US20170088507A1 - Pesticidal compositions and processes related thereto - Google Patents

Pesticidal compositions and processes related thereto Download PDF

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Publication number
US20170088507A1
US20170088507A1 US15/279,902 US201615279902A US2017088507A1 US 20170088507 A1 US20170088507 A1 US 20170088507A1 US 201615279902 A US201615279902 A US 201615279902A US 2017088507 A1 US2017088507 A1 US 2017088507A1
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United States
Prior art keywords
alkyl
halo
alkoxy
substituted
mmol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
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US15/279,902
Inventor
William C. Lo
James E. Hunter
Gerald B. Watson
Akshay Patny
Pravin S. Iyer
Joshodeep Boruwa
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Corteva Agriscience LLC
Original Assignee
Dow AgroSciences LLC
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Application filed by Dow AgroSciences LLC filed Critical Dow AgroSciences LLC
Priority to US15/279,902 priority Critical patent/US20170088507A1/en
Publication of US20170088507A1 publication Critical patent/US20170088507A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/68—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings containing halogen
    • C07C63/70—Monocarboxylic acids
    • 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
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/08—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing solids as carriers or diluents
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
    • A01N33/02—Amines; Quaternary ammonium compounds
    • A01N33/04—Nitrogen directly attached to aliphatic or cycloaliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/10—Aromatic or araliphatic carboxylic acids, or thio analogues thereof; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/18—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing the group —CO—N<, e.g. carboxylic acid amides or imides; Thio analogues thereof
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    • A01N37/34—Nitriles
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    • A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
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    • A01N41/02—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a sulfur atom bound to a hetero atom containing a sulfur-to-oxygen double bond
    • A01N41/10—Sulfones; Sulfoxides
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
    • A01N37/46—N-acyl derivatives
    • C07C2101/02—
    • C07C2102/46—
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    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/46—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing nine carbon atoms

Definitions

  • the invention disclosed in this document is related to the field of processes to produce molecules that are useful as pesticides (e.g., acaricides, insecticides, molluscicides, and nematicides), such molecules, and processes of using such molecules to control pests.
  • pesticides e.g., acaricides, insecticides, molluscicides, and nematicides
  • 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, and hexenyl.
  • Alkenyloxy means an alkenyl further consisting of a carbon-oxygen single bond, for example, allyloxy, butenyloxy, pentenyloxy, hexenyloxy.
  • Alkoxy means an alkyl further consisting of a carbon-oxygen single bond, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and tert-butoxy.
  • Alkyl means an acyclic, saturated, branched or unbranched, substituent consisting of carbon and hydrogen, for example, methyl, ethyl, (C 3 )alkyl which represents n-propyl and isopropyl), (C 4 )alkyl which represents n-butyl, sec-butyl, isobutyl, and tert-butyl.
  • Alkynyl means an acyclic, unsaturated (at least one carbon-carbon triple bond), branched or unbranched, substituent consisting of carbon and hydrogen, for example, ethynyl, propargyl, butynyl, and pentynyl.
  • Alkynyloxy means an alkynyl further consisting of a carbon-oxygen single bond, for example, pentynyloxy, hexynyloxy, heptynyloxy, and octynyloxy.
  • Aryl means a cyclic, aromatic substituent consisting of hydrogen and carbon, for example, phenyl, naphthyl, and biphenyl.
  • (C x -C y ) where the subscripts “x” and “y” are integers such as 1, 2, or 3, means the range of carbon atoms for a substituent—for example, (C 1 -C 4 )alkyl means methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl, each individually.
  • “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, norbornenyl, bicyclo[2.2.2]octenyl, tetrahydronaphthyl, hexahydronaphthyl, and octahydronaphthyl.
  • Cycloalkenyloxy means a cycloalkenyl further consisting of a carbon-oxygen single bond, for example, cyclobutenyloxy, cyclopentenyloxy, norbornenyloxy, and bicyclo[2.2.2]octenyloxy.
  • Cycloalkyl means a monocyclic or polycyclic, saturated substituent consisting of carbon and hydrogen, for example, cyclopropyl, cyclobutyl, cyclopentyl, norbornyl, bicyclo[2.2.2]octyl, and decahydronaphthyl.
  • Cycloalkoxy means a cycloalkyl further consisting of a carbon-oxygen single bond, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, norbornyloxy, and bicyclo[2.2.2]octyloxy.
  • Halo means fluoro, chloro, bromo, and iodo.
  • Haloalkoxy means an alkoxy further consisting of, from one to the maximum possible number of identical or different, halos, for example, fluoromethoxy, trifluoromethoxy, 2,2-difluoropropoxy, chloromethoxy, trichloromethoxy, 1,1,2,2-tetrafluoroethoxy, and pentafluoroethoxy.
  • Haloalkyl means an alkyl further consisting of, from one to the maximum possible number of, identical or different, halos, for example, fluoromethyl, trifluoromethyl, 2,2-difluoropropyl, 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, sulfur, or oxygen. In the case of sulfur, that atom can be in other oxidation states such as a sulfoxide and sulfone.
  • aromatic heterocyclyls include, but are not limited to, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl, benzoxazolyl, benzothienyl, benzothiazolyl, cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolinyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolinyl, thiazolyl, thienyl, triaziny
  • Examples of fully saturated heterocyclyls include, but are not limited to, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl and tetrahydropyranyl.
  • Examples of partially unsaturated heterocyclyls include, but are not limited to, 1,2,3,4-tetrahydroquinolinyl, 4,5-dihydro-oxazolyl, 4,5-dihydro-1H-pyrazolyl, 4,5-dihydro-isoxazolyl, and 2,3-dihydro-[1,3,4]-oxadiazolyl.
  • R1 is selected from
  • R2 is selected from
  • R3 is selected from
  • R4 is selected from
  • R5 is selected from
  • R6 is a (C 1 -C 8 )haloalkyl
  • R7 is selected from H, F, Cl, Br, I, OH, (C 1 -C 8 )alkoxy, and halo(C 1 -C 8 )alkoxy;
  • R8 is selected from H, (C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, OR14, and N(R14)(R15);
  • R9 is selected from H, F, Cl, Br, I, (C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy, halo(C 1 -C 8 )alkoxy, OR14, and N(R14)(R15);
  • R11 is C( ⁇ X5)N(H)((C 0 -C 8 )alkyl)N(R11a)(C( ⁇ X5)(R11b))
  • each R11b is independently selected from (C 1 -C 8 )alkyl, substituted (C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, substituted halo(C 1 -C 8 )alkyl, cyclo(C 3 -C 8 )alkyl, substituted cyclo(C 3 -C 8 )alkyl, (C 2 -C 8 )alkenyl, and (C 2 -C 8 )alkynyl,
  • (l) R12 is selected from (v), H, F, Cl, Br, I, CN, (C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy, halo(C 1 -C 8 )alkoxy, and cyclo(C 3 -C 6 )alkyl;
  • R13 is selected from (v), H, F, Cl, Br, I, CN, (C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy, and halo(C 1 -C 8 )alkoxy;
  • each R14 is independently selected from H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, substituted (C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, substituted halo(C 1 -C 8 )alkyl), (C 1 -C 8 )alkoxy, cyclo(C 3 -C 6 )alkyl, aryl, substituted-aryl, (C 1 -C 8 )alkyl-aryl, (C 1 -C 8 )alkyl-(substituted-aryl), O—(C 1 -C 8 )alkyl-aryl, O—(C 1 -C 8 )alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C 1 -C 8 )alkyl-heterocyclyl, (C 1 -C 8 )alkyl-
  • each R15 is independently selected from H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, substituted (C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, substituted halo(C 1 -C 8 )alkyl), (C 1 -C 8 )alkoxy, cyclo(C 3 -C 6 )alkyl, aryl, substituted-aryl, (C 1 -C 8 )alkyl-aryl, (C 1 -C 8 )alkyl-(substituted-aryl), O—(C 1 -C 8 )alkyl-aryl, O—(C 1 -C 8 )alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C 1 -C 8 )alkyl-heterocyclyl, (C 1 -C 8 )alkyl-
  • each R16 is independently selected from H, (C 1 -C 8 )alkyl, substituted-(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, substituted-halo(C 1 -C 8 )alkyl, cyclo(C 3 -C 6 )alkyl, aryl, substituted-aryl, (C 1 -C 8 )alkyl-aryl, (C 1 -C 8 )alkyl-(substituted-aryl), O—(C 1 -C 8 )alkyl-aryl, O—(C 1 -C 8 )alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C 1 -C 8 )alkyl-heterocyclyl, (C 1 -C 8 )alkyl-(substituted-heterocyclyl), O—(C 1 -C 8 )al
  • each R17 is independently selected from H, (C 1 -C 8 )alkyl, substituted-(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, substituted-halo(C 1 -C 8 )alkyl, cyclo(C 3 -C 6 )alkyl, aryl, substituted-aryl, (C 1 -C 8 )alkyl-aryl, (C 1 -C 8 )alkyl-(substituted-aryl), O—(C 1 -C 8 )alkyl-aryl, O—(C 1 -C 8 )alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C 1 -C 8 )alkyl-heterocyclyl, (C 1 -C 8 )alkyl-(substituted-heterocyclyl), O—(C 1 -C 8 )al
  • (r) X1 is selected from N and CR12;
  • (s) X2 is selected from N, CR9, and CR13;
  • (t) X3 is selected from N and CR9;
  • R12 and R13 together form a linkage containing 3 to 4 atoms selected from C, N, O, and S, wherein said linkage connects back to the ring to form a 5 to 6 member saturated or unsaturated cyclic ring, wherein said linkage has at least one substituent X4 wherein X4 is selected from R14, N(R14)(R15), N(R14)(C( ⁇ O)R14), N(R14)(C( ⁇ S)R14), N(R14)(C( ⁇ O)N(R14)(R14)), N(R14)(C( ⁇ S)N(R14)(R14)), N(R14)(C( ⁇ O)N(R14)(R14)), N(R14)(C( ⁇ O)N(R14)((C 2 -C 8 )alkenyl)), N(R14)(C( ⁇ S)N(R14)((C 2 -C 8 )alkenyl)), wherein each R
  • R1 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, CN, NO 2 , methyl, ethyl, (C 3 )alkyl, (C 4 )alkyl, (C 5 )alkyl, (C 6 )alkyl, (C 7 )alkyl, (C 8 )alkyl, halomethyl, haloethyl, halo(C 3 )alkyl, halo(C 4 )alkyl, halo(C 5 )alkyl, halo(C 6 )alkyl, halo(C 7 )alkyl, halo(C 8 )alkyl, methoxy, ethoxy, (C 3 )alkoxy, (C 4 )alkoxy, (C 5 )alkoxy, (C 6 )alkoxy, (C 7 )alkoxy, (C 8 )alkoxy, halomethoxy
  • R2 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, CN, NO 2 , methyl, ethyl, (C 3 )alkyl, (C 4 )alkyl, (C 5 )alkyl, (C 6 )alkyl, (C 7 )alkyl, (C 8 )alkyl, halomethyl, haloethyl, halo(C 3 )alkyl, halo(C 4 )alkyl, halo(C 5 )alkyl, halo(C 6 )alkyl, halo(C 7 )alkyl, halo(C 8 )alkyl, methoxy, ethoxy, (C 3 )alkoxy, (C 4 )alkoxy, (C 8 )alkoxy, (C 6 )alkoxy, (C 7 )alkoxy, (C 8 )alkoxy, halomethoxy
  • R3 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, CN, NO 2 , methyl, ethyl, (C 3 )alkyl, (C 4 )alkyl, (C 5 )alkyl, (C 6 )alkyl, (C 7 )alkyl, (C 8 )alkyl, halomethyl, haloethyl, halo(C 3 )alkyl, halo(C 4 )alkyl, halo(C 5 )alkyl, halo(C 6 )alkyl, halo(C 7 )alkyl, halo(C 8 )alkyl, methoxy, ethoxy, (C 3 )alkoxy, (C 4 )alkoxy, (C 5 )alkoxy, (C 6 )alkoxy, (C 7 )alkoxy, (C 8 )alkoxy, halomethoxy
  • R4 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, CN, NO 2 , methyl, ethyl, (C 3 )alkyl, (C 4 )alkyl, (C 5 )alkyl, (C 6 )alkyl, (C 7 )alkyl, (C 8 )alkyl, halomethyl, haloethyl, halo(C 3 )alkyl, halo(C 4 )alkyl, halo(C 5 )alkyl, halo(C 6 )alkyl, halo(C 7 )alkyl, halo(C 8 )alkyl, methoxy, ethoxy, (C 3 )alkoxy, (C 4 )alkoxy, (C 5 )alkoxy, (C 6 )alkoxy, (C 7 )alkoxy, (C 8 )alkoxy, halomethoxy
  • R5 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, CN, NO 2 , methyl, ethyl, (C 3 )alkyl, (C 4 )alkyl, (C 5 )alkyl, (C 6 )alkyl, (C 7 )alkyl, (C 8 )alkyl, halomethyl, haloethyl, halo(C 3 )alkyl, halo(C 4 )alkyl, halo(C 5 )alkyl, halo(C 6 )alkyl, halo(C 7 )alkyl, halo(C 8 )alkyl, methoxy, ethoxy, (C 3 )alkoxy, (C 4 )alkoxy, (C 5 )alkoxy, (C 6 )alkoxy, (C 7 )alkoxy, (C 8 )alkoxy, halomethoxy
  • R2 and R4 are selected from F, Cl, Br, I, CN, and NO 2 and R1, R3, and R5 are H.
  • R2, R3, and R4 are selected from F, Cl, Br, I, CN, and NO 2 and R1, and R5 are H.
  • R2, R3, and R4 are independently selected from F and Cl and R1 and R5 are H.
  • R1 is selected from Cl and H.
  • R2 is selected from CF 3 , CH 3 , Cl, F, and H.
  • R3 is selected from OCH 3 , CH 3 , F, Cl, or H.
  • R4 is selected from CF 3 , CH 3 , Cl, F, and H.
  • R5 is selected from F, Cl, and H.
  • R6 may be selected from any combination of one or more of the following—halomethyl, haloethyl, halo(C 3 )alkyl, halo(C 4 )alkyl, halo(C 5 )alkyl, halo(C 6 )alkyl, halo(C 7 )alkyl, and halo(C 8 )alkyl.
  • R6 is trifluoromethyl
  • R7 may be selected from any combination of one or more of the following—H, F, Cl, Br, and I.
  • R7 is selected from H, OCH 3 , and OH.
  • R8 may be selected from any combination of one or more of the following—H, methyl, ethyl, (C 3 )alkyl, (C 4 )alkyl, (C 5 )alkyl, (C 6 )alkyl, (C 7 )alkyl, (C 8 )alkyl, halomethyl, haloethyl, halo(C 3 )alkyl, halo(C 4 )alkyl, halo(C 5 )alkyl, halo(C 6 )alkyl, halo(C 7 )alkyl, and halo(C 8 )alkyl.
  • R8 is selected from CH 3 and H.
  • R9 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, methyl, ethyl, (C 3 )alkyl, (C 4 )alkyl, (C 5 )alkyl, (C 6 )alkyl, (C 7 )alkyl, (C 8 )alkyl, halomethyl, haloethyl, halo(C 3 )alkyl, halo(C 4 )alkyl, halo(C 5 )alkyl, halo(C 6 )alkyl, halo(C 7 )alkyl, halo(C 8 )alkyl, methoxy, ethoxy, (C 3 )alkoxy, (C 4 )alkoxy, (C 5 )alkoxy, (C 6 )alkoxy, (C 7 )alkoxy, (C 8 )alkoxy, halomethoxy, haloethoxy
  • R10 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, CN, methyl, ethyl, (C 3 )alkyl, (C 4 )alkyl, (C 5 )alkyl, (C 6 )alkyl, (C 7 )alkyl, (C 8 )alkyl, halomethyl, haloethyl, halo(C 3 )alkyl, halo(C 4 )alkyl, halo(C 5 )alkyl, halo(C 6 )alkyl, halo(C 7 )alkyl, halo(C 8 )alkyl, methoxy, ethoxy, (C 3 )alkoxy, (C 4 )alkoxy, (C 5 )alkoxy, (C 6 )alkoxy, (C 7 )alkoxy, (C 8 )alkoxy, halomethoxy, halo
  • R10 may be selected from any combination of one or more of the following—H, Cl, Br, CH 3 , and CF 3 .
  • R10 is selected from Br, C( ⁇ NOH)NH 2 , C( ⁇ O)H, C( ⁇ O)NH 2 , C( ⁇ O)OCH 2 CH 3 , C( ⁇ O)OH, CF 3 , CH 2 CH 3 , CH 2 OH, CH 3 , Cl, CN, F, H, NH 2 , NHC( ⁇ O)H, NHCH 3 , NO 2 , OCH 3 , OCHF 2 , and pyridyl.
  • R11 is selected from C( ⁇ O)N(H)N(CH 3 )(C( ⁇ O)CH 2 CH 3 ), C( ⁇ O)N(H)N(CH 3 )(C( ⁇ O)CH 2 CF 3 ), C( ⁇ O)N(H)N(CH 3 )(C( ⁇ O)cyclopropyl), C( ⁇ O)N(H)N(CH 3 )(C( ⁇ S)CH 2 CH 3 ), C( ⁇ O)N(H)N(CH 3 )(C( ⁇ O)CH 2 CN), C( ⁇ O)N(H)N(CH 3 )(H 3 )(C( ⁇ S)cyclopropyl), C( ⁇ O)N(H)N(CH 3 )(C( ⁇ O)CH(CF 3 ) 2 ), C( ⁇ O)N(H)N(CH 3 )(C( ⁇ O)CF(CF 3 ) 2 ), C( ⁇ O)N(H)N(CH 3 )(C( ⁇ O)(
  • R12 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, methyl, ethyl, (C 3 )alkyl, (C 4 )alkyl, (C 5 )alkyl, (C 6 )alkyl, (C 7 )alkyl, (C 8 )alkyl, halomethyl, haloethyl, halo(C 3 )alkyl, halo(C 4 )alkyl, halo(C 5 )alkyl, halo(C 6 )alkyl, halo(C 7 )alkyl, halo(C 8 )alkyl, halomethoxy, haloethoxy, halo(C 3 )alkoxy, halo(C 4 )alkoxy, halo(C 5 )alkoxy, halo(C 6 )alkoxy, halo(C 7 )alkoxy, and
  • R12 is selected from CH 3 , and H.
  • R13 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, methyl, ethyl, (C 3 )alkyl, (C 4 )alkyl, (C 5 )alkyl, (C 6 )alkyl, (C 7 )alkyl, (C 8 )alkyl, halomethyl, haloethyl, halo(C 3 )alkyl, halo(C 4 )alkyl, halo(C 5 )alkyl, halo(C 6 )alkyl, halo(C 7 )alkyl, halo(C 8 )alkyl, halomethoxy, haloethoxy, halo(C 3 )alkoxy, halo(C 4 )alkoxy, halo(C 5 )alkoxy, halo(C 6 )alkoxy, halo(C 7 )alkoxy, and
  • R13 is selected from CH 3 , Cl and H.
  • R12-R13 are a hydrocarbyl linkage containing CH ⁇ CHCH ⁇ CH.
  • R14 may be selected from any combination of one or more of the following—H, methyl, ethyl, (C 3 )alkyl, (C 4 )alkyl, (C 5 )alkyl, (C 6 )alkyl, (C 7 )alkyl, (C 8 )alkyl, halomethyl, haloethyl, halo(C 3 )alkyl, halo(C 4 )alkyl, halo(C 5 )alkyl, halo(C 6 )alkyl, halo(C 7 )alkyl, halo(C 8 )alkyl, methyl-aryl, ethyl-aryl, (C 3 )alkyl-aryl, (C 4 )alkyl-aryl, (C 5 )alkyl-aryl, (C 6 )alkyl-aryl, (C 7 )alkyl-aryl, (C 8 )alkyl, methyl-ary
  • R14 may be selected from any combination of one or more of the following—H, CH 3 , CH 2 CF 3 , CH 2 -halopyridyl, oxo-pyrrolidinyl, halophenyl, thietanyl, CH 2 -phenyl, CH 2 -pyridyl, thietanyl-dioxide, CH 2 -halothiazolyl, C((CH 3 ) 2 )-pyridyl, N(H)(halophenyl), CH 2 -pyrimidinyl, CH 2 -tetrahydrofuranyl, CH 2 -furanyl, O—CH 2 -halopyridyl, and CH 2 C( ⁇ O)N(H)(CH 2 CF 3 ).
  • R15 may be selected from any combination of one or more of the following—H, methyl, ethyl, (C 3 )alkyl, (C 4 )alkyl, (C 5 )alkyl, (C 6 )alkyl, (C 7 )alkyl, (C 8 )alkyl, halomethyl, haloethyl, halo(C 3 )alkyl, halo(C 4 )alkyl, halo(C 5 )alkyl, halo(C 6 )alkyl, halo(C 7 )alkyl, halo(C 8 )alkyl, methyl-aryl, ethyl-aryl, (C 3 )alkyl-aryl, (C 4 )alkyl-aryl, (C 5 )alkyl-aryl, (C 6 )alkyl-aryl, (C 7 )alkyl-aryl, (C 8 )alkyl, methyl-ary
  • R15 may be selected from any combination of one or more of the following—H, CH 3 , CH 2 CF 3 , CH 2 -halopyridyl, oxo-pyrrolidinyl, halophenyl, thietanyl, CH 2 -phenyl, CH 2 -pyridyl, thietanyl-dioxide, CH 2 -halothiazolyl, C((CH 3 ) 2 )-pyridyl, N(H)(halophenyl), CH 2 -pyrimidinyl, CH 2 -tetrahydrofuranyl, CH 2 -furanyl, O—CH 2 -halopyridyl, and CH 2 C( ⁇ O)N(H)(CH 2 CF 3 ).
  • R16 may be selected from any combination of one or more of the following—H, methyl, ethyl, (C 3 )alkyl, (C 4 )alkyl, (C 5 )alkyl, (C 6 )alkyl, (C 7 )alkyl, (C 8 )alkyl, halomethyl, haloethyl, halo(C 3 )alkyl, halo(C 4 )alkyl, halo(C 5 )alkyl, halo(C 6 )alkyl, halo(C 7 )alkyl, halo(C 8 )alkyl, methyl-aryl, ethyl-aryl, (C 3 )alkyl-aryl, (C 4 )alkyl-aryl, (C 5 )alkyl-aryl, (C 6 )alkyl-aryl, (C 7 )alkyl-aryl, (C 8 )alkyl, methyl-ary
  • R16 may be selected from any combination of one or more of the following—H, CH 2 CF 3 , cyclopropyl, thietanyl, thietanyl dioxide, and halophenyl.
  • R17 may be selected from any combination of one or more of the following—H, methyl, ethyl, (C 3 )alkyl, (C 4 )alkyl, (C 5 )alkyl, (C 6 )alkyl, (C 7 )alkyl, (C 8 )alkyl, halomethyl, haloethyl, halo(C 3 )alkyl, halo(C 4 )alkyl, halo(C 5 )alkyl, halo(C 6 )alkyl, halo(C 7 )alkyl, halo(C 8 )alkyl, methyl-aryl, ethyl-aryl, (C 3 )alkyl-aryl, (C 4 )alkyl-aryl, (C 5 )alkyl-aryl, (C 6 )alkyl-aryl, (C 7 )alkyl-aryl, (C 8 )alkyl, methyl-ary
  • R17 may be selected from any combination of one or more of the following—H, CH 2 CF 3 , cyclopropyl, thietanyl, thietanyl dioxide, and halophenyl.
  • X1 is CR12
  • X2 is CR13
  • X3 is CR9.
  • a heterocyclyl has preferably about 6 to 10 atoms in the ring structure, more preferably, 6 to 8 atoms.
  • the molecules of Formula One will generally have a molecular mass of about 100 Daltons to about 1200 Daltons. However, it is generally preferred if the molecular mass is from about 120 Daltons to about 900 Daltons, and it is even more generally preferred if the molecular mass is from about 140 Daltons to about 600 Daltons.
  • the benzyl alcohol of Formula IV wherein R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, can be synthesized in two ways.
  • One way, disclosed in step a of Scheme I, is by treatment of the ketone of Formula II, wherein R1, R2, R3, R4, R5, and R6 are as previously disclosed, with a reducing agent, such as sodium borohydride (NaBH 4 ), under basic conditions, such as aqueous sodium hydroxide (NaOH), in a polar protic solvent, such as methanol (MeOH) at 0° C.
  • a reducing agent such as sodium borohydride (NaBH 4 )
  • NaOH sodium borohydride
  • a polar protic solvent such as methanol (MeOH)
  • an aldehyde of Formula III wherein R1, R2, R3, R4, R5, and R7 are as previously disclosed, is allowed to react with trifluorotrimethylsilane in the presence of a catalytic amount of tetrabutylammonium fluoride in a polar aprotic solvent, such as tetrahydrofuran (THF), as in step b of Scheme I.
  • a catalytic amount of tetrabutylammonium fluoride in a polar aprotic solvent such as tetrahydrofuran (THF)
  • a halogenating reagent such as N-bromosuccinimide and triethyl phosphite
  • thionyl chloride and pyridine in a hydrocarbon solvent, such as
  • a vinylbenzoic acid of Formula VI wherein R11 is (C ⁇ O)OH and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, can be converted in two steps to the vinylbenzamide of Formula VIIa, wherein R11 is (C ⁇ O)N(R14)(R15), and R8, R9, R10, R12, R13, R14, R15, and X are as previously disclosed.
  • step d of Scheme II the benzoic acid of Formula VI is treated with oxalyl chloride in the presence of a catalytic amount of N,N-dimethylformamide (DMF) in a non-reactive solvent such as CH 2 Cl 2 to form the acid chloride, which is subsequently allowed to react with an amine (HN(R14)(R15)), wherein R14 and R15 are as previously disclosed, in the presence of a base, such as triethylamine (TEA), in a polar aprotic solvent, such as THF, to provide the vinyl benzamide of Formula VIIa, wherein R11 is (C ⁇ O)N(R14)(R15), and R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed, as in step e of Scheme II.
  • DMF N,N-dimethylformamide
  • CH 2 Cl 2 non-reactive solvent
  • THF a polar aprotic solvent
  • a halobenzoic acid of Formula VIII wherein R18 is Br or I, R11 is (C ⁇ O)OH and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed can be converted to a vinylbenzoic acid ester of Formula VIIb1 or Formula VIIb2, wherein R18 is Br or I, R11 is (C ⁇ O)O(C 1 -C 6 alkyl), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed.
  • step f of Scheme III the halobenzoic acid of Formula VIII, wherein R18 is Br, is treated with a base, such as f(n-BuLi), and DMF in a polar, aprotic solvent, such as THF, at a temperature of about ⁇ 78° C.
  • a base such as f(n-BuLi)
  • DMF a polar, aprotic solvent
  • the resulting formyl benzoic acid is allowed to react with an acid, such as sulfuric acid (H 2 SO 4 ), in the presence of an alcohol, such as ethyl alcohol (EtOH), as in step g, to provide the formyl benzoic acid ethyl ester of Formula IX, wherein R11 is (C ⁇ O)O(C 1 -C 6 alkyl), and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed.
  • an acid such as sulfuric acid (H 2 SO 4 )
  • an alcohol such as ethyl alcohol (EtOH)
  • EtOH ethyl alcohol
  • the vinyl benzoic acid ester of Formula VIIb1 is accessed via reaction of the compounds of Formula IX, with a base, such as potassium carbonate (K 2 CO 3 ), and methyl triphenyl phosphonium bromide in a polar aprotic solvent, such as 1,4-dioxane, at ambient temperature, as in step h of Scheme III.
  • a base such as potassium carbonate (K 2 CO 3 )
  • methyl triphenyl phosphonium bromide in a polar aprotic solvent, such as 1,4-dioxane
  • step i of Scheme IV the halobenzoic acid of Formula VIII, wherein R18 is Br, R11 is (C ⁇ O)OH, and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, is treated with di-tert-butyl dicarbonate in the presence of a base, such as TEA and a catalytic amount of 4-(dimethylamino)pyridine (DMAP) in a polar aprotic solvent, such as THF, at ambient temperature.
  • a base such as TEA
  • DMAP 4-(dimethylamino)pyridine
  • the resulting benzoic acid tert-butyl ester is allowed to react with vinyl boronic anhydride pyridine complex in the presence of a palladium catalyst, such a tetrakis(triphenylphospine)palladium(0) (Pd(PPh 3 ) 4 ), and a base, such as K 2 CO 3 , in a non-reactive solvent such as toluene at reflux temperature, as in step j, to provide the vinyl benzoic acid ester of Formula VIIb2, wherein R11 is (C ⁇ O)O(C 1 -C 6 alkyl), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed.
  • a palladium catalyst such as tetrakis(triphenylphospine)palladium(0) (Pd(PPh 3 ) 4
  • a base such as K 2 CO 3
  • step k of Scheme V the vinyl benzoic acid ester of Formula VIIb2, wherein R10 is Br, R11 is (C ⁇ O)O(C 1 -C 6 alkyl), and R8, R9, R12, R13, X1, X2, and X3 are as previously defined, can be further transformed into the corresponding vinyl benzoic acid ester of Formula VIIb3, wherein R10 is CN, R11 is (C ⁇ O)O(C 1 -C 6 alkyl), and R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with copper(I) cyanide (CuCN) in a polar aprotic solvent, such as DMF, at 140° C.
  • CuCN copper(I) cyanide
  • Coupling of the compounds of Formula V with the compounds of Formula VIIa, VIIb1, VIIb2 and VIIb3 can be accomplished as in Schemes VI, VII, and VIII.
  • step 1 of Scheme VI a compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the vinylbenzamide of Formula VIIa, wherein R11 is (C ⁇ O)N(R14)(R15), and R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of copper(I) chloride (CuCl) and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C.
  • CuCl copper(I) chloride
  • 2,2-bipyridyl such as 1,2-dichlorobenzene
  • R11 is (C ⁇ O)N(R14)(R15)
  • R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed.
  • step l of Scheme VII the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the vinylbenzoic acid ester of Formula VIIb1, wherein R11 is (C ⁇ O)O(C 1 -C 6 alkyl), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C.
  • a solvent such as 1,2-dichlorobenzene
  • R11 is (C ⁇ O)O(C 1 -C 6 alkyl), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed.
  • the compounds of Formula Xa are then converted to the molecules of Formula One, wherein R11 is (C ⁇ O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed, by either a two-step process as disclosed in steps m and n or in one step as disclosed in step o.
  • step m of Scheme VII the ester of Formula Xa is saponified to the corresponding acid under acidic conditions, such as about 11 Normal (N) hydrochloric acid (HCl), in a polar aprotic solvent, such as 1,4-dioxane, at about 100° C.
  • acidic conditions such as about 11 Normal (N) hydrochloric acid (HCl)
  • a polar aprotic solvent such as 1,4-dioxane
  • the acid can subsequently be coupled to an amine (HN(R14)(R15)), wherein R14 and R15 are as previously disclosed using peptide coupling reagents, such as 1-hydroxybenzotriazole (HOBt), N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (EDC.HCl), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP), 1-hydroxy-7-azabenzotriazole (HOAt), or O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (HBTU) in the presence of a base, such as N,N-diisopropylethylamine (DIPEA) or DMAP
  • the ester of Formula Xa is allowed to react with an amine (HN(R14)(R15)) in the presence of a solution of trimethylaluminum in toluene in a non-reactive solvent, such as CH 2 Cl 2 , at ambient temperature, as in step o of Scheme VII, to access the molecules of Formula One, wherein R11 is (C ⁇ O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed.
  • a non-reactive solvent such as CH 2 Cl 2
  • step l of Scheme VIII the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the vinylbenzoic acid ester of Formula VIIb2 or VIIb3, wherein R11 is (C ⁇ O)O(C 1 -C 6 alkyl), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C.
  • a solvent such as 1,2-dichlorobenzene
  • R11 is (C ⁇ O)OH
  • R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed.
  • the compounds of Formula Xb are then converted to the molecules of Formula One, wherein R11 is (C ⁇ O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed, in one step as disclosed in step n.
  • the acid of Formula Xb can be coupled to an amine (HN(R14)(R15)), wherein R14 and R15 are as previously disclosed, using peptide coupling reagents, such as 1-hydroxybenzotriazole (HOBt), N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (EDC.HCl), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP), 1-hydroxy-7-azabenzotriazole (HOAt), or O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (HBTU) in the presence of a base, such as DIPEA or DMAP to give the molecules of Formula One
  • a base such as
  • step j of Scheme IX the halobenzoketone of Formula VIIIb, wherein R18 is Br, R10 and R11 together form a linkage, having 3-4 carbon atoms and an oxo substituent and with the ring carbon atoms form a 5- or 6-membered cyclic ring, and R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, is allowed to react with vinyl boronic anhydride pyridine complex in the presence of a palladium catalyst, such as Pd(PPh 3 ) 4 , and a base, such as K 2 CO 3 , in a non-reactive solvent such as toluene at reflux temperature, to provide the vinyl benzoketone of Formula VIIb4, wherein R10 and R11 together form a linkage, having 3-4 carbon atoms and an oxo substituent and with the ring carbon atoms form a 5- or 6-membered ring, and R8, R9, R12, R13,
  • step l of Scheme X the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the vinylbenzoketone of Formula VIIb4 as previously disclosed, wherein R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C.
  • a solvent such as 1,2-dichlorobenzene
  • R10 and R11 together form a linkage, having 3-4 carbon atoms and an oxo substituent and with the ring carbon atoms form a 5- or 6-membered ring
  • R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed.
  • the compounds of Formula Xc are then converted to the molecules of Formula Xd, wherein R10 and R11 together form a linkage, having 3-4 carbon atoms and an oxime [(C ⁇ N)(OH)] substituent and with the ring carbon atoms form a 5- or 6-membered ring, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, in step p.
  • step p of Scheme X the ketone of Formula Xc is allowed to react with hydroxylamine hydrochloride in the presence of sodium acetate and in a polar protic solvent, such as EtOH, at a temperature of about 78° C., to give the molecules of Formula Xd as previously disclosed.
  • a polar protic solvent such as EtOH
  • the compounds of Formula Xc are also converted to the molecules of Formula Xe, wherein R10 and R11 together form a linkage, having 3-4 carbon atoms and an amine substituent and with the ring carbon atoms form a 5- or 6-membered ring, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, as demonstrated in step q of Scheme XI.
  • the ketone of Formula Xc is allowed to react with ammonium acetate in the presence of sodium cyanoborohydride and in a polar protic solvent, such as CH 3 OH, at a temperature of about 65° C., to give the molecules of Formula Xe.
  • the compounds of Formula Xe are converted to the molecules of Formula One, wherein R10 and R11 together form a linkage as previously disclosed in (u), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously, in one step as disclosed in steps r or s.
  • step r of Scheme XII the amine of Formula Xe is allowed to react with an isocyanate in a polar, aprotic solvent such as diethyl ether at ambient temperature to provide the molecules of Formula One as previously disclosed.
  • step s of Scheme XII the amine of Formula Xe is coupled to an acid with HOBt.H 2 O and EDC.HCl in the presence of a base, such as DIPEA, in a non-reactive solvent, such as CH 2 Cl 2 , to give the molecules of Formula One, as previously disclosed.
  • a base such as DIPEA
  • a non-reactive solvent such as CH 2 Cl 2
  • step t of Scheme XIII the vinyl benzyl chloride of Formula XIa, wherein R11 is —CH 2 Cl and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously defined, can be transformed into the corresponding phthalimide-protected benzyl amine of Formula XIIa, wherein R11 is CH 2 N(Phthalimide), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with potassium phthalimide in a polar aprotic solvent, such as DMF, at 70° C.
  • a polar aprotic solvent such as DMF
  • step u of Scheme XIV the 4-methylbenzonitrile of Formula XIIIa, wherein R11 is CH 3 and R9, R10, R12, R13, X1, X2, and X3 are as previously defined, can be transformed into the corresponding benzyl bromide of Formula XIVa, wherein R11 is CH 2 Br and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with N-bromosuccinimide (NBS) and azobisisobutyronitrile (AIBN) in a non-reactive solvent, such as carbon tetrachloride at 77° C.
  • NBS N-bromosuccinimide
  • AIBN azobisisobutyronitrile
  • the nitrile group (CN) of Formula XIVa can be reduced to the corresponding aldehyde of Formula XVa, wherein R11 is CH 2 Br and R9, R10, R12, R13, X1, X2, and X3 are as previously defined via reaction with diisobutylaluminum hydride (DIBAL-H) in an aprotic solvent, such as toluene, at 0° C., followed by quenching with 1.0 M hydrochloric acid (HCl) as in step v of Scheme XIV.
  • DIBAL-H diisobutylaluminum hydride
  • HCl hydrochloric acid
  • the compound of Formula XVa can be further transformed to the corresponding phthalimide-protected benzyl amine of Formula XVIa, wherein R11 is CH 2 N(Phthalimide) and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with potassium phthalimide in a polar aprotic solvent, such as DMF, at 60° C. as in step t of Scheme XIV.
  • a polar aprotic solvent such as DMF
  • the aldehyde of Formula XVIa can be converted to the olefin of Formula XIIb, wherein R11 is CH 2 N(Phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with methyl triphenyl phosphonium bromide in a polar aprotic solvent, such as 1,4-dioxane, in the presence of a base, such as K 2 CO 3 , at ambient temperature.
  • a polar aprotic solvent such as 1,4-dioxane
  • the aldehyde of Formula XVa wherein R11 is CH 2 Br and R9, R10, R12, R13, X1, X2, and X3 are as previously defined, can be reacted with a nucleophile, such as 2-aminopyridine, in a polar aprotic solvent, such as N,N-dimethylacetamide (DMA), in the presence of a base, such as K 2 CO 3 , at ambient temperature to provide the compound of Formula XVII, wherein R11 is CH 2 NH(2-pyridine) and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, as in step x of Scheme XV.
