphenyl)thiourea and was isolated as a white solid (157 mg, 44%). l-[(4-Fluoro-2-isopropyl-phenyl)carbamothioyl]-3-[2-[l-[l-[4-(trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4- piperidyljethyljurea (All)
Figure imgf000044_0001
The title compound was synthesized from 2-(l-(l-(4-(trifluoromethoxy)phenyl)-177-l,2,4-triazol-3- yl)piperidin-4-yl)ethanamine (C9) and l-(4-fluoro-2-isopropylphenyl)thiourea and was isolated as a white solid (135 mg, 38%). l-[(5-Chloro-2-isopropyl-phenyl)carbamothioyl]-3-[2-[l-[l-[4-(trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4- piperidyl]ethyl]urea (A12)
Figure imgf000044_0002
The title compound was synthesized from 2-(l-(l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3- yl)piperidin-4-yl)ethanamine (C9) and l-(5-chloro-2-isopropylphenyl)thiourea and was isolated as a white solid (144 mg, 39%). l-[(5-Chloro-2-isopropyl-phenyl)carbamothioyl]-3-[l-[l-[4-(trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-3- piperidyljurea (A24)
Figure imgf000044_0003
The title compound was synthesized from l-( 1 -(4-(trifluoromethoxy)phenyl)-l H-l ,2,4-triazol-3- yl)piperidin-3 -amine (C16) and l-(5-chloro-2-isopropylphenyl)thiourea and was isolated as a white solid (86 mg, 40%).
Example 41: Preparation of (Z)-l-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-(l-(l-(4- (trifhiorornethoxy)phenyl)-l/f-l,2,4-triazol-3-yl)piperidin-4-yl)ethyl)urea (Al)
Figure imgf000045_0001
To a 20 milliliter (mL) vial containing l-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[2-[l-[l-[4- (trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4-piperidyl]ethyl]urea (A2, 114 milligrams (mg), 0.193 millimoles (mmol)) was added sodium acetate (63.4 mg, 0.773 mmol), ethanol (2.0 mL) and methyl 2-bromoacetate (0.037 mL, 0.387 mmol). The vial was capped and the reaction mixture was stirred in a heating block that was warmed to 70 °C overnight. The reaction mixture was concentrated onto Celite®. Purification by silica gel flash chromatography (10 - 70% ethyl acetate in hexanes) afforded the title compound as a light yellow solid (88 mg, 71%).
The following compounds were synthesized in a manner similar to that provided in Example 41. (Z)-l-(3-(2-Isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(l-(l-(4-(trifluoromethoxy)phenyl)-17f- l,2,4-triazol-3-yl)piperidin-4-yl)urea (A4)
Figure imgf000045_0002
The title compound was synthesized from l-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[l-[l-[4- (trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4-piperidyl]urea (A3) and was isolated as a white solid (0.033 g, 65%).
(2)-l-(4-Oxo-3-(o-tolyl)thiazolidin-2-ylidene)-3-(2-(l-(l-(4-(trifluoromethoxy)phenyl)-lZf-l,2,4-triazol-3- yl)piperidin-4-yl)ethyl)urea (A13)
Figure imgf000045_0003
The title compound was synthesized from l-(o-tolylcarbamothioyl)-3-[2-[l-[l-[4- (trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4-piperidyl]ethyl]urea (A5) and was isolated as an off-white solid (82 mg, 81%).
( )-l-(3-(4-Methoxy-2-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-(l-(l-(4-(trifluoromethoxy)phenyl)-12/- l,2,4-triazol-3-yl)piperidin-4-yl)ethyl)urea (Al 4)
Figure imgf000046_0001
The title compound was synthesized from l-[(4-methoxy-2-methyl-phenyl)carbamothioyl]-3-[2-[l-[l-[4- (trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4-piperidyl]ethyl]urea (A6) and was isolated as an orange solid (104 mg, 74%).
(Z)-l-(3-(2-Ethylphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-(l-(l-(4-(trifluoromethoxy)phenyl)-17/-l,2,4-triazol- 3-yl)piperidin-4-yl)ethyl)urea (A15)
Figure imgf000046_0002
The title compound was synthesized from l-[(2-ethylphenyl)carbamothioyl]-3-[2-[l-[l-[4- (trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4-piperidyl]ethyl]urea (A7) and was isolated as a light yellow solid (79 mg, 72%).
(2)-l-(3-(2-Ethyl-6-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-(l-(l-(4-(trifluoromethoxy)phenyl)-l//- l,2,4-triazol-3-yl)piperidin-4-yl)ethyl)urea (Al 6)
Figure imgf000046_0003
The title compound was synthesized from l-[(2-ethyl-6-methyl-phenyl)caibamothioyl]-3-[2-[l-[l-[4- (trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4-piperidyl]ethyl]urea (A8) and was isolated as a white solid (9 mg, 45%).
(Z)-l-(3-(2-Isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-(l-(l-(4-(trifluoromethoxy)phenyl)-llf-l,2,4- triazol-3-yl)piperidin-4-yl)ethyl)urea (Al 7)
Figure imgf000046_0004
The title compound was synthesized from l-[(2-isopropylphenyl)carbamothioyl]-3-[2-[l-[l-[4- (trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4-piperidyl]ethyl]urea (A9) and was isolated as an off-white solid (33 mg, 70%). (2)-l-(3-(2-Isopropyl-4-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-(l-(l-(4-(trifluoromethoxy)phenyl)-
1//-1,2,4-triazol-3-yl)piperidiii-4-yl)ethyl)urea (A18)
Figure imgf000047_0001
The title compound was synthesized from l-[(2-isopropyl-4-methyl-phenyl)carbamothioyl]-3-[2-[l-[l-[4- (trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4-piperidyl]ethyl]urea (A10) and was isolated as a light yellow solid (105 mg, 77%).
(•Z)-l-(3-(4-Fhioro-2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-(l-(l-(4-(trifluoromethoxy)phenyl)- 12f-l,2,4-triazol-3-yl)piperidin-4-yl)ethyl)urea (A19)
Figure imgf000047_0002
The title compound was synthesized from l-[(4-fluoro-2-isopropyl-phenyl)caibamothioyl]-3-[2-[l-[l-[4- (trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4-piperidyl]ethyl]urea (All) and was isolated as a light yellow solid (90 mg, 77%).
(Z)-l-(3-(5-Chloro-2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-(l-(l-(4-(trifluoromethoxy)phenyl)- Hf-l,2,4-triazol-3-yl)piperidin-4-yl)ethyl)urea (A20)
Figure imgf000047_0003
The title compound was synthesized from l-[(5-chloro-2-isopropyl-phenyl)carbamothioyl]-3-[2-[l-[l-[4- (trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-4-piperidyl]ethyl]urea (A12) and was isolated as a light orange solid (83 mg, 66%).
(Z)-l-(3-(5-Chloro-2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(l-(l-(4-(trifluoromethoxy)phenyl)-llf- l,2,4-triazol-3-yl)piperidin-3-yl)urea (A25)
Figure imgf000048_0001
The title compound was synthesized from l-[(5-chloro-2-isopropyl-phenyl)carbamothioyl]-3-[l-[l-[4- (trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]-3-piperidyl]urea (A24) and was isolated as an off-white solid (38 mg, 47%).
(Z)-l-(3-(2-Isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(l-(4-(trifluoromethoxy)phenyl)-l/7- l,2,4-triazol-3-yl)cyclohex-3-en-l-yl)urea (B2)
Figure imgf000048_0002
The title compound was synthesized from l-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[4-[l-[4- (trifluoromethoxy)phenyl]-l,2,4-triazol-3-yl]cyclohex-3-en-l-yl]urea (Bl) and was isolated as a white solid (0.094 g, 63%) after ethyl acetate-water workup and drying at 50 °C at ~25 mm Hg.
Example 42: Preparation of (2)-l-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(l-(l-(4- (perfluoroethoxy)phenyl)-lf/-l,2,4-triazol-3-yl)piperidin-4-yl)urea (A21)
Figure imgf000048_0003
To l-(l-(4-(perfluoroethoxy)phenyl)-lff-l,2,4-triazol-3-yl)piperidin-4-amine (C25, 80 mg, 0.212 mmol) in acetonitrile (2.12 mL) was added (Z)-4-nitrophenyl (3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2- ylidene)carbamate (88 mg, 0.212 mmol). Cesium carbonate (69.1 mg, 0.212 mmol) was added, and the reaction mixture was allowed to stir at room temperature. The mixture was diluted with dichloromethane and concentrated onto silica gel. Purification via silica gel flash chromatography (ethyl acetate-hexanes:dichloromethane 1:1) yielded the title compound as an off-white solid (68 mg, 49%).
The following compounds were synthesized in a manner similar to that provided in Example 42. (Z)-l-(3-(2-Isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(l-(l-(4-(trifluoromethoxy)phenyl)-lJ7- l,2,4-triazol-3-yl)piperidin-3-yl)urea (A22)
Figure imgf000049_0001
The title compound was synthesized from l-(l-(4-(trifluoromethoxy)phenyl)-177-l,2,4-triazol-3- yl)piperidin-3 -amine (C16) and (Z)-4-nitrophenyl (3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2- ylidene)carbamate and was isolated as a pale red foam (41 mg, 44%). (Z)-l-(3-(2-Isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-(4-(l-(4-(trifluoromethoxy)phenyl)-
1//-l,2,4-triazol-3-yl)piperazin-l-yl)ethyl)urea (A23)
Figure imgf000049_0002
The title compound was synthesized from 2-(4-(l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3- yl)piperazin-l-yl)ethan-l -amine (C24) and (Z)-4-nitrophenyl (3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2- ylidene)carbamate and was isolated as a yellow foam (65 mg, 73%).
(Z)-l-(3-(2-Isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-(4-(l-(4-(trifluoromethoxy)phenyl)-
1//-1,2,4-triazol-3-yl)-3,6-dihydropyridin-l(2//)-yl)ethyl)urea (A30)
Figure imgf000049_0003
The title compound was synthesized from 2-(4-(l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3-yl)-3,6- dihydropyridin- 1 (2//)-y I )elhan- 1 -amine (C26) and (Z) -4 -nitrophenyl (3 -(2-isopropyl-5-methylphenyl)-4- oxothiazolidin-2-ylidene)carbamate and was isolated as a yellow foam (20 mg, 19%).
Example 43: Preparation of (Z)-l-(2-fluoro-2-(l-(l-(4-(trifluoromethoxy)phenyl)-1//-1,2,4-triazol-3- yl)piperidin-4-yl)ethyl)-3-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)urea (A27)
Figure imgf000050_0001
To 2-fluoro-2-(l-(l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazol-3-yl)piperidin-4-yl)ethan-l-amine hydrochloride(C18, 30 mg, 0.073 mmol) and bis(2,5-dioxopyrrolidin-l-yl) carbonate (21 mg, 0.081 mmol) in acetonitrile (0.5 mL) was added pyridine (0.01 mL, 0.15 mmol). The reaction mixture was stirred at room temperature. After 30 minutes, the acetonitrile was concentrated under stream of nitrogen, and the residue was dissolved in dichloromethane (0.3 mL). 2-Imino-3-(2-isopropyl-5-methylphenyl)thiazolidin-4-one (20 mg, 0.081 mmol) and sodium bicarbonate (62 mg, 0.73 mmol) were added, followed by water (0.1 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and dichloromethane and filtered through a phase separator directly onto a Celite® cartridge. Purification by flash chromatography (0 - 100% ethyl acetate in hexanes) afforded the title compound as a yellow foam (32 mg, 64%).