  • a nucleophile such as 2-aminopyridine
  • a polar aprotic solvent such as N,N-dimethylacetamide (DMA)
  • DMA N,N-dimethylacetamide
  • step w of Scheme XV the compound of Formula XVII can be converted to the olefin of Formula XVIII, wherein R11 is CH 2 NH(2-pyridine) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed.
  • the compound of Formula XIX can be reacted with the compounds of Formula XX, wherein R10 and R11 are Cl, X1 is N, and R9, R13, X2, and X3 are as previously disclosed, in the presence of a base, such as sodium hydride (NaH), and a polar aprotic solvent, such as DMF, at ambient temperature to provide the compounds of Formula XXI, wherein R10 is Cl, R11 is (CH)NH 2 CO 2 CH 2 CH 3 , X1 is N, and R9, R13, X2, and X3 are as previously defined.
  • a base such as sodium hydride (NaH)
  • a polar aprotic solvent such as DMF
  • Hydrolysis and decarboxylation of the compounds of Formula XXI can be accomplished by reaction under acidic conditions, such as with 3 N HCl, at reflux temperature, to afford the compounds of Formula XXII, wherein R10 is Cl, R11 is CH 2 NH 2 .HCl, X1 is N, and R9, R13, X2, and X3 are as previously disclosed, as in step aa in Scheme XVI.
  • the compounds of Formula XXII can be further transformed to the corresponding phthalimide-protected benzyl amines of Formula XXIIIa, wherein R10 is Cl, R11 is CH 2 N(Phthalimide), X1 is N, and R9, R13, X1, X2, and X3 are as previously disclosed, by reaction with phthalic anhydride in the presence of a base, such as TEA, and an aprotic solvent, such as toluene, at reflux temperature as in step ab of Scheme XVI.
  • a base such as TEA
  • an aprotic solvent such as toluene
  • the bromide of Formula XXIIIa can be converted to the olefin of Formula XIIc, wherein R10 is Cl, R11 is CH 2 N(Phthalimide), X1 is N, and R8, R9, R13, X2 and X3 are as previously disclosed, by reaction with vinyl boronic anhydride pyridine complex in the presence of a palladium catalyst, such as Pd(PPh 3 ) 4 , and a base, such as K 2 CO 3 , in a non-reactive solvent such as toluene at reflux temperature, as in step ac of Scheme XVI.
  • a palladium catalyst such as Pd(PPh 3 ) 4
  • a base such as K 2 CO 3
  • step u of Scheme XVII the 4-methylnaphthonitrile of Formula XIIIb, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH 3 , and R12, R13, X1 and X2 are as previously defined, can be transformed into the corresponding naphthyl bromide of Formula XIVb, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH 2 Br, and R12, R13, X1 and X2 are as previously disclosed, by reaction with N-bromosuccinimide (NBS) and azobisisobutyronitrile (AIBN) in a non-reactive solvent, such as carbon tetrachloride at 77° C.
  • the nitrile group (CN) of Formula XIVb can be reduced to the corresponding aldehyde of Formula XVb, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring (or if desired a non-aromatic ring), R11 is CH 2 Br, and R12, R13, X1 and X2 are as previously defined via reaction with diisobutylaluminum hydride (DIBAL-H) in an aprotic solvent, such as toluene, at 0° C., followed by quenching with 1.0 M HCl as in step v of Scheme XVII.
  • DIBAL-H diisobutylaluminum hydride
  • the compound of Formula XVb can be further transformed to the corresponding phthalimide-protected benzyl amine of Formula XVIb, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH 2 N(Phthalimide), and R12, R13, X1 and X2 are as previously disclosed, by reaction with potassium phthalimide in a polar aprotic solvent, such as DMF, at 60° C. as in step t of Scheme XVII.
  • a polar aprotic solvent such as DMF
  • the aldehyde of Formula XVIb can be converted to the olefin of Formula XIId, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH 2 N(Phthalimide), and R8, R12, R13, X1 and X2 are as previously disclosed, by reaction with methyl triphenyl phosphonium bromide in a polar aprotic solvent, such as 1,4-dioxane, in the presence of a base, such as K 2 CO 3 , at ambient temperature.
  • a polar aprotic solvent such as 1,4-dioxane
  • the compound of Formula XXIV wherein R11 is NHNH 2 .HCl and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, can be transformed into the corresponding phthalimide-protected hydrazine of Formula XXV, wherein R11 is NHN(Phthalimide) and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with phthalic anhydride in glacial acetic acid at reflux temperature as in step ad of Scheme XVIII.
  • the bromide of Formula XXV can be converted to the olefin of Formula XIIe, wherein R11 is NHN(Phthalimide) and R8, R9, R10, R13, X1, X2 and X3 are as previously disclosed, by reaction with vinyl boronic anhydride pyridine complex in the presence of a palladium catalyst, such as Pd(PPh 3 ) 4 , and a base, such as K 2 CO 3 , in a polar aprotic solvent such as 1,2-dimethoxyethane at 150° C. under microwave conditions, as in step ae of Scheme XVIII.
  • a palladium catalyst such as Pd(PPh 3 ) 4
  • a base such as K 2 CO 3
  • step af of Scheme XIX the compound of Formula XXVI, wherein R11 is B(OH) 2 , and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react with 2-hydroxyisoindoline-1,3-dione in the presence of CuCl and pyridine in a solvent, such as 1,2-dichlorobenzene, at ambient temperature to provide the compound of Formula XIIf, wherein R11 is ON(Phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed.
  • a solvent such as 1,2-dichlorobenzene
  • step l of Scheme XX the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIIa, wherein R11 is CH 2 N(Phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C.
  • a solvent such as 1,2-dichlorobenzene
  • the compounds of Formula XXVIIIa can be transformed into the compounds of Formula One, wherein R11 is CH 2 N(C ⁇ O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by acylation with an anhydride, such as acetic anhydride, and a base, such as TEA, in a non-reactive solvent such as CH 2 Cl 2 at 0° C. as in step ah 1 of Scheme XX.
  • anhydride such as acetic anhydride
  • a base such as TEA
  • step l of Scheme XXI the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIIb, wherein R11 is CH 2 N(Phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C.
  • a solvent such as 1,2-dichlorobenzene
  • the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH 2 N(C ⁇ O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with an acid in the presence of HOBt.H 2 O, EDC.HCl and a base, such as DIPEA, in a polar aprotic solvent, such as DMF, as in step ah 2a of Scheme XXI.
  • the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH 2 N(C ⁇ S)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with a thioacid in the presence of HOBt.H 2 O, EDC.HCl and a base, such as DIPEA, in a polar aprotic solvent, such as DMF, as in step ah 2 of Scheme XXI.
  • the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH 2 N(C ⁇ O)N(R14)(R15) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, in two steps.
  • the first step (step ah 3a of Scheme XXI) involves reaction with an aldehyde in a polar protic solvent such as MeOH, followed by reaction with sodium borohydride.
  • the second step involves acylation with an acid chloride, such as cyclopropylcarbonyl chloride, and a base, such as TEA, in a non-reactive solvent such as CH 2 Cl 2 at ambient temperature of Scheme XXI.
  • an acid chloride such as cyclopropylcarbonyl chloride
  • a base such as TEA
  • the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH 2 N(C ⁇ O)N(R14)(R15) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with an isocyanate (step ai 1 of Scheme XXI) or a carbamoyl chloride (step ai 2 of Scheme XXI) in the presence of a base such as TEA and in a non-reactive solvent such as CH 2 Cl 2 at 0° C.
  • a base such as TEA
  • a non-reactive solvent such as CH 2 Cl 2 at 0° C.
  • the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH 2 N(C ⁇ S)N(R14)(R15) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with an isothiocyanate in the presence of a base such as TEA and in a non-reactive solvent such as CH 2 Cl 2 at 0° C., as in steps aj of Scheme XXI.
  • the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH 2 N(C ⁇ O)O(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with a dicarbonate, such as di-tert-butyl dicarbonate in the presence of a base such as TEA and in a non-reactive solvent such as CH 2 Cl 2 at ambient temperature, as in steps ak of Scheme XXI.
  • a dicarbonate such as di-tert-butyl dicarbonate
  • a base such as TEA
  • a non-reactive solvent such as CH 2 Cl 2 at ambient temperature
  • the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH 2 N(C ⁇ O)(C ⁇ O)O(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with a chlorooxalic acid ester, such as 2-chloro-2-oxoacetate in the presence of a base such as TEA and in a non-reactive solvent such as CH 2 Cl 2 at 0° C., as in steps al of Scheme XXI.
  • a chlorooxalic acid ester such as 2-chloro-2-oxoacetate
  • a base such as TEA
  • a non-reactive solvent such as CH 2 Cl 2 at 0° C.
  • step l of Scheme XXII the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIIc, wherein R10 is Cl, R11 is CH 2 N(Phthalimide), X1 is N, and R8, R9, R12, R13, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C.
  • a solvent such as 1,2-dichlorobenzene
  • the compounds of Formula XXVIIIc can be transformed into the compounds of Formula One, wherein R10 is Cl, R11 is CH 2 N(C ⁇ O)(R14), X1 is N, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X2, and X3 are as previously disclosed, by reaction with an acid in the presence of HOBt.H 2 O, EDC.HCl and a base, such as DIPEA, in a polar aprotic solvent, such as CH 2 Cl 2 , as in step ah 2b of Scheme XXII.
  • step l of Scheme XXIII the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIId, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring (or if desired a non-aromatic ring), R11 is CH 2 N(Phthalimide) and R8, R9, R12, R13, X1 and X2 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C.
  • a solvent such as 1,2-dichlorobenzene
  • the compounds of Formula XXVIIId can be transformed into the compounds of Formula One, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH 2 N(C ⁇ O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1 and X2 are as previously disclosed, by reaction with an acid in the presence of HOBt.H 2 O, EDC.HCl and a base, such as DIPEA, in a polar aprotic solvent, such as CH 2 Cl 2 , as in step ah 2b of Scheme XXIII.
  • the compounds of Formula XXVIIId can be transformed into the compounds of Formula One, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH 2 N(C ⁇ O)N(R14)(R15) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1 and X2 are as previously disclosed, by reaction with an isocyanate in the presence of a base such as TEA and in a non-reactive solvent such as CH 2 Cl 2 at 0° C. as in step ai 1 of Scheme XXIII.
  • a base such as TEA
  • a non-reactive solvent such as CH 2 Cl 2 at 0° C.
  • step l of Scheme XXIV the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIIe, wherein R11 is NHN(Phthalimide) and R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C.
  • a solvent such as 1,2-dichlorobenzene
  • the compounds of Formula XXVIIIe can be transformed into the compounds of Formula One, wherein R11 is NHN(C ⁇ O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with an acid in the presence of HOBt.H 2 O, EDC.HCl and a base, such as DIPEA, in a polar aprotic solvent, such as CH 2 Cl 2 , as in step ah 2b of Scheme XXIV.
  • step l of Scheme XXV the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIIf, wherein R11 is ON(Phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C.
  • a solvent such as 1,2-dichlorobenzene
  • the compounds of Formula XXVIIIf can be transformed into the compounds of Formula One, wherein R11 is ON(C ⁇ O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with an acid in the presence of HOBt.H 2 O, EDC.HCl and a base, such as DIPEA, in a polar aprotic solvent, such as CH 2 Cl 2 , as in step ah 2b of Scheme XXV.
  • step l of Scheme XXVI the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XVIII, wherein R11 is CH 2 NH(2-pyridine) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C.
  • a solvent such as 1,2-dichlorobenzene
  • R11 is CH 2 NH(2-pyridine)
  • R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed.
  • the compounds of Formula One can be further elaborated by standard methods.
  • the thioether when R11 contains a thioether, the thioether can be oxidized to the sulfone by treatment with oxone in the presence of an acetone:water mixture at ambient temperature.
  • R11 contains an oxalate ester the compound of Formula One can be transformed into the corresponding oxalamide by reaction with an amine hydrochloride and a solution of trimethylaluminum in toluene in a non-reactive solvent such as CH 2 Cl 2 .
  • a fluorobenzaldehyde of Formula XXIX wherein R10, X1, X2, and X3 are as previously disclosed can be converted to a (1,2,4-triazol-1-yl)benzaldehyde of Formula XXX, wherein R11 is a substituted or unsubstituted 1,2,4-triazol-1-yl group, and R10, X1, X2, and X3 are as previously disclosed by reaction with a substituted or unsubstituted 1,2,4-triazole in the presence of a base, such as potassium carbonate, in a solvent such as DMF as in step aj.
  • a base such as potassium carbonate
  • step ak the (1,2,4-triazol-1-yl)benzaldehyde of Formula XXX is converted to a (1,2,4-triazol-1-yl)vinyl benzene of Formula XXXIa wherein R11 is a substituted or unsubstituted 1,2,4-triazol-1-yl group, and R8, R10, X1, X2, and X3 are as previously disclosed by reaction with triphenyl phosphonium bromide in the presence of a base, such as potassium carbonate, in an aprotic solvent, such as 1,4-dioxane.
  • a base such as potassium carbonate
  • step al the bromofluorobenzene is reacted with a substituted or unsubstituted 1,2,4-triazole in the presence of a base, such as potassium carbonate, in a solvent such as DMF to generate the (1,2,4-triazol-1-yl)bromobenzene.
  • step cl the (1,2,4-triazol-1-yl)bromobenzene is reacted with vinyl boronic anhydride pyridine complex in the presence of a catalyst, such as Pd(PPh 3 ) 4 , and a base, such as potassium carbonate in a solvent such as toluene.
  • step l a compound of Formula V, wherein Y is Br, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and a vinylbenzene of Formula XXXIa or XXXIb, wherein R11 is a substituted or unsubstituted 1,2,4-triazol-1-yl group, and R8, R9, R10, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C.
  • a solvent such as 1,2-dichlorobenzene
  • R11 is a substituted or unsubstituted 1,2,4-triazol-1-yl group
  • R1, R2, R3, R4, R5, R6, R7, R8, R10, X1, X2, and X3 are as previously disclosed.
  • step am the 3-nitro-1,2,4-triazol-1-yl group is reduced to a 3-amino-1,2,4-triazol-1-yl group in the presence of zinc dust and ammonium chloride in a protic solvent, such as MeOH.
  • a protic solvent such as MeOH.
  • the 3-amino-1,2,4-triazol-1-yl group is acylated with an acid chloride, such as cyclopropylcarbonyl chloride or acetyl chloride, in the presence of a base, such as TEA, in a solvent such as CH 2 Cl 2 .
  • step ao of Scheme XXXI a bromophenyl methyl ketone of Formula XXXIV wherein R10, X1, X2, and X3 are as previously disclosed is converted to an phenyl methyl ketone of the Formula XXXV wherein R11 is a 1,2,4-triazol-1-yl group, and R10, X1, X2, and X3 are as previously disclosed by treatment with 1,2,4-triazole in the presence of a base, such as cesium carbonate, and a catalyst, such as copper iodide, in a solvent, such as DMF.
  • a base such as cesium carbonate
  • a catalyst such as copper iodide
  • step ap the 1,2,4-triazolylacetophenone of Formula XXXV is converted to the trimethylsilyl enol ether of Formula XXXVI by treatment with trimethylsilyl triflluoromethanesulfonate in the presence of a base, such as TEA, in an aprotic solvent, such as CH 2 Cl 2 .
  • a base such as TEA
  • aprotic solvent such as CH 2 Cl 2 .
  • step aq the silyl enol ether is reacted with a compound of Formula V, wherein Y is Br, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene at a temperature of about 180° C. to generate a ketone of the Formula XXXVII, wherein R11 is a 1,2,4-triazol-1-yl group, and R1, R2, R3, R4, R5, R6, R7, R10, X1, X2, and X3 are as previously disclosed.
  • a solvent such as 1,2-dichlorobenzene
  • step ar the ketone of the Formula XXXVII is treated with methylmagnesium bromide in an aprotic solvent, such as THF to generate the tertiary alcohol.
  • the tertiary alcohol then undergoes an elimination reaction when treated with a catalytic amount of p-toluenesulfonic acid in a solvent, such as toluene, when heated to a temperature to allow azeotropic removal of water to produce compounds of Formula One wherein R11 is a 1,2,4-triazol-1-yl group, R8 is methyl, and R1, R2, R3, R4, R5, R6, R7, R10, X1, X2, and X3 are as previously disclosed, as in step as.
  • a compound of Formula XXXIX wherein X1, X2, and X3 are as previously disclosed is converted to a molecule of Formula XL, wherein X1, X2, and X3 are as previously disclosed, by treatment with a reducing agent, such as sodium cyanoborohydride, in a solvent, such as acetic acid, as in step au.
  • a reducing agent such as sodium cyanoborohydride
  • a solvent such as acetic acid
  • step au the nitrogen atom is protected with a tert-butyloxycarbonyl (BOC) group by reaction with di-tert-butyl dicarbonate in the presence of a catalyst, such as DMAP, in a solvent, such as acetonitrile.
  • BOC tert-butyloxycarbonyl
  • the bromide of Formula XL can be converted to the olefin of Formula XLI, wherein R8, X1, X2 and X3 are as previously disclosed, by reaction with potassium vinyl trifluoroborate in the presence of a palladium catalyst, such as PdCl 2 (dppf), and a base, such as K 2 CO 3 , in a polar aprotic solvent such as DMSO at 100° C., as in step aw.
  • a palladium catalyst such as PdCl 2 (dppf)
  • a base such as K 2 CO 3
  • step ax a compound of Formula XXXIX, wherein X1, X2, and X3 are as previously disclosed is converted to a molecule of Formula XLII, wherein X1, X2, and X3 are as previously disclosed in two steps.
  • step ax the olefin is formed by treatment of the bromide with potassium vinyl trifluoroborate in the presence of a palladium catalyst, such as PdCl 2 , and a ligand, such as triphenylphosphine, and a base, such as Cs 2 CO 3 , in a solvent mixture such as THF/WATER.
  • a palladium catalyst such as PdCl 2
  • a ligand such as triphenylphosphine
  • base such as Cs 2 CO 3
  • step ay the nitrogen atom is protected with a tert-butyloxycarbonyl (BOC) group by reaction with di-tert-butyl dicarbonate in the presence of a catalyst, such as DMAP, in a solvent, such as acetonitrile.
  • a catalyst such as DMAP
  • step l of Scheme XXXV the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XLI or XLII, wherein R8, X1, X2 and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 150° C. to provide the corresponding compounds of Formula XLIIIa or XLIIIb, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed.
  • a solvent such as 1,2-dichlorobenzene
  • step ba the indoline is treated with sodium nitrite (NaNO 2 ), in an acid, such as concentrated HCl, at a temperature around 5° C., to form the nitrosoindole.
  • step bb the nitrosoindole is reacted with ammonium chloride in the presence of zinc powder in a protic solvent, such as MeOH.
  • step be compounds of the Formula XLV are transformed into compounds of the Formula XLVI, wherein X4 is N(R14)(C( ⁇ O)R14) and R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed, by treatment with and acid, such as 3,3,3-trifluoropropanoic acid, PyBOP, and a base, such as DIPEA, in a polar aprotic solvent, such as CH 2 Cl 2 .
  • acid such as 3,3,3-trifluoropropanoic acid, PyBOP
  • DIPEA a base
  • Compounds of the Formula XLVII can be transformed into compounds of the Formula XLVIII wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed, by reaction with 4-nitrophenyl-2-((tert-butoxycarbonyl)amino)acetate in the presence of potassium fluoride and a crown ether, such as 18-crown-6-ether, in a solvent, such as acetonitrile, as in step be.
  • Compounds of the Formula XLVIII can be transformed into compounds of the Formula XLIX, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed in two steps.
  • step bf the Boc group is removed by treatment with trifluoroacetic acid, in a solvent such as CH 2 Cl 2 .
  • step bg the amine is treated with 3,3,3-trifluoropropanoic acid, PyBOP, and a base, such as DIPEA, in a polar aprotic solvent, such as CH 2 Cl 2 .
  • step bj the olefin of the Formula LIII wherein X1, X2, and X3 are as previously disclosed is formed by treatment of the bromide with potassium vinyl trifluoroborate in the presence of a palladium catalyst, such as PdCl 2 (dppf), and a base, such as K 2 CO 3 , in a solvent mixture such as DMSO.
  • a palladium catalyst such as PdCl 2 (dppf)
  • a base such as K 2 CO 3
  • a solvent mixture such as DMSO.
  • Compounds of the Formula LIV, wherein X1, X2, and X3 are as previously disclosed can be formed from compounds of the Formula LIII by reaction with ethyl bromoacetate, in the presence of a base, such as Cs 2 CO 3 , in a solvent, such as DMF.
  • step l of Scheme XXXIX the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compound of Formula LIV, wherein R8, X1, X2 and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the corresponding compound of Formula LV, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed.
  • a solvent such as 1,2-dichlorobenzene
  • the compound of Formula LV can be further transformed into a compound of the Formula LVI, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed, in two steps.
  • step bl the ester is hydrolyzed to the acid in the presence of HCl and acetic acid, at a temperature of about 100° C.
  • step bm the acid is treated with an amine, such as 2,2,2-trifluoroethylamine, PyBOP, and a base, such as DIPEA, in a polar aprotic solvent, such as CH 2 Cl 2 .
  • step bn of Scheme XL carboxylic acids of the Formula LVII, wherein R11 is C( ⁇ O)OH and R8, R10, X1, X2, and X3 are as previously disclosed and compounds of the Formula V, wherein Y is Br and R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as N-methyl pyrrolidine, at a temperature of about 150° C. to afford compounds of Formula LVIII, wherein R11 is (C ⁇ O)OH and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X1, X2, and X3 are as previously disclosed.
  • Compounds of the Formula LVIII can be further transformed to the corresponding benzamides of Formula LIX, wherein R11 is (C ⁇ O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X1, X2, and X3 are as previously disclosed, by treatment with an amine, such as 2-amino-N-(2,2,2-trifluoroethyl)acetamide, PyBOP, and a base, such as DIPEA, in a polar aprotic solvent, such as CH 2 Cl 2 , as in step bo.
  • an amine such as 2-amino-N-(2,2,2-trifluoroethyl)acetamide
  • PyBOP a base
  • DIPEA a base
  • N-bromosuccinimide N-bromosuccinimide
  • triphenyl phosphite 5.06 g, 16.3 mmol
  • reaction mixture was stirred at reflux for 18 h, cooled to 25° C., quenched with 0.5 N HCl solution (50 mL) and extracted with EtOAc (2 ⁇ 50 mL). The combined organic extracts were washed with brine, dried over Na 2 SO 4 , and concentrated under reduced pressure.
  • reaction mixture was stirred at reflux for 18 h, cooled to 25° C., quenched with 1N HCl solution (50 mL) and extracted with CH 2 Cl 2 (2 ⁇ 50 mL). The combined organic extracts were washed with brine, dried over Na 2 SO 4 , and concentrated under reduced pressure.
  • Example 109b Preparation of (E)-N-(1-Acetylpiperidin-4-yl)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC103)
  • the combined CH 2 Cl 2 layer was washed with 3N HCl and saturated NaHCO 3 solution, the separated CH 2 Cl 2 layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford crude compound.
  • the crude compound was purified by column chromatography (SiO 2 , 100-200 mesh; eluting with 2% MeOH in CH 2 Cl 2 ) to afford the title compound as a off white gummy material (0.035 g, 29.%).
  • the reaction mixture was diluted with CH 2 Cl 2 and washed with 3N HCl (2 ⁇ 20 mL), NaHCO 3 (2 ⁇ 20 mL) and brine solution (2 ⁇ ).
  • the separated CH 2 Cl 2 layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford the crude compound.
  • Ethyl 2-(diphenylmethyleneamino)acetate (10.2 g, 38.2 mmol) was added to sodium hydride (NaH; 3.18 g, 133.52 mmol) in DMF (50 mL) at 0° C., and the mixture was stirred for 30 min. To this was added 5-bromo-2,3-dichloropyridine (12.9 g, 57.23 mmol), and the reaction mixture was stirred for 3 h at ambient temperature. The reaction mixture was quenched with 2 N HCl solution and then stirred for 4 h at ambient temperature. The mixture was extracted with EtOAc.
  • Step 1 (E)-1-(Pyridin-2-yl)-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzyl)methanamine
  • Step 2 (E)-N-(Pyridin-2-ylmethyl)-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzyl)cyclopropanecarboxamide
  • reaction mixture was stirred at reflux for 18 h, cooled to 25° C., quenched with 0.5 N HCl solution (50 mL) and extracted with EtOAc (2 ⁇ 50 mL). The combined organic extracts were washed with brine, dried over Na 2 SO 4 , and concentrated under reduced pressure.

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Abstract

This document discloses molecules having the following formula (“Formula One”):
Figure US20170088507A1-20170330-C00001
and processes associated therewith.

Description

    CROSS REFERENCE TO RELATED APPLICATIONS
  • This application is a continuation of, and claims the benefit of, U.S. patent application Ser. No. 14/880,651, which was filed on Oct. 12, 2015, the entire disclosure of which is hereby expressly incorporated by reference, and which is a continuation of, and claims the benefit of, U.S. patent application Ser. No. 14/132,931, which was filed on Dec. 18, 2013, the entire disclosure of which is hereby expressly incorporated by reference, and which claims the benefit of U.S. provisional patent application Ser. No. 61/739,038 filed Dec. 19, 2012, the entire disclosure of which is hereby expressly incorporated by reference.
    • FIELD OF THE DISCLOSURE
  • The invention disclosed in this document is related to the field of processes to produce molecules that are useful as pesticides (e.g., acaricides, insecticides, molluscicides, and nematicides), such molecules, and processes of using such molecules to control pests.
    • BACKGROUND OF THE DISCLOSURE
  • Pests cause millions of human deaths around the world each year. Furthermore, there are more than ten thousand species of pests that cause losses in agriculture. The world-wide agricultural losses amount to billions of U.S. dollars each year.
  • Termites cause damage to all kinds of private and public structures. The world-wide termite damage losses amount to billions of U.S. dollars each year.
  • Stored food pests eat and adulterate stored food. The world-wide stored food losses amount to billions of U.S. dollars each year, but more importantly, deprive people of needed food.
  • There is an acute need for new pesticides. Certain pests are developing resistance to pesticides in current use. Hundreds of pest species are resistant to one or more pesticides. The development of resistance to some of the older pesticides, such as DDT, the carbamates, and the organophosphates, is well known. But resistance has even developed to some of the newer pesticides, for example, imidacloprid.
  • Therefore, for many reasons, including the above reasons, a need exists for new pesticides.
    • DEFINITIONS
  • The examples given in the definitions are generally non-exhaustive and must not be construed as limiting the invention disclosed in this document. 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.
  • “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, and hexenyl.
  • “Alkenyloxy” means an alkenyl further consisting of a carbon-oxygen single bond, for example, allyloxy, butenyloxy, pentenyloxy, hexenyloxy.
  • “Alkoxy” means an alkyl further consisting of a carbon-oxygen single bond, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and tert-butoxy.
  • “Alkyl” means an acyclic, saturated, branched or unbranched, substituent consisting of carbon and hydrogen, for example, methyl, ethyl, (C3)alkyl which represents n-propyl and isopropyl), (C4)alkyl which represents n-butyl, sec-butyl, isobutyl, and tert-butyl.
  • “Alkynyl” means an acyclic, unsaturated (at least one carbon-carbon triple bond), branched or unbranched, substituent consisting of carbon and hydrogen, for example, ethynyl, propargyl, butynyl, and pentynyl.
  • “Alkynyloxy” means an alkynyl further consisting of a carbon-oxygen single bond, for example, pentynyloxy, hexynyloxy, heptynyloxy, and octynyloxy.
  • “Aryl” means a cyclic, aromatic substituent consisting of hydrogen and carbon, for example, phenyl, naphthyl, and biphenyl.
  • “(Cx-Cy)” where the subscripts “x” and “y” are integers such as 1, 2, or 3, means the range of carbon atoms for a substituent—for example, (C1-C4)alkyl means methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl, each individually.
  • “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, norbornenyl, bicyclo[2.2.2]octenyl, tetrahydronaphthyl, hexahydronaphthyl, and octahydronaphthyl.
  • “Cycloalkenyloxy” means a cycloalkenyl further consisting of a carbon-oxygen single bond, for example, cyclobutenyloxy, cyclopentenyloxy, norbornenyloxy, and bicyclo[2.2.2]octenyloxy.
  • “Cycloalkyl” means a monocyclic or polycyclic, saturated substituent consisting of carbon and hydrogen, for example, cyclopropyl, cyclobutyl, cyclopentyl, norbornyl, bicyclo[2.2.2]octyl, and decahydronaphthyl.
  • “Cycloalkoxy” means a cycloalkyl further consisting of a carbon-oxygen single bond, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, norbornyloxy, and bicyclo[2.2.2]octyloxy.
  • “Halo” means fluoro, chloro, bromo, and iodo.
  • “Haloalkoxy” means an alkoxy further consisting of, from one to the maximum possible number of identical or different, halos, for example, fluoromethoxy, trifluoromethoxy, 2,2-difluoropropoxy, chloromethoxy, trichloromethoxy, 1,1,2,2-tetrafluoroethoxy, and pentafluoroethoxy.
  • “Haloalkyl” means an alkyl further consisting of, from one to the maximum possible number of, identical or different, halos, for example, fluoromethyl, trifluoromethyl, 2,2-difluoropropyl, 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, sulfur, or oxygen. In the case of sulfur, that atom can be in other oxidation states such as a sulfoxide and sulfone. Examples of aromatic heterocyclyls include, but are not limited to, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl, benzoxazolyl, benzothienyl, benzothiazolyl, cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolinyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolinyl, thiazolyl, thienyl, triazinyl, and triazolyl. Examples of fully saturated heterocyclyls include, but are not limited to, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl and tetrahydropyranyl. Examples of partially unsaturated heterocyclyls include, but are not limited to, 1,2,3,4-tetrahydroquinolinyl, 4,5-dihydro-oxazolyl, 4,5-dihydro-1H-pyrazolyl, 4,5-dihydro-isoxazolyl, and 2,3-dihydro-[1,3,4]-oxadiazolyl.
  • Additional examples include the following
  • Figure US20170088507A1-20170330-C00002
    • DETAILED DESCRIPTION OF THE DISCLOSURE
  • This document discloses molecules having the following formula (“Formula One”):
  • Figure US20170088507A1-20170330-C00003
  • wherein:
  • (a) R1 is selected from
      • (1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), N(R14)(R15),
      • (2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and NO2,
      • (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2,
      • (4) substituted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more substituents selected from CN and NO2, and
      • (5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C1-C8)alkoxy has one or more substituents selected from CN and NO2;
  • (b) R2 is selected from
      • (1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), N(R14)(R15),
      • (2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and NO2,
      • (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2,
      • (4) substituted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more substituents selected from CN and NO2, and
      • (5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C1-C8)alkoxy has one or more substituents selected from CN and NO2;
  • (c) R3 is selected from
      • (1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), N(R14)(R15),
      • (2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and NO2,
      • (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2,
      • (4) substituted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more substituents selected from CN and NO2, and
      • (5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C1-C8)alkoxy has one or more substituents selected from CN and NO2;
  • (d) R4 is selected from
      • (1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), N(R14)(R15),
      • (2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and NO2,
      • (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2,
      • (4) substituted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more substituents selected from CN and NO2, and
      • (5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C1-C8)alkoxy has one or more substituents selected from CN and NO2;
  • (e) R5 is selected from
      • (1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), N(R14)(R15),
      • (2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and NO2,
      • (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2,
      • (4) substituted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more substituents selected from CN and NO2, and
      • (5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C1-C8)alkoxy has one or more substituents selected from CN and NO2;
  • (f) R6 is a (C1-C8)haloalkyl;
  • (g) R7 is selected from H, F, Cl, Br, I, OH, (C1-C8)alkoxy, and halo(C1-C8)alkoxy;
  • (h) R8 is selected from H, (C1-C8)alkyl, halo(C1-C8)alkyl, OR14, and N(R14)(R15);
  • (i) R9 is selected from H, F, Cl, Br, I, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, OR14, and N(R14)(R15);
  • (j) R10 is selected from
      • (1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, cyclo(C3-C6)alkyl, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), NR14R15, C(═O)H, C(═O)N(R14)(R15), CN(R14)(R15)(═NOH), (C═O)O(C1-C8)alkyl, (C═O)OH, heterocyclyl, (C2-C8)alkenyl, halo(C2-C8)alkenyl, (C2-C8)alkynyl,
      • (2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from OH, (C1-C8)alkoxy, S(C1-C8)alkyl, S(O)(C1-C8)alkyl, S(O)2(C1-C8)alkyl, NR14R15, and
      • (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from (C1-C8)alkoxy, S(C1-C8)alkyl, S(O)(C1-C8)alkyl, S(O)2(C1-C8)alkyl, and N(R14)(R15);
  • (k) R11 is C(═X5)N(H)((C0-C8)alkyl)N(R11a)(C(═X5)(R11b))
      • wherein each X5 is independently selected from O or S, and
      • wherein each R11a is independently selected from H, (C1-C8)alkyl, substituted (C1-C8)alkyl, halo(C1-C8)alkyl, substituted halo(C1-C8)alkyl, cyclo(C3-C8)alkyl, and substituted cyclo(C3-C8)alkyl,
      • wherein each said substituted (C1-C8)alkyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, OC(═O)H, OH, S(C1-C8)alkyl, S(O)(C1-C8)alkyl, S(O)2(C1-C8)alkyl, OS(O)2aryl, N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, wherein each said substituted aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo, wherein each said substituted heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), C(═O)(C1-C8)alkyl, C(═O)(C3-C6)cycloalkyl, S(═O)2(C1-C8)alkyl, NR14R15, and oxo, wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo,
      • wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2,
      • wherein said substituted cyclo(C3-C8)alkyl, has one or more substituents selected from CN and NO2
  • wherein each R11b is independently selected from (C1-C8)alkyl, substituted (C1-C8)alkyl, halo(C1-C8)alkyl, substituted halo(C1-C8)alkyl, cyclo(C3-C8)alkyl, substituted cyclo(C3-C8)alkyl, (C2-C8)alkenyl, and (C2-C8)alkynyl,
      • wherein each said substituted (C1-C8)alkyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, OC(═O)H, OH, S(C1-C8)alkyl, S(O)(C1-C8)alkyl, S(O)2(C1-C8)alkyl, OS(O)2aryl, N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, wherein each said substituted aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo, wherein each said substituted heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), C(═O)(C1-C8)alkyl, C(═O)(C3-C6)cycloalkyl, S(═O)2(C1-C8)alkyl, NR14R15, and oxo, wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo,
      • wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2,
      • wherein said substituted cyclo(C3-C8)alkyl, has one or more substituents selected from CN and NO2;
  • (l) R12 is selected from (v), H, F, Cl, Br, I, CN, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, and cyclo(C3-C6)alkyl;
  • (m) R13 is selected from (v), H, F, Cl, Br, I, CN, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, and halo(C1-C8)alkoxy;
  • (n) each R14 is independently selected from H, (C1-C8)alkyl, (C2-C8)alkenyl, substituted (C1-C8)alkyl, halo(C1-C8)alkyl, substituted halo(C1-C8)alkyl), (C1-C8)alkoxy, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (C1-C8)alkyl-aryl, (C1-C8)alkyl-(substituted-aryl), O—(C1-C8)alkyl-aryl, O—(C1-C8)alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C1-C8)alkyl-heterocyclyl, (C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl-heterocyclyl, O—(C1-C8)alkyl-(substituted-heterocyclyl), N(R16)(R17), (C1-C8)alkyl-C(═O)N(R16)(R17), C(═O)(C1-C8)alkyl, C(═O)(halo(C1-C8)alkyl), C(═O)(C3-C6)cycloalkyl, (C1-C8)alkyl-C(═O)O(C1-C8)alkyl, C(═O)H
      • wherein each said substituted (C1-C8)alkyl has one or more substituents selected from CN, and NO2,
      • wherein each said substituted halo(C1-C8)alkyl), has one or more substituents selected from CN, and NO2,
      • wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo, and
      • wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, (C3-C6)cycloalkyl S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), heterocyclyl, C(═O)(C1-C8)alkyl, C(═O)O(C1-C8)alkyl, and oxo, (wherein said alkyl, alkoxy, and heterocyclyl, may be further substituted with one or more of F, Cl, Br, I, CN, and NO2);
  • (o) each R15 is independently selected from H, (C1-C8)alkyl, (C2-C8)alkenyl, substituted (C1-C8)alkyl, halo(C1-C8)alkyl, substituted halo(C1-C8)alkyl), (C1-C8)alkoxy, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (C1-C8)alkyl-aryl, (C1-C8)alkyl-(substituted-aryl), O—(C1-C8)alkyl-aryl, O—(C1-C8)alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C1-C8)alkyl-heterocyclyl, (C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl-heterocyclyl, O—(C1-C8)alkyl-(substituted-heterocyclyl), N(R16)(R17), (C1-C8)alkyl-C(═O)N(R16)(R17), C(═O)(C1-C8)alkyl, C(═O)(halo(C1-C8)alkyl), C(═O)(C3-C6)cycloalkyl, (C1-C8)alkyl-C(═O)O(C1-C8)alkyl, C(═O)H
      • wherein each said substituted (C1-C8)alkyl has one or more substituents selected from CN, and NO2,
      • wherein each said substituted halo(C1-C8)alkyl), has one or more substituents selected from CN, and NO2,
      • wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo, and
      • wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, (C3-C6)cycloalkyl S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), heterocyclyl, C(═O)(C1-C8)alkyl, C(═O)O(C1-C8)alkyl, and oxo, (wherein said alkyl, alkoxy, and heterocyclyl, may be further substituted with one or more of F, Cl, Br, I, CN, and NO2);
  • (p) each R16 is independently selected from H, (C1-C8)alkyl, substituted-(C1-C8)alkyl, halo(C1-C8)alkyl, substituted-halo(C1-C8)alkyl, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (C1-C8)alkyl-aryl, (C1-C8)alkyl-(substituted-aryl), O—(C1-C8)alkyl-aryl, O—(C1-C8)alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C1-C8)alkyl-heterocyclyl, (C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl-heterocyclyl, O—(C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl
      • wherein each said substituted (C1-C8)alkyl has one or more substituents selected from CN, and NO2,
      • wherein each said substituted halo(C1-C8)alkyl), has one or more substituents selected from CN, and NO2,
      • wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo, and
      • wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo;
  • (q) each R17 is independently selected from H, (C1-C8)alkyl, substituted-(C1-C8)alkyl, halo(C1-C8)alkyl, substituted-halo(C1-C8)alkyl, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (C1-C8)alkyl-aryl, (C1-C8)alkyl-(substituted-aryl), O—(C1-C8)alkyl-aryl, O—(C1-C8)alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C1-C8)alkyl-heterocyclyl, (C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl-heterocyclyl, O—(C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl
      • wherein each said substituted (C1-C8)alkyl has one or more substituents selected from CN, and NO2,
      • wherein each said substituted halo(C1-C8)alkyl), has one or more substituents selected from CN, and NO2,
      • wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo, and
      • wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo;
  • (r) X1 is selected from N and CR12;
  • (s) X2 is selected from N, CR9, and CR13;
  • (t) X3 is selected from N and CR9; and
  • (v) R12 and R13 together form a linkage containing 3 to 4 atoms selected from C, N, O, and S, wherein said linkage connects back to the ring to form a 5 to 6 member saturated or unsaturated cyclic ring, wherein said linkage has at least one substituent X4 wherein X4 is selected from R14, N(R14)(R15), N(R14)(C(═O)R14), N(R14)(C(═S)R14), N(R14)(C(═O)N(R14)(R14)), N(R14)(C(═S)N(R14)(R14)), N(R14)(C(═O)N(R14)((C2-C8)alkenyl)), N(R14)(C(═S)N(R14)((C2-C8)alkenyl)), wherein each R14 is independently selected.
  • In another embodiment of this invention R1 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.
  • In another embodiment of this invention R2 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C8)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.
  • In another embodiment of this invention R3 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.
  • In another embodiment of this invention R4 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.
  • In another embodiment of this invention R5 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.
  • In another embodiment of this invention R2 and R4 are selected from F, Cl, Br, I, CN, and NO2 and R1, R3, and R5 are H.
  • In another embodiment of this invention R2, R3, and R4 are selected from F, Cl, Br, I, CN, and NO2 and R1, and R5 are H.
  • In another embodiment of this invention R2, R3, and R4 are independently selected from F and Cl and R1 and R5 are H.
  • In another embodiment of this invention R1 is selected from Cl and H.
  • In another embodiment of this invention R2 is selected from CF3, CH3, Cl, F, and H.
  • In another embodiment of this invention R3 is selected from OCH3, CH3, F, Cl, or H.
  • In another embodiment of this invention R4 is selected from CF3, CH3, Cl, F, and H.
  • In another embodiment of this invention R5 is selected from F, Cl, and H.
  • In another embodiment of this invention R6 may be selected from any combination of one or more of the following—halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, and halo(C8)alkyl.
  • In another embodiment of this invention R6 is trifluoromethyl.
  • In another embodiment of this invention R7 may be selected from any combination of one or more of the following—H, F, Cl, Br, and I.
  • In another embodiment of this invention R7 is selected from H, OCH3, and OH.
  • In another embodiment of this invention R8 may be selected from any combination of one or more of the following—H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, and halo(C8)alkyl.
  • In another embodiment of this invention R8 is selected from CH3 and H.
  • In another embodiment of this invention R9 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.
  • In another embodiment of this invention R10 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, CN, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, halo(C8)alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • In another embodiment of this invention R10 may be selected from any combination of one or more of the following—H, Cl, Br, CH3, and CF3.
  • In another embodiment of this invention R10 is selected from Br, C(═NOH)NH2, C(═O)H, C(═O)NH2, C(═O)OCH2CH3, C(═O)OH, CF3, CH2CH3, CH2OH, CH3, Cl, CN, F, H, NH2, NHC(═O)H, NHCH3, NO2, OCH3, OCHF2, and pyridyl.
  • In another embodiment R11 is selected from C(═O)N(H)N(CH3)(C(═O)CH2CH3), C(═O)N(H)N(CH3)(C(═O)CH2CF3), C(═O)N(H)N(CH3)(C(═O)cyclopropyl), C(═O)N(H)N(CH3)(C(═S)CH2CH3), C(═O)N(H)N(CH3)(C(═O)CH2CN), C(═O)N(H)N(CH3)(H3)(C(═S)cyclopropyl), C(═O)N(H)N(CH3)(C(═O)CH(CF3)2), C(═O)N(H)N(CH3)(C(═O)CF(CF3)2), C(═O)N(H)N(CH3)(C(═O)CF2CF3), and C(═O)N(H)N(CH3)(C(═O)C≡CCH3).
  • In another embodiment of this invention R12 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.
  • In another embodiment of this invention R12 is selected from CH3, and H.
  • In another embodiment of this invention R13 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.
  • In another embodiment of this invention R13 is selected from CH3, Cl and H.
  • In another embodiment of this invention R12-R13 are a hydrocarbyl linkage containing CH═CHCH═CH.
  • In another embodiment of this invention R14 may be selected from any combination of one or more of the following—H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methyl-aryl, ethyl-aryl, (C3)alkyl-aryl, (C4)alkyl-aryl, (C5)alkyl-aryl, (C6)alkyl-aryl, (C7)alkyl-aryl, (C8)alkyl-aryl, methyl-(substituted-aryl), ethyl-(substituted-aryl), (C3)alkyl-(substituted-aryl), (C4)alkyl-(substituted-aryl), (C5)alkyl-(substituted-aryl), (C6)alkyl-(substituted-aryl), (C7)alkyl-(substituted-aryl), (C8)alkyl-(substituted-aryl), O-methyl-aryl, O-ethyl-aryl, O—(C3)alkyl-aryl, O—(C4)alkyl-aryl, O—(C5)alkyl-aryl, O—(C6)alkyl-aryl, O—(C7)alkyl-aryl, O—(C8)alkyl-aryl, O-methyl-(substituted-aryl), O-ethyl-(substituted-aryl), O—(C3)alkyl-(substituted-aryl), O—(C4)alkyl-(substituted-aryl), O—(C5)alkyl-(substituted-aryl), O—(C6)alkyl-(substituted-aryl), O—(C7)alkyl-(substituted-aryl), O—(C8)alkyl-(substituted-aryl), methyl-heterocyclyl, ethyl-heterocyclyl, (C3)alkyl-heterocyclyl, (C4)alkyl-heterocyclyl, (C5)alkyl-heterocyclyl, (C6)alkyl-heterocyclyl, (C7)alkyl-heterocyclyl, (C8)alkyl-heterocyclyl, methyl-(substituted-heterocyclyl), ethyl-(substituted-heterocyclyl), (C3)alkyl-(substituted-heterocyclyl), (C4)alkyl-(substituted-heterocyclyl), (C5)alkyl-(substituted-heterocyclyl), (C6)alkyl-(substituted-heterocyclyl), (C7)alkyl-(substituted-heterocyclyl), (C8)alkyl-(substituted-heterocyclyl), O-methyl-heterocyclyl, O-ethyl-heterocyclyl, O—(C3)alkyl-heterocyclyl, O—(C4)alkyl-heterocyclyl, O—(C5)alkyl-heterocyclyl, O—(C6)alkyl-heterocyclyl, O—(C7)alkyl-heterocyclyl, O—(C8)alkyl-heterocyclyl, O-methyl-(substituted-heterocyclyl), O-ethyl-(substituted-heterocyclyl), O—(C3)alkyl-(substituted-heterocyclyl), O—(C4)alkyl-(substituted-heterocyclyl), O—(C5)alkyl-(substituted-heterocyclyl), O—(C6)alkyl-(substituted-heterocyclyl), O—(C7)alkyl-(substituted-heterocyclyl), O—(C8)alkyl-(substituted-heterocyclyl), methyl-C(═O)N(R16)(R17), ethyl-C(═O)N(R16)(R17), (C3)alkyl-C(═O)N(R16)(R17), (C4)alkyl-C(═O)N(R16)(R17), (C5)alkyl-C(═O)N(R16)(R17), (C6)alkyl-C(═O)N(R16)(R17), (C7)alkyl-C(═O)N(R16)(R17), and (C8)alkyl-C(═O)N(R16)(R17).
  • In another embodiment of this invention R14 may be selected from any combination of one or more of the following—H, CH3, CH2CF3, CH2-halopyridyl, oxo-pyrrolidinyl, halophenyl, thietanyl, CH2-phenyl, CH2-pyridyl, thietanyl-dioxide, CH2-halothiazolyl, C((CH3)2)-pyridyl, N(H)(halophenyl), CH2-pyrimidinyl, CH2-tetrahydrofuranyl, CH2-furanyl, O—CH2-halopyridyl, and CH2C(═O)N(H)(CH2CF3).
  • In another embodiment of this invention R15 may be selected from any combination of one or more of the following—H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methyl-aryl, ethyl-aryl, (C3)alkyl-aryl, (C4)alkyl-aryl, (C5)alkyl-aryl, (C6)alkyl-aryl, (C7)alkyl-aryl, (C8)alkyl-aryl, methyl-(substituted-aryl), ethyl-(substituted-aryl), (C3)alkyl-(substituted-aryl), (C4)alkyl-(substituted-aryl), (C5)alkyl-(substituted-aryl), (C6)alkyl-(substituted-aryl), (C7)alkyl-(substituted-aryl), (C8)alkyl-(substituted-aryl), O-methyl-aryl, O-ethyl-aryl, O—(C3)alkyl-aryl, O—(C4)alkyl-aryl, O—(C5)alkyl-aryl, O—(C6)alkyl-aryl, O—(C7)alkyl-aryl, O—(C8)alkyl-aryl, O-methyl-(substituted-aryl), O-ethyl-(substituted-aryl), O—(C3)alkyl-(substituted-aryl), O—(C4)alkyl-(substituted-aryl), O—(C5)alkyl-(substituted-aryl), O—(C6)alkyl-(substituted-aryl), O—(C7)alkyl-(substituted-aryl), O—(C8)alkyl-(substituted-aryl), methyl-heterocyclyl, ethyl-heterocyclyl, (C3)alkyl-heterocyclyl, (C4)alkyl-heterocyclyl, (C5)alkyl-heterocyclyl, (C6)alkyl-heterocyclyl, (C7)alkyl-heterocyclyl, (C8)alkyl-heterocyclyl, methyl-(substituted-heterocyclyl), ethyl-(substituted-heterocyclyl), (C3)alkyl-(substituted-heterocyclyl), (C4)alkyl-(substituted-heterocyclyl), (C5)alkyl-(substituted-heterocyclyl), (C6)alkyl-(substituted-heterocyclyl), (C7)alkyl-(substituted-heterocyclyl), (C8)alkyl-(substituted-heterocyclyl), O-methyl-heterocyclyl, O-ethyl-heterocyclyl, O—(C3)alkyl-heterocyclyl, O—(C4)alkyl-heterocyclyl, O—(C5)alkyl-heterocyclyl, O—(C6)alkyl-heterocyclyl, O—(C7)alkyl-heterocyclyl, O—(C8)alkyl-heterocyclyl, O-methyl-(substituted-heterocyclyl), O-ethyl-(substituted-heterocyclyl), O—(C3)alkyl-(substituted-heterocyclyl), O—(C4)alkyl-(substituted-heterocyclyl), O—(C5)alkyl-(substituted-heterocyclyl), O—(C6)alkyl-(substituted-heterocyclyl), O—(C7)alkyl-(substituted-heterocyclyl), O—(C8)alkyl-(substituted-heterocyclyl), methyl-C(═O)N(R16)(R17), ethyl-C(═O)N(R16)(R17), (C3)alkyl-C(═O)N(R16)(R17), (C4)alkyl-C(═O)N(R16)(R17), (C5)alkyl-C(═O)N(R16)(R17), (C6)alkyl-C(═O)N(R16)(R17), (C7)alkyl-C(═O)N(R16)(R17), and (C8)alkyl-C(═O)N(R16)(R17).
  • In another embodiment of this invention R15 may be selected from any combination of one or more of the following—H, CH3, CH2CF3, CH2-halopyridyl, oxo-pyrrolidinyl, halophenyl, thietanyl, CH2-phenyl, CH2-pyridyl, thietanyl-dioxide, CH2-halothiazolyl, C((CH3)2)-pyridyl, N(H)(halophenyl), CH2-pyrimidinyl, CH2-tetrahydrofuranyl, CH2-furanyl, O—CH2-halopyridyl, and CH2C(═O)N(H)(CH2CF3).
  • In another embodiment of this invention R16 may be selected from any combination of one or more of the following—H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methyl-aryl, ethyl-aryl, (C3)alkyl-aryl, (C4)alkyl-aryl, (C5)alkyl-aryl, (C6)alkyl-aryl, (C7)alkyl-aryl, (C8)alkyl-aryl, methyl-(substituted-aryl), ethyl-(substituted-aryl), (C3)alkyl-(substituted-aryl), (C4)alkyl-(substituted-aryl), (C5)alkyl-(substituted-aryl), (C6)alkyl-(substituted-aryl), (C7)alkyl-(substituted-aryl), (C8)alkyl-(substituted-aryl), O-methyl-aryl, O-ethyl-aryl, O—(C3)alkyl-aryl, O—(C4)alkyl-aryl, O—(C5)alkyl-aryl, O—(C6)alkyl-aryl, O—(C7)alkyl-aryl, O—(C8)alkyl-aryl, O-methyl-(substituted-aryl), O-ethyl-(substituted-aryl), O—(C3)alkyl-(substituted-aryl), O—(C4)alkyl-(substituted-aryl), O—(C5)alkyl-(substituted-aryl), O—(C6)alkyl-(substituted-aryl), O—(C7)alkyl-(substituted-aryl), O—(C8)alkyl-(substituted-aryl), methyl-heterocyclyl, ethyl-heterocyclyl, (C3)alkyl-heterocyclyl, (C4)alkyl-heterocyclyl, (C5)alkyl-heterocyclyl, (C6)alkyl-heterocyclyl, (C7)alkyl-heterocyclyl, (C8)alkyl-heterocyclyl, methyl-(substituted-heterocyclyl), ethyl-(substituted-heterocyclyl), (C3)alkyl-(substituted-heterocyclyl), (C4)alkyl-(substituted-heterocyclyl), (C5)alkyl-(substituted-heterocyclyl), (C6)alkyl-(substituted-heterocyclyl), (C7)alkyl-(substituted-heterocyclyl), (C8)alkyl-(substituted-heterocyclyl), O-methyl-heterocyclyl, O-ethyl-heterocyclyl, O—(C3)alkyl-heterocyclyl, O—(C4)alkyl-heterocyclyl, O—(C5)alkyl-heterocyclyl, O—(C6)alkyl-heterocyclyl, O—(C7)alkyl-heterocyclyl, O—(C8)alkyl-heterocyclyl, O-methyl-(substituted-heterocyclyl), O-ethyl-(substituted-heterocyclyl), O—(C3)alkyl-(substituted-heterocyclyl), O—(C4)alkyl-(substituted-heterocyclyl), O—(C5)alkyl-(substituted-heterocyclyl), O—(C6)alkyl-(substituted-heterocyclyl), O—(C7)alkyl-(substituted-heterocyclyl), and O—(C8)alkyl-(substituted-heterocyclyl).
  • In another embodiment of this invention R16 may be selected from any combination of one or more of the following—H, CH2CF3, cyclopropyl, thietanyl, thietanyl dioxide, and halophenyl.
  • In another embodiment of this invention R17 may be selected from any combination of one or more of the following—H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methyl-aryl, ethyl-aryl, (C3)alkyl-aryl, (C4)alkyl-aryl, (C5)alkyl-aryl, (C6)alkyl-aryl, (C7)alkyl-aryl, (C8)alkyl-aryl, methyl-(substituted-aryl), ethyl-(substituted-aryl), (C3)alkyl-(substituted-aryl), (C4)alkyl-(substituted-aryl), (C5)alkyl-(substituted-aryl), (C6)alkyl-(substituted-aryl), (C7)alkyl-(substituted-aryl), (C8)alkyl-(substituted-aryl), O-methyl-aryl, O-ethyl-aryl, O—(C3)alkyl-aryl, O—(C4)alkyl-aryl, O—(C5)alkyl-aryl, O—(C6)alkyl-aryl, O—(C7)alkyl-aryl, O—(C8)alkyl-aryl, O-methyl-(substituted-aryl), O-ethyl-(substituted-aryl), O—(C3)alkyl-(substituted-aryl), O—(C4)alkyl-(substituted-aryl), O—(C5)alkyl-(substituted-aryl), O—(C6)alkyl-(substituted-aryl), O—(C7)alkyl-(substituted-aryl), O—(C8)alkyl-(substituted-aryl), methyl-heterocyclyl, ethyl-heterocyclyl, (C3)alkyl-heterocyclyl, (C4)alkyl-heterocyclyl, (C5)alkyl-heterocyclyl, (C6)alkyl-heterocyclyl, (C7)alkyl-heterocyclyl, (C8)alkyl-heterocyclyl, methyl-(substituted-heterocyclyl), ethyl-(substituted-heterocyclyl), (C3)alkyl-(substituted-heterocyclyl), (C4)alkyl-(substituted-heterocyclyl), (C5)alkyl-(substituted-heterocyclyl), (C6)alkyl-(substituted-heterocyclyl), (C7)alkyl-(substituted-heterocyclyl), (C8)alkyl-(substituted-heterocyclyl), O-methyl-heterocyclyl, O-ethyl-heterocyclyl, O—(C3)alkyl-heterocyclyl, O—(C4)alkyl-heterocyclyl, O—(C5)alkyl-heterocyclyl, O—(C6)alkyl-heterocyclyl, O—(C7)alkyl-heterocyclyl, O—(C8)alkyl-heterocyclyl, O-methyl-(substituted-heterocyclyl), O-ethyl-(substituted-heterocyclyl), O—(C3)alkyl-(substituted-heterocyclyl), O—(C4)alkyl-(substituted-heterocyclyl), O—(C5)alkyl-(substituted-heterocyclyl), O—(C6)alkyl-(substituted-heterocyclyl), O—(C7)alkyl-(substituted-heterocyclyl), and O—(C8)alkyl-(substituted-heterocyclyl).
  • In another embodiment of this invention R17 may be selected from any combination of one or more of the following—H, CH2CF3, cyclopropyl, thietanyl, thietanyl dioxide, and halophenyl.
  • In another embodiment of this invention X1 is CR12, X2 is CR13, and X3 is CR9.
  • In another embodiment of this invention a heterocyclyl has preferably about 6 to 10 atoms in the ring structure, more preferably, 6 to 8 atoms.
  • The molecules of Formula One will generally have a molecular mass of about 100 Daltons to about 1200 Daltons. However, it is generally preferred if the molecular mass is from about 120 Daltons to about 900 Daltons, and it is even more generally preferred if the molecular mass is from about 140 Daltons to about 600 Daltons.
  • The benzyl alcohol of Formula IV, wherein R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, can be synthesized in two ways. One way, disclosed in step a of Scheme I, is by treatment of the ketone of Formula II, wherein R1, R2, R3, R4, R5, and R6 are as previously disclosed, with a reducing agent, such as sodium borohydride (NaBH4), under basic conditions, such as aqueous sodium hydroxide (NaOH), in a polar protic solvent, such as methanol (MeOH) at 0° C. Alternatively, an aldehyde of Formula III, wherein R1, R2, R3, R4, R5, and R7 are as previously disclosed, is allowed to react with trifluorotrimethylsilane in the presence of a catalytic amount of tetrabutylammonium fluoride in a polar aprotic solvent, such as tetrahydrofuran (THF), as in step b of Scheme I. The compound of Formula IV can be transformed into the compound of Formula V, wherein Y is selected from Br, Cl or I, and R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, by reaction with a halogenating reagent, such as N-bromosuccinimide and triethyl phosphite in a non-reactive solvent, such as dichloromethane (CH2Cl2) at reflux temperature to provide Y=Br, or such as thionyl chloride and pyridine in a hydrocarbon solvent, such as toluene at reflux temperature to provide Y=Cl, as in step c of Scheme I.
  • Figure US20170088507A1-20170330-C00004
  • Formation of the styrene coupling partners can be accomplished as in Schemes II, III IV and V.
  • In Scheme II, a vinylbenzoic acid of Formula VI, wherein R11 is (C═O)OH and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, can be converted in two steps to the vinylbenzamide of Formula VIIa, wherein R11 is (C═O)N(R14)(R15), and R8, R9, R10, R12, R13, R14, R15, and X are as previously disclosed. As in step d of Scheme II, the benzoic acid of Formula VI is treated with oxalyl chloride in the presence of a catalytic amount of N,N-dimethylformamide (DMF) in a non-reactive solvent such as CH2Cl2 to form the acid chloride, which is subsequently allowed to react with an amine (HN(R14)(R15)), wherein R14 and R15 are as previously disclosed, in the presence of a base, such as triethylamine (TEA), in a polar aprotic solvent, such as THF, to provide the vinyl benzamide of Formula VIIa, wherein R11 is (C═O)N(R14)(R15), and R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed, as in step e of Scheme II.
  • Figure US20170088507A1-20170330-C00005
  • In Schemes III and IV, a halobenzoic acid of Formula VIII, wherein R18 is Br or I, R11 is (C═O)OH and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed can be converted to a vinylbenzoic acid ester of Formula VIIb1 or Formula VIIb2, wherein R18 is Br or I, R11 is (C═O)O(C1-C6 alkyl), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. In step f of Scheme III, the halobenzoic acid of Formula VIII, wherein R18 is Br, is treated with a base, such as f(n-BuLi), and DMF in a polar, aprotic solvent, such as THF, at a temperature of about −78° C. The resulting formyl benzoic acid is allowed to react with an acid, such as sulfuric acid (H2SO4), in the presence of an alcohol, such as ethyl alcohol (EtOH), as in step g, to provide the formyl benzoic acid ethyl ester of Formula IX, wherein R11 is (C═O)O(C1-C6 alkyl), and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The vinyl benzoic acid ester of Formula VIIb1 is accessed via reaction of the compounds of Formula IX, with a base, such as potassium carbonate (K2CO3), and methyl triphenyl phosphonium bromide in a polar aprotic solvent, such as 1,4-dioxane, at ambient temperature, as in step h of Scheme III.
  • Figure US20170088507A1-20170330-C00006
  • In step i of Scheme IV, the halobenzoic acid of Formula VIII, wherein R18 is Br, R11 is (C═O)OH, and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, is treated with di-tert-butyl dicarbonate in the presence of a base, such as TEA and a catalytic amount of 4-(dimethylamino)pyridine (DMAP) in a polar aprotic solvent, such as THF, at ambient temperature. The resulting benzoic acid tert-butyl ester is allowed to react with vinyl boronic anhydride pyridine complex in the presence of a palladium catalyst, such a tetrakis(triphenylphospine)palladium(0) (Pd(PPh3)4), and a base, such as K2CO3, in a non-reactive solvent such as toluene at reflux temperature, as in step j, to provide the vinyl benzoic acid ester of Formula VIIb2, wherein R11 is (C═O)O(C1-C6 alkyl), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed.
  • Figure US20170088507A1-20170330-C00007
  • In step k of Scheme V, the vinyl benzoic acid ester of Formula VIIb2, wherein R10 is Br, R11 is (C═O)O(C1-C6 alkyl), and R8, R9, R12, R13, X1, X2, and X3 are as previously defined, can be further transformed into the corresponding vinyl benzoic acid ester of Formula VIIb3, wherein R10 is CN, R11 is (C═O)O(C1-C6 alkyl), and R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with copper(I) cyanide (CuCN) in a polar aprotic solvent, such as DMF, at 140° C.
  • Figure US20170088507A1-20170330-C00008
  • Coupling of the compounds of Formula V with the compounds of Formula VIIa, VIIb1, VIIb2 and VIIb3 can be accomplished as in Schemes VI, VII, and VIII. In step 1 of Scheme VI, a compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the vinylbenzamide of Formula VIIa, wherein R11 is (C═O)N(R14)(R15), and R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of copper(I) chloride (CuCl) and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the molecules of Formula One, wherein R11 is (C═O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed.
  • Figure US20170088507A1-20170330-C00009
  • In step l of Scheme VII, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the vinylbenzoic acid ester of Formula VIIb1, wherein R11 is (C═O)O(C1-C6 alkyl), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the compounds of Formula Xa, wherein R11 is (C═O)O(C1-C6 alkyl), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The compounds of Formula Xa are then converted to the molecules of Formula One, wherein R11 is (C═O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed, by either a two-step process as disclosed in steps m and n or in one step as disclosed in step o. In step m of Scheme VII, the ester of Formula Xa is saponified to the corresponding acid under acidic conditions, such as about 11 Normal (N) hydrochloric acid (HCl), in a polar aprotic solvent, such as 1,4-dioxane, at about 100° C. The acid can subsequently be coupled to an amine (HN(R14)(R15)), wherein R14 and R15 are as previously disclosed using peptide coupling reagents, such as 1-hydroxybenzotriazole (HOBt), N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (EDC.HCl), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP), 1-hydroxy-7-azabenzotriazole (HOAt), or O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (HBTU) in the presence of a base, such as N,N-diisopropylethylamine (DIPEA) or DMAP to give the molecules of Formula One, wherein R11 is (C═O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed. Alternatively, the ester of Formula Xa is allowed to react with an amine (HN(R14)(R15)) in the presence of a solution of trimethylaluminum in toluene in a non-reactive solvent, such as CH2Cl2, at ambient temperature, as in step o of Scheme VII, to access the molecules of Formula One, wherein R11 is (C═O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed.
  • Figure US20170088507A1-20170330-C00010
  • In step l of Scheme VIII, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the vinylbenzoic acid ester of Formula VIIb2 or VIIb3, wherein R11 is (C═O)O(C1-C6 alkyl), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the compounds of Formula Xb, wherein R11 is (C═O)OH, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed. The compounds of Formula Xb are then converted to the molecules of Formula One, wherein R11 is (C═O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed, in one step as disclosed in step n. In step n of Scheme VIII, the acid of Formula Xb can be coupled to an amine (HN(R14)(R15)), wherein R14 and R15 are as previously disclosed, using peptide coupling reagents, such as 1-hydroxybenzotriazole (HOBt), N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (EDC.HCl), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP), 1-hydroxy-7-azabenzotriazole (HOAt), or O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (HBTU) in the presence of a base, such as DIPEA or DMAP to give the molecules of Formula One, wherein R11 is (C═O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed.
  • Figure US20170088507A1-20170330-C00011
  • In step j of Scheme IX, the halobenzoketone of Formula VIIIb, wherein R18 is Br, R10 and R11 together form a linkage, having 3-4 carbon atoms and an oxo substituent and with the ring carbon atoms form a 5- or 6-membered cyclic ring, and R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, is allowed to react with vinyl boronic anhydride pyridine complex in the presence of a palladium catalyst, such as Pd(PPh3)4, and a base, such as K2CO3, in a non-reactive solvent such as toluene at reflux temperature, to provide the vinyl benzoketone of Formula VIIb4, wherein R10 and R11 together form a linkage, having 3-4 carbon atoms and an oxo substituent and with the ring carbon atoms form a 5- or 6-membered ring, and R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed.
  • Figure US20170088507A1-20170330-C00012
  • In step l of Scheme X, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the vinylbenzoketone of Formula VIIb4 as previously disclosed, wherein R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the compounds of Formula Xc, wherein R10 and R11 together form a linkage, having 3-4 carbon atoms and an oxo substituent and with the ring carbon atoms form a 5- or 6-membered ring, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed. The compounds of Formula Xc are then converted to the molecules of Formula Xd, wherein R10 and R11 together form a linkage, having 3-4 carbon atoms and an oxime [(C═N)(OH)] substituent and with the ring carbon atoms form a 5- or 6-membered ring, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, in step p. In step p of Scheme X, the ketone of Formula Xc is allowed to react with hydroxylamine hydrochloride in the presence of sodium acetate and in a polar protic solvent, such as EtOH, at a temperature of about 78° C., to give the molecules of Formula Xd as previously disclosed.
  • Figure US20170088507A1-20170330-C00013
  • The compounds of Formula Xc are also converted to the molecules of Formula Xe, wherein R10 and R11 together form a linkage, having 3-4 carbon atoms and an amine substituent and with the ring carbon atoms form a 5- or 6-membered ring, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, as demonstrated in step q of Scheme XI. The ketone of Formula Xc is allowed to react with ammonium acetate in the presence of sodium cyanoborohydride and in a polar protic solvent, such as CH3OH, at a temperature of about 65° C., to give the molecules of Formula Xe.
  • Figure US20170088507A1-20170330-C00014
  • The compounds of Formula Xe are converted to the molecules of Formula One, wherein R10 and R11 together form a linkage as previously disclosed in (u), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously, in one step as disclosed in steps r or s. In step r of Scheme XII, the amine of Formula Xe is allowed to react with an isocyanate in a polar, aprotic solvent such as diethyl ether at ambient temperature to provide the molecules of Formula One as previously disclosed. In step s of Scheme XII, the amine of Formula Xe is coupled to an acid with HOBt.H2O and EDC.HCl in the presence of a base, such as DIPEA, in a non-reactive solvent, such as CH2Cl2, to give the molecules of Formula One, as previously disclosed.
  • Figure US20170088507A1-20170330-C00015
  • In step t of Scheme XIII, the vinyl benzyl chloride of Formula XIa, wherein R11 is —CH2Cl and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously defined, can be transformed into the corresponding phthalimide-protected benzyl amine of Formula XIIa, wherein R11 is CH2N(Phthalimide), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with potassium phthalimide in a polar aprotic solvent, such as DMF, at 70° C.
  • Figure US20170088507A1-20170330-C00016
  • In step u of Scheme XIV, the 4-methylbenzonitrile of Formula XIIIa, wherein R11 is CH3 and R9, R10, R12, R13, X1, X2, and X3 are as previously defined, can be transformed into the corresponding benzyl bromide of Formula XIVa, wherein R11 is CH2Br and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with N-bromosuccinimide (NBS) and azobisisobutyronitrile (AIBN) in a non-reactive solvent, such as carbon tetrachloride at 77° C. The nitrile group (CN) of Formula XIVa can be reduced to the corresponding aldehyde of Formula XVa, wherein R11 is CH2Br and R9, R10, R12, R13, X1, X2, and X3 are as previously defined via reaction with diisobutylaluminum hydride (DIBAL-H) in an aprotic solvent, such as toluene, at 0° C., followed by quenching with 1.0 M hydrochloric acid (HCl) as in step v of Scheme XIV. The compound of Formula XVa can be further transformed to the corresponding phthalimide-protected benzyl amine of Formula XVIa, wherein R11 is CH2N(Phthalimide) and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with potassium phthalimide in a polar aprotic solvent, such as DMF, at 60° C. as in step t of Scheme XIV. In step w of Scheme XIV, the aldehyde of Formula XVIa can be converted to the olefin of Formula XIIb, wherein R11 is CH2N(Phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with methyl triphenyl phosphonium bromide in a polar aprotic solvent, such as 1,4-dioxane, in the presence of a base, such as K2CO3, at ambient temperature.
  • Figure US20170088507A1-20170330-C00017
  • The aldehyde of Formula XVa, wherein R11 is CH2Br and R9, R10, R12, R13, X1, X2, and X3 are as previously defined, can be reacted with a nucleophile, such as 2-aminopyridine, in a polar aprotic solvent, such as N,N-dimethylacetamide (DMA), in the presence of a base, such as K2CO3, at ambient temperature to provide the compound of Formula XVII, wherein R11 is CH2NH(2-pyridine) and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, as in step x of Scheme XV. In step w of Scheme XV, the compound of Formula XVII can be converted to the olefin of Formula XVIII, wherein R11 is CH2NH(2-pyridine) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed.
  • Figure US20170088507A1-20170330-C00018
  • In a two-step, one-pot reaction as in steps y and z of Scheme XVI, the compound of Formula XIX can be reacted with the compounds of Formula XX, wherein R10 and R11 are Cl, X1 is N, and R9, R13, X2, and X3 are as previously disclosed, in the presence of a base, such as sodium hydride (NaH), and a polar aprotic solvent, such as DMF, at ambient temperature to provide the compounds of Formula XXI, wherein R10 is Cl, R11 is (CH)NH2CO2CH2CH3, X1 is N, and R9, R13, X2, and X3 are as previously defined. Hydrolysis and decarboxylation of the compounds of Formula XXI can be accomplished by reaction under acidic conditions, such as with 3 N HCl, at reflux temperature, to afford the compounds of Formula XXII, wherein R10 is Cl, R11 is CH2NH2.HCl, X1 is N, and R9, R13, X2, and X3 are as previously disclosed, as in step aa in Scheme XVI. The compounds of Formula XXII can be further transformed to the corresponding phthalimide-protected benzyl amines of Formula XXIIIa, wherein R10 is Cl, R11 is CH2N(Phthalimide), X1 is N, and R9, R13, X1, X2, and X3 are as previously disclosed, by reaction with phthalic anhydride in the presence of a base, such as TEA, and an aprotic solvent, such as toluene, at reflux temperature as in step ab of Scheme XVI. The bromide of Formula XXIIIa can be converted to the olefin of Formula XIIc, wherein R10 is Cl, R11 is CH2N(Phthalimide), X1 is N, and R8, R9, R13, X2 and X3 are as previously disclosed, by reaction with vinyl boronic anhydride pyridine complex in the presence of a palladium catalyst, such as Pd(PPh3)4, and a base, such as K2CO3, in a non-reactive solvent such as toluene at reflux temperature, as in step ac of Scheme XVI.
  • Figure US20170088507A1-20170330-C00019
  • In step u of Scheme XVII, the 4-methylnaphthonitrile of Formula XIIIb, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH3, and R12, R13, X1 and X2 are as previously defined, can be transformed into the corresponding naphthyl bromide of Formula XIVb, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2Br, and R12, R13, X1 and X2 are as previously disclosed, by reaction with N-bromosuccinimide (NBS) and azobisisobutyronitrile (AIBN) in a non-reactive solvent, such as carbon tetrachloride at 77° C. The nitrile group (CN) of Formula XIVb can be reduced to the corresponding aldehyde of Formula XVb, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring (or if desired a non-aromatic ring), R11 is CH2Br, and R12, R13, X1 and X2 are as previously defined via reaction with diisobutylaluminum hydride (DIBAL-H) in an aprotic solvent, such as toluene, at 0° C., followed by quenching with 1.0 M HCl as in step v of Scheme XVII. The compound of Formula XVb can be further transformed to the corresponding phthalimide-protected benzyl amine of Formula XVIb, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2N(Phthalimide), and R12, R13, X1 and X2 are as previously disclosed, by reaction with potassium phthalimide in a polar aprotic solvent, such as DMF, at 60° C. as in step t of Scheme XVII. In step w of Scheme XVII, the aldehyde of Formula XVIb can be converted to the olefin of Formula XIId, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2N(Phthalimide), and R8, R12, R13, X1 and X2 are as previously disclosed, by reaction with methyl triphenyl phosphonium bromide in a polar aprotic solvent, such as 1,4-dioxane, in the presence of a base, such as K2CO3, at ambient temperature.
  • Figure US20170088507A1-20170330-C00020
  • The compound of Formula XXIV, wherein R11 is NHNH2.HCl and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, can be transformed into the corresponding phthalimide-protected hydrazine of Formula XXV, wherein R11 is NHN(Phthalimide) and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with phthalic anhydride in glacial acetic acid at reflux temperature as in step ad of Scheme XVIII. The bromide of Formula XXV can be converted to the olefin of Formula XIIe, wherein R11 is NHN(Phthalimide) and R8, R9, R10, R13, X1, X2 and X3 are as previously disclosed, by reaction with vinyl boronic anhydride pyridine complex in the presence of a palladium catalyst, such as Pd(PPh3)4, and a base, such as K2CO3, in a polar aprotic solvent such as 1,2-dimethoxyethane at 150° C. under microwave conditions, as in step ae of Scheme XVIII.
  • Figure US20170088507A1-20170330-C00021
  • In step af of Scheme XIX, the compound of Formula XXVI, wherein R11 is B(OH)2, and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react with 2-hydroxyisoindoline-1,3-dione in the presence of CuCl and pyridine in a solvent, such as 1,2-dichlorobenzene, at ambient temperature to provide the compound of Formula XIIf, wherein R11 is ON(Phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed.
  • Figure US20170088507A1-20170330-C00022
  • In step l of Scheme XX, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIIa, wherein R11 is CH2N(Phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the corresponding compounds of Formula XXVIIa, wherein R11 is CH2N(Phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIIa is removed as in step ag of Scheme XX by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90° C. to provide the compounds of Formula XXVIIIa, wherein R11 is CH2NH2 and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The compounds of Formula XXVIIIa can be transformed into the compounds of Formula One, wherein R11 is CH2N(C═O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by acylation with an anhydride, such as acetic anhydride, and a base, such as TEA, in a non-reactive solvent such as CH2Cl2 at 0° C. as in step ah1 of Scheme XX.
  • Figure US20170088507A1-20170330-C00023
  • In step l of Scheme XXI, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIIb, wherein R11 is CH2N(Phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the corresponding compounds of Formula XXVIIb, wherein R11 is CH2N(Phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIIb is removed as in step ag of Scheme XXI by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90° C. to provide the compounds of Formula XXVIIIb, wherein R11 is CH2NH2 and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C═O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with an acid in the presence of HOBt.H2O, EDC.HCl and a base, such as DIPEA, in a polar aprotic solvent, such as DMF, as in step ah2a of Scheme XXI.