The following compounds were synthesized in a manner similar to that provided in Example 43.
(Z)-l-(2-Fluoro-2-(l-(l-(4-(trifluoromethoxy)phenyl)-l//-l,2,4-triazol-3-yl)piperidin-4-yl)ethyl)-3-(3-(5- methyl-2-(2,2,2-trifluoroethoxy)phenyl)-4-oxothiazolidin-2-ylidene)urea (A28)
Figure imgf000050_0002
The title compound was synthesized from 2-fluoro-2-( l-( 1 -(4-(trifluoroincthoxy)phenyl)-l//-l ,2,4-triazol- 3-yl)piperidin-4-yl)ethan-l-amine hydrochloride (C18) and 2-imino-3-(5-methyl-2 -(2,2,2- trifluoroethoxy)phenyl)thiazolidin-4-one and was isolated as a yellow oil (20 mg, 32%).
(2)-l-(3-(5-Methyl-2-(3,3,3-trifluoropropoxy)phenyl)-4-oxothiazolidin-2-ylidene)-3-(2-(4-(l-(4-
(trifluorometlioxy)plienyl)-l//-l,2,4-ti iazol-3-yl)piperazin-l-yl)etliyl)urea (A29)
Figure imgf000050_0003
The title compound was synthesized from 2-(4-( 1 -(4-(trifluoromethoxy)phenyl)-l H-l ,2,4-triazol-3- y l)piperazin- 1 -y l)ethan- 1 -amine (C24) and JV-(5 -methy 1-2 -(3 ,3 , 3 -trifluoropropoxy )pheny l)-2-thiocy anatoacetamide (C49) and was isolated as a clear oil (24 mg, 22%). (2)-l-(2-Fluoro-2-(4-(l-(4-(trifluoromethoxy)phenyl)-lJ/-l,2,4-triazol-3-yl)cyclohexyl)ethyl)-3-(3-(2-isopropyl-
5-methylphenyl)-4-oxothiazolidin-2-ylidene)urea (B3)
Figure imgf000051_0001
The title compound was synthesized from 2-fluoro-2-(4-(l-(4-(trifluoromethoxy)phenyl)-177-l,2,4-triazol- 3-yl)cyclohexyl)ethan-l-amine (C43) and 2-imino-3-(2-isopropyl-5-methylphenyl)thiazolidin-4-one and was isolated as a clear oil (20 mg, 43%).
(Z)-l-(2-Fluoro-2-(4-(l-(4-(trifluoromethoxy)phenyl)-l//-l,2,4-triazol-3-yl)cyclohex-3-en-l-yl)ethyl)-3-(3-(2- isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)urea (B4)
Figure imgf000051_0002
The title compound was synthesized from 2-fluoro-2-(4-(l-(4-(trifluoromethoxy)phenyl)-l//-l,2,4-triazol- 3 -yl)cyclo hex-3 -en-l-yl)ethan-l -amine (C42) and 2-imino-3-(2-isopropyl-5-methylphenyl)thiazolidin-4-one and was isolated as a pale yellow oil (35 mg, 62%).
(2)-l-(2-Fluoro-2-(4-(l-(4-(trifluoromethoxy)phenyl)-lJ/-l,2,4-triazol-3-yl)cyclohexyl)ethyl)-3-(3-(5-methyl-2- (3,3,3-trifluoropropoxy)phenyl)-4-oxothiazolidin-2-ylidene)urea (B5 and B6)
Figure imgf000051_0003
The title compound was synthesized from 2-fluoro-2-(4-( I -(4-(trifluoromctho.\y)phcnyl)-l//-l ,2.4-triazol- 3-yl)cyclohexyl)ethan-l-amine (C43) and jV-(5-methyl-2-(3,3,3-trifluoropropoxy)phenyl)-2-thiocyanatoacetamide (C49) and was isolated as a single diastereomer (B5) as a white foam (38 mg) and as a mixture of diastereomers (B6) as a clear oil (172 mg). Total yield (210 mg, 37%).
(2)-l-(3-(2-Isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(l-(4-(l-(4-(trifluoromethoxy)phenyl)- 1//-1,2,4-triazol-3-vl)-3,6-dihvdropyridin-l(2/f)-yl)propan-2-yl)urea (A31)
Figure imgf000052_0001
The title compound was synthesized from l-(4-(l-(4-(trifluoromethoxy)phenyl)-lW-l,2,4-triazol-3-yl)-3,6- dihydropyridin-l (2//)-yl)propan-2-aminc (C22) and 2-imino-3-(2-isopropyl-5-methylphenyl)thiazolidin-4-one and was isolated as a yellow oil (5 mg, 17%).
Example 44: Preparation of l-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[4-[l-[4- (trifhioromethoxy)phenyl]-l,2,4-triazol-3-yl]cyclohex-3-en-l-yl]urea (Bl)
Figure imgf000052_0002
The title compound was prepared from 4-(l-(4-(trifluoromethoxy)phenyl)-lW-l,2,4-triazol-3-yl)cyclohex- 3 -ene-1 -carbonyl azide (C47) by methods disclosed herein and known in the art and was isolated as a white solid (0.189 g).
Example 45: Bioassays
The compounds in Table 1 A and Table IB were tested against various pests.
The following bioassays against beet armyworm (Spodoptera exigua), cabbage looper (Trichoplusia nt), and yellow fever mosquito (Aedes aegypti), are included herein due to the damage they inflict. Furthermore, the beet armyworm and cabbage looper are two good indicator species for a broad range of chewing pests. The results show the broad usefulness of the compounds of Formula One and Formula Two in controlling pests in Phyla Arthropoda, Mollusca, and Nematoda (Drewes et al., High-Throughput Screening in Agrochemical Research, Modern Methods in Crop Protection Research, Part I, Methods for the Design and Optimization of New Active Ingredients, Edited by Jeschke, P., Kramer, W., Schirmer, U., and Matthias W., p. 1-20, 2012).
Insecticidal test for beet armyworm (Spodoptera exigua, LAPHEG, “BAW”)
Beet army worm is a serious pest of economic concern for alfalfa, asparagus, beets, citrus, com, cotton, onions, peas, peppers, potatoes, soybeans, sugar beets, sunflowers, tobacco, and tomatoes, among other crops. It is native to Southeast Asia but is now found in Africa, Australia, Japan, North America, and Southern Europe. The larvae may feed in large swarms causing devastating crop losses. It is known to be resistant to several pesticides.
Bioassays on beet armyworm (BAW; Spodoptera exigua: Lepidoptera) were conducted using a 128-well diet tray assay. One to five second instar BAW larvae were placed in each well (3 mL) of the diet tray that had been previously filled with 1 mL of artificial diet to which 50 pg/cm2 of the test compound (dissolved in 50 pl. of 90:10 acetone-water mixture) had been applied (to each of eight wells) and then allowed to dry. Trays were covered with a clear self-adhesive cover, vented to allow gas exchange, and held at 25 °C, 14:10 hght-dark for five to seven days. Percent mortality was recorded for the larvae in each well; activity in the eight wells was then averaged.
Insecticidal test for cabbage looper (Trichlophisia ni, TRIPNI, “CL”)
Cabbage looper is a serious pest found throughout the world. It attacks alfalfa, beans, beets, broccoli, Brussel sprouts, cabbage, cantaloupe, cauliflower, celery, collards, cotton, cucumbers, eggplant, kale, lettuce, melons, mustard, parsley, peas, peppers, potatoes, soybeans, spinach, squash, tomatoes, turnips, and watermelons, among other crops. This species is very destructive to plants due to its voracious appetite. The larvae consume three times their weight in food daily. The feeding sites are marked by large accumulations of sticky, wet, fecal material, which may contribute to higher disease pressure thereby causing secondary problems on the plants in the site. It is known to be resistant to several pesticides.
Bioassays on cabbage looper (CL; Trichloplusia ni: Lepidoptera) were conducted using a 128-well diet tray assay. One to five second instar CL larvae were placed in each well (3 mL) of the diet tray that had been previously filled with 1 mL of artificial diet to which 50 pg/cm2 of the test compound (dissolved in 50 pL of 90: 10 acetonewater mixture) had been applied (to each of eight wells) and then allowed to dry. Trays were covered with a clear self-adhesive cover, vented to allow gas exchange, and held at 25 °C, 14:10 light-dark for five to seven days. Percent mortality was recorded for the larvae in each well; activity in the eight wells is then averaged.
Consequently, because of the above factors control of these pests is important. Furthermore, molecules that control these pests (B AW and CL), which are known as chewing pests, will be useful in controlling other pests that chew on plants. In the reporting of the results, the “BAW & CL Rating Table” was used (See Table Section).
Insecticidal test for green peach aphid (Myzus persicae, MYZUPE) (“GPA”)
GPA is the most significant aphid pest of peach trees, causing decreased growth, shriveling of the leaves, and the death of various tissues. It is also hazardous because it acts as a vector for the transport of plant viruses, such as potato virus Y and potato leafroll virus to members of the nightshade/potato family Solanaceae, and various mosaic viruses to many other food crops. GPA attacks such plants as broccoli, burdock, cabbage, carrot, cauliflower, daikon, eggplant, green beans, lettuce, macadamia, papaya, peppers, sweet potatoes, tomatoes, watercress, and zucchini, among other crops. GPA also attacks many ornamental crops such as carnation, chrysanthemum, flowering white cabbage, poinsettia, and roses. GPA has developed resistance to many pesticides. Currently, it is a pest that has the third largest number of reported cases of insect resistance (Sparks et aL). Consequently, because of the above factors control of this pest is important. Furthermore, molecules that control this pest (GPA), which is known as a sap-feeding pest, are useful in controlling other pests that feed on the sap from plants.
Certain molecules disclosed in this document were tested against GPA using procedures described in the following example. In the reporting of the results, the “GPA & YFM Rating Table” was used (See Table Section).