  • In another embodiment, the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C═S)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with a thioacid in the presence of HOBt.H2O, EDC.HCl and a base, such as DIPEA, in a polar aprotic solvent, such as DMF, as in step ah2 of Scheme XXI.
  • In another embodiment, the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C═O)N(R14)(R15) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, in two steps. The first step (step ah3a of Scheme XXI) involves reaction with an aldehyde in a polar protic solvent such as MeOH, followed by reaction with sodium borohydride. The second step (step ah3b of Scheme XXI) involves acylation with an acid chloride, such as cyclopropylcarbonyl chloride, and a base, such as TEA, in a non-reactive solvent such as CH2Cl2 at ambient temperature of Scheme XXI.
  • In another embodiment, the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C═O)N(R14)(R15) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with an isocyanate (step ai1 of Scheme XXI) or a carbamoyl chloride (step ai2 of Scheme XXI) in the presence of a base such as TEA and in a non-reactive solvent such as CH2Cl2 at 0° C.
  • In another embodiment, the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C═S)N(R14)(R15) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with an isothiocyanate in the presence of a base such as TEA and in a non-reactive solvent such as CH2Cl2 at 0° C., as in steps aj of Scheme XXI.
  • In another embodiment, the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C═O)O(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with a dicarbonate, such as di-tert-butyl dicarbonate in the presence of a base such as TEA and in a non-reactive solvent such as CH2Cl2 at ambient temperature, as in steps ak of Scheme XXI.
  • In yet another embodiment, the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C═O)(C═O)O(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with a chlorooxalic acid ester, such as 2-chloro-2-oxoacetate in the presence of a base such as TEA and in a non-reactive solvent such as CH2Cl2 at 0° C., as in steps al of Scheme XXI.
  • Figure US20170088507A1-20170330-C00024
  • In step l of Scheme XXII, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIIc, wherein R10 is Cl, R11 is CH2N(Phthalimide), X1 is N, and R8, R9, R12, R13, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the corresponding compounds of Formula XXVIIc, wherein R10 is Cl, R11 is CH2N(Phthalimide), X1 is N, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X2, and X3 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIIc is removed as in step ag of Scheme XXII by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90° C. to provide the compounds of Formula XXVIIIc, wherein R10 is Cl, R11 is CH2NH2, X1 is N, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X2, and X3 are as previously disclosed. The compounds of Formula XXVIIIc can be transformed into the compounds of Formula One, wherein R10 is Cl, R11 is CH2N(C═O)(R14), X1 is N, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X2, and X3 are as previously disclosed, by reaction with an acid in the presence of HOBt.H2O, EDC.HCl and a base, such as DIPEA, in a polar aprotic solvent, such as CH2Cl2, as in step ah2b of Scheme XXII.
  • Figure US20170088507A1-20170330-C00025
  • In step l of Scheme XXIII, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIId, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring (or if desired a non-aromatic ring), R11 is CH2N(Phthalimide) and R8, R9, R12, R13, X1 and X2 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the corresponding compounds of Formula XXVIId, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2N(Phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1 and X2 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIId is removed as in step ag of Scheme XXIII by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90° C. to provide the compounds of Formula XXVIIId, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2NH2 and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1 and X2 are as previously disclosed. The compounds of Formula XXVIIId can be transformed into the compounds of Formula One, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2N(C═O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1 and X2 are as previously disclosed, by reaction with an acid in the presence of HOBt.H2O, EDC.HCl and a base, such as DIPEA, in a polar aprotic solvent, such as CH2Cl2, as in step ah2b of Scheme XXIII.
  • In another embodiment, the compounds of Formula XXVIIId can be transformed into the compounds of Formula One, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2N(C═O)N(R14)(R15) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1 and X2 are as previously disclosed, by reaction with an isocyanate in the presence of a base such as TEA and in a non-reactive solvent such as CH2Cl2 at 0° C. as in step ai1 of Scheme XXIII.
  • Figure US20170088507A1-20170330-C00026
  • In step l of Scheme XXIV, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIIe, wherein R11 is NHN(Phthalimide) and R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the corresponding compounds of Formula XXVIIe, wherein R11 is NHN(Phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIIe is removed as in step ag of Scheme XXIV by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90° C. to provide the compounds of Formula XXVIIIe, wherein R11 is NHNH2 and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed. The compounds of Formula XXVIIIe can be transformed into the compounds of Formula One, wherein R11 is NHN(C═O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with an acid in the presence of HOBt.H2O, EDC.HCl and a base, such as DIPEA, in a polar aprotic solvent, such as CH2Cl2, as in step ah2b of Scheme XXIV.
  • Figure US20170088507A1-20170330-C00027
  • In step l of Scheme XXV, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIIf, wherein R11 is ON(Phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the corresponding compounds of Formula XXVIIf, wherein R11 is ON(Phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIIf is removed as in step ag of Scheme XXV by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90° C. to provide the compounds of Formula XXVIIIf, wherein R11 is ONH2 and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The compounds of Formula XXVIIIf can be transformed into the compounds of Formula One, wherein R11 is ON(C═O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with an acid in the presence of HOBt.H2O, EDC.HCl and a base, such as DIPEA, in a polar aprotic solvent, such as CH2Cl2, as in step ah2b of Scheme XXV.
  • Figure US20170088507A1-20170330-C00028
  • In step l of Scheme XXVI, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XVIII, wherein R11 is CH2NH(2-pyridine) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the corresponding compounds of Formula One, wherein R11 is CH2NH(2-pyridine), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed.
  • The compounds of Formula One can be further elaborated by standard methods. For example, when R11 contains a thioether, the thioether can be oxidized to the sulfone by treatment with oxone in the presence of an acetone:water mixture at ambient temperature. When R11 contains an oxalate ester, the compound of Formula One can be transformed into the corresponding oxalamide by reaction with an amine hydrochloride and a solution of trimethylaluminum in toluene in a non-reactive solvent such as CH2Cl2.
  • Figure US20170088507A1-20170330-C00029
  • In Scheme XXVII, a fluorobenzaldehyde of Formula XXIX, wherein R10, X1, X2, and X3 are as previously disclosed can be converted to a (1,2,4-triazol-1-yl)benzaldehyde of Formula XXX, wherein R11 is a substituted or unsubstituted 1,2,4-triazol-1-yl group, and R10, X1, X2, and X3 are as previously disclosed by reaction with a substituted or unsubstituted 1,2,4-triazole in the presence of a base, such as potassium carbonate, in a solvent such as DMF as in step aj. In step ak, the (1,2,4-triazol-1-yl)benzaldehyde of Formula XXX is converted to a (1,2,4-triazol-1-yl)vinyl benzene of Formula XXXIa wherein R11 is a substituted or unsubstituted 1,2,4-triazol-1-yl group, and R8, R10, X1, X2, and X3 are as previously disclosed by reaction with triphenyl phosphonium bromide in the presence of a base, such as potassium carbonate, in an aprotic solvent, such as 1,4-dioxane.
  • Figure US20170088507A1-20170330-C00030
  • In Scheme XXVIII, a bromofluorobenzene of Formula XXXII, wherein R10, X1, X2, and X3 are as previously disclosed can be converted to a (1,2,4-triazol-1-yl)vinylbenzene of Formula XXXIb, wherein R11 is a substituted or unsubstituted 1,2,4-triazol-1-yl group, and R8, R10, X1, X2, and X3 are as previously disclosed in two steps. In step al, the bromofluorobenzene is reacted with a substituted or unsubstituted 1,2,4-triazole in the presence of a base, such as potassium carbonate, in a solvent such as DMF to generate the (1,2,4-triazol-1-yl)bromobenzene. In step cl, the (1,2,4-triazol-1-yl)bromobenzene is reacted with vinyl boronic anhydride pyridine complex in the presence of a catalyst, such as Pd(PPh3)4, and a base, such as potassium carbonate in a solvent such as toluene.
  • Figure US20170088507A1-20170330-C00031
  • Coupling of the compounds of Formula V with compounds of Formula XXXIa and XXXIb can be accomplished as in Schemes XXIX. In step l, a compound of Formula V, wherein Y is Br, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and a vinylbenzene of Formula XXXIa or XXXIb, wherein R11 is a substituted or unsubstituted 1,2,4-triazol-1-yl group, and R8, R9, R10, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the molecules of Formula One, wherein R11 is a substituted or unsubstituted 1,2,4-triazol-1-yl group, and R1, R2, R3, R4, R5, R6, R7, R8, R10, X1, X2, and X3 are as previously disclosed.
  • Figure US20170088507A1-20170330-C00032
  • In Scheme XXX, compounds of Formula XXXIII wherein R11 is a 3-nitro-1,2,4-triazol-1-yl group, and R1, R2, R3, R4, R5, R6, R7, R8, R10, X1, X2, and X3 are as previously disclosed can be converted to compounds of Formula One, wherein R11 is a 3-amido-1,2,4-triazol-1-yl group, and R1, R2, R3, R4, R5, R6, R7, R8, R10, X1, X2, and X3 are as previously disclosed by a two step process. In step am, the 3-nitro-1,2,4-triazol-1-yl group is reduced to a 3-amino-1,2,4-triazol-1-yl group in the presence of zinc dust and ammonium chloride in a protic solvent, such as MeOH. In step an, the 3-amino-1,2,4-triazol-1-yl group is acylated with an acid chloride, such as cyclopropylcarbonyl chloride or acetyl chloride, in the presence of a base, such as TEA, in a solvent such as CH2Cl2.
  • Figure US20170088507A1-20170330-C00033
  • In step ao of Scheme XXXI, a bromophenyl methyl ketone of Formula XXXIV wherein R10, X1, X2, and X3 are as previously disclosed is converted to an phenyl methyl ketone of the Formula XXXV wherein R11 is a 1,2,4-triazol-1-yl group, and R10, X1, X2, and X3 are as previously disclosed by treatment with 1,2,4-triazole in the presence of a base, such as cesium carbonate, and a catalyst, such as copper iodide, in a solvent, such as DMF. In step ap, the 1,2,4-triazolylacetophenone of Formula XXXV is converted to the trimethylsilyl enol ether of Formula XXXVI by treatment with trimethylsilyl triflluoromethanesulfonate in the presence of a base, such as TEA, in an aprotic solvent, such as CH2Cl2. In step aq, the silyl enol ether is reacted with a compound of Formula V, wherein Y is Br, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene at a temperature of about 180° C. to generate a ketone of the Formula XXXVII, wherein R11 is a 1,2,4-triazol-1-yl group, and R1, R2, R3, R4, R5, R6, R7, R10, X1, X2, and X3 are as previously disclosed. In step ar, the ketone of the Formula XXXVII is treated with methylmagnesium bromide in an aprotic solvent, such as THF to generate the tertiary alcohol. The tertiary alcohol then undergoes an elimination reaction when treated with a catalytic amount of p-toluenesulfonic acid in a solvent, such as toluene, when heated to a temperature to allow azeotropic removal of water to produce compounds of Formula One wherein R11 is a 1,2,4-triazol-1-yl group, R8 is methyl, and R1, R2, R3, R4, R5, R6, R7, R10, X1, X2, and X3 are as previously disclosed, as in step as.
  • Figure US20170088507A1-20170330-C00034
    Figure US20170088507A1-20170330-C00035
  • In Scheme XXXII, a compound of Formula XXXVIII, wherein R10 and R11 together form a linkage, having 3-4 carbon atoms and an oxo substituent and with the ring carbon atoms form a 5- or 6-membered cyclic ring, and R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed is converted to a molecule of Formula One, wherein R10 and R11 together form a linkage, having 3-4 carbon atoms and an alkylamine substituent with the ring carbon atoms form a 5- or 6-membered cyclic ring and R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed, by treatment with an alkylamine, such as 3,3,3-trifluoropropylamine, in the presence of a reducing agent, such as sodium cyanoborohydride, in a solvent, such as DCE.
  • Figure US20170088507A1-20170330-C00036
  • In Scheme XXXIII, a compound of Formula XXXIX, wherein X1, X2, and X3 are as previously disclosed is converted to a molecule of Formula XL, wherein X1, X2, and X3 are as previously disclosed, by treatment with a reducing agent, such as sodium cyanoborohydride, in a solvent, such as acetic acid, as in step au. In step av, the nitrogen atom is protected with a tert-butyloxycarbonyl (BOC) group by reaction with di-tert-butyl dicarbonate in the presence of a catalyst, such as DMAP, in a solvent, such as acetonitrile. The bromide of Formula XL can be converted to the olefin of Formula XLI, wherein R8, X1, X2 and X3 are as previously disclosed, by reaction with potassium vinyl trifluoroborate in the presence of a palladium catalyst, such as PdCl2(dppf), and a base, such as K2CO3, in a polar aprotic solvent such as DMSO at 100° C., as in step aw.
  • Figure US20170088507A1-20170330-C00037
  • In Scheme XXXIV, a compound of Formula XXXIX, wherein X1, X2, and X3 are as previously disclosed is converted to a molecule of Formula XLII, wherein X1, X2, and X3 are as previously disclosed in two steps. In step ax, the olefin is formed by treatment of the bromide with potassium vinyl trifluoroborate in the presence of a palladium catalyst, such as PdCl2, and a ligand, such as triphenylphosphine, and a base, such as Cs2CO3, in a solvent mixture such as THF/WATER. In step ay, the nitrogen atom is protected with a tert-butyloxycarbonyl (BOC) group by reaction with di-tert-butyl dicarbonate in the presence of a catalyst, such as DMAP, in a solvent, such as acetonitrile.
  • Figure US20170088507A1-20170330-C00038
  • In step l of Scheme XXXV, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XLI or XLII, wherein R8, X1, X2 and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 150° C. to provide the corresponding compounds of Formula XLIIIa or XLIIIb, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed.
  • Figure US20170088507A1-20170330-C00039
  • In Scheme XXXVI, a compound of Formula XLIIIa, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed is converted to a molecule of Formula XLIV, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed by treatment with trifluoroacetic acid, in a solvent such as CH2Cl2, as in step az. Compounds of the Formula XLIV can then be transformed into compounds of the Formula XLV wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed, in two steps. In step ba, the indoline is treated with sodium nitrite (NaNO2), in an acid, such as concentrated HCl, at a temperature around 5° C., to form the nitrosoindole. In step bb, the nitrosoindole is reacted with ammonium chloride in the presence of zinc powder in a protic solvent, such as MeOH. In step be, compounds of the Formula XLV are transformed into compounds of the Formula XLVI, wherein X4 is N(R14)(C(═O)R14) and R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed, by treatment with and acid, such as 3,3,3-trifluoropropanoic acid, PyBOP, and a base, such as DIPEA, in a polar aprotic solvent, such as CH2Cl2.
  • Figure US20170088507A1-20170330-C00040
  • In Scheme XXXVII, a compound of Formula XLIIIb, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed is converted to an indole of Formula XLVII, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed by treatment with trifluoroacetic acid, in a solvent such as CH2Cl2, as in step bd. Compounds of the Formula XLVII can be transformed into compounds of the Formula XLVIII wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed, by reaction with 4-nitrophenyl-2-((tert-butoxycarbonyl)amino)acetate in the presence of potassium fluoride and a crown ether, such as 18-crown-6-ether, in a solvent, such as acetonitrile, as in step be. Compounds of the Formula XLVIII can be transformed into compounds of the Formula XLIX, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed in two steps. In step bf, the Boc group is removed by treatment with trifluoroacetic acid, in a solvent such as CH2Cl2. In step bg, the amine is treated with 3,3,3-trifluoropropanoic acid, PyBOP, and a base, such as DIPEA, in a polar aprotic solvent, such as CH2Cl2.
  • Figure US20170088507A1-20170330-C00041
  • In Scheme XXXVIII, a compound of Formula L, wherein X1, X2, and X3 are as previously disclosed is converted to a compound of the Formula LI, wherein X1, X2, and X3 are as previously disclosed by treatment with copper (II) sulfate pentahydrate and Zn powder in a base, such as sodium hydroxide as in step bh. Compounds of the Formula LI can be transformed into compounds of the Formula LII wherein X1, X2, and X3 are as previously disclosed, by reaction with hydrazine, in a solvent such as water, at a temperature around 95° C., as in step bi. In step bj, the olefin of the Formula LIII wherein X1, X2, and X3 are as previously disclosed is formed by treatment of the bromide with potassium vinyl trifluoroborate in the presence of a palladium catalyst, such as PdCl2(dppf), and a base, such as K2CO3, in a solvent mixture such as DMSO. Compounds of the Formula LIV, wherein X1, X2, and X3 are as previously disclosed, can be formed from compounds of the Formula LIII by reaction with ethyl bromoacetate, in the presence of a base, such as Cs2CO3, in a solvent, such as DMF.
  • Figure US20170088507A1-20170330-C00042
  • In step l of Scheme XXXIX, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compound of Formula LIV, wherein R8, X1, X2 and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the corresponding compound of Formula LV, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed. The compound of Formula LV can be further transformed into a compound of the Formula LVI, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed, in two steps. In step bl, the ester is hydrolyzed to the acid in the presence of HCl and acetic acid, at a temperature of about 100° C. In step bm, the acid is treated with an amine, such as 2,2,2-trifluoroethylamine, PyBOP, and a base, such as DIPEA, in a polar aprotic solvent, such as CH2Cl2.
  • Figure US20170088507A1-20170330-C00043
  • In step bn of Scheme XL, carboxylic acids of the Formula LVII, wherein R11 is C(═O)OH and R8, R10, X1, X2, and X3 are as previously disclosed and compounds of the Formula V, wherein Y is Br and R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as N-methyl pyrrolidine, at a temperature of about 150° C. to afford compounds of Formula LVIII, wherein R11 is (C═O)OH and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X1, X2, and X3 are as previously disclosed. Compounds of the Formula LVIII can be further transformed to the corresponding benzamides of Formula LIX, wherein R11 is (C═O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X1, X2, and X3 are as previously disclosed, by treatment with an amine, such as 2-amino-N-(2,2,2-trifluoroethyl)acetamide, PyBOP, and a base, such as DIPEA, in a polar aprotic solvent, such as CH2Cl2, as in step bo.
  • Figure US20170088507A1-20170330-C00044
    • EXAMPLES
  • The examples are for illustration purposes and are not to be construed as limiting the invention disclosed in this document to only the embodiments disclosed in these examples.
  • Starting materials, reagents, and solvents that were obtained from commercial sources were used without further purification. Anhydrous solvents were purchased as Sure/Seal™ from Aldrich and were used as received. Melting points were 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 naming programs within ISIS Draw, ChemDraw, or ACD Name Pro. If such programs are unable to name a molecule, the molecule is named using conventional naming rules. 1H NMR spectral data are in ppm (δ) and were recorded at 300, 400, or 600 MHz, and 13C NMR spectral data are in ppm (δ) and were recorded at 75, 100, or 150 MHz, unless otherwise stated.
    • Example 1: Preparation of 1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (AI1)
  • Figure US20170088507A1-20170330-C00045
    • Step 1 Method A. 1-(3,5-Dichlorophenyl)-2,2,2-trifluoroethanol (AI2)
  • To a stirred solution of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone (procured from Rieke Metals, UK; 5.0 grams (g), 20.5 millimoles (mmol)) in MeOH (100 mL) at 0° C. were added sodium borohydride (NaBH4; 3.33 g, 92.5 mL) and 1 Normal (N) aqueous sodium hydroxide solution (NaOH; 10 mL). The reaction mixture was warmed to 25° C. and stirred for 2 hours (h). After the reaction was deemed complete by thin layer chromatography (TLC), saturated (satd) aqueous (aq) ammonium chloride (NH4Cl) solution was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was diluted with diethyl ether (Et2O) and washed with water (3×50 mL). The organic layer was dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure to afford the title compound as a liquid (4.0 g, 79%): 1H NMR (400 MHz, CDCl3) δ 7.41 (m, 3H), 5.00 (m, 2H), 2.74 (s, 1H); ESIMS m/z 242.97 ([M−H]−).
    • Step 1 Method B. 1-(3,5-Dichlorophenyl)-2,2,2-trifluoroethanol (AI2)
  • To a stirred solution of 3,5-dichlorobenzaldehyde (10 g, 57 mmol) in THF (250 mL) were added trifluoromethyltrimethylsilane (9.79 g, 69.2 mmol) and a catalytic amount of tetrabutylammonium fluoride (TBAF). The reaction mixture was stirred at 25° C. for 8 h. After the reaction was deemed complete by TLC, the reaction mixture was diluted with 3 N hydrochloric acid (HCl) and then was stirred for 16 h. The reaction mixture was diluted with water and was extracted with ethyl acetate (EtOAc; 3×). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a liquid (8.41 g, 60%).
  • The following compounds were made in accordance with the procedures disclosed in Step 1 Method B of Example 1 above.
    • 2,2,2-Trifluoro-1-(3,4,5-trichlorophenyl)ethanol (AI3)
  • Figure US20170088507A1-20170330-C00046
  • The product was isolated as a pale yellow liquid (500 mg, 65%): 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 2H), 5.00 (m, 1H), 2.80 (s, 1H); ESIMS m/z 278 ([M+H]+); IR (thin film) 3420, 1133, 718 cm−1.
    • 1-(3,5-Dichloro-4-fluorophenyl)-2,2,2-trifluoroethanol (AI4)
  • Figure US20170088507A1-20170330-C00047
  • The product was isolated as a pale yellow liquid (500 mg, 65%): 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 2H), 5.00 (m, 1H), 2.80 (s, 1H); ESIMS m/z 262 ([M+H]+); IR (thin film) 3420, 1133, 718 cm−1.
    • 1-(3,4-Dichlorophenyl)-2,2,2-trifluoroethanol (AI5)
  • Figure US20170088507A1-20170330-C00048
  • The product was isolated as a pale yellow liquid (500 mg, 65%): 1H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 7.51 (m, 1H), 7.35 (m, 1H), 5.01 (m, 1H), 2.60 (s, 1H); EIMS m/z 244 ([M]+).
    • Step 2. 1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (AI1)
  • To a stirred solution of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanol (4.0 g, 16.3 mmol) in CH2Cl2 (50 mL), were added N-bromosuccinimide (NBS; 2.9 g, 16.3 mmol) and triphenyl phosphite (5.06 g, 16.3 mmol), and the resultant reaction mixture was heated at reflux for 18 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to 25° C. and was concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 100% pentane) afforded the title compound as a liquid (2.0 g, 40%): 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 3H), 5.00 (m, 1H); EIMS m/z 306 ([M]+).
  • The following compounds were made in accordance with the procedures disclosed in Step 2 of Example 1.
    • 5-(1-Bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (AI6)
  • Figure US20170088507A1-20170330-C00049
  • The product was isolated as a colorless oil (300 mg, 60%): 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 2H), 5.00 (m, 1H); EIMS m/z 340.00 ([M]+).
    • 5-(1-Bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-fluorobenzene (AI7)
  • Figure US20170088507A1-20170330-C00050
  • The product was isolated as a colorless oil (320 mg, 60%): 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 2H), 5.00 (m, 2H); EIMS m/z 324.00 ([M]+).
    • 4-(1-Bromo-2,2,2-trifluoroethyl)-1,2-dichlorobenzene (AI8)
  • Figure US20170088507A1-20170330-C00051
  • The product was isolated as a colorless oil (300 mg, 60%): 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.51 (m, 1H), 7.35 (m, 1H), 5.01 (m, 1H); EIMS m/z 306.00 ([M]+).
    • Example 2: Preparation of N-Methyl-4-vinylbenzamide (AI9)
  • Figure US20170088507A1-20170330-C00052
    • Step 1. 4-Vinylbenzoyl chloride (AI10)
  • To a stirred solution of 4-vinylbenzoic acid (1 g, 6.75 mmol) in CH2Cl2 (20 mL) at 0° C. were added a catalytic amount of DMF and oxalyl chloride (1.27 g, 10.12 mmol) dropwise over a period of 15 minutes (min). The reaction mixture was stirred at 25° C. for 6 h. After the reaction was deemed complete by TLC, the reaction mixture was concentrated under reduced pressure to give the crude acid chloride.
    • Step 2. N-Methyl-4-vinylbenzamide (AI9)
  • To 1 M N-methylamine in THF (13.5 mL, 13.5 mmol) at 0° C. were added TEA (1.34 mL, 10.12 mmol) and the acid chloride from Step 1 above in THF (10 mL), and the reaction mixture was stirred at 25° C. for 3 h. After the reaction was deemed complete by TLC, the reaction mixture was quenched with water and then was extracted with EtOAc (3×). The combined EtOAc layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (650 mg, 60%): 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 6.79 (m, 1H), 6.20 (br s, 1H), 5.82 (d, J=17.6 Hz, 1H), 5.39 (d, J=10.8 Hz, 1H); ESIMS m/z 161.95 ([M+H]+).
  • The following compounds were made in accordance with the procedures disclosed in accordance with Example 2.
    • N,N-Dimethyl-4-vinylbenzamide (AI11)
  • Figure US20170088507A1-20170330-C00053
  • The product was isolated as an off-white solid (650 mg, 60%): 1H NMR (400 MHz, CDCl3) δ 7.42 (m, 4H), 6.71 (m, 1H), 5.80 (d, J=17.6 Hz, 1H), 5.31 (d, J=10.8 Hz, 1H), 3.05 (s, 3H), 3.00 (s, 3H); ESIMS m/z 176.01 ([M+H]+).
    • N-(2,2,3-Trifluoromethyl)-4-vinylbenzamide (AI12)
  • Figure US20170088507A1-20170330-C00054
  • The product was isolated as an off-white solid (900 mg, 60%): 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 6.79 (m, 1H), 6.20 (br s, 1H), 5.82 (d, J=17.6 Hz, 1H), 5.39 (d, J=10.8 Hz, 1H), 4.19 (m, 2H); ESIMS m/z 230.06 ([M+H]+).
    • Morpholino(4-vinylphenyl)methanone (AI13)
  • Figure US20170088507A1-20170330-C00055
  • The product was isolated as a white solid (850 mg, 60%): ESIMS m/z 218.12 ([M+H]+).
    • Example 3: Preparation of Ethyl 2-methyl-4-vinylbenzoate (AI14)
  • Figure US20170088507A1-20170330-C00056
    • Step 1. 4-Formyl-2-methylbenzoic acid (AI15)
  • To a stirred solution of 4-bromo-2-methylbenzoic acid (10 g, 46.4 mmol) in dry THF (360 mL) at −78° C. was added n-BuLi (1.6 M solution in hexane; 58.17 mL, 93.0 mmol) and DMF (8 mL). The reaction mixture was stirred at −78° C. for 1 h then was warmed to 25° C. and stirred for 1 h. The reaction mixture was quenched with 1 N HCl solution and extracted with EtOAc. The combined EtOAc extracts were washed with brine and dried over Na2SO4 and concentrated under reduced pressure. The residue was washed with n-hexane to afford the title compound as a solid (3.0 g, 40%): mp 196-198° C.; 1H NMR (400 MHz, DMSO-d6) δ 13.32 (br s, 1H), 10.05 (s, 1H), 7.98 (m, 1H), 7.84 (m, 2H), 2.61 (s, 3H); ESIMS m/z 163.00 ([M−H]−).
    • Step 2. Ethyl 4-formyl-2-methylbenzoate (AI16)
  • To a stirred solution of 4-formyl-2-methylbenzoic acid (3 g, 18.2 mmol) in ethyl alcohol (EtOH; 30 mL) was added sulfuric acid (H2SO4, x M; 2 mL), and the reaction mixture was heated at 80° C. for 18 h. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was diluted with EtOAc and washed with water. The combined EtOAc extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a solid (2.8 g, 80%): 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 8.04 (m, 1H), 7.75 (m, 2H), 4.43 (m, 2H), 2.65 (s, 3H), 1.42 (m, 3H).
    • Step 3. Ethyl 2-methyl-4-vinylbenzoate (AI14)
  • To a stirred solution of ethyl 4-formyl-2-methylbenzoate (2.8 g, 4 mmol) in 1,4-dioxane (20 mL) were added potassium carbonate (K2CO3; 3.01 g, 21.87 mmol) and methyltriphenyl phosphonium bromide (7.8 g, 21.87 mmol) at 25° C. Then the reaction mixture was heated at 100° C. for 18 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to 25° C. and filtered, and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 25-30% EtOAc in n-Hexane) to afford the title compound as a solid (2.0 g, 72%): 1H NMR (400 MHz, CDCl3) δ 7.86 (m, 1H), 7.27 (m, 2H), 6.68 (dd, J=17.6, 10.8 Hz, 1H), 5.84 (d, J=17.6 Hz, 1H), 5.39 (d, J=10.8 Hz, 1H), 4.39 (m, 2H), 2.60 (s, 3H), 1.40 (m, 3H); ESIMS m/z 191.10 ([M−H]−); IR (thin film) 2980, 1716, 1257 cm−1.
    • Example 4: Preparation of tert-Butyl 2-chloro-4-vinylbenzoate (AI17)
  • Figure US20170088507A1-20170330-C00057
    • Step 1. tert-Butyl 4-bromo-2-chlorobenzoate (AI18)
  • To a stirred solution of 4-bromo-2-chlorobenzoic acid (5 g, 21.37 mmol) in THF (30 mL) was added di-tert-butyl dicarbonate (25.5 g, 25.58 mmol), TEA (3.2 g, 31.98 mmol) and DMAP (0.78 g, 6.398 mmol), and the reaction mixture was stirred at 25° C. for 18 h. The reaction mixture was diluted with EtOAc and washed with water. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 2-3% EtOAc in n-hexane) to afford the title compound as a liquid (3.2 g, 51%): 1H NMR (400 MHz, CDCl3) δ 7.62 (m, 2H), 7.44 (d, J=8.4 Hz, 1H), 1.59 (s, 9H); ESIMS m/z 290.10 ([M+H]+); IR (thin film) 1728 cm−1.
  • The following compounds were made in accordance with the procedures disclosed in Step 1 of Example 4.
    • tert-Butyl 2-bromo-4-iodobenzoate (AI19)
  • Figure US20170088507A1-20170330-C00058
  • The product was isolated as a colorless oil (1.2 g, 50%): 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 1.59 (s, 9H); ESIMS m/z 382.10 ([M+H]+); IR (thin film) 1727 cm−1.
    • tert-Butyl 4-bromo-2-(trifluoromethyl)benzoate (AI20)
  • Figure US20170088507A1-20170330-C00059
  • The product was isolated as a colorless oil (1 g, 52%): 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 1.57 (s, 9H); ESIMS m/z 324.10 ([M+H]+); IR (thin film) 1725 cm−1.
    • Step 2. tert-Butyl 2-chloro-4-vinylbenzoate (AI17)
  • To a stirred solution of tert-butyl 4-bromo-2-chlorobenzoate (1.6 g, 5.50 mmol) in toluene (20 mL) was added tetrakis(triphenylphospine)palladium(0) (Pd(PPh3)4; (0.31 mg, 0.27 mmol), K2CO3 (2.27 g, 16.5 mmol) and vinylboronic anhydride pyridine complex (2.0 g, 8.3 mmol) and the reaction mixture was heated to reflux for 16 h. The reaction mixture was filtered, and the filtrate was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 5-6% EtOAc in n-hexane) afforded the title compound as a liquid (0.6 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=8.1 Hz, 1H), 7.44 (m, 1H), 7.31 (d, J=8.0 Hz, 1H), 6.69 (dd, J=17.6, 10.8 Hz, 1H), 5.85 (d, J=17.6 Hz, 1H), 5.40 (d, J=10.8 Hz, 1H), 1.60 (s, 9H); ESIMS m/z 238.95 ([M+H]+); IR (thin film) 2931, 1725, 1134 cm−1.
  • The following compounds were made in accordance with the procedures disclosed in Step 2 of Example 4.
    • tert-Butyl 2-bromo-4-vinylbenzoate (AI21)
  • Figure US20170088507A1-20170330-C00060
  • The product was isolated as a colorless oil (1 g, 52%): 1H NMR (400 MHz, CDCl3) δ 7.68 (m, 2H), 7.36 (d, J=8.0 Hz, 1H), 6.68 (dd, J=17.6, 10.8 Hz, 1H), 5.84 (d, J=17.6 Hz, 1H), 5.39 (d, J=10.8 Hz, 1H), 1.60 (s, 9H); ESIMS m/z 282.10 ([M+H]+); IR (thin film) 2978, 1724, 1130 cm−1.
    • tert-Butyl 2-(trifluoromethyl)-4-vinylbenzoate (AI22)
  • Figure US20170088507A1-20170330-C00061
  • The product was isolated as a colorless oil (1.2 g, 50%): 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=6.4 Hz, 2H), 7.59 (d, J=7.6 Hz, 1H), 6.77 (dd, J=17.6, 10.8 Hz, 1H), 5.89 (d, J=17.6 Hz, 1H), 5.44 (d, J=10.8 Hz, 1H), 1.58 (s, 9H); ESIMS m/z 272.20 ([M+H]+); IR (thin film) 2982, 1727, 1159 cm−1.
    • Example 5: Preparation of tert-Butyl 2-cyano-4-vinylbenzoate (AI23)
  • Figure US20170088507A1-20170330-C00062
  • To a stirred solution of tert-butyl 2-bromo-4-vinylbenzoate (0.5 g, 1.77 mmol) in DMF (20 mL) was added copper(I) cyanide (CuCN; 0.23 g, 2.65 mmol), and the reaction mixture was heated at 140° C. for 3 h. The reaction mixture was cooled to 25° C., diluted with water, and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 15% EtOAc in n-hexane) to afford the title compound as a white solid (0.3 g, 72%): mp 51-53° C.; 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.77 (s, 1H), 7.64 (d, J=8.4 Hz, 1H), 6.75 (dd, J=17.6, 10.8 Hz, 1H), 5.93 (d, J=17.6 Hz, 1H), 5.51 (d, J=10.8 Hz, 1H), 1.65 (s, 9H); ESIMS m/z 229.84 ([M+H]+); IR (thin film) 2370, 1709, 1142 cm−1.
    • Example 6: Preparation of Ethyl 2-bromo-4-iodobenzoate (AI46)
  • Figure US20170088507A1-20170330-C00063
  • To a stirred solution of 4-iodo-2-bromobenzoic acid (5 g, 15.29 mmol) in ethyl alcohol (EtOH; 100 mL) was added sulfuric acid (H2SO4; 5 mL), and the reaction mixture was heated at 80° C. for 18 h. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was diluted with EtOAc (2×100 mL) and washed with water (100 mL). The combined EtOAc extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the compound as a pale yellow solid (5 g, 92%): 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J=1.2 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 4.41 (q, J=7.2 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H).
  • The following compounds were made in accordance with the procedures disclosed in Example 6.
    • Ethyl 4-bromo-2-chlorobenzoate (AI47)
  • Figure US20170088507A1-20170330-C00064
  • The title compound was isolated as an off-white solid (2.0 g, 80%): 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J=1.2 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 4.65 (q, J=7.2 Hz, 2H), 1.56 (t, J=7.2 Hz, 3H).
    • Ethyl 4-bromo-2-methylbenzoate (AI48)
  • Figure US20170088507A1-20170330-C00065
  • The title compound was isolated as a pale yellow liquid (3.0 g, 83%): 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.4 Hz, 1H), 7.41 (s, 1H), 7.39 (d, J=8.4 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 2.60 (s, 3H), 1.40 (t, J=7.2 Hz, 3H) ESIMS m/z 229.11 ([M+H]+); IR (thin film) 1725 cm−1.
    • Ethyl 4-bromo-2-fluorolbenzoate (AI49)
  • Figure US20170088507A1-20170330-C00066
  • The title compound was isolated as a colorless liquid (9.0 g, 79%): 1H NMR (400 MHz, DMSO-d6) δ 7.84 (t, J=8.4 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.58 (d, J=1.6 Hz, 1H), 4.34 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H); ESIMS m/z 246.99 ([M+H]+), IR (thin film) 1734 cm−1.
    • Example 7: Preparation of Ethyl 4-bromo-2-ethylbenzoate (AI50)
  • Figure US20170088507A1-20170330-C00067
  • To a stirred solution of 4-bromo-2-fluorobenzoic acid (2.0 g, 9.17 mmol) in THF (16 mL), was added 1.0 M ethyl magnesium bromide in THF (32 mL, 32.0 mmol) dropwise at 0° C. and the resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was quenched with 2 N HCl and extracted with ethyl acetate. The combined ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude 4-bromo-2-ethylbenzoic acid as a colorless liquid that was used in the next step without purification (0.4 g): 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J=8.4 Hz, 1H), 7.47 (m, 1H), 7.43 (m, 1H), 2.95 (q, J=4.0 Hz, 2H), 1.32 (t, J=4.0 Hz, 3H); ESIMS m/z 228.97 ([M+H]+).
  • The title compound was synthesized from 4-bromo-2-ethylbenzoic acid in accordance to the procedure in Example 6, isolated as a colorless liquid (0.15 g, 68%): 1H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J=8.4 Hz, 1H), 7.47 (m, 2H), 4.40 (q, J=7.2 Hz, 2H), 3.06 (q, J=7.6 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H), 1.26 (t, J=7.6 Hz, 3H); ESIMS m/z 226.96 ([M−H]−); IR (thin film) 3443, 1686, 568 cm−1.
    • Example 8: Preparation of Ethyl 2-bromo-4-vinylbenzoate (AI51)
  • Figure US20170088507A1-20170330-C00068
  • To a stirred solution of ethyl 2-bromo-4-iodobenzoate (5 g, 14.3 mmol) in THF/water (100 mL, 9:1) was added potassium vinyltrifluoroborate (1.89 g, 14.3 mmol), Cs2CO3 (18.27 g, 56.07 mmol) and triphenylphosphine (0.22 g, 0.85 mmol) and the reaction mixture was degassed with argon for 20 min, then charged with PdCl2 (0.05 g, 0.28 mmol). The reaction mixture was heated to reflux for 16 h. The reaction mixture was cooled to ambient temperature and filtered through a celite bed and washed with ethyl acetate. The filtrate was again extracted with ethyl acetate and the combined organic layers washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to afford crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; eluting with 2% ethyl acetate/petroleum ether) to afford the title compound as a light brown gummy material (2 g, 56%): 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J=8.4 Hz, 1H), 7.71 (d, J=1.2 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 6.69 (dd, J=17.6, 10.8 Hz, 1H), 5.86 (d, J=17.6 Hz, 1H), 5.42 (d, J=11.2 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 1.43 (t, J=3.6 Hz, 3H); ESIMS m/z 255.18 ([M+H]+); IR (thin film) 1729 cm−1.
  • The following compounds were made in accordance with the procedures disclosed in Example 8.
    • Ethyl 2-methyl-4-vinylbenzoate (AI52)
  • Figure US20170088507A1-20170330-C00069
  • The title compound was isolated as a colorless liquid (0.8 g, 80%): 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8.4 Hz, 1H), 7.27 (m, 2H), 6.79 (dd, J=17.6, 10.8 Hz, 1H), 5.86 (d, J=17.6 Hz, 1H), 5.42 (d, J=11.2 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 2.60 (s, 3H), 1.43 (t, J=7.2 Hz, 3H); ESIMS m/z 191.10 ([M+H]+); IR (thin film) 1717, 1257 cm−1.
    • Ethyl 2-fluoro-4-vinylbenzoate (AI53)
  • Figure US20170088507A1-20170330-C00070
  • The title compound was isolated as a pale yellow liquid (2.0 g, 50%): 1H NMR (400 MHz, DMSO-d6) δ 7.87 (t, J=8.0 Hz, 1H), 7.51 (d, J=16.0 Hz, 1H), 7.48 (d, J=16.0 Hz, 1H), 6.82 (dd, J=17.6, 10.8 Hz, 1H), 6.09 (d, J=17.6 Hz, 1H), 5.50 (d, J=10.8 Hz, 1H), 4.35 (q, J=7.2 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H); ESIMS m/z 195.19 ([M+H]+); IR (thin film) 1728 cm−1.
    • Example 9: Preparation of Ethyl 2-chloro-4-vinylbenzoate (AI54)
  • Figure US20170088507A1-20170330-C00071
  • To a stirred solution of ethyl 2-chloro-4-bromobenzoate (2 g, 7.63 mmol) in dimethylsulfoxide (20 mL) was added potassium vinyltrifluoroborate (3.06 g, 22.9 mmol) and potassium carbonate (3.16 g, 22.9 mmol). The reaction mixture was degassed with argon for 30 min. Bistriphenylphosphine(diphenylphosphinoferrocene)palladium dichloride (0.27 g, 0.38 mmol) was added and the reaction mixture was heated to 80° C. for 1 h. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (2×50 mL), washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain the compound as brown gummy material (1.1 g, 69%): 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J=8.4 Hz, 1H), 7.46 (s, 1H), 7.33 (d, J=8.4 Hz, 1H), 6.70 (dd, J=17.6, 11.2 Hz, 1H), 5.87 (d, J=17.6 Hz, 1H), 5.42 (d, J=10.8 Hz, 1H), 4.41 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H); ESIMS m/z 211.22 ([M+H]+); IR (thin film) 1729, 886 cm−1.
  • The following compounds were made in accordance with the procedures disclosed in Example 9.
    • Ethyl 2-ethyl-4-vinylbenzoate (AI55)
  • Figure US20170088507A1-20170330-C00072
  • The title compound was isolated as a color less liquid (1.0 g, 66%): 1H NMR (300 MHz, CDCl3) δ 7.85 (m, 1H), 7.29 (m, 2H), 6.76 (d, J=10.8 Hz, 1H), 5.86 (d, J=17.6 Hz, 1H), 5.36 (d, J=10.5 Hz, 1H), 4.41 (q, J=7.2 Hz, 2H), 3.10 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H), 1.30 (t, J=7.2 Hz, 3H); ESIMS m/z 205.26 ([M+H]+); IR (thin film) 1720, 1607, 1263 cm−1.
    • Methyl 2-methoxy-4-vinylbenzoate (AI56)
  • Figure US20170088507A1-20170330-C00073
  • The title compound was isolated as a pale yellow liquid (1.2 g, 75%): 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.0 Hz, 1H), 7.04 (d, J=1.2 Hz, 1H), 6.97 (s, 1H), 6.74 (dd, J=11.2, 11.2 Hz, 1H), 5.86 (d, J=17.6 Hz, 1H), 5.39 (d, J=17.6 Hz, 1H) 3.93 (s, 3H), 3.91 (s, 3H). ESIMS m/z 193.18 ([M+H]+); IR (thin film) 1732 cm−1.
    • Example 10: Preparation of (E)-Ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoate (AI24)
  • Figure US20170088507A1-20170330-C00074
  • To a stirred solution of ethyl 2-methyl-4-vinylbenzoate (2.0 g, 10.5 mmol) in 1,2-dichlorobenzene (25 mL) were added 1-(1-bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (6.44 g, 21.0 mmol), copper(I) chloride (CuCl; 208 mg, 21 mmol) and 2,2bipyridyl (0.65 g, 4.1 mmol). The reaction mixture was degassed with argon for 30 min and then stirred at 180° C. for 24 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to 25° C. and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; eluting with 25-30% EtOAc in petroleum ether) afforded the title compound as a solid (1.7 g, 40%): 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J=8.0 Hz, 1H), 7.37 (m, 1H), 7.27-7.24 (m, 4H), 6.59 (d, J=16.0 Hz, 1H), 6.59 (dd, J=16.0, 8.0 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 4.08 (m, 1H), 2.62 (s, 3H), 1.42 (t, J=7.2 Hz, 3H); ESIMS m/z 415.06 ([M−H]−); IR (thin film) 1717, 1255, 1114 cm−1.
  • Compounds AI25, AI57-AI68 and AC1-AC5 (Table 1) were made in accordance with the procedures disclosed in Example 10.
    • (E)-Ethyl 4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)-benzoic acid (AI25)
  • Figure US20170088507A1-20170330-C00075
  • The product was isolated as a pale brown gummy liquid (500 mg, 40%): 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.0 Hz, 1H), 7.71 (m, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.42 (s, 2H), 6.70 (d, J=16.0 Hz, 1H), 6.57 (dd, J=16.0, 8.0 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 4.19 (m, 1H), 1.40 (t, J=7.6 Hz, 3H); ESIMS m/z 502.99 ([M−H]−); IR (thin film) 1730, 1201, 1120, 749 cm−1.
    • (E)-Ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-fluorobenzoate (AI57)
  • Figure US20170088507A1-20170330-C00076
  • 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H), 7.26 (s, 3H), 7.21 (d, J=8.4 Hz, 1H), 7.16 (d, J=11.6 Hz, 1H), 6.59 (d, J=16.0 Hz, 1H), 6.47 (dd, J=, 16.0, 8.0 Hz, 1H), 4.41 (q, J=6.8 Hz, 2H), 4.18 (m, 1H), 1.41 (t, J=6.8 Hz, 3H); ESIMS m/z 419.33 ([M−H]−); IR (thin film) 1723, 1115, 802 cm−1.
    • (E)-Ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-bromobenzoate (AI58)
  • Figure US20170088507A1-20170330-C00077
  • 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.0 Hz, 1H), 7.67 (s, 1H), 7.38 (m, 2H), 7.26 (m, 2H), 6.56 (d, J=16.0 Hz, 1H), 6.45 (dd, J=16.0, 7.6 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 4.39 (m, 1H), 1.42 (t, J=7.2 Hz, 3H); ESIMS m/z 481.22 ([M−H]−); IR (thin film) 1727, 1114, 801, 685 cm−1.
    • (E)-Ethyl 2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl) but-1-enyl)benzoate (AI59)
  • Figure US20170088507A1-20170330-C00078
  • 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.0 Hz, 1H), 7.67 (d, J=1.6 Hz, 1H), 7.40 (s, 2H), 7.36 (d, J=1.6 Hz, 1H), 6.56 (d, J=16.0 Hz, 1H), 6.44 (dd, J=16.0, 7.6 Hz, 1H), 4.42 (q, J=6.8 Hz, 2H), 4.15 (m, 1H), 1.42 (t, J=6.8 Hz, 3H); ESIMS m/z 514.74 ([M−H]−); IR (thin film) 1726, 1115, 808, 620 cm−1.
    • (E)-Ethyl 2-methyl-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl) but-1-enyl)benzoate (AI60)
  • Figure US20170088507A1-20170330-C00079
  • The title compound was isolated as a light brown gummy material: 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J=8.8 Hz, 1H), 7.34 (d, J=6.0 Hz, 2H), 7.25 (d, J=7.2 Hz, 2H), 6.59 (d, J=16.0 Hz, 1H), 6.42 (dd, J=16.0, 8.0 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 4.19 (m, 1H), 2.63 (s, 3H), 1.41 (t, J=7.2 Hz, 3H).
    • (E)-Ethyl 2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl) but-1-enyl)benzoate (AI61)
  • Figure US20170088507A1-20170330-C00080
  • 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J=8.0 Hz, 1H), 7.46 (d, J=1.6 Hz, 1H), 7.40 (s, 2H), 7.31 (d, J=1.6 Hz, 1H), 6.57 (d, J=16.0 Hz, 1H), 6.44 (dd, J=16.0 Hz, 8.0 Hz, 1H), 4.42 (q, J=6.8 Hz, 2H), 4.15 (m, 1H), 1.42 (t, J=6.8 Hz, 3H); ESIMS m/z 470.73 ([M−H]−); IR (thin film) 1726, 1115, 809, 3072 cm−1.
    • (E)-Ethyl 4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzoate (AI62)
  • Figure US20170088507A1-20170330-C00081
  • The title compound was isolated as a pale brown liquid (1.0 g, 46.3%): 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.0 Hz, 1H), 7.71 (s, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.41 (s, 2H) 6.65 (d, J=16.0 Hz, 1H), 6.49 (dd, J=16.0, 8.0 Hz, 1H), 4.42 (q, J=7.6 Hz, 2H), 4.15 (m, 1H), 1.42 (t, J=7.6 Hz, 3H); ESIMS m/z 502.99 ([M−H]−); IR (thin film) 1730, 1202, 1120, 750 cm−1.
    • (E)-Ethyl 2-chloro-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate
  • Figure US20170088507A1-20170330-C00082
  • 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J=6.0 Hz, 1H), 7.46 (d, J=1.8 Hz, 2H), 7.34 (m, 1H), 7.24 (m, 1H), 6.57 (d, J=16.2 Hz, 1H), 6.45 (dd, J=16.2, 7.2 Hz, 1H), 4.43 (q, J=7.2 Hz, 2H), 4.13 (m, 1H), 1.41 (t, J=7.2 Hz, 3H); ESIMS m/z 455.0 ([M+H]+); IR (thin film) 1728, 1115, 817 cm−1.
    • (E)-Ethyl 2-fluoro-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate (AI64)
  • Figure US20170088507A1-20170330-C00083
  • 1H NMR (400 MHz, CDCl3) δ 7.93 (t, J=7.6 Hz, 1H), 7.34 (d, J=5.6 Hz, 2H), 7.21 (d, J=8.0 Hz, 1H), 7.16 (d, J=11.6 Hz, 1H), 6.59 (d, J=16.0 Hz, 1H), 6.49 (dd, J=16.0, 7.6 Hz, 1H), 4.42 (q, J=7.6 Hz, 2H), 4.13 (m, 1H), 1.41 (t, J=7.6 Hz, 3H); ESIMS m/z 436.81 ([M−H]−); IR (thin film) 1725 cm−1.
    • (E)-Ethyl 2-bromo-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate (AI65)
  • Figure US20170088507A1-20170330-C00084
  • 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J=8.0 Hz, 1H), 7.67 (s, 1H), 7.36 (m, 3H), 6.56 (d, J=15.6 Hz, 1H), 6.44 (dd, J=15.6, 8.0 Hz, 1H), 4.42 (q, J=6.8 Hz, 2H), 4.10 (m, 1H), 1.42 (t, J=6.8 Hz, 3H); ESIMS m/z 498.74 ([M−H]−); IR (thin film) 1726, 1114, 820, 623 cm−1.
    • (E)-Ethyl 2-methyl-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate (AI66)
  • Figure US20170088507A1-20170330-C00085
  • The title compound was isolated as a brown semi-solid: 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J=8.8 Hz, 1H), 7.34 (d, J=6.0 Hz, 2H), 7.25 (d, J=7.2 Hz, 2H), 6.59 (d, J=16.0 Hz, 1H), 6.42 (dd, J=16.0 Hz, 8.0 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 4.19 (m, 1H), 2.63 (s, 3H), 1.41 (t, J=7.2 Hz, 3H); ESIMS m/z 432.90 ([M−H]−); IR (thin film) 1715 cm−1.
    • (E)-Methyl 2-methoxy-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate (AI67)
  • Figure US20170088507A1-20170330-C00086
  • 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J=8.4 Hz, 1H), 7.35 (d, J=6.0 Hz, 2H), 7.03 (d, J=1.2 Hz, 1H), 6.92 (s, 1H), 6.59 (d, J=15.6 Hz, 1H), 6.42 (dd, J=15.6, 8.0 Hz, 1H), 4.13 (m, 1H), 3.93 (s, 3H), 3.88 (s, 3H); ESIMS m/z 437.29 ([M+H]+); IR (thin film) 1724 cm−1.
    • (E)-Ethyl 2-ethyl-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate (AI68)
  • Figure US20170088507A1-20170330-C00087
  • 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J=8.0 Hz, 1H), 7.35 (d, J=9.6 Hz, 2H), 7.26 (m, 1H), 7.24 (m, 1H), 6.60 (d, J=15.6 Hz, 1H), 6.42 (dd, J=15.6, 8.0 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 4.14 (m, 1H), 3.01 (q, J=7.6 Hz 2H), 1.41 (t, J=7.2 Hz, 3H), 1.26 (t, J=7.6 Hz, 3H); ESIMS m/z 447.05 ([M−H]−); IR (thin film) 1715, 1115, 817 cm−1.
    • Example 11: Preparation of (E)-4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoic acid (AI32)
  • Figure US20170088507A1-20170330-C00088
  • To a stirred solution of (E)-ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoate (1.7 g, 4.0 mmol) in 1,4-dioxane (10 mL) was added 11 N HCl (30 mL), and the reaction mixture was heated at 100° C. for 48 h. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was diluted with water and extracted with chloroform (CHCl3). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure, and the crude compound was washed with n-hexane to afford the title compound as a white solid (0.7 g, 50%): mp 142-143° C.; 1H NMR (400 MHz, DMSO-d6) δ 12.62 (br s, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.66 (s, 3H), 7.52-7.44 (m, 2H), 6.89 (dd, J=16.0, 8.0 Hz, 1H), 6.78-6.74 (d, J=16.0 Hz, 1H), 4.84 (m, 1H), 2.50 (s, 3H); ESIMS m/z 387.05 ([M−H]−); IR (thin film) 3448, 1701, 1109, 777 cm−1.
  • The following compounds were made in accordance with the procedures disclosed in Example 11.
    • (E)-2-Methyl-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (AI26)
  • Figure US20170088507A1-20170330-C00089
  • The product was isolated as a pale brown gummy liquid (1 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 7.65 (m, 1H), 7.41 (s, 2H), 6.68 (d, J=16.0 Hz, 1H), 6.53 (dd, J=16.0, 8.0 Hz, 1H), 4.16 (m, 1H), 2.50 (s, 3H); ESIMS m/z 422.67 ([M−H]−).
    • (E)-2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (AI27)
  • Figure US20170088507A1-20170330-C00090
  • The product was isolated as an off-white semi-solid (1 g, 45%): 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=8.4 Hz, 1H), 7.50 (m, 1H), 7.40 (s, 1H), 7.36 (m, 2H), 6.59 (d, J=15.6 Hz, 1H), 6.48 (dd, J=15.6, 7.6 Hz, 1H), 4.14 (m, 1H); ESIMS m/z 442.72 ([M−H]−); IR (thin film) 3472, 1704, 1113, 808 cm−1.
    • (E)-2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (AI28)
  • Figure US20170088507A1-20170330-C00091
  • The product was isolated as a brown solid (1 g, 45%): mp 70-71° C.; 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=8.0 Hz, 1H), 7.72 (s, 1H), 7.40 (m, 3H), 6.58 (d, J=16.0 Hz, 1H), 6.48 (dd, J=16.0, 8.0 Hz, 1H), 4.14 (m, 1H); ESIMS m/z 484.75 ([M−H]−); IR (thin film) 3468, 1700 cm−1.
    • (E)-2-Cyano-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (AI29)
  • Figure US20170088507A1-20170330-C00092
  • The product was isolated as an off-white solid (500 mg, 45%): mp 100-101° C.; 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.65 (br s, 1H), 7.42 (s, 2H), 6.73 (d, J=16.0 Hz, 1H), 6.58 (dd, J=16.0, 8.0 Hz, 1H), 4.19 (m, 1H); ESIMS m/z 431.93 ([M−H]−).
    • E)-4-(3-(3,4-Dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoic acid (AI30)
  • Figure US20170088507A1-20170330-C00093
  • The product was isolated as a pale brown liquid (500 mg, 46%): 1H NMR (400 MHz, CDCl3) δ 8.03 (m, 1H), 7.49 (m, 2H), 7.29 (m, 1H), 7.22 (m, 2H), 6.73 (d, J=16.0 Hz, 1H), 6.58 (dd, J=16.0, 7.8 Hz, 1H), 4.16 (m, 1H), 2.64 (s, 3H); ESIMS m/z 386.84 ([M−H]−); IR (thin film) 3428, 1690, 1113, 780 cm−1.
    • (E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoic acid (AI31)
  • Figure US20170088507A1-20170330-C00094
  • The product was isolated as a white solid (500 mg, 50%): mp 91-93° C.; 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J=8.0 Hz, 1H), 7.35 (d, J=5.6 Hz, 1H), 7.30 (m, 3H), 6.61 (d, J=16.0 Hz, 1H), 6.48 (dd, J=16.0, 8.0 Hz, 1H), 4.13 (m, 1H), 2.65 (s, 3H); ESIMS m/z 406.87 ([M−H]−).
    • (E)-4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzoic acid (AI33)
  • Figure US20170088507A1-20170330-C00095
  • The product was isolated as a white solid (500 mg, 45%): mp 142-143 OC; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 7.65 (m, 1H), 7.41 (s, 2H), 6.68 (d, J=16.0 Hz, 1H), 6.53 (dd, J=16.0, 8.0 Hz, 1H), 4.16 (m, 1H); ESIMS m/z 474.87 ([M−H]−).
    • (E)-2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (AI69)
  • Figure US20170088507A1-20170330-C00096
  • The title compound was isolated as a brown solid (0.8 g, 28%): 1H NMR (400 MHz, CDCl3) δ 13.42 (br, 1H), 7.98 (d, J=1.5 Hz, 1H), 7.94 (m, 2H), 7.75 (d, J=8.1 Hz, 1H), 7.65 (m, 1H), 7.06 (dd, J=15.9, 9.0 Hz, 1H), 6.80 (d, J=15.9 Hz, 1H), 4.91 (m, 1H); ESIMS m/z 484.75 ([M−H]−); IR (thin film) 3469, 1700 cm−1.
    • (E)-2-Bromo-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoic acid (AI70)
  • Figure US20170088507A1-20170330-C00097
  • The title compound was isolated as a yellow liquid (0.3 g, crude): 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J=8.1 Hz, 1H), 7.67 (s, 1H), 7.34 (m, 3H), 6.56 (d, J=15.9 Hz, 1H), 6.45 (dd, J=15.9, 7.6 Hz, 1H), 4.43 (m, 1H); ESIMS m/z 471.0 ([M−H]−).
    • (E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-ethylbenzoic acid (AI71)
  • Figure US20170088507A1-20170330-C00098
  • The title compound was isolated as a brown gummy material (0.2 g, crude): 1H NMR (300 MHz, DMSO-d6) δ 12.5 (br, 1H), 7.85 (d, J=6.3 Hz, 2H), 7.75 (d, J=8.1 Hz, 1H), 7.52 (m, 2H), 6.96 (dd, J=8.7, 8.7 Hz, 1H), 6.78 (d, J=15.6 Hz, 1H), 4.80 (m, 1H), 4.06 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H); ESIMS m/z 419.06 ([M−H]−).
    • (E)-2-Chloro-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoic acid (AI72)
  • Figure US20170088507A1-20170330-C00099
  • The title compound was isolated as a yellow liquid (0.7 g, 95%): 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J=6.0 Hz, 1H), 7.46 (d, J=1.8 Hz, 1H), 7.41 (s, 3H), 6.57 (d, J=16.0 Hz, 1H), 6.45 (dd, J=16.0, 8.0 Hz, 1H), 4.16 (m, 1H); ESIMS m/z 455.0 ([M+H]+); IR (thin film) 1728, 1115, 817 cm−1.
    • (E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoic acid (AI73)
  • Figure US20170088507A1-20170330-C00100
  • The title compound was isolated as a light brown gummy material (0.7 g, 38%): mp 91-93° C.; 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J=8.0 Hz, 1H), 7.35 (d, J=5.6 Hz, 1H), 7.30 (m, 3H), 6.10 (d, J=16.0 Hz, 1H), 6.46 (dd, J=16.0, 8.0 Hz, 1H), 4.03 (m, 1H), 2.65 (s, 3H); ESIMS m/z 406.87 ([M−H]−).
    • (E)-4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-fluorobenzoic acid (AI74)
  • Figure US20170088507A1-20170330-C00101
  • The title compound was isolated as a light brown liquid (0.3 g, crude): ESIMS m/z 393.15 ([M−H]−).
    • (E)-2-Bromo-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)benzoic acid (AI75)
  • Figure US20170088507A1-20170330-C00102
  • The title compound was isolated as a light brown liquid (0.35 g, crude): ESIMS m/z 451.91 ([M−H]−).
  • Prophetically, compounds AI34, AI36-AI41, AI44-AI45 (Table 1) could be made in accordance with the procedures disclosed in Example 10, or Examples 10 and 11.
    • Example 12: Preparation of (E)-4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methyl-N-(2,2,2-trifluoroethyl)benzamide (AC6)
  • Figure US20170088507A1-20170330-C00103
  • To a stirred solution of (E)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoic acid in DMF was added 2,2,2-trifluoroethylamine, 1-hydroxybenzotriazole hydrate (HOBt.H2O), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC.HCl) and DIPEA, and the reaction mixture was stirred at 25° C. for 18 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with hexane:EtOAc afforded a white semi-solid (110 mg, 50%): 1H NMR (400 MHz, CDCl3) 7.40 (m, 2H), 7.26 (m, 3H), 6.56 (d, J=16.0 Hz, 1H), 6.48 (dd, J=16.0, 8.0 Hz, 1H), 5.82 (br s, 1H), 4.08 (m, 3H), 2.52 (s, 3H); ESIMS m/z 468.40 ([M−H]−); IR (thin film) 1657, 1113, 804 cm−1.
  • Compounds AC7-AC38, AC40-AC58, AC110-AC112, AC117, and AC118 (Table 1) were made in accordance with the procedures disclosed in Example 12.
    • Example 13: Preparation of 4-((E)-3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methyl-N-((pyrimidin-5-yl)methyl)benzamide (AC39)
  • Figure US20170088507A1-20170330-C00104
  • To a stirred solution of (pyrimidin-5-yl)methanamine (0.15 g, 1.43 mmol) in CH2Cl2 (10 mL) was added drop wise trimethylaluminum (2 M solution in toluene; 0.71 mL, 1.43 mmol), and the reaction mixture was stirred at 25° C. for 30 min. A solution of ethyl 4-((E)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoate (0.3 g, 0.71 mmol) in CH2Cl2 was added drop wise to the reaction mixture at 25° C. The reaction mixture was stirred at reflux for 18 h, cooled to 25° C., quenched with 0.5 N HCl solution (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 40% EtOAc in n-hexane) to afford the title compound (0.18 g, 55%): mp 141-144° C.; 1H (400 MHz, CDCl3) δ 9.19 (s, 1H), 8.79 (s, 2H), 7.37 (m, 2H), 7.23 (m, 2H), 7.21 (m, 1H), 6.57 (d, J=16.0 Hz, 1H), 6.40 (dd, J=16.0, 7.6 Hz 1H), 6.21 (m, 1H), 4.65 (s, 2H), 4.11 (m, 1H), 2.46 (s, 3H); ESIMS m/z 477.83 ([M−H]−).
    • Example 14: Preparation of (E)-2-Chloro-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC64)
  • Figure US20170088507A1-20170330-C00105
  • To a stirred solution of glycine amide (0.15 g, 0.58 mmol) in CH2Cl2 (5 mL) was added trimethylaluminum (2 M solution in toluene; 1.45 mL, 2.91 mmol) dropwise, and the reaction mixture was stirred at 28° C. for 30 min. A solution of (E)-ethyl 2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoate (0.3 g, 0.58 mmol) in CH2Cl2 (5 mL) was added drop wise to the reaction mixture at 28° C. The reaction mixture was stirred at reflux for 18 h, cooled to 25° C., quenched with 1N HCl solution (50 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 40% EtOAc in n-hexane) to afford the title compound as yellow solid (0.15 g, 50%): mp 83-85° C.; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=8.0 Hz, 1H), 7.44 (s, 1H), 7.40 (s, 2H), 7.36 (d, J=6.8 Hz, 1H), 7.05 (t, J=5.2 Hz, 1H), 6.70 (t, J=5.2 Hz, 1H), 6.57 (d, J=15.6 Hz, 1H), 6.44 (dd, J=15.6, 8.0 Hz, 1H), 4.23 (d, J=5.6 Hz, 2H), 4.15 (m, 1H), 4.01 (m, 2H); ESIMS m/z 580.72 ([M−H]−).
  • Compounds AC59-AC75 (Table 1) were made in accordance with the procedures disclosed in Example 14.
    • Example 15: Preparation of (E)-2-Bromo-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide (AC79)
  • Figure US20170088507A1-20170330-C00106
  • To a stirred solution of (E)-2-bromo-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoic acid (300 mg, 0.638 mmol) in CH2Cl2 (5.0 mL) was added 2-amino-N-(2,2,2-trifluoroethyl)acetamide (172. mg, 0.638 mmol) followed by benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (364.5 mg, 0.701 mmol) and DIPEA (0.32 mL, 1.914 mmol), and the resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 40% ethyl acetate/petroleum ether) afforded the title compound as an off-white solid (121 mg, 31%): 1H NMR (400 MHz, CDCl3) δ 8.69 (t, J=6.0 Hz, 1H), 8.58 (t, J=6.0 Hz, 1H), 7.92 (s, 1H), 7.87 (d, J=6.4 Hz, 2H), 7.62 (d, J=8.4 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.0 (m, 1H), 6.76 (d, J=15.6 Hz, 1H), 4.83 (t, J=8.0 Hz, 1H), 3.98 (m, 4H); ESIMS m/z 610.97 ([M+H]+); IR (thin film) 3303, 1658, 1166, 817 cm−1.
  • Compounds AC76-AC80, AC96-AC102, and AC113 (Table 1) were made in accordance with the procedures disclosed in Example 15.
    • Example 16: Preparation of (E)-4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N-(1,1-dioxidothietan-3-yl)-2-fluorobenzamide (AC83)
  • Figure US20170088507A1-20170330-C00107
  • To a stirred solution of (E)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-fluoro-N-(thietan-3-yl)benzamide (100 mg, 0.2159 mmol) in acetone/water (1:1, 5.0 mL) was added oxone (266 mg, 0.4319 mmol) and the resultant reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 30% ethyl acetate/pet ether) afforded the title compound as a off white solid (70.0 mg, 66%): 1H NMR (400 MHz, CDCl3) δ 8.07 (t, J=8.4 Hz, 1H), 7.39 (t, J=1.6 Hz, 1H), 7.31 (d, J=1.2 Hz, 1H), 7.26 (m, 2H), 7.23 (m, 2H), 7.19 (d, J=1.6 Hz, 1H), 6.60 (d, J=16.8 Hz, 1H), 6.49 (dd, J=16.8, 7.6 Hz, 1H), 4.90 (m, 1H), 4.64 (m, 2H), 4.14 (m, 2H); ESIMS m/z 493.83 ([M−H]−); IR (thin film) 1527, 1113, 801, 1167, 1321 cm−1.
  • Compounds AC81-AC87 (Table 1) were made in accordance with the procedures disclosed in Example 16.
    • Example 17: Preparation of (E)-N-((5-Cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-methylbenzamide (AC89)
  • Figure US20170088507A1-20170330-C00108
  • A solution of (E)-N-(2-(2-(cyclopropanecarbonyl)hydrazinyl)-2-oxoethyl)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzamide (200 mg, 0.379 mmol) in POCl3 (2.0 mL) was stirred at ambient temperature for 10 min, then the resultant reaction mixture was heated to 50° C. for 1 h. The reaction mixture was quenched with ice water at 0° C. and extracted with ethyl acetate. The combined ethyl acetate layer was washed with saturated NaHCO3 solution and brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 50% ethyl acetate/pet ether) afforded the title compound as a light brown gummy material (70.0 mg, 36%): 1H NMR (400 MHz, CDCl3) δ 7.43 (m, 2H), 7.27 (m, 2H), 7.23 (m, 2H), 6.58 (d, J=16.0 Hz, 1H), 6.41 (dd, J=16.0, 7.6 Hz, 1H), 4.79 (d, J=5.6 Hz, 2H), 4.14 (m, 1H), 2.48 (s, 3H), 2.18 (m, 1H), 1.16 (m, 4H); ESIMS m/z 509.89 ([M+H]+); IR (thin film) 1666, 1166, 1112, 800 cm−1.
    • Example 18: Preparation of (E)-2-Bromo-N-(2-thioxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzothioamide (AC90)
  • Figure US20170088507A1-20170330-C00109
  • To a stirred solution of (E)-2-bromo-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (400 mg, 0.638 mmol) in 5 mL of THF at ambient temperature was added 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's reagent) (336 mg, 0.830 mmol) in one portion. The resulting reaction mixture was stirred for 18 h. TLC showed the reaction was not complete, therefore additional Lawesson's reagent (168 mg, 0.415 mmol) was added and reaction stirred for 48 h. After the reaction was deemed complete by TLC, the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 230-400 mesh; eluting with 20% EtOAc in hexanes) afforded the title compound as a yellow glassy oil (188 mg, 44.7%): 1H NMR (400 MHz, CDCl3) δ 8.34 (m, 1H), 8.27 (m, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.49 (d, J=8.0 Hz, 2H), 7.40 (s, 2H), 7.36 (dd, J=8.2, 1.7 Hz, 1H), 6.53 (d, J=16.0 Hz, 1H), 6.38 (dd, J=15.9, 7.9 Hz, 1H), 4.89 (d, J=8.4, 5.5 Hz, 2H), 4.48 (qd, J=9.0, 6.0 Hz, 2H), 4.11 (m, 1H); ESIMS m/z 656.9 ([M−H]−).
    • Example 19: Preparation of (E)-2-(2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenylthioamido)-N-(2,2,2-trifluoroethyl)acetamide (AC91)
  • Figure US20170088507A1-20170330-C00110
  • To a stirred solution of (E)-2-bromo-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (400 mg, 0.638 mmol) in 5 mL of THF at ambient temperature was added Lawesson's reagent (64.5 mg, 0.160 mmol) in one portion. The resulting reaction mixture was stirred for 18 h, after which time, the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 230-400 mesh; eluting with 20% EtOAc in hexanes) afforded the title compounds as a yellow oil (18.5 mg, 4.51%): 1H NMR (400 MHz, CDCl3) δ 8.18 (t, J=5.0 Hz, 1H), 7.58 (d, J=1.6 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.40 (s, 2H), 7.34 (dd, J=8.1, 1.6 Hz, 1H), 6.52 (m, 2H), 6.37 (dd, J=15.9, 7.9 Hz, 1H), 4.54 (d, J=4.9 Hz, 2H), 4.12 (m, 1H), 3.99 (qd, J=8.9, 6.5 Hz, 2H); ESIMS m/z 640.9 ([M−H]−).
  • The following compound was made in accordance with the procedures disclosed in Example 19.
    • (E)-2-Bromo-N-(2-thioxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC92)
  • Figure US20170088507A1-20170330-C00111
  • The product was isolated as a colorless oil (17.9 mg, 4.36%): 1H NMR (400 MHz, CDCl3) δ 9.16 (d, J=6.1 Hz, 1H), 7.65 (d, J=1.6 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.41 (m, 3H), 7.21 (t, J=5.6 Hz, 1H), 6.55 (d, J=15.9 Hz, 1H), 6.41 (dd, J=15.9, 7.8 Hz, 1H), 4.59 (d, J=5.6 Hz, 2H), 4.45 (qd, J=9.0, 6.0 Hz, 2H), 4.12 (q, J=7.2 Hz, 1H); ESIMS m/z 640.9 ([M−H]−).
    • Example 106: Preparation of Ethyl (Z) 2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoate (AI76)
  • Figure US20170088507A1-20170330-C00112
  • The title compound was made in accordance with the procedure disclosed in Example 88 and was isolated as a yellow viscous oil (416 mg, 23%): 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J=8.0 Hz, 1H), 7.40 (d, J=1.7 Hz, 1H), 7.35 (s, 2H), 7.12 (dd, J=8.0, 1.7 Hz, 1H), 6.86 (d, J=11.4 Hz, 1H), 6.23-5.91 (m, 1H), 4.42 (q, J=7.1 Hz, 2H), 4.33-4.10 (m, 1H), 1.42 (t, J=7.2 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −69.34 (d, J=8.3 Hz); EIMS m/z 514.10 ([M]−); IR (thin film) 2983, 1727, 1247, 1204, 1116 cm−1.
    • Example 107: Preparation of (Z)-2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (AI77)
  • Figure US20170088507A1-20170330-C00113
  • To a stirred solution of (Z)-ethyl 2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoate (360 mg, 0.70 mmol) in CH3CN (1.0 mL) was added iodotrimethylsilane (0.28 mL, 2.8 mmol). The reaction mixture was heated to reflux for 20 h, allowed to cool to ambient temperature and partitioned between CH2Cl2 and aq. 10% Na2S2O3. Organic phase was washed once with aq. 10% Na2S2O3 and dried over MgSO4 and concentrated in vacuo. Passing the material through a silica plug with 10% EtOAc in hexanes, followed by 20% MeOH in CH2Cl2) as the eluting solvents afforded the title compound as a yellow foam (143 mg, 42%): mp 54-64° C.; 1H NMR (400 MHz, CDCl3) δ 11.36 (s, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.30 (s, 2H), 7.14 (d, J=7.9 Hz, 1H), 6.85 (d, J=11.4 Hz, 1H), 6.15 (t, J=10.9 Hz, 1H), 4.36-4.09 (m, 1H); 19F NMR (376 MHz, CDCl3) δ −69.30.
    • Example 108: Preparation of (Z)-2-Bromo-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC95)
  • Figure US20170088507A1-20170330-C00114
  • To a stirred solution of (Z)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (200 mg, 0.41 mmol) in anhydrous THF (5.0 mL) was added DCI (82 mg, 0.51 mmol). The mixture was heated in a 50° C. oil bath for 1.5 h, treated with 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (109 mg, 0.057 mmol) and the resulting mixture heated to reflux for 8 h. After cooling to ambient temperature, the mixture was taken up in Et2O and washed twice with aq. 5% NaHSO4 (2×) and once with sat. NaCl (1×). After dying over MgSO4, concentration in vacuo and purification by medium pressure chromatography on silica with EtOAc/Hexanes as the eluents, the title compound was obtained as a white foam (160 mg, 41%) mp 48-61° C.: 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=7.9 Hz, 1H), 7.44-7.29 (m, 3H), 7.14 (dd, J=7.9, 1.6 Hz, 1H), 6.86 (d, J=11.4 Hz, 1H), 6.76 (t, J=5.9 Hz, 1H), 6.59 (br s, 1H), 6.21-6.04 (m, 1H), 4.23 (d, J=5.5 Hz, 1H), 3.98 (qd, J=9.0, 6.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ −69.31, −72.3; EIMS m/z 626.9 ([M+1]+).
    • Example 109a: Preparation of (E)-2-Bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC114)
  • Figure US20170088507A1-20170330-C00115
  • (E)-tert-Butyl 4-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamido)piperidine-1-carboxylate (0.75 g, 1.11 mmol) was added to dioxane HCl (10 mL) at 0° C. and was stirred for 18 h. The reaction mixture was concentrated under reduced pressure and triturated with diethylether to afford the compound as a light brown solid (0.6 g, 88%).
    • Example 109b: Preparation of (E)-N-(1-Acetylpiperidin-4-yl)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC103)
  • Figure US20170088507A1-20170330-C00116
  • To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol) in CH2Cl2 (10.0 mL) was added TEA (0.046 mL, 0.35 mmol) and stirred for 10 min. Then acetyl chloride (0.014, 0.18 mmol) was added and stirred for 16 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution and brine solution. The combined CH2Cl2 layer was dried over Na2SO4 and concentrated under reduced pressure to afford crude compound. The crude compound was washed with 5% diethyl ether/n-pentane to afford the title compound as a white solid (0.054 g, 50%).