Cabbage seedlings grown in 3-inch pots, with 2-3 small (3-5 cm) hue leaves, were used as test substrate. The seedlings were infested with 20-50 GPA (wingless adult and nymph stages) one day prior to chemical application. Four pots with individual seedlings were used for each treatment. Test molecules (2 mg) were dissolved in 2 mL of acetone/methanol (1:1) solvent, forming stock soludons of 1000 ppm test molecule. The stock solutions were diluted 5X with 0.025% Tween 20 in water to obtain the solution at 200 ppm test molecule. A hand-held aspirator-type sprayer was used for spraying a solution to both sides of cabbage leaves until runoff. Reference plants (solvent check) were sprayed with the diluent only containing 20% by volume of aceto ne/methanol (1:1) solvent. Treated plants were held in a holding room for three days at approximately 25 °C and ambient relative humidity (RH) prior to grading. Evaluation was conducted by counting the number of live aphids per plant under a microscope. Percent control was measured using Abbott’s correction formula (W. S. Abbott, “A Method of Computing the Effectiveness of an Insecticide” J. Econ. Entomol. 18 (1925), pp.265-267) as follows. Corrected % Control = 100 * (X - Y) / X where X = No. of live aphids on solvent check plants and Y = No. of live aphids on treated plants. The results are indicated in the table entitled “Table ABC: Biological Results” (See Table Section).
Insecticidal test for yellow fever mosquito (Aedes aegypti, AEDSAE) (“YEM”)
YFM prefers to feed on humans during the daytime and is most frequently found in or near human habitations. YFM is a vector for transmitting several diseases. It is a mosquito that can spread the dengue fever and yellow fever viruses. Yellow fever is the second most dangerous mosquito-borne disease after malaria. Yellow fever is an acute viral hemorrhagic disease and up to 50% of severely affected persons without treatment will die from yellow fever. There are an estimated 200,000 cases of yellow fever, causing 30,000 deaths worldwide each year. Dengue fever is a nasty, viral disease; it is sometimes called "breakbone fever" or "break-heart fever" because of the intense pain it can produce. Dengue fever kills about 20,000 people annually.
Master plates containing 400 pg of a compound dissolved in 100 pL of dimethyl sulfoxide (DMSO) (equivalent to a 4000 ppm solution) were used. A master plate of assembled compounds contained 15 pL per well. To this plate, 135 pL of a 90:10 water/acetone mixture was added to each well. A robot (Biomek® NXP Laboratory Automation Workstation) was programmed to dispense 15 pL aspirations from the master plate into an empty 96- well shallow plate (“daughter” plate). There were 6 reps (“daughter” plates) created per master. The created “daughter” plates were then immediately infested with YFM larvae.
The day before plates were to be treated, mosquito eggs were placed in Millipore water containing liver powder to begin hatching (4 g into 400 mL). After the “daughter” plates were created using the robot, they were infested with 220 pL of the liver powder/larval mosquito mixture (about 1 day-old larvae). After plates were infested with mosquito larvae, a non-evaporative lid was used to cover the plate to reduce drying. Plates were held at room temperature for 3 days prior to grading. After 3 days, each well was observed and scored based on mortality.
Consequently, because of the above factors control of this pest is important. Furthermore, molecules that control this pest (YFM), which is known as a sucking pest, are useful in controlling other pests that cause human and non-human animal suffering. In the reporting of the results, the “GPA & YFM Rating Table” was used (See Table Section).
Acid and Salt Derivatives and Solvates
The compounds disclosed herein can be in the form of pesticidally acceptable acid addition salts. By way of non-limiting example, an amine function can form salts with hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, benzoic, citric, malonic, salicylic, malic, fumaric, oxalic, succinic, tartaric, lactic, gluconic, ascorbic, maleic, aspartic, benzenesulfonic, methanesulfonic, ethanesulfonic, hydroxymethanesulfonic, and hydroxyethanesulfonic acids.
Additionally, by way of non-limiting example, an acid function can form salts including those derived from alkali or alkaline earth metals and those derived from ammonia and amines. Examples of preferred cations include sodium, potassium, magnesium, and aminium cations.
The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia, and sodium bicarbonate. As an example, in many cases, a pesticide is modified to a more water soluble form e g., 2,4-dichlorophenoxy acetic acid dimethyl amine salt is a more water soluble form of 2,4-dichlorophenoxy acetic acid, a well-known herbicide.
The compounds disclosed herein can also form stable complexes with solvent molecules that remain intact after the non-complexed solvent molecules are removed from the compounds. These complexes are often referred to as "solvates.” Stereoisomers
Certain compounds disclosed in this document can exist as one or more stereoisomers. The various stereoisomers include geometric isomers, diastereomers, and enantiomers. Thus, the compounds disclosed herein include racemic mixtures, individual stereoisomers, and optically active mixtures. It will be appreciated by those skilled in the art that one stereoisomer may be more active than the others. Individual stereoisomers and optically active mixtures may be obtained by selective synthetic procedures, by conventional synthetic procedures using resolved starting materials, or by conventional resolution procedures.
Formulations
A pesticide is rarely suitable for application in its pure form. It is usually necessary to add other substances so that the pesticide can be used at the required concentration and in an appropriate form, permitting ease of application, handling, transportation, storage, and maximum pesticide activity. Thus, pesticides are formulated into, for example, baits, concentrated emulsions, dusts, emulsifiable concentrates, iumigants, gels, granules, microencapsulations, seed treatments, suspension concentrates, suspoemulsions, tablets, water soluble liquids, water dispersible granules or dry flowables, wettable powders, and ultra-low volume solutions.
Pesticides are applied most often as aqueous suspensions or emulsions prepared from concentrated formulations of such pesticides. Such water-soluble, water-suspendable, or emulsifiable formulations, are either solids, usually known as wettable powders, or water dispersible granules, or liquids usually known as emulsifiable concentrates, or aqueous suspensions. Wettable powders, which may be compacted to form water dispersible granules, comprise an intimate mixture of the pesticide, a carrier, and surfactants. The concentration of the pesticide is usually from about 10% to about 90% by weight. The carrier is usually chosen from among the attapulgite clays, the montmorillonite clays, the diatomaceous earths, or the purified silicates. Effective surfactants, comprising from about 0.5% to about 10% of the wettable powder, are found among sulfonated lignins, condensed naphthalenesulfonates, naphthalenesulfonates, alkylbenzenesulfonates, alkyl sulfates, and nonionic surfactants such as ethylene oxide adducts of alkyl phenols. Emulsifiable concentrates of pesticides comprise a convenient concentration of a pesticide, such as from about 50 to about 500 grams per liter of liquid dissolved in a carrier that is either a water miscible solvent or a mixture of water-immiscible organic solvent and emulsifiers. Useful organic solvents include aromatics, especially xylenes and petroleum fractions, especially the high-boiling naphthalenic and olefinic portions of petroleum such as heavy aromatic naphtha. Other organic solvents may also be used, such as the terpenic solvents including rosin derivatives, aliphatic ketones such as cyclohexanone, and complex alcohols such as 2-ethoxyethanol. Suitable emulsifiers for emulsifiable concentrates are chosen from conventional anionic and nonionic surfactants.
Aqueous suspensions comprise suspensions of water-insoluble pesticides dispersed in an aqueous carrier at a concentration in the range from about 5% to about 50% by weight. Suspensions are prepared by finely grinding the pesticide and vigorously mixing it into a carrier comprised of water and surfactants. Ingredients, such as inorganic salts and synthetic or natural gums, may also be added, to increase the density and viscosity of the aqueous carrier. It is often most effective to grind and mix the pesticide 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.
Pesticides may also be applied as granular compositions that are particularly useful for applications to the soil. Granular compositions usually contain from about 0.5% to about 10% by weight of the pesticide, dispersed in a carrier that comprises clay or a similar substance. Such compositions are usually prepared by dissolving the pesticide in a suitable solvent and applying it to a granular carrier which has been pre-formed to the appropriate particle size, in the range of from about 0.5 to about 3 mm. Such compositions may also be formulated by making a dough or paste of the carrier and compound and crashing and drying to obtain the desired granular particle size.
Dusts containing a pesticide are prepared by intimately mixing the pesticide in powdered form with a suitable dusty agricultural carrier, such as kaolin clay, ground volcanic rock, and the like. Dusts can suitably contain from about 1% to about 10% of the pesticide. They can be applied as a seed dressing or as a foliage application with a dust blower machine.
It is equally practical to apply a pesticide in the form of a solution in an appropriate organic solvent, usually petroleum oil, such as the spray oils, which are widely used in agricultural chemistry.
Pesticides can also be applied in the form of an aerosol composition. In such compositions the pesticide is dissolved or dispersed in a carrier, which is a pressure-generating propellant mixture. The aerosol composition is packaged in a container from which the mixture is dispensed through an atomizing valve.
Pesticide baits are formed when the pesticide is mixed with food or an attractant or both. When the pests eat the bait, they also consume the pesticide. Baits may take the form of granules, gels, flowable powders, liquids, or solids. They are used in pest harborages.
Fumigants are pesticides that have a relatively high vapor pressure and hence can exist as a gas in sufficient concentrations to kill pests in soil or enclosed spaces. The toxicity of the fumigant is proportional to its concentration and the exposure time. They are characterized by a good capacity for diffusion and act by penetrating the pest’s respiratoiy system or being absorbed through the pest’s cuticle. Fumigants are applied to control stored product pests under gas proof sheets, in gas sealed rooms or buildings or in special chambers. Pesticides can be microencapsulated by suspending the pesticide particles or droplets in plastic polymers of various types. By altering the chemistry of the polymer or by changing factors in the processing, microcapsules can be formed of various sizes, solubility, wall thicknesses, and degrees of penetrability. These factors govern the speed with which the active ingredient within is released, which in turn, affects the residual performance, speed of action, and odor of the product.
Oil solution concentrates are made by dissolving pesticide in a solvent that will hold the pesticide in solution. Oil solutions of a pesticide usually provide faster knockdown and kill of pests than other formulations due to the solvents themselves having pesticidal action and the dissolution of the waxy covering of the integument increasing the speed of uptake of the pesticide. Other advantages of oil solutions include better storage stability, better penetration of crevices, and better adhesion to greasy surfaces.
Another embodiment is an oil-in-water emulsion, wherein the emulsion comprises oily globules which are each provided with a lamellar liquid crystal coating and are dispersed in an aqueous phase, wherein each oily globule comprises at least one compound which is agriculturally active, and is individually coated with a monolameliar or oligolamellar layer comprising: (1) at least one nonionic lipophilic surface-active agent, (2) at least one nonionic hydrophilic surface-active agent and (3) at least one ionic surface-active agent, wherein the globules having a mean particle diameter of less than 800 nanometers. Further information on the embodiment is disclosed in U.S. patent publication 20070027034 published February 1, 2007, having Patent Application serial number 11/495,228. For ease of use this embodiment will be referred to as “OIWE”.
Other Formulation Components
Generally, the compounds disclosed herein when used in a formulation, such formulation can also contain other components. These components include, but are not limited to, (this is a non-exhaustive and non-mutually exclusive list) wetters, spreaders, stickers, penetrants, buffers, sequestering agents, drift reduction agents, compatibility agents, anti-foam agents, cleaning agents, and emulsifiers. A few components are described forthwith.
A wetting agent is a substance that when added to a liquid increases the spreading or penetration power of the liquid by reducing the interfacial tension between the liquid and the surface on which it is spreading. Wetting agents are used for two main lunctions in agrochemical formulations: during processing and manufacture to increase the rate of wetting of powders in water to make concentrates for soluble liquids or suspension concentrates; and during mixing of a product with water in a spray tank to reduce the wetting time of wettable powders and to improve the penetration of water into water-dispersible granules. Examples of wetting agents used in wettable powder, suspension concentrate, and water-dispersible granule formulations are: sodium lauiyl sulfate; sodium dioctyl sulfosuccinate; alkyl phenol ethoxylates; and aliphatic alcohol ethoxylates.