    • Example 110: Preparation of (E)-2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N-(1-(3,3,3-trifluoropropanoyl)piperidin-4-yl)benzamide (AC104)
  • Figure US20170088507A1-20170330-C00117
  • To a stirred solution of 3,3,3-trifluoropropanoic acid (0.02 g, 0.16 mmol) in CH2Cl2 (10.0 mL), (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol), PYBOP (0.09 g, 0.17 mmol), and DIPEA (0.06 g, 0.48 mmol) were added at ambient temperature. The reaction mixture was stirred at ambient temperature for 5 h. The reaction mixture was diluted with CH2Cl2. The combined CH2Cl2 layer was washed with 3N HCl and saturated NaHCO3 solution, the separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; eluting with 2% MeOH in CH2Cl2) to afford the title compound as a off white gummy material (0.035 g, 29.%).
    • Example 111: Preparation of (E)-2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzamide (AC105)
  • Figure US20170088507A1-20170330-C00118
  • To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol) in THF (5.0 mL) was added TEA (0.06 mL, 0.64 mmol) and stirred for 10 min. Then 2,2,2-trifluoroethyl triflluoromethanesulfonate (0.03, 0.16 mmol) was added and stirred for 16 h at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 solution and brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a brown solid (0.05 g, 44%).
    • Example 112: Preparation of (E)-2-Bromo-N-(1-methylpiperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC106)
  • Figure US20170088507A1-20170330-C00119
  • A solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol), formaldehyde (30% in water) (0.1 mL, 0.16 mmol) and acetic acid (0.01 mL) in MeOH (5.0 mL) was stirred at ambient temperature for 30 min. After that NaBH3CN (0.01 g, 0.16 mmol) was added at 0° C. and the reaction was stirred for 8 h at ambient temperature. The solvent was removed under reduced pressure to obtain residue which was diluted with ethyl acetate and washed with saturated aq. NaHCO3 solution and brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to obtain a residue, which was triturated with diethyl ether/pentane to afford the title compound as a pale yellow gummy material (0.06 g, 59%).
    • Example 113: Preparation of ((E)-2-Bromo-N-(1-(cyanomethyl)piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC107)
  • Figure US20170088507A1-20170330-C00120
  • To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.25 g, 0.43 mmol) in THF (10.0 mL) was added TEA (0.16 mL, 1.29 mmol) and the reaction was stirred for 10 min. Then 2-bromoacetonitrile (0.07, 0.65 mmol) was added and the reaction was stirred for 8 h at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (0.125 g, 46.8%).
    • Example 114: Preparation of (E)-2-Bromo-N-(1-(oxetan-3-yl)piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC108)
  • Figure US20170088507A1-20170330-C00121
  • A solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.2 g, 0.35 mmol), oxetan-3-one (0.027 g, 0.38 mmol) and acetic acid (0.01 mL) in MeOH (5.0 mL) was stirred at ambient temperature for 30 min. After that NaBH3CN (0.022 g, 0.35 mmol) was added at 0° C. slowly lot wise over the period of 10 min and the reaction was stirred for 8 h at ambient temperature. The solvent was removed under reduced pressure to obtain a residue which was diluted with ethyl acetate and washed with saturated NaHCO3 solution and brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to obtain a residue, which was triturated with diethyl ether/pentane to afford the title compound as an off-white solid (0.05 g, 23%).
    • Example 115: Preparation of (E)-2-Bromo-N-(1-(2-hydroxyethyl)piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC109)
  • Figure US20170088507A1-20170330-C00122
  • To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.25 g, 0.43 mmol) in THF (10.0 mL) was added TEA (0.16 mL, 1.29 mmol) and the reaction was stirred for 10 min. Then 2-chloroethanol (0.05, 0.65 mmol) was added and the reaction was stirred for 8 h at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (0.09 g, 34%).
    • Example 116: Preparation of (E)-2-(2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamido)acetic acid (AI78)
  • Figure US20170088507A1-20170330-C00123
  • To a stirred solution of (E)-tert-butyl 2-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamido)acetate (440 mg, 0.734 mmol) in CH2Cl2 (36.0 ml), was added TFA (4.0 mL) and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was concentrated under reduced pressure to obtain residue which was washed with n-pentane to afford the title compound as an off-white solid (310 mg, 78%): 1H NMR (400 MHz, CDCl3) δ 13.0 (s, 1H), 8.75 (t, J=5.7 Hz, 1H), 7.93 (m, 2H), 7.62 (d, J=7.5 Hz, 1H), 7.40 (d, J=8.1 Hz, 1H), 6.96 (dd, J=15.3, 9.3 Hz, 1H), 6.78 (d, J=15.3 Hz, 1H), 4.83 (m, 1H), 3.90 (d, J=5.7 Hz, 2H); ESIMS m/z 543.61 ([M+H]+); IR (thin film) 3429, 1635, 1114, 772 cm−1.
    • Example 117: Preparation of (E)-N-((6-Chloropyridin-3-yl)methyl)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-methylbenzothioamide (AC115)
  • Figure US20170088507A1-20170330-C00124
  • To the stirred solution of (E)-N-((6-chloropyridin-3-yl)methyl)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzamide (0.06 g, 0.117 mmol) in toluene (3 mL) was added Lawesson's reagent (0.14 g, 0.351 mmol) and the reaction was irradiated at 100° C. for 1 h, then cooled to ambient temperature and concentrated under reduced pressure to provide crude compound. The crude product was purified by preparative HPLC to afford the product as yellow color solid (0.03 g, 49%).
    • Example 118: Preparation of (E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-2-(trifluoromethoxy)benzamide (AC116)
  • Figure US20170088507A1-20170330-C00125
    • Step 1. 2-(Trifluoromethoxy)-4-vinylbenzoic acid (AI79)
  • To a stirred solution of 4-bromo-2-(trifluoromethoxy)benzoic acid (1 g, 3.67 mmol) in DMSO (20 mL) was added potassium vinyltrifluoroborate (1.47 g, 11.02 mmol) and potassium carbonate (1.52 g, 11.02 mmol). The reaction mixture was degassed with argon for 30 min. Bistriphenylphosphine(diphenylphosphinoferrocene)palladium dichloride (0.13 g, 0.18 mmol) was added and the reaction mixture was heated to 80° C. for 1 h. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (2×50 mL), washed with brine, and dried over Na2SO4. Concentration under reduced pressure furnished the crude compound which was purified by flash column chromatography to afford the product as pale yellow gummy material (0.4 g, 47%): 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J=8.1 Hz, 1H), 7.44 (d, J=1.8 Hz, 1H), 7.35 (s, 1H), 6.78 (dd, J=17.4.1, 11.1 Hz, 1H), 5.92 (d, J=17.4 Hz, 1H), 5.51 (d, J=10.8 Hz, 1H); ESIMS m/z 232.97 ([M+H]+).
    • Step 2. (E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-(trifluoromethoxy)benzoic acid (AI80)
  • To a stirred solution of 2-(trifluoromethoxy)-4-vinylbenzoic acid (0.356 g, 1.53 mmol) in 1N methyl pyrrolidine (5.0 mL) was added 1-(1-bromo-2,2,2-trifluoroethyl)-3,5-dichloro 4-fluorobenzene (1.0 g, 3.07 mmol), copper(I) chloride (CuCl; 0.03 g, 0.307 mmol) and 2,2 bipyridyl (0.095 g, 0.614 mmol). The reaction mixture was stirred at 150° C. for 1 h. After the reaction was complete by TLC, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain the crude compound which was purified by flash column chromatography to afford the product as pale yellow gummy material (0.3 g, 21%): 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J=8.0 Hz, 1H), 7.45 (d, J=1.6 Hz, 1H), 7.35 (s, 3H), 6.63 (d, J=16.0 Hz, 1H), 6.50 (dd, J=16.0, 8.0 Hz, 1H), 4.15 (m, 1H); ESIMS m/z 474.81 ([M−H]−).
    • Step 3. (E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-2-(trifluoromethoxy)benzamide (AC116)
  • A mixture of (E)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-(trifluoromethoxy)benzoic acid (0.25 g, 0.52 mmol), 2-amino-N-(2,2,2-trifluoroethyl)acetamide (0.158 g, 0.62 mmol), PyBOP (0.40 g, 0.78 mmol) and DIPEA (0.134 g, 1.04 mmol) in CH2Cl2 (10.0 mL) were stirred at ambient temperature for 16 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 20% ethyl acetate/pet ether) afforded the title compound as a pale yellow gummy material (0.15 g, 47%).
    • Example 20: Preparation of 5-Vinyl-2,3-dihydro-1H-inden-1-one (BI1)
  • Figure US20170088507A1-20170330-C00126
  • To a stirred solution of 5-bromo-2,3-dihydro-1H-inden-1-one (5 g, 23.7 mmol) in toluene were added vinylboronic anhydride pyridine complex (8.55 g, 35.54 mmol), Pd(PPh3)4 (0.1 g, 0.094 mmol), K2CO3 (22.88 g, 165.83 mmol). The resultant reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to 25° C. and filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc and washed with water and brine. The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (SiO2, 5% EtOAc in petroleum ether) afforded the title compound as a solid (1.8 g, 48%): 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=7.2 Hz, 1H), 7.49 (br s, 1H), 7.44 (d, J=7.2 Hz, 1H), 6.82 (m, 1H), 5.90 (d, J=7.4 Hz, 1H), 5.42 (d, J=6.4 Hz, 1H), 3.20 (m, 2H), 2.70 (m, 2H); ESIMS m/z 159.06 ([M+H]−).
  • The following compound was made in accordance with the procedures disclosed in Example 20.
    • 6-Vinyl-3,4-dihydronaphthalen-1(2H)-one (BI2)
  • Figure US20170088507A1-20170330-C00127
  • The product was isolated as an off-white solid (5 g, 48%): 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J=8.4 Hz, 1H), 7.48 (m, 2H), 6.82 (m, 1H), 6.02 (d, J=7.4 Hz, 1H), 5.44 (d, J=6.4 Hz, 1H), 2.95 (m, 2H), 2.60 (m, 2H), 2.00 (m, 2H); ESIMS m/z 173.14 ([M−H]−); IR (thin film) 1681 cm−1.
    • Example 21: Preparation of (E)-5-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-one (BI3)
  • Figure US20170088507A1-20170330-C00128
  • 5-(1-Bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (4 g, 11.7 mmol), 5-vinyl-2,3-dihydro-1H-inden-1-one (0.92 g, 5.8 mmol), CuCl (0.115 g, 1.171 mmol) and 2,2-bipyridyl (0.053 g, 0.34 mmol) in 1,2-dichlorobenzene (25 mL) were heated at 180° C. for 16 h. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 5% EtOAc in petroleum ether) to afford the title compound as a liquid (1.28 g, 25%): 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=7.4 Hz, 1H), 7.52 (m, 3H), 6.68 (d, J=7.4 Hz, 1H), 6.52 (m, 1H), 4.18 (m, 1H), 3.18 (m, 2H), 2.75 (m, 2H); ESIMS m/z 419.14 ([M+H]−); IR (thin film) 1708.94, 1113.60, 807.77 cm−1.
  • The following compound was made in accordance with the procedures disclosed in Example 21.
    • (E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2,3-dihydro-1H-inden-1-one (BI4)
  • Figure US20170088507A1-20170330-C00129
  • The product was isolated as a brown semi-solid (1.2 g, 16%): 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=7.4 Hz, 1H), 7.54 (m, 3H), 7.30 (s, 1H), 6.68 (d, J=7.4 Hz, 1H), 6.52 (m, 1H), 4.18 (m, 1H), 3.18 (m, 2H), 2.75 (m, 2H); ESIMS m/z 400.84 ([M−H]−); IR (thin film) 815, 1113, 1709 cm−1.
    • (E)-6-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-3,4-dihydronaphthalen-1(2H)-one (BI5)
  • Figure US20170088507A1-20170330-C00130
  • The product was isolated as a pale yellow semi solid (1.2 g, 30%): 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=8.0 Hz, 1H), 7.42 (s, 2H), 7.35 (m, 1H), 7.24 (m, 2H), 6.62 (d, J=16 Hz, 1H), 6.46 (m, 1H), 4.18 (m, 1H), 2.95 (m, 2H), 2.65 (m, 2H), 2.19 (m, 2H); ESIMS m/z 432.94 ([M−H]−); IR (thin film) 1680, 1113, 808 cm−1.
    • Example 22: Preparation of (E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-fluoro-2,3-dihydro-1H-inden-1-one (BI6)
  • Figure US20170088507A1-20170330-C00131
  • To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2,3-dihydro-1H-inden-1-one (0.5 g, 1.24 mmol) in acetonitrile (20 mL), was added Selectfluor® (0.52 g, 1.48 mmol) and the reaction was heated to reflux temperature for 16 h. The reaction mixture was cooled to ambient temperature, concentrated under reduced pressure and diluted with CH2Cl2. The solution was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which was purified by flash column chromatography (SiO2, 100-200 mesh; 15% EtOAc in petroleum ether) to afford the title compound as a pale yellow semi solid (0.1 g, 24%): 1H NMR (400 MHz, CDCl3) δ 7.80 (m, 1H), 7.48 (m, 2H), 7.32 (m, 2H), 6.65 (d, J=16.0 Hz, 1H), 6.54 (dd, J=16.0, 8.0 Hz, 1H), 5.38 (m, 1H), 4.18 (m, 1H), 3.62 (m, 1H), 3.32 (m, 1H); ESIMS m/z 419.06 ([M−H]−); IR (thin film) 1728, 1114, 817 cm−1.
    • Example 23: Preparation of (E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N-(3,3,3-trifluoropropyl)-2,3-dihydro-1H-inden-1-amine (BC10)
  • Figure US20170088507A1-20170330-C00132
  • To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2,3-dihydro-1H-inden-1-one (0.15 g, 0.35 mmol) in DCE (10 mL), was added trifluoropropyl amine (0.048 g, 0.42 mmol) and sodium cyanoborohydride (0.055 g, 0.875 mmol) in cooling and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with DCE, was washed with water and brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the crude compound, which was purified by flash column chromatography (SiO2, 100-200 mesh; 10-15% EtOAc in petroleum ether) to afford the title compound as a colorless gummy material (0.042 g, 24%): 1H NMR (400 MHz, CDCl3) δ 7.38-7.20 (m, 5H), 6.62 (d, J=16.0 Hz, 1H), 6.34 (dd, J=16.0, 8.0 Hz, 1H), 5.83 (br, 1H), 5.52 (m, 1H), 4.12 (m, 1H), 3.02 (m, 3H), 2.82 (m, 1H), 2.50 (m, 2H), 1.82 (m, 1H), 1.42 (m, 1H); ESIMS m/z 497.98 ([M−H]−); IR (thin film) 3027, 1654, 815 cm−1.
    • Example 24: Preparation of 6-((E)-4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-3,4-dihydronaphthalen-1(2H)-one oxime (BI5a)
  • Figure US20170088507A1-20170330-C00133
  • To a stirred solution of ((E)-6-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-3,4-dihydronaphthalen-1(2H)-one (0.4 g, 0.92 mmol) in EtOH (50 mL) were added hydroxylamine hydrochloride (0.128 g, 1.85 mmol) and sodium acetate (0.23 g, 2.77 mmol), and the reaction mixture was heated at reflux for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude compound, which was purified by flash column chromatography (SiO2, 100-200 mesh; 10-15% EtOAc in petroleum ether). The title compound was isolated as a solid (0.3 g, 73%): mp 155-158° C.; 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8.4 Hz, 1H), 7.41 (s, 2H), 7.24 (m, 1H), 7.17 (m, 1H), 6.57 (d, J=16 Hz, 1H), 6.46 (dd, J=16.0, 8.0 Hz, 1H), 4.13 (m, 1H), 2.82 (m, 4H), 2.04 (m, 2H); ESIMS m/z 445.95 ([M−H]−).
    • Example 25: Preparation of (E)-5-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-amine (BI5b)
  • Figure US20170088507A1-20170330-C00134
  • To a stirred solution of (E)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-one (1 g, 2.39 mmol) in CH3OH (10 mL) were added ammonium acetate (1.84 g, 23.9 mmol) and sodium cyanoborohydride (NaCNBH3; 0.44 g, 7.17 mmol) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with EtOAc. The combined organic extracts were washed with water and saturated aqueous sodium bicarbonate (satd aq NaHCO3) solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the title compound as a liquid (500 mg, crude): 1H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 2H), 7.40 (s, 1H), 7.30 (s, 2H), 6.71 (s, 2H), 4.78 (m, 1H), 4.2 (m, 1H), 2.80 (m, 1H), 2.73 (m, 1H), 1.60 (m, 2H); ESIMS m/z 419.02 ([M+H]+); IR (thin film) 2924, 1552, 1112, 807 cm−1.
  • The following compound was made in accordance with the procedures disclosed in Example 25.
    • (E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2,3-dihydro-1H-inden-1-amine (BI7)
  • Figure US20170088507A1-20170330-C00135
  • The product was isolated as a light brown gummy material, taken as such to the next step (0.15 g, crude compound): ESIMS m/z 401.97 ([M−H]−).
    • (E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-fluoro-2,3-dihydro-1H-inden-1-amine (BI8)
  • Figure US20170088507A1-20170330-C00136
  • The product was isolated as a light brown gummy material, taken as such to the next step (0.15 g, crude compound): ESIMS m/z 420.15 ([M−H]−).
    • (E)-6-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-1,2,3,4-tetrahydronaphthalen-1-amine (BI9)
  • Figure US20170088507A1-20170330-C00137
  • The product was isolated as a pale yellow liquid (500 mg crude).
    • Example 26: Preparation of (E)-1-Methyl-3-(5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)-but-1-enyl)-2,3-dihydro-1H-inden-1-yl)thiourea (BC1)
  • Figure US20170088507A1-20170330-C00138
  • To a stirred solution of (E)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-amine (0.1 g, 0.23 mmol) in Et2O (5 mL) was added methylisothiocyanate (0.026 g, 0.35 mmol), and the mixture was stirred for 2 h at 25° C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (SiO2, 20% EtOAc in petroleum ether). The title compound was isolated as a liquid (65 mg, 50%): 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 2H), 7.25-7.18 (m, 3H), 6.58 (d, J=16.0 Hz, 1H), 6.30 (dd, J=16.0, 8.4 Hz, 1H), 5.91-5.70 (br, 2H), 4.05 (m, 1H), 3.05-2.80 (m, 6H), 2.70 (m, 1H), 1.81 (m, 1H); ESIMS m/z 492.17 ([M+H]+); IR (thin film) 3211, 1569, 1113, 806 cm−1.
  • Compounds BC2-BC3 in Table 1 were made in accordance with the procedures disclosed in Example 26.
    • Example 27: Preparation of (E)-3,3,3-Trifluoro-N-(5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-yl)propanamide (BC4)
  • Figure US20170088507A1-20170330-C00139
  • To a stirred solution of (E)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-amine (0.1 g, 0.23 mmol) in CH2Cl2 (10 mL) were added trifluoropropionic acid (0.044 g, 0.34 mmol), EDC.HCl (0.038 g, 0.35 mmol), HOBt.H2O (0.07 g, 0.46 mmol) and DIPEA (0.074 g, 0.57 mmol), and the reaction mixture was stirred for 16 h at 25° C. The reaction mixture was diluted with CH2Cl2 and washed with water. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (SiO2, 15% EtOAc in petroleum ether) to afford the title compound as a liquid (65 mg, 65%): 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 2H), 7.25-7.20 (m, 3H), 6.34 (d, J=16.0 Hz, 1H), 6.30 (dd, J=16.0, 8.0 Hz, 1H), 5.81 (br, 1H), 5.48 (m, 1H), 4.10 (m, 1H), 3.10 (m, 2H), 2.86-3.07 (m, 2H), 2.86 (m, 1H), 1.81 (m, 1H); ESIMS m/z 529.02 ([M+H]+); IR (thin film) 3283, 1652, 1241, 811 cm−1.
  • Compounds BC5-BC9, BC11 in Table 1 were made in accordance with the procedures disclosed in Example 27.
    • Example 28: Preparation of tert-Butyl 5-vinylindoline-1-carboxylate (BI10)
  • Figure US20170088507A1-20170330-C00140
    • Step 1. 5-Bromo-indoline (BI11)
  • To 5-Bromo-1H-indole (2.5 g, 12.82 mmol) in acetic acid (10.0 mL), NaCNBH3 (2.38 g, 38.46 mmol) was added portion wise at 10° C. over the period of 20 min. After that the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with saturated NaHCO3, water and brine solution. The combined ether layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford title compound as a pale yellow semi-solid (1.8 g, 71%).
    • Step 2. tert-Butyl-5-bromoindoline-1-carboxylate (BI12)
  • To a stirred solution of 5-bromo-indoline (3.0 g, 15 mmol) in acetonitrile (100 ml), was added DMAP (0.185 g, 1.522 mmol) and di-tert-butyl dicarbonate (3.98 g, 18.3 mmol) and the reaction was stirred at ambient temperature for 16 h. The reaction mixture was concentrated on reduced pressure to obtain a residue which was diluted with diethyl ether and washed with water and brine solution (2×). The combined ether layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product as a off-white solid, which was used in the next step without further purification (3.0 g).
    • Step 3. tert-Butyl-5-vinylindoline-1-carboxylate (BI10)
  • A stirred solution of tert-butyl-5-bromoindoline-1-carboxylate (2.0 g, 6.73 mmol), potassium vinyl trifluoroborate (2.6 g, 20.20 mmol) and K2CO3 (2.78 g, 20.2 mmol) in DMSO (50.0 mL) was degassed with argon for 20 min at ambient temperature. PdCl2(dppf) (0.49 g, 0.67 mmol) was added at ambient temperature, then the reaction mixture was heated to 100° C. for 3 h. The reaction mixture was cooled to ambient temperature and filtered through a celite bed under vacuum and washed with diethyl ether. The reaction mixture was extracted with diethyl ether. The combined diethyl ether layer was dried over Na2SO4 and concentrated under reduced pressure to afford crude product. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; eluting with 2% ethyl acetate/petroleum ether) to afford the title compound as a off-white solid (1.2 g, 73%): Mp 85.5-88.6° C.; 1H NMR (400 MHz, CDCl3) δ 7.23 (m, 3H), 6.69 (dd, J=17.4, 10.8 Hz, 1H), 5.64 (d, J=10.5 Hz, 1H), 5.13 (d, J=10.5 Hz, 1H), 4.00 (t, J=9.0 Hz, 2H), 3.10 (t, J=9.0 Hz, 2H), 1.55 (bs, 9H).
    • Example 29: Preparation of (E)-tert-Butyl 5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)indoline-1-carboxylate (BI13)
  • Figure US20170088507A1-20170330-C00141
  • To a stirred solution of tert-butyl-5-vinylindoline-1-carboxylate (1.28 g, 5.23 mmol) in 1,2-dichlorobenzene (10.0 mL), was added 5-(1-bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-fluorobenzene (3.4 g, 10 mmol), CuCl (103 mg, 1.05 mmol) and 2,2-bipyridyl (0.326 g, 2.092 mmol) and the resultant reaction mixture was degassed with argon for 30 min and heated to 150° C. for 1 h. The reaction mixture was cooled to ambient temperature and filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2% ethyl acetate/petroleum ether) to afford the title compound as a pale yellow gummy solid (0.3 g, 61%): 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=6.0 Hz, 2H), 7.22 (s, 2H), 7.16 (d, J=8.4 Hz, 1H), 6.52 (d, J=16.0 Hz, 1H), 6.21 (dd, J=16.0, 7.6 Hz, 1H), 4.07 (m, 3H), 3.10 (t, J=8.4 Hz, 2H), 1.55 (s, 9H); ESIMS m/z 433.79 ([M−H]−); IR (thin film) 1168, 858 cm−1.
    • Example 30: Preparation of (E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)indolin-1-amine (BI14)
  • Figure US20170088507A1-20170330-C00142
    • Step 1. (E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)indoline (BI15)
  • To a stirred solution of (E)-tert-butyl-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)indoline-1-carboxylate (0.2 g, 0.4 mmol) in CH2Cl2 (10.0 mL) was added TFA (0.6 mL) and the reaction was stirred at ambient temperature for 2 h. The reaction mixture was diluted with CH2Cl2, washed with saturated aq NaHCO3, water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product as a light brown gummy material which was used in the next step without further purification (0.12 g): 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=6.4 Hz, 2H), 7.21 (s, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 6.49 (d, J=15.6 Hz, 1H), 6.21 (dd, J=15.6, 8.4 Hz, 1H), 4.07 (m, 1H), 3.61 (t, J=8.4 Hz, 2H), 3.05 (t, J=8.4 Hz, 2H); ESIMS m/z 389.89 ([M+H]+); IR (thin film) 3385, 1112, 816 cm−1.
    • Step 2. 5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1-nitrosoindoline (BI16)
  • To (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)indoline (0.2 g, 0.5 mmol) in concentrated HCl (5.0 ml) at 5° C., was added slowly NaNO2 in water and the reaction was allowed to stir at ambient temperature for 2 h. The reaction mixture was diluted with CH2Cl2, and the CH2Cl2 layer washed with water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product as a pale yellow solid that was used in the next step without further purification (0.2 g): 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=8.4 Hz, 1H), 7.39 (m, 4H), 6.61 (d, J=16.0 Hz, 1H), 6.35 (dd, J=16.0, 8.4 Hz, 1H), 4.07 (m, 3H), 3.23 (t, J=8.4 Hz, 2H); ESIMS m/z 418.82 ([M+H]+); IR (thin film) 1488, 1112, 860 cm−1.
    • Step 3. (E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)indolin-1-amine (BI14)
  • To (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1-nitrosoindoline (0.1 g, 0.2 mmol) in MeOH (10.0 mL) was added zinc powder (77.5 mg) and NH4Cl (36.9 mg, 0.69 mmol) in water (2.0 mL). The reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with CH2Cl2 and the CH2Cl2 layer was washed with water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound, which was purified by column chromatography (SiO2, 100-200 mesh; eluting with 2% ethyl acetate/petroleum ether) to afford the title compound as a light brown gummy material (0.08 g): ESIMS m/z 404.86 ([M+H]+).
    • Example 31: Preparation of (E)-N-(5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)indolin-1-yl)-3,3,3-trifluoropropanamide (BC12)
  • Figure US20170088507A1-20170330-C00143
  • To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)indoline-1-amine (0.1 g, 0.247 mmol) in CH2Cl2 (10.0 ml) was added 3,3,3-trifluoropropanoic acid (0.038 g, 0.297 mmol), PyBOP (0.192 g, 0.370 mmol) and DIPEA (0.047 g, 0.370 mmol) and the reaction was stirred at ambient temperature for 18 h. The reaction mixture was diluted with CH2Cl2, and the separated CH2Cl2 layer dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 20-25% ethyl acetate/petroleum ether) to afford the title compound as a light brown gummy material (0.12 g, 33%): 1H NMR (400 MHz, CDCl3) δ 7.32, (d, J=6.0 Hz, 2H) 7.28 (m, 1H), 7.20 (d, J=8.0, 1H), 7.14 (d, J=8.8, 1H), 6.70 (d, J=8.0 Hz, 1H), 6.60 (m, 2H), 4.15 (m, 1H), 3.85 (m, 1H), 3.65 (m, 1H), 3.46 (m, 2H), 3.19 (m, 2H); ESIMS m/z 514.86 ([M+H]+); IR (thin film) 3428, 1112, 857 cm−1.
    • Example 32: Preparation of tert-Butyl-5-vinyl-1H-indole-1-carboxylate (BI17)
  • Figure US20170088507A1-20170330-C00144
    • Step 1. 5-Vinyl-1H-indole (BI18)
  • A mixture of 5-bromo-1H-indole (2.5 g, 12.82 mmol), potassium vinyltrifluoroborate (2.57 g, 19.2 mmol), Cs2CO3 (12.53 g, 38.46 mmol) and triphenylphosphine (201 mg, 0.769 mmol) in THF/water (9:1, 75 ml) was degassed with argon for 20 min, then charged with PdCl2 (45.3 mg, 0.256 mmol). The reaction mixture was heated to reflux for 16 h, then cooled to ambient temperature, filtered through celite bed and washed with ethyl acetate. The filtrate was again extracted with ethyl acetate, and the combined organic layer washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2% ethyl acetate/petroleum ether) to afford the title compound as a light brown gummy material (1.5 g, 83%): 1H NMR (400 MHz, CDCl3) δ 8.20 (br, 1H), 7.68 (s, 1H), 7.45 (s, 2H), 7.21 (m, 1H), 6.90 (dd, J=16.0, 10.8 Hz, 1H), 6.55 (m, 1H), 5.75 (d, J=10.5 Hz, 1H), 5.21 (d, J=10.5 Hz, 1H); ESIMS m/z 142.05 ([M−H]−).
    • Step 2. tert-Butyl-5-vinyl-1H-indole-1-carboxylate (BI17)
  • To a stirred solution of 5-vinyl-1H-indole (0.7 g, 4.89 mmol) in acetonitrile (20 ml) was added DMAP (59.65 mg, 0.489 mmol) and di-tert-butyl dicarbonate (1.38 g, 6.36 mmol), and the reaction was stirred at ambient temperature for 3 h. The reaction mixture was concentrated under reduced pressure to obtain a residue which was diluted with CH2Cl2 and washed with water and brine solution. The combined CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2% ethyl acetate/petroleum ether) to afford the title compound as an off-white semi-solid (0.7 g, 59%): 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J=8.0 Hz, 1H), 7.60 (s, 2H), 7.30 (d, J=8.4 Hz, 1H), 7.21 (m, 1H), 6.90 (dd, J=16.0, 10.8 Hz, 1H), 6.59 (s, 1H), 5.75 (d, J=10.5 Hz, 1H), 5.21 (d, J=10.5 Hz, 1H), 1.65 (s, 9H); ESIMS m/z 242.10 ([M−H]−); IR (thin film) 1630 cm−1.
    • Example 33: Preparation of (E)-tert-Butyl 5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1H-indole-1-carboxylate (BI19)
  • Figure US20170088507A1-20170330-C00145
  • To a stirred solution of tert-butyl 5-vinyl-1H-indole-1-carboxylate (0.65 g, 2.67 mmol), in 1,2-dichlorobenzene (10.0 mL) was added 5-(1-bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-fluorobenzene (1.74 g, 5.37 mmol), CuCl (53 mg, 0.537 mmol) and 2,2-bipyridyl (167 mg, 1.07 mmol). The resultant reaction mixture was degassed with argon for 30 min and heated to 150° C. for 2 h. The reaction mixture was cooled to ambient temperature and filtered, and the filtrate concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2% ethyl acetate/petroleum ether) to afford the title compound as a light brown gummy material (0.25 g, 10%): 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=8.0 Hz, 1H), 7.60 (m, 2H), 7.39 (m, 3H), 6.69 (d, J=16.0 Hz, 1H), 6.55 (d, J=10.5 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 4.10 (m, 1H), 1.65 (s, 9H); ESIMS m/z 485.91 ([M−H]−); IR (thin film) 1165, 854 cm−1.
    • Example 34: Preparation of (E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1H-indole (BI20)
  • Figure US20170088507A1-20170330-C00146
  • To a stirred solution of (E)-tert-butyl 5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indole-1-carboxylate (0.2 g, 0.40 mmol) in CH2Cl2 (10.0 mL) was added TFA (70 mg, 0.61 mmol) and the reaction was stirred at ambient temperature for 2 h.
  • The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution, water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound as a light brown solid (0.2 g, 97%): mp 132.9-138.8° C.; 1H NMR (400 MHz, CDCl3) δ 11.19 (br, 1H), 8.20 (d, J=8.0 Hz, 1H), 7.60 (m, 2H), 7.39 (m, 3H), 6.69 (d, J=16.0 Hz, 1H), 6.55 (d, J=10.5 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 4.82 (m, 1H); ESIMS m/z 387.98 ([M+H]+).
    • Example 35: Preparation of 4-Nitrophenyl 2-((tert-butoxycarbonyl)amino)acetate (BI21)
  • Figure US20170088507A1-20170330-C00147
  • To a stirred solution of 4-nitrophenol (1.0 g, 7.19 mmol) in CH2Cl2 (20.0 mL) was added N-Boc glycine (1.38 g, 7.91 mmol) and EDC HCl (2.05 g, 10.785 mmol) and the reaction was stirred at ambient temperature for 24 h. The reaction mixture was diluted with CH2Cl2 and washed with water and saturated brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound as a light brown gummy material that was used in the next step without further purification (1.1 g): 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J=9.2 Hz, 2H), 7.33 (d, J=8.8 Hz, 2H), 5.07 (br, 1H), 4.20 (s, 2H), 1.47 (s, 9H); ESIMS m/z 296.27 ([M+H]+).
    • Example 36: Preparation of (E)-tert-Butyl (2-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1H-indol-1-yl)-2-oxoethyl)carbamate (BI22)
  • Figure US20170088507A1-20170330-C00148
  • To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indole (0.1 g, 0.258 mmol) in acetonitrile (5.0 mL) was added 4-nitrophenyl 2-(tert-butoxycarbonylamino) acetate (0.114 g, 0.387 mmol), potassium fluoride (0.03 g, 0.516 mmol), 18-crown-6-ether (0.075 g, 0.283 mmol) and DIPEA (0.0332 g, 0.258 mmol) and the reaction was stirred at ambient temperature for 16 h. The reaction mixture was concentrated to obtain a residue which was diluted with CH2Cl2 and washed with water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude title compound as a light brown gummy material which was used in the next step without further purification (0.1 g): ESIMS m/z 545.23 ([M+H]+).
    • Example 37: Preparation of (E)-N-(2-(5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1H-indol-1-yl)-2-oxoethyl)-3,3,3-trifluoropropanamide (BC13)
  • Figure US20170088507A1-20170330-C00149
    • Step 1. (E)-2-amino-1-(5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indol-1-yl)ethanone (BI23)
  • To a stirred solution of (E)-tert-butyl 2-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indol-1-yl)-2-oxoethylcarbamate (0.05 g, 0.09 mmol) in CH2Cl2 (5.0 mL) was added TFA (0.01 mL) and the reaction was stirred at ambient temperature for 16 h. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution, water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude title compound which was used in the next step without further purification (50 mg).
    • Step 2. (E)-N-(2-(5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1H-indol-1-yl)-2-oxoethyl)-3,3,3-trifluoropropanamide (BC13)
  • To a stirred solution of (E)-2-amino-1-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indol-1-yl) ethanone (0.04 g, 0.09 mmol) in CH2Cl2 (5.0 ml) was added 3,3,3-trifluoropropanoic acid (17.5 mg, 0.136 mmol), PyBOP (70 mg, 0.135 mmol) and DIPEA (29 mg, 0.225 mmol) and the reaction was stirred at ambient temperature for 16 h. The reaction mixture was diluted with CH2Cl2, and the CH2Cl2 layer was washed with water and saturated brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound, which was purified by column chromatography (SiO2, 100-200 mesh; 10% ethyl acetate/petroleum ether) to afford the title compound as an off-white solid (30 mg, 60%): mp 121-126° C.; 1H NMR (400 MHz, CDCl3) δ 8.33 (br, 1H), 7.59 (s, 1H), 7.45 (m, 4H), 6.72 (d, J=3.6 Hz, 3H), 6.39 (m, 1H), 4.71 (t, J=7.2 Hz, 2H), 4.15 (m, 1H), 3.51 (m, 1H), 3.28 (m, 1H); ESIMS m/z 553.06 ([M−H]−).
    • Example 38: Preparation of Ethyl 2-(1-oxo-6-vinylphthalazin-2(1H)-yl)acetate (BI24)
  • Figure US20170088507A1-20170330-C00150
    • Step 1. 5-Bromo-3-hydroxyisoindoline-1-one (BI25)
  • A mixture of Zn powder (1.73 g, 26.154 mmol), copper (II) sulfate pentahydrate (0.02 g, 0.08 mmol) and 2M aq NaOH (27 mL) were cooled to 0° C. 5-Bromoisoindoline-1,3-dione (5 g, 22 mmol) was added at the same temperature over the period of 30 min. The reaction mixture was stirred at 0° C. for 30 min and 3 h at ambient temperature. The reaction mixture was filtered and the filtrate was neutralized with concentrated HCl. The reaction mixture was diluted with ethanol and extracted with ethyl acetate. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to afford the crude title compound as a brown solid, which was used in the next step without further purification (1.3 g): mp 258-261° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.03 (br, 1H), 7.81 (m, 2H), 7.69 (m, 1H), 6.44 (m, 1H), 5.88 (d, J=9.3 Hz, 1H); ESIMS m/z 225.83 ([M−H]−); IR (thin film) 1684, 3246, 606 cm−1.
    • Step 2. 6-Bromophthalazine-1(2H)-one (BI26)
  • To a stirred solution of 5-bromo-3-hydroxyisoindoline-1-one (1.0 g, 4.40 mmol) in water, was added hydrazine hydrate (0.45 g, 8.80 mmol) and heated to 95° C. for 5 h. The reaction mixture was cooled to ambient temperature, filtered and washed with diethyl ether and pentane (1:1) to afford the title compound as a white solid that was used in the next step without further purification (0.5 g): ESIMS m/z 225.15 ([M+H]+).
    • Step 3. 6-Vinylphthalazine-1(2H)-one (BI27)
  • A solution of 6-bromophthalazine-1(2H)-one (0.25 g, 1.11 mmol), potassium vinyl trifluoroborate (0.446 g, 3.33 mmol) and K2CO3 (0.46 g, 3.33 mmol) in DMSO (2 mL) was degassed with argon for 20 min at ambient temperature. PdCl2(dppf) (0.04 g, 0.055 mmol) was added at ambient temperature, and the reaction mixture was heated to 80° C. for 2 h. The reaction mixture was cooled to ambient temperature and filtered through celite bed under vacuum and washed with ethyl acetate. The reaction mixture was extracted with ethyl acetate and the combined ethyl acetate layer dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 50% ethyl acetate/petroleum ether) to afford the title compound as a brown solid (0.12 g, 63%): 1H NMR (400 MHz, DMSO-d6) δ 13.61 (br, 1H), 8.33 (m, 1H), 8.19 (m, 1H), 8.01 (m, 2H), 6.97 (m, 1H), 6.15 (m, 1H), 5.56 (d, J=10.8 Hz, 1H); ESIMS m/z 172.93 ([M+H]+); IR (thin film) 1748, 1655, 3241 cm−1.
    • Step 4. Ethyl-2-(1-oxo-6-vinylphthalazine-2(1H)-yl acetate (BI24)
  • To a stirred solution of 6-vinylphthalazine-1(2H)-one (0.5 g, 2.90 mmol) in DMF (5.0 mL) was added Cs2CO3 (0.94 g, 2.90 mmol) and the reaction was stirred for 10 min. Ethyl bromoacetate (0.48 g, 2.90 mmol) was added to the reaction mixture at ambient temperature and the reaction was stirred for 8 h at ambient temperature. The reaction mixture was diluted and extracted with ethyl acetate, and the ethyl acetate layer was washed with water and brine solution (2×). The separated ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 25% ethyl acetate/petroleum ether) to afford the title compound as a brown solid (0.34 g, 45%): 1H NMR (400 MHz, DMSO-d6) δ 8.45 (m, 1H), 8.24 (m, 1H), 8.04 (m, 2H), 7.01 (m, 1H), 6.17 (d, J=2.1 Hz, 1H), 5.56 (d, J=10.8 Hz, 1H), 4.92 (s, 2H), 4.19 (m, 2H), 1.23 (m, 3H). ESIMS m/z 259.10 ([M+H]+); IR (thin film) 1750, 1660 cm−1.
    • Example 39: Preparation of (E)-Ethyl 2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1-oxophthalazin-2(1H)-yl)acetate (BI28)
  • Figure US20170088507A1-20170330-C00151
  • To a stirred solution of ethyl-2-(1-oxo-6-vinylphthalazine-2(1H)-yl acetate (0.07 g, 0.27 mmol) in 1,2-dichlorobenzene (1.0 mL) was added 5-(1-bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2fluorobenzene (0.17 g, 0.54 mmol), CuCl (0.005 g, 0.05 mmol) and 2,2-bipyridyl (0.016 g, 0.10 mmol) and the resultant reaction mixture was degassed with argon for 30 min and heated to 180° C. for 12 h. The reaction mixture was cooled to ambient temperature and filtered and the filtrated was concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 10-15% ethyl acetate/petroleum ether) to afford the title compound as a brown solid (40 mg, 29%): 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J=8.4 Hz, 1H), 7.84 (d, J=1.5 Hz, 1H), 7.65 (s, 1H), 7.37 (d, J=6.3 Hz, 2H), 6.76 (d, J=16.0 Hz, 1H), 6.59 (dd, J=16.0, 8.0 Hz, 1H), 4.96 (s, 2H), 4.29 (m, 3H), 1.31 (t, J=7.2 Hz, 3H); ESIMS m/z 503.0 ([M+H]+); IR (thin film) 1660, 1114, 817 cm−1.
    • Example 40: Preparation of (E)-2-(6-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1-oxophthalazin-2(1H)-yl)acetic acid (BI29)
  • Figure US20170088507A1-20170330-C00152
  • A solution of (E)-ethyl-2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1-oxophthalazin-2(1H)-yl) acetate (0.04 g, 0.07 mmol) in HCl (0.5 mL) and acetic acid (0.5 mL) was heated to 100° C. for 3 h. The solvent was removed under reduced pressure and the residue diluted with water. The aqueous layer was extracted with ethyl acetate and the separated ethyl acetate layer dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was triturated with diethyl ether-pentane mixture to afford the title compound as a brown solid (0.03 g): 1H NMR (400 MHz, DMSO-d6) δ 13.0 (br s, 1H), 8.43 (m, 1H), 8.23 (d, J=8.1 Hz, 1H), 8.14 (m, 2H), 7.91 (m, 2H), 7.16 (dd, J=16.0, 8.0 Hz, 1H), 6.99 (d, J=16.0 Hz, 1H), 4.96 (m, 3H); ESIMS m/z 473.0 ([M−H]−); IR (thin film) 1629, 1168, 817 cm−1.
    • Example 41: Preparation of (E)-2-(6-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1-oxophthalazin-2(1H)-yl)-N-(2,2,2-trifluoroethyl)acetamide (BC14)
  • Figure US20170088507A1-20170330-C00153
  • To a stirred solution of (E)-2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1-oxophthalazin-2(1H)-yl)acetic acid (0.15 g, 0.31 mmol) in CH2Cl2 (20.0 ml) was added 2,2,2,-trifluoroethanamine (0.03 g, 0.31 mmol), PyBOP (0.17 g, 0.34 mmol) and DIPEA (0.15 ml, 0.93 mmol) at ambient temperature, and the reaction was stirred for 18 h. The reaction mixture was diluted with CH2Cl2 and washed with 3N HCl (2×20 mL), NaHCO3 (2×20 mL) and brine solution (2×). The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 20-25% ethyl acetate/petroleum ether) to afford the title compound as a brown solid (0.11 g): mp 172-175° C.; 1H NMR (400 MHz, CDCl3) δ 8.83 (t, J=6.6 Hz, 1H), 8.42 (t, J=14.7 Hz, 1H), 8.22 (d, J=8.1 Hz, 1H), 8.13 (t, J=6.3 Hz, 1H), 7.98-7.86 (m, 2H), 7.16-7.07 (m, 1H), 7.01-6.93 (m, 1H), 4.96-4.81 (m, 3H), 4.00-3.88 (m, 2H); ESIMS m/z 554.0 ([M−H]−).
    • Example 42: Preparation of 2-(4-Vinylbenzyl)isoindoline-1,3-dione (CI1)
  • Figure US20170088507A1-20170330-C00154
  • To a stirred solution of 1-(chloromethyl)-4-vinylbenzene (10 g, 66 mmol) in DMF (100 mL) was added potassium phthalimide (13.3 g, 72.1 mmol), and the resultant reaction mixture was heated at 70° C. for 16 h. The reaction mixture was diluted with water and extracted with CHCl3. The combined CHCl3 layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Recrystallization from CH3OH afforded the title compound as an off-white solid (8 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.83 (m, 2H), 7.71 (m, 2H), 7.39 (m, 4H), 6.65 (dd, J=17.6, 10.8 Hz, 1H), 5.72 (d, J=17.6 Hz, 1H), 5.21 (d, J=10.8 Hz, 1H), 4.82 (s, 2H); GCMS m/z 263.2 ([M]+); IR (thin film) 3420, 1133, 718 cm−1.
    • Example 43: Preparation of (E)-2-(4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)isoindoline-1,3-dione (CI2)
  • Figure US20170088507A1-20170330-C00155
  • Using the procedure of Example 10 with 2-(4-vinylbenzyl)isoindoline-1,3-dione and 1-(1-bromoethyl)-3,5-dichlorobenzene as the starting materials, the title compound was isolated as an off-white solid (0.3 g, 40-50%): mp 142-145° C.; 1H NMR (400 MHz, CDCl3) δ 7.86 (m, 2H), 7.74 (m, 2H), 7.42 (m, 2H), 7.36 (m, 3H), 7.27 (m, 2H), 6.58 (d, J=16.0 Hz, 1H), 6.32 (dd, J=16.0, 8.0 Hz, 1H), 4.82 (s, 2H), 4.05 (m, 1H); ESIMS m/z 488.17 ([M−H]−).
  • The following compound was made in accordance with the procedures disclosed in Example 43.
    • (E)-2-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)isoindoline-1,3-dione (CI3)
  • Figure US20170088507A1-20170330-C00156
  • The title compound was isolated as an off white solid (0.3 g, 56%): mp 145-146° C.; 1H NMR (400 MHz, CDCl3) δ 7.86 (m, 2H), 7.74 (m, 2H), 7.42-7.31 (m, 6H), 6.58 (d, J=16.0 Hz, 1H), 6.53 (dd, J=16.0, 8.0 Hz, 1H), 4.82 (s, 2H), 4.05 (m, 1H); ESIMS m/z 522.2 ([M−H]−); IR (thin film) 1716, 1110, 712 cm−1.
  • Prophetically, compounds CI4-CI5 (Table 1) could be made in accordance with the procedures disclosed in Example 43.
    • Example 44: Preparation of (E)-(4-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (CI6)
  • Figure US20170088507A1-20170330-C00157
  • To a stirred solution of (E)-2-(4-(3-(3,5-dichlorophenyl)but-1-en-1-yl)benzyl)-isoindoline-1,3-dione (1.2 g, 2.45 mmol) in EtOH was added hydrazine hydrate (0.61 g, 12 mmol), and the resultant reaction mixture was heated at 90° C. for 1 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2Cl2, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the crude title compound as a gummy liquid (0.9 g) which was used without further purification.
  • The following compounds were made in accordance with the procedures disclosed in Example 44.
    • (E)-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)methanamine (CI7)
  • Figure US20170088507A1-20170330-C00158
  • The title compound was isolated and used without further purification.
  • Prophetically, compounds CI8-CI9 (Table 1) could be made in accordance with the procedures disclosed in Example 44.
    • Example 45: Preparation of 4-(Bromomethyl)-3-chlorobenzonitrile (CI10)
  • Figure US20170088507A1-20170330-C00159
  • To a stirred solution of 3-chloro-4-methylbenzonitrile (5 g, 25.4 mmol) in carbon tetrachloride (CCl4; 50 mL) under an argon atmosphere was added NBS (5.16 g, 29 mmol), and the mixture was degassed for 30 min. To this was added azobisisobutyronitrile (AIBN; 0.3 g, 1.8 mmol), and the resultant reaction mixture was heated at reflux for 4 h. The reaction mixture was cooled to ambient temperature, washed with water, and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in n-Hexane) to afford the title compound as a white solid (4.8 g, 68%): mp 87-88° C.; 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.59 (s, 2H), 4.60 (s, 2H); ESIMS m/z 229.77 ([M+H]+); IR (thin film) 2235, 752, 621 cm−1.
  • The following compounds were made in accordance with the procedures disclosed in Example 45.
    • 4-(Bromomethyl)-3-(trifluoromethyl)benzonitrile (CI11)
  • Figure US20170088507A1-20170330-C00160
  • The title compound was isolated as an off-white gummy material (5 g, 66%): 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 4.62 (s, 2H); ESIMS m/z 262.11 ([M−H]−); IR (thin film) 2236, 1132, 617 cm−1.
    • 3-Bromo-4-(bromomethyl)benzonitrile (CI12)
  • Figure US20170088507A1-20170330-C00161
  • The title compound was isolated as an off-white solid (5 g, 67%): mp 82-83° C.; 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.61 (m, 2H), 4.62 (s, 2H); EIMS m/z 272.90; IR (thin film) 2229, 618 cm−1.
    • 4-(Bromomethyl)-3-fluorobenzonitrile (CI13)
  • Figure US20170088507A1-20170330-C00162
  • The title compound was isolated as an off-white solid (2 g, 60%): mp 79-81° C.; 1H NMR (400 MHz, CDCl3) δ 7.54 (t, J=8.0 Hz, 1H), 7.48 (dd, J=8.0 Hz, 8.0, 1H), 7.38 (dd, J=5 Hz, 1H), 4.5 (s, 2H); EIMS m/z 215.
    • Example 46: Preparation of 4-(Bromomethyl)-3-chlorobenzaldehyde (CI14)
  • Figure US20170088507A1-20170330-C00163
  • To a stirred solution of 4-(bromomethyl)-3-chlorobenzonitrile (4.8 g, 17 mmol) in toluene (50 mL) at 0° C. was added dropwise diisobutylaluminum hydride (DIBAL-H, 1.0 M solution in toluene; 23.9 mL), and the reaction mixture was stirred at 0° C. for 1 h. 10 M HCl in water (5 mL) was added until the reaction mixture turned to a white slurry and then additional 1 N HCl (20 mL) was added. The organic layer was collected and the aqueous layer was extracted with CHCl3. The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in n-Hexane) to afford the title compound as a white solid (3.8 g, 80%): mp 64-66° C.; 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 7.92 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 4.60 (s, 2H); ESIMS m/z 232.78 ([M+H]+).
  • The following compounds were made in accordance with the procedures disclosed in Example 46.
    • 4-(Bromomethyl)-3-(trifluoromethyl)benzaldehyde (CI15)
  • Figure US20170088507A1-20170330-C00164
  • The title compound was isolated as a pale yellow low-melting solid (5 g, 60%): 1H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 8.19 (s, 1H), 8.09 (m, 1H), 7.81 (m, 1H), 4.61 (s, 2H); ESIMS m/z 265.04 ([M−H]−); IR (thin film) 1709, 1126, 649 cm−1.
    • 3-Bromo-4-(bromomethyl)benzaldehyde (CI16)
  • Figure US20170088507A1-20170330-C00165
  • The title compound was isolated as a pale yellow solid (5 g, 62%): mp 94-95° C.; 1H NMR (400 MHz, CDCl3) δ 9.96 (s, 1H), 8.05 (s, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 4.60 (s, 2H); EIMS m/z 275.90.
    • 4-(Bromomethyl)-3-fluorobenzaldehyde (CI17)
  • Figure US20170088507A1-20170330-C00166
  • The title compound was isolated as an off-white solid (5 g, 61%): mp 43-45° C.; 1H NMR (400 MHz, CDCl3) δ 9.1 (s, 1H), 7.54 (t, J=8 Hz, 1H), 7.48 (d, J=8 Hz, 1H), 7.38 (d, J=5 Hz, 1H), 4.5 (s, 2H); EIMS m/z 216.
    • Example 47: Preparation of 3-Chloro-4-((1,3-dioxoisoindolin-2-yl)methyl)benzaldehyde (CI18)
  • Figure US20170088507A1-20170330-C00167
  • To a stirred solution of 4-(bromomethyl)-3-chlorobenzaldehyde (3.8 g, 14 mmol) in DMF (40 mL) was added potassium pthalimide (3.54 g, 19.14 mmol), and the mixture was heated at 60° C. for 6 h. The reaction mixture was cooled to ambient temperature and diluted with water (100 mL). The solid obtained was separated by filtration and dried under vacuum to afford the title compound as a white solid (2.8 g, 60%): mp 123-126° C.; 1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 8.21 (s, 1H), 7.91 (m, 3H), 7.80 (m, 2H), 7.20 (m, 1H), 5.05 (s, 2H); ESIMS m/z 298.03 ([M−H]−).
  • The following compounds were made in accordance with the procedures disclosed in Example 47.
    • 4-((1,3-Dioxoisoindolin-2-yl)-3-(trifluoromethyl)benzaldehyde (CI19)
  • Figure US20170088507A1-20170330-C00168
  • The title compound was isolated as an off white solid (1 g, 62%): mp 142-143° C.; 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 8.15 (s, 1H), 7.91 (m, 2H), 7.80 (m, 3H), 7.27 (m, 1H), 5.19 (s, 2H); ESIMS m/z 332.03 ([M−H]−).
    • 3-Bromo-4-((1,3-dioxoisoindolin-2-yl)methyl)benzaldehyde (CI20)
  • Figure US20170088507A1-20170330-C00169
  • The title compound was isolated as an off-white solid (0.5 g, 64%): mp 159-161° C.; 1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 8.21 (s, 1H), 7.91 (m, 3H), 7.80 (m, 2H), 7.20 (m, 1H), 5.05 (s, 2H); ESIMS m/z 314.00 ([M-CHO]−).
    • 4-((1,3-Dioxoisoindolin-2-yl)-3-fluorobenzaldehyde (CI21)
  • Figure US20170088507A1-20170330-C00170
  • The title compound was isolated as a white solid (2 g, 60%): mp 154-156° C.; 1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 7.9 (m, 2H), 7.75 (m, 2H), 7.6 (m, 2H), 7.5 (t, J=7.6 Hz, 1H), 5.05 (s, 2H); EIMS m/z 283.1.
    • Example 48: Preparation of 2-(2-Chloro-4-vinylbenzyl)isoindoline-1,3-dione (CI22)
  • Figure US20170088507A1-20170330-C00171
  • To a stirred solution of 3-chloro-4-((1,3-dioxoisoindolin-2-yl)methyl)benzaldehyde (2.8 g, 8.2 mmol) in 1,4-dioxane (30 mL) were added K2CO3 (1.68 g, 12.24 mmol) and methyl triphenyl phosphonium bromide (4.37 g, 12.24 mmol) at ambient temperature. Then the resultant reaction mixture was heated at 100° C. for 18 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; 20% EtOAc in n-Hexane) to afford the title compound as a white solid (1.94 g, 70%): mp 141-143° C.; 1H NMR (400 MHz, CDCl3) δ 7.85 (m, 2H), 7.70 (m, 2H), 7.41 (m, 1H), 7.21 (m, 2H), 6.71 (dd, J=17.6, 10.8 Hz, 1H), 5.72 (d, J=17.6 Hz, 1H), 5.23 (d, J=10.8 Hz, 1H), 4.92 (s, 2H); ESIMS m/z 298.10 ([M−H]−).
  • The following compounds were made in accordance with the procedures disclosed in Example 48.
    • 2-(2-(Trifluoromethyl)-4-vinylbenzyl)isoindoline-1,3-dione (CI23)
  • Figure US20170088507A1-20170330-C00172
  • The title compound was isolated as a light brown solid (0.5 g, 60%): mp 134-135° C.; 1H NMR (400 MHz, CDCl3) δ 7.92 (m, 2H), 7.80 (m, 2H), 7.71 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 6.65 (m, 1H), 5.80 (d, J=17.8 Hz, 1H), 5.19 (d, J=10.8 Hz, 1H), 5.09 (s, 2H); ESIMS m/z 332.10 ([M+H]+).
    • 2-(2-Bromo-4-vinylbenzyl)isoindoline-1,3-dione (CI24)
  • Figure US20170088507A1-20170330-C00173
  • The title compound was isolated as a off white solid (0.5 g, 62%): mp 126-128° C.; 1H NMR (400 MHz, CDCl3) δ 7.92 (m, 2H), 7.79 (m, 2H), 7.62 (s, 1H), 7.21 (m, 1H), 7.16 (d, J=8.0 Hz, 1H), 6.62 (m, 1H), 5.72 (d, J=17.8 Hz, 1H), 5.15 (d, J=10.8 Hz, 1H), 4.95 (s, 2H); EIMS m/z 341.10.
    • 2-(2-Fluoro-4-vinylbenzyl)isoindoline-1,3-dione (CI25)
  • Figure US20170088507A1-20170330-C00174
  • The title compound was isolated as a white solid (0.5 g, 61%): mp 140-142° C.; 1H NMR (400 MHz, CDCl3) δ 7.85 (m, 2H), 7.72 (m, 2H), 7.25 (m, 1H), 7.11 (m, 2H), 6.63 (m, 1H), 5.80 (d, J=17.6 Hz, 1H), 5.28 (d, J=10.8 Hz, 1H), 4.92 (s, 2H); EIMS m/z 282.08.
    • Example 49: Preparation of (E)-2-(2-Chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl) 1 isoindoline-1,3-dione (CI26)
  • Figure US20170088507A1-20170330-C00175
  • To a stirred solution of 2-(2-chloro-4-vinylbenzyl)isoindoline-1,3-dione (2.0 g, 6.51 mmol) in 1,2-dichlorobenzene (25 mL) were added 1-(1-bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (3.48 g, 11.36 mmol), CuCl (112 mg, 1.13 mmol) and 2,2-bipyridyl (0.35 g). The resultant reaction mixture was degassed with argon for 30 min and then was stirred at 180° C. for 24 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in n-hexane) to afford the title compound as solid (1.3 g, 50%): mp 141-143° C.; 1H NMR (400 MHz, CDCl3) δ 7.92 (m, 2H), 7.79 (m, 2H), 7.42 (m, 2H), 7.24 (m, 2H), 7.20 (m, 2H), 6.54 (d, J=16.0 Hz, 1H), 6.34 (dd, J=16.0, 8.0 Hz, 1H), 5.00 (s, 2H), 4.10 (m, 1H); ESIMS m/z 524.07 ([M+H]+).
  • The following compounds were made in accordance with the procedures disclosed in Example 49.
    • (E)-2-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)isoindoline-1,3-dione (CI27)
  • Figure US20170088507A1-20170330-C00176
  • The title compound was isolated as a pale white solid (0.2 g, 55%): mp 128-129° C.; 1H NMR (400 MHz, CDCl3) δ 7.92 (m, 2H), 7.79 (m, 2H), 7.42 (m, 3H), 7.22 (m, 2H), 6.52 (d, J=16.0 Hz, 1H), 6.32 (dd, J=16.0, 8.0 Hz, 1H), 5.00 (s, 2H), 4.05 (m, 1H); ESIMS m/z 557.99 ([M+H]+).
    • (E)-2-(2-Chloro-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)isoindoline-1,3-dione (CI28)
  • Figure US20170088507A1-20170330-C00177
  • The title compound was isolated as a off white solid (0.2 g, 54%): mp 177-180° C.; 1H NMR (400 MHz, CDCl3) δ 7.90 (m, 2H), 7.77 (m, 2H), 7.42 (s, 1H), 7.32 (d, J=8.0 Hz, 2H), 7.21 (m, 2H), 6.52 (d, J=16.0 Hz, 1H), 6.32 (dd, J=16.0, 8.0 Hz, 1H), 5.00 (s, 2H), 4.05 (m, 1H); ESIMS m/z 540.08 ([M−H]−); IR (thin film) 1716 cm−1.
    • (E)-2-(2-Chloro-4-(3-(3,4-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)isoindoline-1,3-dione (CI29)
  • Figure US20170088507A1-20170330-C00178
  • The title compound was isolated as an off-white solid (0.2 g, 59%): 1H NMR (400 MHz, CDCl3) δ 7.89 (m, 2H), 7.76 (m, 2H), 7.47 (m, 3H), 7.21 (m, 3H), 6.50 (d, J=16.0 Hz, 1H), 6.32 (dd, J=16.0, 7.6 Hz, 1H), 4.97 (s, 2H), 4.11 (m, 1H); ESIMS m/z 522.27 ([M−H]); IR (thin film) 3064, 1717, 1111, 715 cm−1.
    • (E)-2-(4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(trifluoromethyl)-benzyl)isoindoline-1,3-dione (CI30)
  • Figure US20170088507A1-20170330-C00179
  • The title compound was isolated as an off-white solid (0.2 g, 54%): mp 141-142° C.; 1H NMR (400 MHz, CDCl3) 7.94 (m, 2H), 7.80 (m, 2H), 7.69 (s, 1H), 7.44 (m, 1H), 7.38 (m, 1H), 7.24 (m, 2H), 7.19 (m, 1H), 6.60 (d, J=16.0 Hz, 1H), 6.39 (dd, J=16.0, 7.6 Hz, 1H), 5.10 (s, 2H), 4.11 (m, 1H); ESIMS m/z 556.00 ([M−H]−).
    • (E)-2-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)-benzyl)isoindoline-1,3-dione (CI31)
  • Figure US20170088507A1-20170330-C00180
  • The title compound was isolated as an off-white solid (0.2 g, 56%): mp 130-132° C.; 1H NMR (400 MHz, CDCl3) δ 7.94 (m, 2H), 7.80 (m, 2H), 7.69 (s, 1H), 7.44 (m, 3H), 7.19 (m, 1H), 6.61 (d, J=16.0 Hz, 1H), 6.38 (dd, J=16.0, 7.6 Hz, 1H), 5.10 (s, 2H), 4.12 (m, 1H); ESIMS m/z 589.57 ([M-2H]−).
    • (E)-2-(2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-isoindoline-1,3-dione (CI32)
  • Figure US20170088507A1-20170330-C00181
  • The title compound was isolated as a pale yellow solid (0.2 g, 55%): mp 160-162° C.; 1H NMR (400 MHz, CDCl3) δ 7.92 (m, 2H), 7.80 (m, 2H), 7.62 (s, 1H), 7.39 (s, 2H), 7.24 (m, 1H), 7.16 (m, 1H), 6.52 (d, J=16.0 Hz, 1H), 6.32 (dd, J=16.0, 8.0 Hz, 1H), 4.98 (s, 2H), 4.12 (m, 1H); ESIMS m/z 599.78 ([M−H]−).
    • (E)-2-(2-Fluoro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-isoindoline-1,3-dione (CI33)
  • Figure US20170088507A1-20170330-C00182
  • The title compound was isolated as an off-white solid (0.2 g, 55%): mp 72-74° C.; 1H NMR (400 MHz, CDCl3) δ 7.88 (m, 2H), 7.74 (m, 2H), 7.38 (s, 2H), 7.34 (m, 1H), 7.18 (m, 2H), 6.54 (d, J=16.0 Hz, 1H), 6.32 (dd, J=16.0, 8.0 Hz, 1H), 4.91 (s, 2H), 4.08 (m, 1H); ESIMS m/z 539.89 ([M−H]−); IR (thin film) 1773 cm−1.
  • Prophetically, compounds CI34-CI41 (Table 1) could be made in accordance with the procedures disclosed in Example 49.
    • Example 50: Preparation of (E)-(2-Chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (CI42)
  • Figure US20170088507A1-20170330-C00183
  • To a stirred solution of (E)-2-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)isoindoline-1,3-dione (0.4 g, 0.76 mmol) in EtOH was added hydrazine hydrate (0.38 g, 7.6 mmol), and the resultant reaction mixture was heated at 80° C. for 2 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2Cl2, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a gummy liquid (0.3 g), which was carried on to the next step without further purification.
  • The following compounds were made in accordance with the procedures disclosed in Example 50.
    • (E)-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)-methanamine (CI43)
  • Figure US20170088507A1-20170330-C00184
  • The product obtained in this reaction was carried on to the next step without further purification.
    • (E)-(2-Chloro-4-(3-(3,4-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)-methanamine (CI44)
  • Figure US20170088507A1-20170330-C00185
  • The product obtained in this reaction was carried on to the next step without further purification: 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J=8.4 Hz, 2H), 7.39 (m, 2H), 7.23 (m, 2H), 6.52 (d, J=16.0 Hz, 1H), 6.38 (dd, J=16.0, 7.6 Hz, 1H), 4.12 (m, 1H), 3.90 (s, 2H); ESIMS m/z 391.90 ([M−H]−); IR (thin film) 3370, 3280, 1111, 817 cm−1.
    • (E)-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)-phenyl)methanamine (CI45)
  • Figure US20170088507A1-20170330-C00186
  • The title compound was isolated as a gummy material. The product obtained in this reaction was carried on to the next step without further purification.
    • (E)-(2-Bromo-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)-methanamine (CI46)
  • Figure US20170088507A1-20170330-C00187
  • The title compound was isolated as a gummy material: The product obtained in this reaction was carried on to the next step without further purification.
    • (E)-(2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)-methanamine (CI47)
  • Figure US20170088507A1-20170330-C00188
  • The title compound was isolated as a gummy material. The product obtained in this reaction was carried on to the next step without further purification.
    • (E)-(2-Fluoro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)-methanamine (CI48)
  • Figure US20170088507A1-20170330-C00189
  • The title compound was isolated as a gummy material: 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 2H), 7.33 (t, J=7.6 Hz, 1H), 7.13 (m, 2H), 6.56 (d, J=16.0 Hz, 1H), 6.33 (dd, J=16.0, 7.6 Hz, 1H), 4.08 (m, 1H), 3.90 (s, 2H); ESIMS m/z 413.84 ([M+H]+); IR (thin film) 3368, 3274, 1114, 808 cm−1.
  • Prophetically, compounds CI49-CI57 (Table 1) could be made in accordance with the procedures disclosed in Example 50.
    • Example 51: Preparation of 3-Chloro-4-((pyridin-2-ylamino)methyl)benzaldehyde (CI58)
  • Figure US20170088507A1-20170330-C00190
  • To a stirred solution of 4-(bromomethyl)-3-chlorobenzaldehyde (2 g, 9 mmol) in N,N-dimethylacetamide (DMA; 20 mL) was added K2CO3 (2.36 g, 17.16 mmol) and 2-aminopyridine (0.84 g, 8.58 mmol), and the reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was diluted with water and extracted with EtOAc.
  • The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 100-200 mesh; 20% EtOAc in n-Hexane) to afford the title compound as off-white solid (1.05 g, 50%): mp 122-123° C.; 1H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 8.11 (s, 1H), 7.88 (s, 1H), 7.72 (d, J=4.8 Hz, 1H), 7.62 (d, J=5.7 Hz, 1H), 7.4 (m, 1H), 6.64 (d, J=3.9 Hz, 1H), 6.38 (d, J=6.3 Hz, 1H), 5.04 (br s, 1H), 4.71 (s, 2H); ESIMS m/z 246.97 ([M+H]+).
    • Example 52: Preparation of N-(2-Chloro-4-vinylbenzyl)pyridin-2-amine (CI59)
  • Figure US20170088507A1-20170330-C00191
  • To a stirred solution of 3-chloro-4-((pyridin-2-ylamino)methyl)benzaldehyde (1 g, 4. mmol) in 1,4-dioxane (20 mL) were added K2CO3 (0.84 g, 6.09 mmol) and methyl triphenyl phosphonium bromide (2.17 g, 6.09 mmol) at ambient temperature. Then the resultant reaction mixture was heated at 100° C. for 18 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; 10% EtOAc in n-Hexane) to afford the title compound as a white solid (0.5 g, 50%): mp 119-121° C.; 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.42-7.40 (m, 3H), 7.26 (s, 1H), 6.66 (m, 2H), 6.36 (d, J=6.3 Hz, 1H), 5.75 (d, J=13.2 Hz, 1H), 4.92 (br s, 1H), 4.60 (s, 2H); ESIMS m/z 245.05 ([M+H]+).
    • Example 53: Preparation of Ethyl 2-amino-2-(5-bromo-3-chloropyridin-2-yl)acetate (CI60)
  • Figure US20170088507A1-20170330-C00192
  • Ethyl 2-(diphenylmethyleneamino)acetate (10.2 g, 38.2 mmol) was added to sodium hydride (NaH; 3.18 g, 133.52 mmol) in DMF (50 mL) at 0° C., and the mixture was stirred for 30 min. To this was added 5-bromo-2,3-dichloropyridine (12.9 g, 57.23 mmol), and the reaction mixture was stirred for 3 h at ambient temperature. The reaction mixture was quenched with 2 N HCl solution and then stirred for 4 h at ambient temperature. The mixture was extracted with EtOAc. The combined EtOAc layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (20-30% EtOAc in hexane) afforded the title compound as a liquid (1.3 g, 20%): 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.89 (s, 1H), 5.09 (s 1H), 4.23 (m, 2H), 2.27 (br s, 2H), 1.26 (m, 3H); ESIMS m/z 293.05 ([M+H]+); IR (thin film) 3381, 3306, 1742, 759, 523 cm−1.
    • Example 54: Preparation of (5-Bromo-3-chloropyridin-2-yl)methanamine hydrochloride (CI61)
  • Figure US20170088507A1-20170330-C00193
  • A stirred solution of ethyl 2-amino-2-(5-bromo-3-chloropyridin-2-yl)acetate (0.5 g, 1.7 mmol) in 3 N HCl (25 mL) was heated at reflux for 4 h. The reaction mixture was washed with diethyl ether and water. The combined ether layer was concentrated under reduced pressure to afford the title compound as an off-white solid (400 mg, 65%): 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.70 (br s, 2H), 8.45 (s, 1H), 4.56 (m, 2H); ESIMS m/z 221.15 ([M+H]+).
    • Example 55: Preparation of 2-((5-Bromo-3-chloropyridin-2-yl)methyl)isoindoline-1,3-dione (CI62)
  • Figure US20170088507A1-20170330-C00194
  • To a stirred solution of (5-bromo-3-chloropyridin-2-yl)methanamine hydrochloride (0.3 g, 1.4 mmol) in toluene (40 mL) was added TEA (0.41 g, 4.08 mmol) and phthalic anhydride (0.24 g, 1.63 mmol), and the reaction mixture was heated at reflux for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with EtOAc. The combined EtOAc layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (20-30% EtOAc in hexane) to afford the title compound as a white solid (0.25 g, 65%): 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.45 (s, 1H), 7.88 (m, 2H), 7.74 (m, 2H), 4.56 (m, 2H); ESIMS m/z 349 ([M−H]−); IR (thin film) 3307, 1665, 1114, 813 cm−1.
    • Example 56: Preparation of 2-((3-Chloro-5-vinylpyridin-2-yl)methyl)isoindoline-1,3-dione (CI63)
  • Figure US20170088507A1-20170330-C00195
  • To a stirred solution of 2-((5-bromo-3-chloropyridin-2-yl)methyl)isoindoline-1,3-dione (0.23 g, 0.65 mmol) in toluene (10 mL) were added Pd(PPh3)4 (3.7 mg, 0.003 mmol), K2CO3 (0.269 g, 1.95 mmol) and vinyl boronic anhydride pyridine complex (0.78 g, 3.28 mmol), and the reaction mixture was heated at reflux for 16 h. The reaction mixture was filtered, and the filtrate was washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (20-30% EtOAc in hexane) afforded the title compound as an off-white solid (0.2 g, 65%): 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.91 (m, 2H), 7.77 (m, 3H), 7.72 (m, 1H), 6.63 (m, 1H), 5.79 (d, J=16.0 Hz, 1H), 5.39 (d, J=16.0 Hz, 1H), 5.12 (s, 2H); ESIMS m/z 299.20 ([M+H]+).
    • Example 57: Preparation of (E)-2-((3-Chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichloro-phenyl)but-1-en-1-yl)pyridin-2-yl)methyl)isoindoline-1,3-dione (CI64)
  • Figure US20170088507A1-20170330-C00196
  • To a stirred solution of 2-((3-chloro-5-vinylpyridin-2-yl)methyl)isoindoline-1,3-dione (0.35 g, 1.17 mmol) in 1,2-dichlorobenzene (10 mL) were added 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (0.8 g, 2.3 mmol), CuCl (23 mg, 0.12 mmol), 2,2-bipyridyl (0.073 g, 0.234 mmol), and the reaction mixture was heated at 180° C. for 16 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (20-30% EtOAc in hexane) to afford the title compound as a liquid (0.4 g, 50%): mp 79-82° C.; 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.91 (m, 2H), 7.77 (m, 3H), 7.36 (s, 2H), 6.51 (d, J=15.6 Hz, 1H), 6.32 (dd, J=15.6, 8.0 Hz, 1H), 5.30 (s, 2H), 4.13 (m, 1H); ESIMS m/z 559 ([M+H]+).
    • Example 58: Preparation of (E)-(3-Chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)pyridin-2-yl)methanamine (CI65)
  • Figure US20170088507A1-20170330-C00197
  • To a stirred solution of (E)-2-((3-chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)pyridin-2-yl)methyl)isoindoline-1,3-dione (200 mg, 0.358 mmol) in EtOH (5 mL) was added hydrazine hydrate (89.6 mg, 1.79 mmol), and the reaction mixture was heated at reflux for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in CH2Cl2. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (100 mg). The product obtained in this reaction was carried on to the next step without further purification.
    • Example 59: Preparation of 4-(Bromomethyl)-1-naphthonitrile (CI66)
  • Figure US20170088507A1-20170330-C00198
  • To a stirred solution of 4-methyl-1-naphthonitrile (5 g, 30 mmol) in CCl4 (50 mL) under argon atmosphere was added NBS (6.06 g, 34.09 mmol), and the reaction mixture was degassed for 30 min. AIBN (0.3 g, 2.1 mmol) was added, and the resultant reaction mixture was heated at reflux for 4 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with CH2Cl2 (3×100 mL). The combined CH2Cl2 layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in n-Hexane) to afford the title compound as a white solid (3.8 g, 52%): mp 131-133° C.; 1H NMR (400 MHz, CDCl3) δ 8.33 (m, 1H), 8.24 (m, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.78 (m, 2H), 7.62 (d, J=8.0 Hz, 1H), 4.95 (s, 2H); ESIMS m/z 245.92 ([M+H]+); IR (thin film) 2217 cm−1.
    • Example 60: Preparation of 4-(Bromomethyl)-1-naphthaldehyde (CI67)
  • Figure US20170088507A1-20170330-C00199
  • To a stirred solution of 4-(bromomethyl)-1-naphthonitrile (8 g, 33 mmol) in toluene (100 mL) at 0° C. was added dropwise DIBAL-H (1.0 M solution in toluene; 43 mL), and the reaction mixture was stirred at 0° C. for 1 h. 3 N HCl in water (50 mL) was added to the mixture until it became a white slurry and then additional 1 N HCl (20 mL) was added. The organic layer was collected and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in petroleum ether) afforded the title compound as a white solid (7 g, 88%): mp 115-116° C.; 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 9.35 (m, 1H), 8.22 (m, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.75 (m, 3H), 4.95 (s, 2H); ESIMS m/z 248.88 ([M+H]+).
    • Example 61: Preparation of 4-((1,3-Dioxoisoindolin-2-yl)methyl)-1-naphthaldehyde (CI68)
  • Figure US20170088507A1-20170330-C00200
  • To a stirred solution of 4-(bromomethyl)-1-naphthaldehyde (7 g, 28. mmol) in DMF (100 mL) was added potassium phthalimide (7.3 g, 39.5 mmol), and the mixture was heated at 85° C. for 2 h. The reaction mixture was cooled to ambient temperature and diluted with water (100 mL). The obtained solid was separated by filtration and dried under vacuum to afford the title compound as a white solid (8.8 g, 98%): mp 190-192° C.; 1H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 9.25 (m, 1H), 8.41 (m, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.95 (m, 4H), 7.80 (m, 4H), 7.61 (m, 4H), 5.39 (s, 2H); ESIMS m/z 316.09 ([M+H]+); IR (thin film) 1708 cm−1.