A dispersing agent is a substance which adsorbs onto the surface of a particles and helps to preserve the state of dispersion of the particles and prevents them from reaggregating. Dispersing agents are added to agrochemical formulations to facilitate dispersion and suspension during manufacture, and to ensure the particles redisperse into water in a spray tank. They are widely used in wettable powders, suspension concentrates and water- dispersible granules. Surfactants that are used as dispersing agents have the ability to adsorb strongly onto a particle surface and provide a charged or steric barrier to reaggregation of particles. The most commonly used surfactants are anionic, nonionic, or mixtures of the two types. For wettable powder formulations, the most common dispersing agents are sodium lignosulfonates. For suspension concentrates, very good adsorption and stabilization are obtained using polyelectrolytes, such as sodium naphthalene sulfonate formaldehyde condensates. Tristyrylphenol ethoxylate phosphate esters are also used. Nonionics such as alkylarylethylene oxide condensates and EO-PO block copolymers are sometimes combined with anionics as dispersing agents for suspension concentrates. In recent years, new types of veiy high molecular weight polymeric surfactants have been developed as dispersing agents. These have very long hydrophobic ‘backbones’ and a large number of ethylene oxide chains forming the ‘teeth’ of a ‘comb’ surfactant. These high molecular weight polymers can give very good long-term stability to suspension concentrates because the hydrophobic backbones have many anchoring points onto the particle surfaces. Examples of dispersing agents used in agrochemical formulations are: sodium lignosulfonates; sodium naphthalene sulfonate formaldehyde condensates; tristyrylphenol ethoxylate phosphate esters; aliphatic alcohol ethoxylates; alkyl ethoxylates; EO-PO block copolymers; and graft copolymers.
An emulsifying agent is a substance which stabilizes a suspension of droplets of one liquid phase in another liquid phase. Without the emulsifying agent the two liquids would separate into two immiscible liquid phases. The most commonly used emulsifier blends contain alkylphenol or aliphatic alcohol with twelve or more ethylene oxide units and the oil-soluble calcium salt of dodecylbenzenesulfonic acid. A range of hydrophile-lipophile balance (“HLB”) values from 8 to 18 will normally provide good stable emulsions. Emulsion stability can sometimes be improved by the addition of a small amount of an EO-PO block copolymer surfactant.
A solubilizing agent is a surfactant which will form micelles in water at concentrations above the critical micelle concentration. The micelles are then able to dissolve or solubilize water-insoluble materials inside the hydrophobic part of the micelle. The type of surfactants usually used for solubilization are nonionics: sorbitan monooleates; sorbitan monooleate ethoxylates; and methyl oleate esters.
Surfactants are sometimes used, either alone or with other additives such as mineral or vegetable oils as adjuvants to spray -tank mixes to improve the biological performance of the pesticide on the target. The types of surfactants used for bioenhancement depend generally on the nature and mode of action of the pesticide. However, they are often nonionics such as: alkyl ethoxylates; linear aliphatic alcohol ethoxylates; aliphatic amine ethoxylates.
A carrier or diluent in an agricultural formulation is a material added to the pesticide to give a product of the required strength. Carriers are usually materials with high absorptive capacities, while diluents are usually materials with low absorptive capacities. Carriers and diluents are used in the formulation of dusts, wettable powders, granules, and water-dispersible granules.
Organic solvents are used mainly in the formulation of emulsifiable concentrates, ULV (ultra-low volume) formulations, and to a lesser extent granular formulations. Sometimes mixtures of solvents are used. The first main groups of solvents are aliphatic paraffinic oils such as kerosene or refined paraffins. The second main group and the most common comprises the aromatic solvents such as xylene and higher molecular weight fractions of C9 and CIO aromatic solvents. Chlorinated hydrocarbons are useful as cosolvents to prevent ciystallization of pesticides when the formulation is emulsified into water. Alcohols are sometimes used as cosolvents to increase solvent power. Thickeners or gelling agents are used mainly in the formulation of suspension concentrates, emulsions and suspoemulsions to modify the rheology or flow properties of the liquid and to prevent separation and settling of the dispersed particles or droplets. Thickening, gelling, and anti-settling agents generally fall into two categories, namely water-insoluble particulates, and water-soluble polymers. It is possible to produce suspension concentrate formulations using clays and silicas. Examples of these types of materials, include, but are limited to, montmorillonite, e g., bentonite; magnesium aluminum silicate; and attapulgite. Water-soluble polysaccharides have been used as thickening-gelling agents for many years. The types of polysaccharides most commonly used are natural extracts of seeds and seaweeds or are synthetic derivatives of cellulose. Examples of these types of materials include, but are not limited to, guar gum; locust bean gum; carrageenam; alginates; methyl cellulose; sodium carboxymethyl cellulose (SCMC); hydroxyethyl cellulose (HEC). Other types of anti-settling agents are based on modified starches, polyacrylates, polyvinyl alcohol and polyethylene oxide. Another good anti-settling agent is xanthan gum.
Microorganisms cause spoilage of formulated products. Therefore, preservation agents are used to eliminate or reduce their effect. Examples of such agents include, but are not limited to: propionic acid and its sodium salt; sorbic acid and its sodium or potassium salts; benzoic acid and its sodium salt; p-hydroxybcnzoic acid sodium salt; methyl p-hydroxybenzoate: and l,2-benzisothiazalin-3-one (BIT).
The presence of surfactants, which lower interfacial tension, often causes water-based formulations to foam during mixing operations in production and in application through a spray tank. In order to reduce the tendency to foam, anti-foam agents are often added either during the production stage or before filling into bottles. Generally, there are two types of anti-foam agents, namely silicones and non-silicones. Silicones are usually aqueous emulsions of dimethyl polysiloxane while the non-silicone anti-foam agents are water-insoluble oils, such as octanol and nonanol, or silica. In both cases, the function of the anti-foam agent is to displace the surfactant from the air-water interface.
“Green” agents (e g., adjuvants, surfactants, solvents) can reduce the overall environmental footprint of crop protection formulations. Green agents are biodegradable and generally derived from natural and/or sustainable sources, e.g., plant and animal sources. Specific examples are vegetable oils, seed oils, and esters thereof, also alkoxylated alkyl poly glucosides.
For further information, see “Chemistry and Technology of Agrochemical Formulations” edited by D. A. Knowles, copyright 1998 by Kluwer Academic Publishers. Also see “Insecticides in Agriculture and Environment - Retrospects and Prospects” by A.S. Perry, I. Yamamoto, I. Ishaaya, and R. Perry, copyright 1998 by Springer- Verlag.
Pests
In another embodiment, the compounds disclosed herein can be used to control pests.
In another embodiment, the compounds disclosed herein can be used to control pests of the Phylum Nematoda.
In another embodiment, the compounds disclosed herein can be used to control pests of the Phylum Arthropoda. In another embodiment, the compounds disclosed herein can be used to control pests of the Subphylum Chelicerata.
In another embodiment, the compounds disclosed herein can be used to control pests of the Class Arachnida.
In another embodiment, the compounds disclosed herein can be used to control pests of the Subphylum Myriapoda.
In another embodiment, the compounds disclosed herein can be used to control pests of the Class Symphyla.
In another embodiment, the compounds disclosed herein can be used to control pests of the Subphylum Hexapoda.
In another embodiment, the compounds disclosed herein can be used to control pests of the Class Insecta.
In another embodiment, the compounds disclosed herein can be used to control Coleoptera (beetles).
In another embodiment, the compounds disclosed herein can be used to control Dermaptera (earwigs).
In another embodiment, the compounds disclosed herein can be used to control Dictyoptera (cockroaches).
In another embodiment, the compounds disclosed herein can be used to control Diptera (true flies).
In another embodiment, the compounds disclosed herein can be used to control Hemiptera (true bugs).
In another embodiment, the compounds disclosed herein can be used to control Homoptera (aphids, scales, whiteflies, leafhoppers).
In another embodiment, the compounds disclosed herein can be used to control Hymenoptera (ants and wasps).
In another embodiment, the compounds disclosed herein can be used to control Isoptera (termites).
In another embodiment, the compounds disclosed herein can be used to control Lepidoptera (moths and butterflies).
In another embodiment, the compounds disclosed herein can be used to control Mallophaga (chewing lice).
In another embodiment, the compounds disclosed herein can be used to control Orthoptera (grasshoppers, locusts, and crickets).
In another embodiment, the compounds disclosed herein can be used to control Phthiraptera (sucking lice).
In another embodiment, the compounds disclosed herein can be used to control Siphonaptera (fleas).
In another embodiment, the compounds disclosed herein can be used to control Thysanoptera (thrips).
In another embodiment, the compounds disclosed herein can be used to control Thysanura (bristletails).
In another embodiment, the compounds disclosed herein can be used to control Acarina (mites and ticks).
In another embodiment, the compounds disclosed herein can be used to control Nematoda (nematodes).
In another embodiment, the compounds disclosed herein can be used to control Symphyla (symphylans).
Applications
Controlling pests of Phyla Nematoda, Arthropoda, and/or Mollusca generally means that pest populations, pest activity, or both, are reduced in a locus. This can come about when:
(a) pest populations are repulsed from a locus; (b) pests are incapacitated in, or around, a locus; or
(c) pests are exterminated in, or around, a locus.
Of course, a combination of these results can occur. Generally, pest populations, activity, or both are desirably reduced more than fifty percent, preferably more than 90 percent, and most preferably more than 98 percent. Generally, the locus is not in, or on, a human; consequently, the locus is generally a non-human locus.
In another embodiment, the locus to which a molecule of Formula One is applied can be any locus that is inhabited, or that may become inhabited, or that may be traversed, by a pest of Phyla Nematoda, Arthropoda, and/or Mollusca. For example, the locus can be:
(a) where crops, trees, fruits, cereals, fodder species, vines, turf, and/or ornamental plants, are growing;
(b) where domesticated animals are residing;
(c) the interior or exterior surfaces of buildings (such as places where grains are stored);
(d) the materials of construction used in buildings (such as impregnated wood); and
(e) the soil around buildings.
Particular crop areas to use a molecule of Formula One include areas where apples, com, sunflowers, cotton, soybeans, canola, wheat, rice, sorghum, barley, oats, potatoes, oranges, alfalfa, lettuce, strawberries, tomatoes, peppers, crucifers, pears, tobacco, almonds, sugar beets, beans and other valuable crops are growing or the seeds thereof are going to be planted. It is also advantageous to use ammonium sulfate with a molecule of Formula One when growing various plants.
The actual amount of pesticide to be applied to loci of pests is generally not critical and can readily be determined by those skilled in the art. In general, concentrations from about 0.01 grams of pesticide per hectare to about 5000 grams of pesticide per hectare are expected to provide good control.
The locus to which a pesticide is applied can be any locus inhabited by an pest, for example, vegetable crops, fruit and nut trees, grape vines, ornamental plants, domesticated animals, the interior or exterior surfaces of buildings, and the soil around buildings. Controlling pests generally means that pest populations, activity, or both, are reduced in a locus. This can come about when: pest populations are repulsed from a locus; when pests are incapacitated in or around a locus; or pests are exterminated, in whole or in part, in or around a locus. Of course, a combination of these results can occur. Generally, pest populations, activity, or both are desirably reduced more than fifty percent, preferably more than 90 percent.
Generally, with baits, the baits are placed in the ground where, for example, termites can come into contact with the bait. Baits can also be applied to a surface of a building, (horizontal, vertical, or slant surface) where, for example, ants, termites, cockroaches, and flies, can come into contact with the bait.
Because of the unique ability of the eggs of some pests to resist pesticides repeated applications may be desirable to control newly emerged larvae.
Systemic movement of pesticides in plants may be utilized to control pests on one portion of the plant by applying the pesticides to a different portion of the plant. For example, control of foliar-feeding insects can be controlled by drip irrigation or furrow application, or by treating the seed before planting. Seed treatment can be applied to all types of seeds, including those from which plants genetically transformed to express specialized traits will germinate. Representative examples include those expressing proteins toxic to invertebrate pests, such as Bacillus thuringiensis or other insecticidal toxins, those expressing herbicide resistance, such as “Roundup Ready” seed, or those with “stacked” foreign genes expressing insecticidal toxins, herbicide resistance, nutritionenhancement, or any other beneficial traits. Furthermore, such seed treatments with the compounds disclosed herein can further enhance the ability of a plant to better withstand stressful growing conditions. This results in a healthier, more vigorous plant, which can lead to higher yields at harvest time.
It should be readily apparent that the compounds disclosed herein can be used with plants genetically transformed to express specialized traits, such as Bacillus thuringiensis or other insecticidal toxins, or those expressing herbicide resistance, or those with “stacked” foreign genes expressing insecticidal toxins, herbicide resistance, nutrition-enhancement, or any other beneficial traits.
Before a pesticide can be used or sold commercially, such pesticide undergoes lengthy evaluation processes by various governmental authorities (local, regional, state, national, international). Voluminous data requirements are specified by regulatory authorities and must be addressed through data generation and submission by the product registrant or by another on the product registrant's behalf. These governmental authorities then review such data and if a determination of safety is concluded, provide the potential user or seller with product registration approval. Thereafter, in that locality where the product registration is granted and supported, such user or seller may use or sell such pesticide.
TABLE SECTION
Table 1A
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Table IB
Figure imgf000068_0002
Figure imgf000069_0002
While these embodiments have been expressed, other embodiments and combinations of these expressed embodiments and other embodiments are possible.
Table 2: Analytical Data for Compounds in Tables 1A and IB
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
BAW & CL Rating Table
Figure imgf000077_0002
GPA & YFM Rating Table
Figure imgf000077_0003
Figure imgf000078_0001
Table 3 : Biological Data for Compounds in Tables 1 A and IB
Figure imgf000079_0001
A25 A A C c
A27 A A C c
A28* A A c c
A29 A A c c
Bl A A c c
B2 A A A c
B3* A A c c
B4 A A c B
B5 A A A C
B6 A A c c
*tested at 5 pg/cm2
Consequently, in light of the above, the following details (d) are provided.
A compound having the structure of Formula One or Formula Two: wherein:
Figure imgf000080_0001
(A) Ar1 is selected from
(1) furanyl, phenyl, pyridazinyl, pyridyl, pyrimidinyl, thienyl, or
(2) substituted furanyl, substituted phenyl, substituted pyridazinyl, substituted pyridyl, substituted pyrimidinyl, or substituted thienyl, wherein said substituted furanyl, substituted phenyl, substituted pyridazinyl, substituted pyridyl, substituted pyrimidinyl, and substituted thienyl have one or more substituents independently selected from H, F, Cl, Br, I, CN, OH, SH, NOz, oxo, thioxo, NR’R5', Ci-Cg alkyl, Ci-Cs haloalkyl, Cj-Cg cycloalkyl, Cs-Cg halocycloalkyl, Cs-Cs cycloalkoxy, Ch-Cg halocycloalkoxy, Ci-C8 alkoxy, Ci-Q haloalkoxy, Ch-Cg alkenyl, Ch-Cg cycloalkenyl, C2- C8 haloalkenyl, C2-C8 alkynyl, S (=0 ) ,,( Ci-Cx cycloalkyl), S(=O)n(Ci-Cg halocycloalkyl), S(=0)n(Ci-C8 alkyl),
S(=O)n(Ci-C8 haloalkyl), OSO2(Ci-C8 alkyl), OSO2(Ci-C8 haloalkyl), C(=O)NRXR’', (Ci-C8 alkyONRW, C(=O)C(=O)(C1-C8 alkyl), C(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 haloalkyl), C(=O)O(Ci-C8 haloalkyl), C(=O)(C3-C8 cycloalkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(C2-C8 alkenyl), C(=O)O(Cj-C8 alkenyl), (Ci-C8 alkyl)O(Ci-C8 alkyl), (Ci-C8 alkyl)S(=O)n(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)(Ci-C8 alkyl), (Ci- C8 alkyl)phenyl, (Ci-C8 alkyl)-O-phenyl, phenyl, phenoxy, Si(Ci-C8 alkyl)3, or S(=O)nNRxRy, or (Het-1), wherein each alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkenyl, cycloalkenyl, haloalkenyl, alkynyl, phenyl, phenoxy, and (Het-1) substituent may be optionally substituted with one or more substituents independently selected from H, F, Cl, Br, I, CN, OH, SH, NO,, oxo, thioxo, NRxRy, Ci-C8 alkyl, Ci-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, Ci-C8 alkoxy, Ci-C8 haloalkoxy, C2-C8 alkenyl, C3-C8 cycloalkenyl, C2-C8 haloalkenyl, CS-Ck alkynyl, S(=O)n(C3-C8 cycloalkyl), S(=O)n(C3-C8 halocycloalkyl), S(=O)n(Ci-C8 alkyl), S(=O)n(Ci-C8 haloalkyl), OSO2(Ci-C8 alkyl), OSO2(Ci-C8 haloalkyl), C(=O)NRxRy, (Ci-C8 alkyl)NRxRy, C(=O)(Ci-C8 alkyl), C(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 haloalkyl), C(=O)O(Ci-C8 haloalkyl), C(=O)(C3-C8 cycloalkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(C2-C8 alkenyl), C(=O)O(C2-C8 alkenyl), (Ci-C8 alkyl)O(Ci-C8 alkyl), (Ci-C8 alkyl)S(=O)„(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)phenyl, (Ci-C8 alkyl)-O-phenyl, phenyl, phenoxy, Si(Ci-C8 alkyl)3, S(=O)nNRxRy, or (Het-1);
(B) Het is a 5- or 6-membered, saturated or unsaturated, heterocyclic ring, containing one or more heteroatoms independently selected from nitrogen, sulfur, or oxygen, and where said heterocyclic ring may also be substituted with one or more substituents independently selected from H, F, Cl, Br, I, CN, OH, SH, NO2, oxo, thioxo, NRxRy, Ci-C8 alkyl, Ci-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, Ci-C8 alkoxy, Ci-C8 haloalkoxy, C3-C8 alkenyl, C3-C8 cycloalkenyl, C3-C8 haloalkenyl, C3-C8 alkynyl, S(=O)n(C3-C8 cycloalkyl), S(=O)n(C3-C8 halocycloalkyl), S(=O)n(Ci-C8 alkyl), S(=O)n(Ci-C8 haloalkyl), OSO2(Ci-C8 alkyl), OSO2(Ci-C8 haloalkyl), C(=O)NRxRy, (Ci-C8 alkyl)NRxRy, C(=O)(Ci-C8 alkyl), C(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 haloalkyl), C(=O)O(Ci-C8 haloalkyl), C(=O)(C3-C8 cycloalkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(C2-C8 alkenyl), C(=O)O(C2-C8 alkenyl), (Ci-C8 alkyl)O(Ci-C8 alkyl), (Ci-C8 alkyl)S(=O)n(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)phenyl, (Ci-C8 alkyl)-O-phenyl, phenyl, phenoxy, Si(Ci-C8 alkyl)3, or S(=O)nNRxRy, wherein each alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkenyl, cycloalkenyl, haloalkenyl, alkynyl, phenyl, and phenoxy substituent may be optionally substituted with one or more substituents independently selected fromH, F, Cl, Br, I, CN, OH, SH, NO3, oxo, thioxo, NRxRy, Ci-C8 alkyl, Ci-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, Ci-C8 alkoxy, Ci-C8 haloalkoxy, CS-Cs alkenyl, C3-C8 cycloalkenyl, C3-C8 haloalkenyl, C3-C8 alkynyl, S(=O)n(C3-C8 cycloalkyl), S(=O)n(C3-C8 halocycloalkyl), S(=O)n(Ci-C8 alkyl), S(=O)„(Ci-C8 haloalkyl), OSO2(Ci-C8 alkyl), OSO2(Ci-C8 haloalkyl), C(=O)NRxRy, (Ci-C8 alkyl)NRxRy, C(=O)(Ci-C8 alkyl), C(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 haloalkyl), C(=O)O(Ci-C8 haloalkyl), C(=O)(C3-C8 cycloalkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(C2-C8 alkenyl), C(=O)O(C2-C8 alkenyl), (Ci-C8 alkyl)O(Ci-C8 alkyl), (Ci-C8 alkyl)S(=O)„(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)(Ci-C8 alkyl), (Ci-Cs alkyl)OC(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)phenyl, (Ci-C8 alkyl)-O-phenyl, phenyl, phenoxy, Si(Ci-C8 alkyl)3, or S(=O)nNRxRy;
(C) A is a
(1) 3-, 4-, 5-, 6-, or 7-membered saturated or partially unsaturated, heterocyclic ring, containing one or two nitrogen atoms, the remainder of the ring atoms being carbon; wherein said carbon ring atoms are optionally substituted with one or more substituents independently selected from the group consisting of H, Cl, Br, F, I, CN, oxo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylthio, Ci-Ce haloalkylthio, G-G, alkenyl, and C2-C6 haloalkenyl; or
(2) a 6-membered saturated or partially unsaturated carbocyclic ring, optionally substituted with one or more substituents independently selected from H, Cl, Br, F, I, CN, oxo, Ci-Ce alkyl, Ci-Ce -haloalkyl, Ci-Ce alkoxy, Ci-Cg haloalkoxy, Ci-Ce alkylthio, Ci-Cs haloalkylthio, C2-C6 alkenyl, C2-Ce haloalkenyl, and C2-Ce haloalkenyl;
(D) L is a linker selected from
(1) a bond,
Figure imgf000082_0001
wherein each of Ra, Rb, Rc, Rd, Re, and Rf is selected from H, F, Cl, Br, I, CN, OH, SH, NO2, oxo, thioxo,
NR’R1', Ci-C8 alkyl, Ci-C8 haloalkyl, Ci-C8 alkoxy, Ci-C8 haloalkoxy, C2-C8 alkenyl, C2-C8 haloalkenyl, C2-C8 alkynyl, C2-C8 haloalkynyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, C3- C8 cycloalkenyl, C3-C8 halocycloalkenyl, C(=O)(Ci-C6 alkyl), C(=O)O(Ci-Ce alkyl), C(=O)(C3-C6 cycloalkyl), CG0)0(G-G, cycloalkyl), CGOXG-G, alkenyl), C(=O)O(C2-C6 alkenyl), (Ci-C6 alkyl)O(Ci-C6 alkyl), (Ci-C6 alkyl)S(=O)„(Ci-C6 alkyl), C(=O)(Ci-C6 alkyl)C(=O)O(Ci-C6 alkyl), S(=O)n(Ci-C8 alkyl), S(=O)„(C3-C8 cycloalkyl), S(=O)n(Ci-C8 haloalkyl), S(=O)n(C3-C8 halocycloalkyl), phenyl, or phenoxy;
(E) Ra and Rc together can optionally form a 3- to 7-membered saturated or unsaturated ring which may contain C=O, C=S, N, S or O, and is optionally substituted with H, OH, F, Cl, Br, I, CN, NO2, NRxRy, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, C3-Ce cycloalkyl, C3-Ce halocycloalkyl, G-G hydroxycycloalkyl, G-G cycloalkoxy, C3-C« halocycloalkoxy, G-G, hydroxycycloalkoxy, Ci-Ce alkoxy, C -G haloalkoxy, C2-Ce alkenyl, C3-Ce cycloalkenyl, C2-Ce alkynyl, C3-Ce cycloalkynyl, S(=O)n(Ci-C6 alkyl), S(=O)n(Ci-C6 haloalkyl), OSO2(Ci-C6 alkyl), OSO2(Ci-C6 haloalkyl), C(=O)H, C(=O)OH, C(=O)NRxRy, (Ci-C6 alkyl)NRxRy, C(=O)(Ci-C6 alkyl), C(=O)O(Ci-C6 alkyl), C(=O)(Ci-C6 haloalkyl), C(=O)O(Ci-C6 haloalkyl), C(=O)(C3-C6 cycloalkyl), C(=O)O(C3-C6 cycloalkyl), C(=O)(C2-C6 alkenyl), C(=O)O(C2-C6 alkenyl), (Ci-C6 alkyl)O(Ci-C6 alkyl), (Ci-C6 alkyl)S(=O)n(Ci-C6 alkyl), C(=O)(Ci-C6 alkyl)C(=O)O(Ci-Ce alkyl), phenyl, phenoxy, and Het-1;
(F) each of Q1 and Q2 is independently selected from O or S;
(G) each of R1, R4, and RJ is independently selected from H, Ci-C8 alkyl, Ci-C8 haloalkyl, Ci-C8 alkoxy, Ci-C8 haloalkoxy, phenyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)O(Ci-C8 alkyl), (Ci-Cs alkyl)S(=O)n(Ci-C8 alkyl), (Ci-C8 alkyl)phenyl, (Ci-C8 alkyl)-O-phenyl, C(=O)(Het-l), (Het-1), (Ci- C8 alkyl)(Het-l), (Ci-C8 alkyl)C(=O)(Ci-C8 alkyl), (Ci-Cs alkyl)OC(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)NR'R'. (Ci-C8alkyl)C(=O)N(Rx)(Ci-C8 alkyl)(Het-l), (Ci-C8alkyl)C(=O)(Het-l), (Ci- C8 alkyl)C(=O)N(Rx)(Ci-C8 alkyl)N(Ry)C(=O)OH, (Ci-C8alkyl)C(=O)N(Rx)(Ci-C8 alkyl)N(Rx)(Ry), (Ci-C8 alkyl)C(=O)N(Rx)(Ci-C8 alkyl)N(Ry)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)N(Rx)(Ci-C8 alkyl)(N(Ry)C(=O)O(Ci-C8 alkyl)C(=O)OH, (Ci-C8alkyl)C(=O)(Het-l)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)(C3-C8 cycloalkyl), (Ci-C8 alkyl)OC(=O)(Het-l), (Ci-C8alkyl)OC(=O)(Ci-C8 alkyl)N(Rx)C(=O)O(Ci- C8 alkyl), (Ci-C8 alkyl)-NRxRy, (Ci-C8 alkyl)S(Het-l), (Ci-C8 alkyl)S(=O)n(Het-l), or (Ci-C8 alkyl)O(Het-l), wherein each alkyl, cycloalkyl, phenyl, and (Het-1) are optionally substituted with one or more substituents independently selected fromH, F, Cl, Br, I, CN, OH, SH, NO2, oxo, thioxo, NRxRy, Ci-C8 alkyl, Ci-C8 haloalkyl, C’,-C>< cycloalkyl, C3-C8 halocycloalkyl, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, Ci-C8 alkoxy, Ci-C8 haloalkoxy, Ci-Cs alkenyl, C3-C8 cycloalkenyl, C3-C8 haloalkenyl, C2-C8 alkynyl, S(=O)n(C3-C8 cycloalkyl), S(“O)n(C3-C8 halocycloalkyl), S(=O)n(Ci-C8 alkyl), S(=O)n(Ci-C8 haloalkyl), OSO2(Ci-C8 alkyl), OSO2(Ci-C8 haloalkyl), C(=O)H, C(=O)OH, C(=O)NRxRy, (Ci-C8 alkyl)NRxRy, C(=O)(Ci-C8 alkyl), C(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 haloalkyl), C(=O)O(Ci-C8 haloalkyl), C(=O)(C3-C8 cycloalkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(C2-C8 alkenyl), C(=O)O(C2-C8 alkenyl), (Ci-C8 alkyl)O(Ci-C8 alkyl), (Ci-C8 alkyl)S(=O)„(Ci-C8 alkyl), (Ci- C8 alkyl)OC(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci- C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)phenyl, (Ci-C8 alkyl)-O-phenyl, phenyl, phenoxy, Si(Ci-C8 alkyl)3, S(=O)nNRxRy, or (Het-1);
(H) R2 is selected from H, OH, SH, Ci-C8 alkyl, Ci-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, Ci-C8 alkoxy, Ci-C8 haloalkoxy, C2-C8 alkenyl, C3-C8 cycloalkenyl, C2-C8 haloalkenyl, C2-C8 alkynyl, S(=O)n(C3-C8 cycloalkyl), S(=O)n(C3-C8 halocycloalkyl), S(=O)n(Ci-C8 alkyl), S(=O)n(Ci-C8 haloalkyl), OSO2(Ci-C8 alkyl), OSO2(Ci-C8 haloalkyl), C(=O)H, C(=O)(Ci-C8 alkyl), C(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 haloalkyl), C(=O)O(Ci-C8 haloalkyl), C(=O)(C3-C8 cycloalkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(C2-C8 alkenyl), C(=O)O(C2-C8 alkenyl), (Ci-C8 alkyl)O(Ci-C8 alkyl), (Ci-C8 alkyl)S(=O)n(Ci-C8 alkyl), (Ci- C8 alkyl)OC(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci- C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)phenyl, (Ci-C8 alkyl)-O-phenyl, phenyl, C(=O)(Het-l), (Het-1), (Ci-C8 alkyl)(Het-l), (Ci-C8 alkyl)OC(=O)NRxRy, (Ci-C8 alkyl)C(=O)N(Rx)(Ci-C8 alkyl)(Het-l), (Ci-C8alkyl)C(=O)(Het-l), (Ci-C8 alkyl)C(=O)N(Rx)(Ci-C8 alkyl)N(Ry)C(=O)OH, (Ci-C8 alkyl)C(=O)N(Rx)(Ci-C8 alkyl)N(Rx)(Ry), (Ci-C8 alkyl)C(=O)N(Rx)(Ci-C8 alkyl)N(Ry)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)N(Rx)(Ci-C8 alkyl)(N(Ry)C(=O)O(Ci-C8 alkyl)C(=O)OH, (Ci-C8alkyl)C(=O)(Het-l)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)(C3-C8 cycloalkyl), (Ci-C8alkyl)OC(=O)(Het-l), (Ci-C8 alkyl)OC(=O)(Ci-C8 alkyl)N(Rx)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)-NRxRy, (Ci-C8 alkyl)S(Het-l), (Ci-C8 alkyl)S(=O)n(Het-l), or (Ci- C8 alkyl)O(Het-l), wherein each alkyl, haloalkyl, cycloalkyl, halocycloalkyl, cycloalkoxy, halocycloalkoxy, alkoxy, haloalkoxy, alkenyl, cycloalkenyl, haloalkenyl, alkynyl, phenyl, and (Het-1), are optionally substituted with one or more substituents independently selected from H, F, Cl, Br, I, CN, OH, SH, NO2, oxo, thioxo, Ci-C8 alkyl, Ci-C8 haloalkyl, C3-C8 cycloalkyl, C -Cx halocycloalkyl, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, Ci-C8 alkoxy, Ci-C8 haloalkoxy, C2-C8 alkenyl, C -C8 cycloalkenyl, C2-C8 haloalkenyl, C2-Cs alkynyl, S(=O)n(C3-C8 cycloalkyl), S(= O)n(C3-C8 halocycloalkyl), S(=O)n(Ci-C8 alkyl), S(=O)n(Ci-C8 haloalkyl), OSO2(Ci-C8 alkyl), OSO2(Ci-C8 haloalkyl), C(=O)H, C(=O)OH, C(=O)(Ci-C8 alkyl), C(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 haloalkyl), C(=O)O(Ci-C8 haloalkyl), C(=O)(C3-C8 cycloalkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(C2-C8 alkenyl), C(=O)O(C2-C8 alkenyl), (Ci-C8 alkyl)O(Ci-C8 alkyl), (Ci-C8 alkyl)S(=O)n(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)phenyl, (Ci-C8 alkyl)-O-phenyl, phenyl, halophenyl, phenoxy, and (Het-1);
(I) R3 is selected from C3-C8 cycloalkyl, phenyl, (Ci-C8 alkyl)phenyl, (Ci-C8 alkyl)-O-phenyl, (C2-C8 alkenyl)- O-phenyl, (Het-1), (Ci-C8 alkyl)(Het-l), (Ci-C8 alkyl)O(Het-l), wherein the C3-C8 cycloalkyl, phenyl, (Ci-C8 alkyl)phenyl, (Ci-C8 alkyl)-O-phenyl, (C2-C8 alkenyl)-O- phenyl, (Het-1), (Ci-C8 alkyl)(Het-l), or (Ci-C8 alkyl)O(Het-l) may be optionally substituted with one or more substituents independently selected from H, F, Cl, Br, I, CN, OH, SH, NO2, oxo, thioxo, NRxRy, Ci-C8 alkyl, Ci-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C’,-C8 cycloalkoxy, C.-Cx halocycloalkoxy, Ci-C8 alkoxy, Ci-C8 haloalkoxy, C2-C8 alkenyl, C3-C8 cycloalkenyl, C2-C8 haloalkenyl, C2-C8 alkynyl, S(=O)n(C3-C8 cycloalkyl), S(=O)n(C3-C8 halocycloalkyl), S(=O)n(Ci-C8 alkyl), S(=O)„(Ci-C8 haloalkyl), OSO2(Ci-C8 alkyl), OSO2(Ci-C8 haloalkyl), C(=O)(Ci-C8 alkyl), C(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 haloalkyl), C(=O)O(Ci-C8 haloalkyl), C(=O)(C3-C8 cycloalkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(C2-C8 alkenyl), C(=O)O(C2-C8 alkenyl), (Ci-C8 alkyl)O(Ci-C8 alkyl), (Ci-C8 alkyl)O(Ci-C8 haloalkyl), (Ci-C8 alkyl)S(=O)„(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)(Ci- C8 alkyl), (Ci-C8 alkyl)OC(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)O(Ci- C8 alkyl), (Ci-C8 alkyl)C(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)phenyl, (Ci-C8 alkyl)-O-phenyl, phenyl, phenoxy, Si(Ci-C8 alkyl)3, S(=O)nNRxRy, or (Het-1) or wherein two adjacent substituents form a 5- or 6-membered saturated or unsaturated, hydrocarbyl link, which may contain one or more heteroatoms selected from nitrogen, sulfur, and oxygen, and wherein said hydrocarbyl link may optionally be substituted with one or more substituents independently selected fromH, F, Cl, Br, I, CN, OH, SH, NO2, NRxRy, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, S(=O)n(Ci-C6 alkyl), S(=O)n(Ci-Cc haloalkyl), phenyl, and oxo;
(J) R2 and R4 together may optionally form a 1- to 4-membered saturated or unsaturated, hydrocarbyl link, which may contain one or more heteroatoms selected from nitrogen, sulfur, and oxygen, and together with (Q2)(C)(N) forms a 4- to 7-membered cyclic structure, wherein said hydrocarbyl link may optionally be substituted with one or more substituents independently selected from H, F, Cl, Br, I, CN, OH, SH, NO2, oxo, thioxo, NRxRy, Ci-C8 alkyl, Ci-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, Ci-Cs alkoxy, Ci-C8 haloalkoxy, C2-C8 alkenyl, C3-C8 cycloalkenyl, C2-C8 haloalkenyl, C2-C8 alkynyl, S(=O)n(C3-C8 cycloalkyl), S(=O)n(C3-C8 halocycloalkyl), S(=O)n(Ci-C8 alkyl), S(=O)n(Ci-C8 haloalkyl), OSO2(Ci-C8 alkyl), OSO2(Ci-C8 haloalkyl), C(=O)H, C(=O)(Ci-C8 alkyl), C(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 haloalkyl), C(=O)O(Ci- C8 haloalkyl), C(=O)(C3-C8 cycloalkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(C2-C8 alkenyl), C(=O)O(C2-C8 alkenyl), (Ci-C8 alkyl)O(Ci-C8 alkyl), (Ci-C8 alkyl)S(=O)n(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)(Ci-Cs alkyl), (Ci-C8 alkyl)phenyl, (C'l-Cx alkyl)-O-phenyl, phenyl, substituted phenyl, phenoxy, or (Het-1);
(K) Rx and Ry are independently selected from H, OH, SH, Ci-C8 alkyl, Ci-C8 haloalkyl, C3-C8 cycloalkyl, C3- Cs halocycloalkyl, C -Cx cycloalkoxy, C3-C8 halocycloalkoxy, Ci-C8 alkoxy, Ci-C8 haloalkoxy, C2-Cx alkenyl, C - Cx cycloalkenyl, C2-C8 haloalkenyl, C2-C8 alkynyl, S(=O)„(Ci-Cx cycloalkyl), S(=O)n(C3-Cs halocycloalkyl), S(=O)n(Ci-Cs alkyl), S(=O)„(Ci-C8 haloalkyl), OSO2(Ci-C8 alkyl), OSO2(Ci-C8 haloalkyl), C(=O)H, C(=O)(Ci-C8 alkyl), C(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 haloalkyl), C(=O)O(Ci-C8 haloalkyl), C(=O)(C3-C8 cycloalkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(C2-C8 alkenyl), C(=O)O(C2-C8 alkenyl), (Ci-C8 alkyl)O(Ci-C8 alkyl), (Ci-C8 alkyl)S(=O)„(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)phenyl, (Ci-C8 alkyl)-O-phenyl, phenyl, C(=O)(Het-l), (Het-1), (Ci-C8 alkyl)(Het-l), (Ci-C8 alkyl)C(=O)(Het- 1), (Ci-C8alkyl)C(=O)(Het-l)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)(C3-C8 cycloalkyl), (Ci-C8 alkyl)OC(=O)(Het-l), (Ci-C8 alkyl)S(Het-l), (Ci-C8 alkyl)S(=O)n(Het-l), or (Ci-C8 alkyl)O(Het-l), wherein each alkyl, haloalkyl, cycloalkyl, halocycloalkyl, cycloalkoxy, halocycloalkoxy, alkoxy, haloalkoxy, alkenyl, cycloalkenyl, haloalkenyl, alkynyl, phenyl, and (Het-1), are optionally substituted with one or more substituents independently selected from H, F, Cl, Br, I, CN, OH, SH, NO2, oxo, thioxo, Ci-C8 alkyl, Ci-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C3-C8 cycloalkoxy, C3-Cs halocycloalkoxy, Ci-Cs alkoxy, Ci-Cs haloalkoxy, C2-C8 alkenyl, C3-C8 cycloalkenyl, C2-C8 haloalkenyl, C2-C8 alkynyl, S(=O)n(C3-Cs cycloalkyl), S(=O)n(C3-C8 halocycloalkyl), S(=O)n(Ci-C8 alkyl), S(=O)„(Ci-C8 haloalkyl), OSO2(Ci-C8 alkyl), OSO2(Ci-C8 haloalkyl), C(=O)H, C(=O)OH, C(=O)(Ci-C8 alkyl), C(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 haloalkyl), C(=O)O(Ci-C8 haloalkyl), C(=O)(C3-C8 cycloalkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(C2-C8 alkenyl), C(=O)O(C2-C8 alkenyl), (Ci-C8 alkyl)O(Ci-C8 alkyl), (Ci-Cs alkyl)S(=O)n(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)OC(-O)O(C -Cx alkyl), C(=O)(Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)phenyl, (Ci-C8 alkyl)-O-phenyl, phenyl, halophenyl, phenoxy, and (Het-1), or Rx and Ry together can optionally form a 5- to 7-membered saturated or unsaturated cyclic group which may contain one or more heteroatoms selected from nitrogen, sulfur, and oxygen, and where said cyclic group may be substituted with H, F, Cl, Br, I, CN, OH, SH, NO2, oxo, thioxo, Ci-C8 alkyl, Ci-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, Ci-C8 alkoxy, Ci-C8 haloalkoxy, C2-C8 alkenyl, C3-C8 cycloalkenyl, C2-C8 haloalkenyl, C2-C8 alkynyl, S(=O)n(C3-C8 cycloalkyl), S(=O)n(C3-C8 halocycloalkyl), S(=O)n(Ci-C8 alkyl), S(=O)n(Ci-C8 haloalkyl), OSO2(Ci-C8 alkyl), OSO2(Ci-C8 haloalkyl), C(=O)(Ci-C8 alkyl), C(=O)O(C1-C8 alkyl), C(=O)(Ci-C8 haloalkyl), C(=O)O(Ci-C8 haloalkyl), C(=O)(C3-C8 cycloalkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(C2-C8 alkenyl), C(=O)O(C2-C8 alkenyl), (Ci-C8 alkyl)O(Ci-C8 alkyl), (Ci-C8 alkyl)S(=O)n(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)OC(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)(Ci-C8 alkyl), (Ci-C8 alkyl)phenyl, (Ci-C8 alkyl)-O- phenyl, phenyl, substituted phenyl, phenoxy, and (Het-1);
(L) (Het-1) is a 5- or 6-membered, saturated or unsaturated, heterocyclic ring, containing one or more heteroatoms independently selected from nitrogen, sulfur or oxygen, wherein said heterocyclic ring may also be substituted with one or more substituents independently selected from H, F, Cl, Br, I, CN, OH, SH, NO2, oxo, thioxo, NRxRy, Ci-Cg alkyl, Ci-Cg haloalkyl, C3-Cg cycloalkyl, C3-Cg halocycloalkyl, Ca-Cs cycloalkoxy, Ca-Cg halocycloalkoxy, Ci-Cs alkoxy, Ci-Cs haloalkoxy, Ca-Cg alkenyl, Ca-Cg cycloalkenyl, Ca-Cg haloalkenyl, Ca-Cg alkynyl, S(=O)n(Ca-Cg cycloalkyl), S(=O)n(Ca-Cg halocycloalkyl), S(=O)n(Ci-C8 alkyl), S(=O)n(Ci-Cg haloalkyl), OSO2(Ci-Cg alkyl), OSO2(Ci-C8 haloalkyl), C(=O)NRxRy, (Ci-Cg alkyl)NRxRy, C(=O)(Ci-Cg alkyl), C(=O)O(Ci-Cg alkyl), C(=O)(Ci-C8 haloalkyl), C(=O)O(Ci-Cg haloalkyl), C(=O)(C3-C8 cycloalkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(Ca-Cg alkenyl), C(=O)O(Ca-Cg alkenyl), (Ci-Cg alkyl)O(Ci-C8 alkyl), (Ci-Cg alkyl)O(Ci-Cg haloalkyl), (Ci- C8 alkyl)S(=O)n(Ci-Cg alkyl), (Ci-Cg alkyl)OC(=O)(Ci-Cg alkyl), (Ci-Cg alkyl)OC(=O)O(Ci-C8 alkyl), C(=O)(Ci-Cg alkyl)C(=O)O(Ci-Cg alkyl), (Ci-Cg alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)(Ci-C8 alkyl), (Ci-Cg alkyl)phenyl, (Ci-C8 alkyl)-O-phenyl, phenyl, and phenoxy, wherein each alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, phenyl, and phenoxy may be optionally substituted with one or more substituents independently selected from H, F, Cl, Br, I, CN, OH, SH, NOa, oxo, thioxo, NRxRy, Ci-Cg alkyl, Ci-Cg haloalkyl, Ca-Cg cycloalkyl, Ca-Cg halocycloalkyl, Ca-Cg cycloalkoxy, Ca-Cg halocycloalkoxy, Ci-Cg alkoxy, Ci-Cg haloalkoxy, Ca-Cg alkenyl, Ca-Cg cycloalkenyl, C2-Cg haloalkenyl, C2-C8 alkynyl, S(=O)n(C3-Cg cycloalkyl), S(=O)n(Ca-C8 halocycloalkyl), S(=O)n(Ci-C8 alkyl), S(=O)n(Ci-C8 haloalkyl), OSO2(Ci-C8 alkyl), OSO2(Ci-C8 haloalkyl), C(=O)H, C(=O)NR'R'. (Ci-Cg alkyl)NRxRy, C(=O)(Ci-Cg alkyl), C(=O)O(Ci-Cg alkyl), C(=O)(Ci-C8 haloalkyl), C(=O)O(Ci-Cg haloalkyl), C(=O)(C3-C8 cycloalkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(Ca-C8 alkenyl), C(=O)O(C2-C8 alkenyl), (Ci-C8 alkyl)O(Ci-Cg alkyl), (Ci-Cg alkyl)S(=O)n(Ci-C3 alkyl), (Ci-Cg alkyl)OC(=O)(Ci-C8 alkyl), (Ci-Cg alkyl)OC(=O)O(Ci-C8 alkyl), C(=O)(Ci-C8 alkyl)C(=O)O(Ci-C8 alkyl), (Ci-Cg alkyl)C(=O)O(Ci-C8 alkyl), (Ci-C8 alkyl)C(=O)(Ci-Cg alkyl), (Ci-Cg alkyl)phenyl, (Ci-C8 alkyl)-O- phenyl, phenyl, and phenoxy; and (M) n is each individually 0, 1, or 2.
2d. A compound according to Id, wherein:
(a) Ar1 is a phenyl or a substituted phenyl having one or more substituents independently selected from Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy;
(b) Het is a triazolyl, imidazolyl, pyrrolyl, or pyrazolyl;
(c) A is a
(1) 3-, 4-, 5-, 6-, or 7-membered nitrogen containing non-aromatic ring containing between 0 and 1 additional nitrogen atoms optionally substituted with one or more substituents independently selected from H, Cl, Br, F, I, CN, oxo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylthio, Ci-Ce haloalkylthio, Ca-G alkenyl, and Ca-G. haloalkenyl; or
(2) a 6-membered non-aromatic carbocyclic ring optionally substituted with one or more substituents independently selected fromH, Cl, Br, F, I, CN, oxo, Ci-Ce alkyl, Ci-Ce -haloalkyl, Ci-Cs alkoxy, Ci-Cs haloalkoxy, Ci-Ce alkylthio, Ci-Ce haloalkylthio, G-G, alkenyl, and G-G, haloalkenyl;
(d) L is a linker selected from a bond or -CRaRb-CRcRd, wherein each of Ra, Rb, Rc, and Rd is selected from H, F, Cl, Br, I, CN, OH, SH, NOz, oxo, thioxo, NR'R' .
Ci-Cs alkyl, Ci-Cg haloalkyl, Ci-Cs alkoxy, and Ci-Cs haloalkoxy,
(e) Q1 is O and Q2 is S;
(f) each of R1, R4, and R5 is independently selected from H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or phenyl;
(g) R2 is selected from H, Ci-Ce alkyl, or (i); and
(i) in the case of Formula One, optionally R2 and R4 together may form a 1- to 4-membered saturated or unsaturated, hydrocarbyl link, which may contain one or more heteroatoms selected from nitrogen, sulfur, and oxygen, and together with (Q2)(C)(N) forms a 4- to 7-membered cyclic structure, wherein said hydrocarbyl link, wherein said hydrocarbyl link group may optionally be substituted with one or more R6, wherein each R6 is independently selected fromH, F, Cl, Br, I, CN, Ci-Cg alkyl, oxo, thioxo, Ci-Cg haloalkyl, Ci-Cg alkoxy, Ci-Ce haloalkoxy, phenyl, and phenoxy;
(h) R3 is selected from phenyl, Ci-Ce alkyl-phenyl, or Ci-Cg alkyl-O-phenyl, wherein each alkyl and phenyl is optionally substituted with one or more substituents independently selected from F, Cl, Br, I, CN, NO2, oxo, thioxo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, phenyl, or phenoxy.
3d. The compound according to any of the previous details, wherein Ar1 is phenyl.
4d. The compound according to any of the previous details, wherein Ar1 is a substituted phenyl having one or more substituents independently selected from OCF3, OCF2CF3, and CF3.
5d. The compound according to any of the previous details, wherein Het is 1,2,4-triazolyl.
6d. The compound according to any of the previous details Id through 5d, wherein A is azetidinyl, cyclo hexyl, cyclohexenyl, cyclohexadienyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, substituted cyclohexyl, substituted cyclohexenyl, substituted cyclohexadienyl, substituted pyrrolidinyl, substituted piperidinyl, substituted tetrahydropyridinyl, or substituted piperazinyl.
7d. The compound according to 6d, wherein A is a substituted piperidinyl, substituted tetrahydropyridinyl, or substituted piperazinyl having one or more substituents independently selected from H, Cl, Br, F, I, oxo, Ci-Cg alkyl, Ci-Ce -haloalkyl, Ci-Ce alkoxy, and Ci-Ce haloalkoxy.
8d. The compound according to 6d, wherein A is a substituted cyclohexyl, substituted cyclohexenyl, or substituted cyclohexadienyl having one or more substituents independently selected from H, Cl, Br, F, I, oxo, Ci-Ce alkyl, Ci-Cs haloalkyl, Ci-Ce alkoxy, and Ci-Ce haloalkoxy. 9d. The compound according to any of the previous details, wherein L is a bond, -CFHCH2-, -CH2CH(CH3)-, or -CH2CH2-. lOd. The compound according to any of the previous details, wherein each of R1, R4, and R5 is independently H or Ci-C6 alkyl.
1 Id. The compound according to any of the previous details, wherein R3 is a substituted phenyl having one or more substituents independently selected from F, Cl, Br, I, Ci-Ce alkyl, Ci-Cs haloalkyl, Ci-Cs alkoxy, and Ci-Cg haloalkoxy.
12d. The compound according to any of the previous details, having the structure of Formula Three or Formula
Four:
Figure imgf000088_0002
wherein
A is selected from the group consisting of
Figure imgf000088_0001
A4 A5 J A6
; ; and
L is a bond, -CRaRb-, -CRaRb-CRcRd-, or -CRaRb-CRcRd-CReRf, wherein each of Ra, Rb, Rc, Rd, Re, and Rf is selected from the group consisting of H, F, Cl, and C1-C3 alkyl; each of Q1 and Q2 is independently selected from O or S;
R1, R2, and R5 are each independently selected from the group consisting of H and CH ,: R3 is a substituted phenyl with 1, 2, 3, 4, or 5 substituents R7 independently selected from the group consisting of F, Cl, Br, I, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; and
R8 is selected from the group consisting of C1-C4 haloalkyl and C1-C4 haloalkoxy.
13d. The compound according to 12d, wherein R8 is selected from CF3, OCF3, and OCF2CF3.
14d. The compound according to 12d or 13d, wherein R1, R2, and R5 are each H.
15d. The compound according to 12d through 14d inclusive, wherein Q1 is O and Q2 is S.
16d. The compound according to 12d through 15d inclusive, wherein L is a bond, -CH2CH2-, -CHFCH2-, or -
CH2CH(CH3)-.
17d. The compound according to 12d through 16d inclusive, wherein the 1, 2, 3, 4, or 5 substituents R7 are each independently F, Cl, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy.
18d. The compound according to 17d, wherein the 1, 2, 3, 4, or 5 substituents R7 are each independently F, Cl, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CF3, and OCH2CH2CF3.
19d. The compound according to any of the previous details having a structure from compounds listed in Table 1 A or Table IB.
20d. A composition comprising a compound according to any of the previous details and a carrier.
2 Id. A process comprising applying (a) a compound according to any of the previous details Id through 19d inclusive, or (b) a composition according to 20d, to an area to control a pest, in an amount sufficient to control such pest.
22d. The process according to 2 Id, wherein said pest is beet armyworm (BAW), cabbage looper (CL), green peach aphid (GPA), or yellow fever mosquito (YFM).
23d. A process comprising applying (a) a compound according to any of the previous details Id through 19d inclusive, or (b) a composition according to 20d, to a genetically modified plant, or genetically -modified seed, which has been genetically modified to express one or more specialized traits. 24d. A process comprising: orally administering or topically applying (a) a compound according to any of the previous details Id through 19d inclusive, or (b) a composition according to 20d, to a non-human animal, to control endoparasites, ectoparasites, or both. 25d. A composition comprising a compound according to any of the previous details Id through 19d inclusive and a seed.

Claims

WE CLAIM
1. A compound of Formula Three or Formula Four:
Figure imgf000091_0002
wherein:
A is selected from the group consisting of
Figure imgf000091_0001
A4 A5 A6
; ; and
L is a bond, -CRaRb-, -CRaRb-CRcRd-, or -CRaRb-CRcRd-CReRf, wherein each of Ra, Rb, Rc, Rd, Re, and Rf is selected from the group consisting of H, F, Cl, and C1-C3 alkyl; each of Q1 and Q2 is independently selected from O or S;
R1, R2, and R5 are each independently selected from the group consisting of H and CH3;
R3 is a substituted phenyl with 1, 2, 3, 4, or 5 substituents R7 independently selected from the group consisting of F, Cl, Br, I, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; and
R8 is selected from the group consisting of C1-C4 haloalkyl and C1-C4 haloalkoxy.
2. The compound of claim 1, wherein R8 is selected from the group consisting of selected from CF ,. OCF3, and OCF2CF3.
3. The compound of claim 1 or 2, wherein R1, R2, and R5 are each H.
4. The compound of any one of claims 1, 2, or 3, wherein Q1 is O and Q2 is S.
5. The compound of any one of claims 1, 2, 3, or 4, wherein L is a bond, -CH2CH2-, -CHFCH2-, or - CH2CH(CH3)-.
6. The compound of any one of claims 1, 2, 3, 4, or 5, wherein the 1, 2, 3, 4, or 5 substituents R7 are each independently F, Cl, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy.
7. The compound of claim 6, wherein the 1, 2, 3, 4, or 5 substituents R7 are each independently F, Cl, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CF3, and OCH2CH2CF3.
8. A composition comprising a compound of any one of claims 1, 2, 3, 4, 5, 6, or 7 and a carrier.
9. A process comprising applying (a) a compound of any one of claims 1, 2, 3, 4, 5, 6, or 7, or (b) a composition according to claim 8, to an area to control a pest, in an amount sufficient to control such pest.
10. The process of claim 9, wherein said pest is beet armyworm (BAW), cabbage looper (CL), green peach aphid (GPA), or yellow fever mosquito (YFM).
11. A process comprising applying (a) a compound of any one of claims 1, 2, 3, 4, 5, 6, or 7, or (b) a composition according to claim 8, to a genetically modified plant, or genetically -modified seed, which has been genetically modified to express one or more specialized traits.
12. A process comprising: orally administering; or topically applying (a) a compound of any one of claims 1, 2, 3, 4, 5, 6, or 7, or (b) a composition according to claim 8, to a non-human animal, to control endoparasites, ectoparasites, or both.
13. A composition comprising a compound of any one of claims 1, 2, 3, 4, 5, 6, or 7 and a seed.
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