    • Example 62: Preparation of 2-((4-Vinylnaphthalen-1-yl)methyl) isoindoline-1,3-dione (CI69)
  • Figure US20170088507A1-20170330-C00201
  • To a stirred solution of 4-((1,3-dioxoisoindolin-2-yl)methyl)-1-naphthaldehyde (9 g, 28.5 mmol) in 1,4-dioxane (100 mL) were added K2CO3 (6 g, 42.8 mmol) and methyl triphenyl phosphonium bromide (15.3 g, 35.7 mmol) at ambient temperature. The reaction mixture was heated at 100° C. for 14 h and then was cooled to ambient temperature. The reaction mixture was filtered, and the obtained filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 20% EtOAc in petroleum ether) afforded the title compound as a white solid (6 g, 67%): mp 146-147° C.; 1H NMR (400 MHz, CDCl3) δ 8.35 (m, 2H), 7.95 (m, 4H), 7.65 (m, 4H), 7.39 (m, 1H), 5.81 (m, 1H), 5.45 (m, 1H), 5.21 (s, 2H); ESIMS m/z 314.13 ([M+H]+).
    • Example 63: Preparation of (E)-2-((4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methyl)isoindoline-1,3-dione (CI70)
  • Figure US20170088507A1-20170330-C00202
  • To a stirred solution of 2-((4-vinylnaphthalen-1-yl)methyl)isoindoline-1,3-dione (1.5 g, 4.79 mmol) in 1,2-dichlorobenzene (15 mL) were added 1-(1-bromo-2,2,2-trifluoroethyl)-3,4,5-trichlorobenzene (3.2 g, 9.5 mmol), CuCl (24 mg, 0.24 mmol) and 2,2-bipyridyl (0.149 g, 0.95 mmol), and the resultant reaction mixture was degassed with argon for 30 min and then stirred at 180° C. for 14 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) afforded the title compound as an off-white solid (1.5 g, 56%): mp 158-160° C.; 1H NMR (400 MHz, CDCl3) δ 8.40 (m, 1H), 7.89 (m, 2H), 7.74 (m, 2H), 7.64 (m, 2H), 7.58 (m, 2H), 7.46 (s, 2H), 7.36 (m, 2H), 6.31 (m, 1H), 5.30 (s, 2H), 4.21 (m, 1H); ESIMS m/z 572.08 ([M−H]−).
    • Example 64: Preparation of (E)-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methanamine (CI71)
  • Figure US20170088507A1-20170330-C00203
  • To a stirred solution of (E)-2-((4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methyl)isoindoline-1,3-dione (0.4 g, 0.7 mmol) in EtOH was added hydrazine hydrate (0.18 g, 3.5 mmol), and the resultant reaction mixture was heated at 80° C. for 2 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2Cl2, and the solution was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The title compound was isolated as a gummy liquid (150 mg, 50%). The product obtained in this reaction was carried on to the next step without further purification.
    • Example 65: Preparation of 2-((4-Bromophenyl)amino)isoindoline-1,3-dione (CI72)
  • Figure US20170088507A1-20170330-C00204
  • To a stirred solution of (4-bromophenyl)hydrazine hydrochloride (0.5 g, 2.2 mmol) in glacial acetic acid (8 mL) was added phthalic anhydride (0.398 g, 2.690 mmol), and the reaction mixture was stirred at 130° C. for 1 h under a nitrogen atmosphere. The reaction mixture was quenched with satd aq. NaHCO3 solution and filtered to give a solid. Purification by column chromatography (SiO2, 0-10% EtOAc in petroleum ether) afforded the title compound as a solid (60 mg, 84%): mp 205-206° C.; 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 7.99 (m, 4H), 7.32 (d, J=8.8 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H); ESIMS m/z 314.95 ([M−H]−).
    • Example 66: Preparation of 2-((4-Vinylphenyl)amino)isoindoline-1,3-dione (CI73)
  • Figure US20170088507A1-20170330-C00205
  • To a solution of 2-(4-bromophenylamino)isoindoline-1,3-dione (2 g, 6. mmol) in 1,2-dimethoxyethane (20 mL) and water (4 mL) were added vinyl boronic anhydride pyridine complex (4.57 g, 18.98 mmol) and K2CO3 (1.3 g, 9.5 mmol) followed by Pd(PPh3)4 (0.219 g, 0.189 mmol). The resultant reaction mixture was heated at 150° C. in a microwave for 30 min and then was concentrated under reduced pressure. Purification by column chromatography (SiO2, 15% EtOAc in petroleum ether) afforded the title compound as a solid (200 mg, 13%): mp 174-176° C.; 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.94 (m, 4H), 7.29 (d, J=8.4 Hz, 2H), 6.72 (d, J=8.4 Hz, 2H), 6.61 (m, 1H), 5.61 (d, J=17.6 Hz, 1H), 5.05 (d, J=11.2 Hz, 1H); ESIMS m/z 263.18 ([M−H]−).
    • Example 67: Preparation of (E)-2-((4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)amino)isoindoline-1,3-dione (CI74)
  • Figure US20170088507A1-20170330-C00206
  • To a stirred solution of 2-(4-vinylphenylamino)isoindoline-1,3-dione (0.3 g, 1.1 mmol) in 1,2-dichlorobenzene (5 mL) were added CuCl (0.022 g, 0.273 mmol), 2,2-bipyridyl (0.07 g, 0.46 mmol) and 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (0.77 g, 2.27 mmol). The reaction mixture was degassed with argon for 30 min and was heated at 180° C. for 2 h. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, 0-30% EtOAc in petroleum ether) to afford the title compound as a solid (450 mg, 75%): mp 187-189° C.; 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 7.96 (m, 4H), 7.82 (s, 2H), 7.37 (d, J=8.8 Hz, 1H), 6.73 (d, J=8.4 Hz, 2H), 6.61 (m, 2H), 6.58 (m, 1H), 4.59 (m, 1H); ESIMS m/z 523.05 ([M−H]−).
    • Example 68: Preparation of (E)-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)hydrazine (CI75)
  • Figure US20170088507A1-20170330-C00207
  • To a stirred solution of (E)-2-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)phenylamino)isoindoline-1,3-dione (0.16 g, 0.31 mmol) in EtOH (5 mL), was added hydrazine hydrate (0.076 g, 1.52 mmol), and the reaction mixture was heated at 85° C. for 1 h. The reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a solid (0.08 g, 66%) which was carried on to the next step without further purification.
    • Example 69: Preparation of 2-(4-Vinylphenoxy)isoindoline-1,3-dione (CI76)
  • Figure US20170088507A1-20170330-C00208
  • To a stirred solution of 4-vinylphenylboronic acid (2 g, 13 mmol), 2-hydroxyisoindoline-1,3-dione (3.63 g, 24.53 mmol), and CuCl (1.214 g 12.26 mmol) in 1,2-dichloroethane (50 mL) was added pyridine (1.065 g, 13.48 mmol), and the resultant reaction mixture was stirred at ambient temperature for 48 h. The reaction mixture was diluted with water and extracted with CHCl3. The combined CHCl3 layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2; 20% EtOAc in petroleum ether) afforded the title compound as a white solid (2 g, 63%): mp 129-131° C.; 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J=2.0 Hz, 2H), 7.82 (d, J=3.2 Hz, 2H), 7.38 (d, J=2.0 Hz, 2H), 7.14 (d, J=2.0 Hz, 2H), 6.70 (m, 1H), 5.83 (d, J=16.0 Hz, 1H), 5.22 (d, J=10.8 Hz, 1H); ESIMS m/z 266.12 ([M+H]+).
    • Example 70: Preparation of (E)-2-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenoxy)isoindoline-1,3-dione (CI77)
  • Figure US20170088507A1-20170330-C00209
  • To a stirred solution of 2-(4-vinylphenoxy)isoindoline-1,3-dione (0.3 g, 1.1 mmol) in 1,2-dichlorobenzene (10 mL) was added 1-(1-bromoethyl)-3,4,5-trichlorobenzene (769 mg, 2.26 mmol), CuCl (22 mg, 0.22 mmol) and 2,2-bipyridyl (35 mg, 0.44 mmol), and the resultant reaction mixture was degassed with argon for 30 min and heated to 180° C. for 24 h. The reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, 100-200 mesh; 20% EtOAc in petroleum ether) to afford the title compound as a solid (0.29 g, 50%): 1H NMR (400 MHz, CDCl3) δ 7.90 (m, 1H), 7.62 (m, 2H), 7.50 (m, 1H), 7.40 (s, 2H), 7.12 (s, 1H), 6.90 (m, 2H), 6.60 (m, 2H), 6.20 (m, 1H), 4.08 (m, 1H); ESIMS m/z 524.09 ([M−H]−).
    • Example 71: Preparation of (E)-O-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)hydroxylamine (CI78)
  • Figure US20170088507A1-20170330-C00210
  • To a stirred solution of (E)-2-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)phenoxy)isoindoline-1,3-dione (0.2 g, 0.4 mmol) in EtOH was added hydrazine hydrate (0.1 g, 1.9 mmol), and the resultant reaction mixture was heated at 90° C. for 1 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2Cl2. washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude title compound as a gummy liquid (0.08 g, 53%): 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 2H), 6.98 (s, 1H), 6.82 (s, 2H), 6.48 (m, 1H), 6.20 (m, 1H), 5.02 (s, 1H), 4.08 (m, 1H); ESIMS m/z 394.94 ([M−H]−).
    • Example 72: Preparation of (E)-N-(4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-enyl)benzyl)acetamide (CC1)
  • Figure US20170088507A1-20170330-C00211
  • To a stirred solution of (E)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.3 g, 0.8 mmol) in CH2Cl2 (10 mL) was added acetic anhydride (0.12 mL, 1.14 mmol), and TEA (0.217 mL, 1.52 mmol), and the resultant reaction mixture was stirred at ambient temperature for 6 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 30-50% ethyl acetate in hexane) afforded the title compound as a off-white solid (0.2 g, 60%) mp 107-109° C.; 1H NMR (400 MHz, CDCl3) δ 7.37 (m, 3H), 7.28 (m, 4H), 6.60 (d, J=16.0 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 5.75 (br s, 1H), 4.46 (d, J=6 Hz, 2H), 4.01 (m, 1H), 2.11 (s, 3H); ESIMS m/z 402.00 ([M+H]+).
  • Compounds CC2-CC6 in Table 1 were made in accordance with the procedures disclosed in Example 72. In addition, compound DC56 in Table 1 was made from compound DC55 in accordance with the procedures disclosed in Example 72.
    • Example 73: Preparation of (E)-N-(2-Chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)acetamide (CC7)
  • Figure US20170088507A1-20170330-C00212
  • To a stirred solution of (E)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.3 g, 0.8 mmol) in DMF (5 mL) was added 2,2,2-trifluoropropanoic acid (97 mg, 0.76 mmol), HOBt.H2O (174 mg, 1.14 mmol) and EDC.HCl (217 mg, 1.14 mmol) and DIPEA (196 mg, 1.52 mmol), and the resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined EtOAc layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; ethyl acetate in hexane (30-50% afforded the title compound as a off-white solid (0.2 g, 60%): mp 127-128° C.; 1H NMR (400 MHz, CDCl3) δ 7.42 (m, 4H), 7.24 (m, 2H), 6.53 (d, J=16.0 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 5.86 (br s, 1H), 4.51 (d, J=6.0 Hz, 2H), 4.05 (m, 1H), 2.02 (s, 3H); ESIMS m/z 436.03 ([M+H]+).
  • Compounds CC8-CC28 in Table 1 were made in accordance with the procedures disclosed in Example 73.
    • Example 74: Preparation of (E)-N-(Pyridin-2-ylmethyl)-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzyl)cyclopropanecarboxamide (CC29)
  • Figure US20170088507A1-20170330-C00213
    • Step 1: (E)-1-(Pyridin-2-yl)-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzyl)methanamine
  • (E)-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)phenyl)methanamine (0.46 g, 1 mmol) was dissolved in CH3OH (3 mL). To this was added pyridine-2-carbaldehyde (0.107 g, 1 mmol).
  • The reaction mixture was stirred for 1 h. After 1 h, NaBH4 (0.076 g, 2 mmol) was added and left at ambient temperature for 3 h. The reaction mixture was concentrated to give an oily residue. Purification by flash column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a pale yellow liquid (0.22 g, 40%): 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=4.8 Hz, 1H), 7.74 (m, 1H), 7.62 (m, 2H), 7.52 (m, 1H), 7.4 (s, 2H), 7.3 (m, 1H), 7.2 (m, 2H), 6.60 (d, J=16.0 Hz, 1H), 6.38 (dd, J=16.0, 8.0 Hz, 1H), 4.10 (m, 1H), 4.02 (s, 2H), 3.96 (s, 2H); ESIMS m/z 552.95 ([M+H]+); IR (thin film) 3338, 1114, 808 cm−1.
    • Step 2: (E)-N-(Pyridin-2-ylmethyl)-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzyl)cyclopropanecarboxamide
  • (E)-1-(Pyridin-2-yl)-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzyl)methanamine (0.27 g, 0.05 mmol) was taken up in CH2Cl2 (3 mL). To this was added TEA (0.14 mL, 0.1 mmol). The reaction mixture was stirred for 10 min. After 10 min, the reaction mixture was cooled to 0° C., and cyclopropylcarbonyl chloride (0.08 mL, 0.075 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 h and then was washed with water and satd aq NaHCO3 solution. The organic layer was dried over anhydrous Na2SO4 and evaporated to obtain pale yellow gummy material (0.15 g, 50%): 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=4.6 Hz, 1H), 7.74 (m, 1H), 7.62 (m, 2H), 7.52 (m, 1H), 7.4 (s, 2H), 7.3 (m, 1H), 7.2 (m, 2H), 6.60 (d, J=16.0 Hz, 1H), 6.38 (dd, J=16.0, 8.0 Hz, 1H), 5.02 (s, 1H), 4.8 (s, 1H), 4.8 (d, J=10 Hz, 2H), 4.10 (m, 1H), 1.8 (m, 1H), 1.2 (m, 2H), 0.6 (m, 2H); ESIMS m/z 620.86 ([M−H]−); IR (thin film) 1645, 1115, 808 cm−1.
    • Example 75: Preparation of (E)-N-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-3-(methylsulfonyl)propanamide (CC30)
  • Figure US20170088507A1-20170330-C00214
  • (E)-N-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-3-(methylthio)propanamide (0.15 g, 0.28 mmol) was treated with oxone (0.175 g, 0.569 mmol) in 1:1 acetone:water (20 mL) for 4 h at ambient temperature. The acetone was evaporated to obtain a white solid (0.095 g, 60%): mp 101-104° C.; 1H NMR (400 MHz, CDCl3) δ 7.41 (m, 4H), 7.24 (m, 1H), 6.53 (d, J=16.0 Hz, 1H), 6.35 (dd, J=16.0, 8.0 Hz, 1H), 6.12 (br s, 1H), 4.53 (m, 2H), 4.10 (m, 1H), 3.42 (m, 2H), 2.91 (s, 3H), 2.78 (m, 2H); ESIMS m/z 559.75 ([M−H]−).
    • Example 76: Preparation of (E)-1-(2-Chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)-3-ethylurea (CC31)
  • Figure US20170088507A1-20170330-C00215
  • To a stirred solution of (E)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added TEA (0.141 mL, 1 mmol) and ethylisocyanate (0.053 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.141 g, 60%): mp 177-178° C.; 1H NMR (400 MHz, CDCl3) δ 7.58 (m, 2H), 7.41 (m, 3H), 7.24 (m, 1H), 6.53 (d, J=16.0 Hz, 1H), 6.35 (dd, J=16.0, 8.0 Hz, 1H), 4.70 (br s, 1H), 4.43 (s, 2H), 4.08 (m, 1H), 3.21 (m, 2H), 1.25 (m, 3H); ESIMS m/z 463 ([M−H]−).
  • Compounds CC32-CC35 in Table 1 were made in accordance with the procedures disclosed in Example 76.
    • Example 77: Preparation of (E)-3-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-1,1-dimethylurea (CC36)
  • Figure US20170088507A1-20170330-C00216
  • To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added TEA (0.141 mL, 1 mmol) and N,N-dimethylcarbamoyl chloride (0.08 g, 0.075 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.15 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.39 (m, 4H), 7.28 (m, 1H), 6.54 (d, J=16.0 Hz, 1H), 6.34 (dd, J=16.0, 8.0 Hz, 1H), 4.97 (br s, 1H), 4.38 (d, J=6.0 Hz, 2H), 4.10 (m, 1H), 2.9 (s, 3H), 2.7 (s, 3H); ESIMS m/z 497 ([M−H]−); IR (thin film) 3350, 1705, 1114, 808 cm−1.
    • Example 78: Preparation of (E)-1-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-3-ethylthiourea (CC37)
  • Figure US20170088507A1-20170330-C00217
  • To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added TEA (0.141 mL, 1 mmol) and ethyl isothicyanate (0.053 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.14 g, 60%): mp 88-91° C.; 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J=8 Hz, 1H), 7.41 (d, J=7.2 Hz, 2H), 7.26 (m, 2H), 6.50 (d, J=16 Hz, 1H), 6.35 (dd, J=16.0, 8.0 Hz, 1H), 6.0 (br s, 1H), 5.73 (br s, 1H), 4.80 (br s, 2H), 4.09 (m, 1H), 1.23 (m, 3H); ESIMS m/z 515.01 ([M+H]+).
  • Compound CC38 in Table 1 was made in accordance with the procedures disclosed in Example 78.
    • Example 79: Preparation of (E)-tert-Butyl (2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)-3-ethylurea (CC39)
  • Figure US20170088507A1-20170330-C00218
  • To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol in CH2Cl2 (5 mL) at 0° C. were added TEA (0.141 mL, 1 mmol) and di-tert-butyl dicarbonate (0.163 mL, 0.75 mmol), and the reaction mixture was stirred for 4 h at ambient temperature. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 10-20% EtOAc in hexane) afforded the title compound as a white solid (0.147 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.39 (m, 4H), 7.28 (m, 1H), 6.54 (d, J=16.0 Hz, 1H), 6.34 (dd, J=16.0, 8.0 Hz, 1H), 4.97 (br s, 1H), 4.38 (d, J=6.0 Hz, 2H), 4.10 (m, 1H), 1.53 (s, 9H); ESIMS m/z 526.09 ([M−H]−); IR (thin film) 3350, 1705, 1114, 808 cm−1.
  • Compound CC40 in Table 1 was made in accordance with the procedures disclosed in Example 79.
    • Example 80: Preparation of (E)-Methyl 2-((2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)amino)-2-oxoacetate (CC41)
  • Figure US20170088507A1-20170330-C00219
  • To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added TEA (0.141 mL, 1 mmol) and methyl 2-chloro-2-oxoacetate (0.09 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 20% EtOAc in hexane) afforded the title compound as a solid (0.12 g, 50%): 1H NMR (400 MHz, CDCl3) δ 7.48 (m, 1H). 7.43 (m, 3H), 7.38 (m, 1H), 7.23 (s, 1H), 6.55 (d, J=16.0 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 4.60 (d, J=4.4 Hz, 2H), 4.18 (m, 1H), 3.85 (s, 3H); ESIMS m/z 512.22 ([M−H]−); IR (thin film) 1740, 1701, 1114, 808 cm−1.
    • Example 81: Preparation of (E)-N1-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-N2-(2,2,2-trifluoroethyl)oxalamide (CC42)
  • Figure US20170088507A1-20170330-C00220
  • To a stirred solution of 2,2,2-trifluoroethylamine hydrochloride (0.1 g, 0.77 mmol) in CH2Cl2 (10 mL) was added dropwise trimethylaluminum (2 M solution in toluene; 0.39 mL, 0.77 mmol), and the reaction mixture was stirred at 25° C. for 30 min. A solution of (E)-methyl 2-((2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-2-oxoacetate (0.2 g, 0.38 mmol) in CH2Cl2 (5 mL) was added dropwise to the reaction mixture at 25° C. The reaction mixture was stirred at reflux for 18 h, cooled to 25° C., quenched with 0.5 N HCl solution (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh; 20%-40% EtOAc in n-hexane) to afford the title compound (0.13 g, 60%): mp 161-163° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.45 (br s, 2H), 7.90 (s, 2H), 7.75 (s, 1H), 7.46 (s, 1H), 7.28 (s, 1H), 6.93 (m, 1H), 6.75 (m, 1H), 4.80 (m, 1H), 4.40 (s, 2H), 3.90 (s, 2H); ESIMS m/z 578.96 ([M−H]−).
    • Example 82: Preparation of (E)-N-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)pyridin-2-amine (CC43)
  • Figure US20170088507A1-20170330-C00221
  • To a stirred solution of N-(2-chloro-4-vinylbenzyl)pyridin-2-amine (0.3 g, 1.22 mmol) in 1,2-dichlorobenzene (5 mL) were added 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (0.83 g, 2.44 mmol), CuCl (24 mg, 0.24 mmol) and 2,2-bipyridyl (76 mg, 0.48 mmol). The resultant reaction mixture was degassed with argon for 30 min and then stirred at 180° C. for 24 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 15% EtOAc in n-hexane) afforded the title compound as an off-white solid (0.2 g, 35%): mp 140-142° C.; 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=4.0 Hz, 1H), 7.40 (m, 5H), 7.22 (m, 1H), 6.61 (m, 2H), 6.35 (m, 2H), 4.94 (br s, 1H), 4.61 (d, J=6.4 Hz, 2H), 4.11 (m, 1H); ESIMS m/z 505.39 ([M+H]+).
    • Example 83: Preparation of (E)-N-((3-Chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)-but-1-en-1-yl)pyridin-2-yl)methyl)-3,3,3-trifluoropropanamide (CC44)
  • Figure US20170088507A1-20170330-C00222
  • To a stirred solution of (E)-(3-chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)pyridin-2-yl)methanamine (0.1 g, 0.2 mmol) in CH2Cl2 (5 mL) were added 3,3,3-trifluoropropanoic acid (45 mg, 0.350 mmol), EDC.HCl (67 mg, 0.350 mmol), HOBt.H2O (71 mg, 0.467 mmol) and DIPEA (60.2 mg, 0.467 mmol), and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with CH2Cl2 and washed with water. The combined CH2Cl2 layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 15% EtOAc in petroleum ether) afforded the title compound as a pale yellow liquid (30 mg, 35%): 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.77 (s, 1H), 7.47 (br s, 1H), 7.40 (s, 2H), 6.58 (d, J=16.0 Hz, 1H), 6.45 (dd, J=16.0, 8.0 Hz, 1H), 4.68 (d, J=4.0 Hz, 2H), 4.14 (m, 1H), 3.24 (q, J=10.8 Hz, 2H); ESIMS m/z 536.88 ([M−H]−); IR (thin film) 3320, 1674, 1114, 808.
  • Compound CC45 in Table 1 was made in accordance with the procedures disclosed in Example 83.
    • Example 84: Preparation of (E)-3,3,3-Trifluoro-N-((4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methyl)propanamide (CC46)
  • Figure US20170088507A1-20170330-C00223
  • To a stirred solution of (E)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methanamine (0.1 g, 0.22 mmol) in CH2Cl2 (8 mL) were added 3,3,3-trifluoropropanoic acid (0.032 g, 0.24 mmol), HOBt.H2O (52 mg, 0.33 mmol), EDC.HCl (0.065 g, 0.33 mmol) and DIPEA (0.044 g, 0.45 mmol), and the resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with water and extracted with EtOAc (3×30 mL). The combined EtOAc layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 15% EtOAc in n-hexane) afforded the title compound as a gummy material (60 mg, 50%): mp 151-153° C.; 1H NMR (400 MHz, CDCl3) δ 8.06 (m, 1H), 7.61 (m, 4H), 7.48 (s, 2H), 7.44 (d, J=8.0 Hz, 1H), 7.38 (m, 1H), 6.42 (m, 1H), 5.92 (br s, 1H), 4.92 (m, 2H), 4.24 (m, 1H), 3.12 (m, 2H); ESIMS m/z 554.04 ([M−H]−).
  • Compounds CC47-CC48 in Table 1 were made in accordance with the procedures disclosed in Example 84.
    • Example 85: Preparation of (E)-1-Ethyl-3-((4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methyl)urea (CC49)
  • Figure US20170088507A1-20170330-C00224
  • To a stirred solution of (E)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methanamine (0.1 g, 0.22 mmol) in CH2Cl2 at 0° C. were added TEA (0.064 mL, 0.44 mmol) and ethylisocyanate (0.023 mL, 0.33 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30% EtOAc in hexane) afforded the title compound as a solid (0.07 g, 60%): mp 84-87° C.; 1H NMR (400 MHz, CDCl3) δ 8.06 (m, 1H), 7.98 (m, 1H), 7.61 (m, 3H), 7.48 (s, 2H), 7.44 (d, J=8.0 Hz, 1H), 7.38 (m, 2H), 6.42 (m, 1H), 4.92 (s, 2H), 4.6 (br s, 1H), 4.24 (m, 1H), 3.21 (m, 2H), 1.2 (t, J=4.6 Hz, 3H); ESIMS m/z 515.33 ([M+H]+).
    • Example 86: Preparation of (E)-N′-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)cyclopropanecarbohydrazide (CC50)
  • Figure US20170088507A1-20170330-C00225
  • To a stirred solution of (E)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)hydrazine (0.1 g, 0.3 mmol) in CH2Cl2 (10 mL) was added DIPEA (65 mg, 0.51 mmol), HOBt.H2O (59 mg, 0.38 mmol), EDC.HCl (73 mg, 0.38 mmol) and cyclopropanecarbonyl chloride (0.024 g, 0.28 mmol), and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with satd aq NaHCO3 solution and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2; 5-25% EtOAc in petroleum ether) afforded the title compound as a solid (65 mg, 55%): mp 138-140° C.; 1H NMR (400 MHz, CDCl3) δ 9.81 (s, 1H), 7.90 (s, 1H), 7.84 (s, 2H), 7.34 (d, J=8.4 Hz, 2H), 6.65 (d, J=15.6 Hz, 1H), 6.61 (m, 1H), 6.57 (s, 1H), 6.48 (dd, J=15.6, 8.8 Hz, 1H), 4.74 (m, 1H), 1.64 (m, 1H), 0.75 (m, 4H); ESIMS m/z 461.32 ([M−H]−).
  • Compound CC51 in Table 1 was made in accordance with the procedures disclosed in Example 86.
    • Example 87: Preparation of (E)-N-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenoxy)cyclopropanecarboxamide (CC52)
  • Figure US20170088507A1-20170330-C00226
  • To a stirred solution of (E)-O-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)hydroxylamine (0.15 g, 0.38 mmol) in CH2Cl2 (5 mL) was added EDC.HCl (0.109 g, 0.569 mmol), HOBt.H2O (0.087 g, 0.569 mmol), DIPEA (0.097 g, 0.758 mmol) and cyclopropanecarboxylic acid (0.049 g, 0.569 mmol). The resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with water and extracted with CHCl3 (35 mL) The combined CHCl3 layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2; 20% EtOAc in hexane) afforded the title compound as a brown liquid (0.06 g, 34%): 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 2H), 7.18 (s, 1H), 7.08 (s, 1H), 6.85 (m, 1H), 6.45 (m, 1H), 6.65 (m, 1H), 6.20 (m, 1H), 5.55 (s, 1H), 4.08 (m, 1H), 1.90 (m, 1H), 1.30-1.10 (m, 4H); ESIMS m/z 464.87 ([M−H]−).
  • Compound CC53 in Table 1 was made in accordance with the procedures disclosed in Example 87.
    • Example 88: Preparation of (Z)-3,3,3-Trifluoro-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)propanamide (CC54)
  • Figure US20170088507A1-20170330-C00227
  • A silicon borate vial was charged with (E)-3,3,3-trifluoro-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)propanamide (133 mg, 0.269 mmol) and dimethyl sulfoxide (DMSO; 10 mL). The mixture was placed within 0.6 to 1 meter (m) of a bank of eight 115 watt Sylvania FR48T12/350BL/VHO/180 Fluorescent Tube Black Lights and four 115 watt Sylvania (daylight) F48T12/D/VHO Straight T12 Fluorescent Tube Lights for 72 h. The mixture was concentrated in vacuo and purified by reverse phase chromatography to give the title compound as a colorless oil (11 mg, 8%): 1H NMR (300 MHz, CDCl3) δ 7.28 (s, 2H), 7.25 (m, 2H), 7.10 (d, J=8.0 Hz, 2H), 6.89 (d, J=11.4 Hz, 1H), 6.07 (br s, 1H), 6.01 (m, 1H), 4.51 (d, J=5.8 Hz, 2H), 4.34 (m, 1H), 3.12 (q, J=7.5 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 162.44, 137.20, 135.38, 135.23, 134.82, 134.68, 131.71, 129.00, 128.80, 128.69, 128.10, 127.96, 122.63, 76.70, 47.33 (q, J=28 Hz), 43.59, 42.12 (q, J=30 Hz); ESIMS m/z 504 ([M+H]+).
  • Compounds DC46, AC93. AC94 in Table 1 were made in accordance with the procedures disclosed in Example 88.
    • Example 89: Preparation of 1-(1-Bromo-2,2,2-trifluoroethyl)-3-chlorobenzene (DI2)
  • Figure US20170088507A1-20170330-C00228
  • The title compound was synthesized in two steps via 1-(3-chlorophenyl)-2,2,2-trifluoroethanol (DI1, prepared as in Step 1, Method B in Example 1); isolated as a colorless viscous oil (1.5 g, 75%): 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.42-7.35 (m, 3H), 5.02 (m, 1H), 2.65 (br s, 1H)) and Step 2 in Example 1 and isolated (0.14 g, 22%): 1H NMR (400 MHz, CDCl3) δ 7.50 (br s, 1H), 7.42-7.35 (m, 3H), 5.07 (m, 1H).
  • The following compounds were made in accordance with the procedures disclosed in Example 89.
    • (1-Bromo-2,2,2-trifluoroethyl)benzene (DI4)
  • Figure US20170088507A1-20170330-C00229
  • 2,2,2-Trifluoro-1-phenylethanol (DI3) was isolated (10 g, 80%): 1H NMR (300 MHz, CDCl3) δ 7.48 (m, 2H), 7.40 (m, 3H), 5.02 (m, 1H), 2.65 (d, J=7.1 Hz, 1H). The title compound (DI4) was isolated as a liquid (8.0 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.50 (m, 2H), 7.40 (m, 3H), 5.00 (q, J=7.5 Hz, 1H).
    • 1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-dimethylbenzene (DI20)
  • Figure US20170088507A1-20170330-C00230
  • 1-(3,5-Dimethylphenyl)-2,2,2-trifluoroethanol (DI19) was isolated an off white solid: 1H NMR (400 MHz, CDCl3) δ 7.05 (s, 2H), 7.02 (s, 1H), 4.95 (m, 1H), 2.32 (s, 6H); ESIMS m/z 204 ([M]−). The title compound (DI20) was isolated (3.0 g, 51%).
    • 1-(1-Bromo-2,2,2-trifluoroethyl)-2,4-dichlorobenzene (DI22)
  • Figure US20170088507A1-20170330-C00231
  • 1-(2,4-Dichlorophenyl)-2,2,2-trifluoroethanol (DI21) was isolated as an off white powder (5.3 g, 61%): mp 49-51° C.; 1H NMR (400 MHz, CDCl3) δ 7.62-7.66 (d, 1H), 7.42-7.44 (d, 1H), 7.32-7.36 (d, 1H), 5.6 (m, 1H), 2.7 (s, 1H); ESIMS m/z 244 ([M]+). The title compound (DI22) was isolated (3.2 g, 50%): 1H NMR (400 MHz, CDCl3) δ 7.62-7.72 (m, 1H), 7.4-7.42 (m, 1H), 7.3-7.38 (m, 1H), 5.7-5.8 (m, 1H).
    • 1-(1-Bromo-2,2,2-trifluoroethyl)-2,3-dichlorobenzene (DI24)
  • Figure US20170088507A1-20170330-C00232
  • 1-(2,3-Dichlorophenyl)-2,2,2-trifluoroethanol (DI23) was isolated as a pale yellow oil (5.2 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.62-7.64 (d, 1H), 7.52-7.54 (m, 1H), 7.29-7.33 (t, 1H), 5.6-5.76 (m, 1H), 2.7 (s, 1H); ESIMS m/z 243.9 ([M]+). The title compound (DI24) was isolated as an oil (8.7 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.62-7.71 (m, 1H), 7.44-7.52 (m, 1H), 7.27-7.3 (s, 1H), 5.81-5.91 (m, 1H).
    • 2-(1-Bromo-2,2,2-trifluoroethyl)-1,4-dichlorobenzene (DI26)
  • Figure US20170088507A1-20170330-C00233
  • 1-(2,5-Dichlorophenyl)-2,2,2-trifluoroethanol (DI25) was isolated as a yellow oil (4.1 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.68-7.7 (s, 1H), 7.3-7.37 (m, 2H), 5.51-5.6 (m, 1H), 2.7 (s, 1H); ESIMS m/z 244 ([M]+)). The title compound (DI26) was isolated (3.0 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.7-7.78 (m, 1H), 7.3-7.4 (m, 2H), 5.7-5.8 (m, 1H).
    • 1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-bis(trifluoromethyl)benzene (DI28)
  • Figure US20170088507A1-20170330-C00234
  • 1-(3,5-Bis(trifluoromethyl)phenyl)-2,2,2-trifluoroethanol (DI27) was isolated (3.8 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.98 (m, 3H), 5.25 (m, 1H), 3.2 (br, 1H); ESIMS m/z 312.2 ([M]+). The title compound (DI28) was prepared and carried on crude.
    • 1-(1-Bromo-2,2,2-trifluoroethyl)-2,3,5-trichlorobenzene (DI30)
  • Figure US20170088507A1-20170330-C00235
  • 2,2,2-Trifluoro-1-(2,3,5-trichlorophenyl)ethanol (DI29) was isolated as a white solid (4.0 g, 60%): mp 113-115° C.; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, 1H), 7.50 (d, 1H), 5.60-5.70 (m, 1H), 2.75 (s, 1H); ESIMS m/z 278.0 ([M+]). The title compound (DI30) was isolated (2.9 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.70 (d, 1H), 7.50 (d, 1H), 5.72-5.82 (m, 1H).
    • 1-(1-Bromo-2,2,2-trifluoroethyl)-3-chloro-5-(trifluoromethyl)benzene (DI32)
  • Figure US20170088507A1-20170330-C00236
  • 1-(3-Chloro-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroethanol (DI31) was isolated as a pale yellow oil (2.0 g, 50%): 1H NMR (400 MHz, CDCl3) δ 7.51 (m, 3H), 5.08 (m, 1H), 2.81 (s, 1H); ESIMS m/z 278.1 ([M]+). The title compound (DI32) was isolated oil (2.0 g, 40%): ESIMS m/z 342 ([M]+).
    • 5-(1-Bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-methoxybenzene (DI34)
  • Figure US20170088507A1-20170330-C00237
  • 1-(3,5-Dichloro-4-methoxyphenyl)-2,2,2-trifluoroethanol (DI33) was isolated as an off white solid (0.8 g, 60%); mp 92-95° C.: 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 2H), 5.00 (m, 1H), 3.89 (s, 3H), 2.64 (m, 1H); ESIMS m/z 274 ([M]+). The title compound (DI34) was isolated as a colorless liquid (0.6 g, 57%).
    • Example 90: Preparation of 1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-difluorobenzene (DI36)
  • Figure US20170088507A1-20170330-C00238
  • The title compound was synthesized in two steps via 1-(3,5-difluorophenyl)-2,2,2-trifluoroethanol (DI35, prepared as in Step 1, Method A in Example 1; isolated as a colorless oil (0.2 g, 75%): 1H NMR (400 MHz, CDCl3) δ 7.05 (m, 2H), 6.88 (m, 1H), 5.06 (m, 1H), 2.66 (s, 1H); ESIMS m/z 212 ([M]+) and Step 2 in Example 1 and isolated (3.2 g, 50%); 1H NMR (400 MHz, CDCl3) δ 7.05 (m, 2H), 6.86 (m, 1H), 5.03 (q, J=7.4 Hz, 1H).
  • The following compounds were made in accordance with the procedures disclosed in Example 90.
    • 1-(1-Bromo-2,2,2-trifluoroethyl)-4-chlorobenzene (DI38)
  • Figure US20170088507A1-20170330-C00239
  • 1-(4-Chlorophenyl)-2,2,2-trifluoroethanol (DI37) was isolated as a colorless oil (5.0 g, 99%): 1H NMR (400 MHz, CDCl3) δ 7.44-7.38 (m, 4H), 5.05 (m, 1H), 2.55 (s, 1H); ESIMS m/z 210 ([M]+). The title compound (DI38) was isolated (3.0 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=8.2 Hz, 2H), 7.37 (d, J=8.2 Hz, 2H), 5.10 (q, J=7.2 Hz, 1H).
    • 1-(1-Bromo-2,2,2-trifluoroethyl)-4-methoxybenzene (DI40)
  • Figure US20170088507A1-20170330-C00240
  • 2,2,2-Trifluoro-1-(4-methoxyphenyl)ethanol (DI39) was isolated as a pale yellow liquid: 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=8.8 Hz, 2H), 6.95 (m, J=8.8 Hz, 2H), 5.00 (m, 1H), 3.82 (s, 3H), 2.44 (s, 1H); ESIMS m/z 206.1 ([M]+). The title compound (DI40) was isolated (3.8 g, 62%).
    • 1-(1-Bromo-2,22-trifluoroethyl)-4-fluorobenzene (DI42)
  • Figure US20170088507A1-20170330-C00241
  • 2,2,2-Trifluoro-1-(4-fluorophenyl)ethanol (DI41) was isolated as a colorless oil (5 g, 99%): 1H NMR (400 MHz, CDCl3) δ 7.48-7.45 (m, 2H), 7.13-7.07 (m, 2H), 5.06 (m, 1H), 2.53 (s, 1H); ESIMS m/z 194 ([M]+). The title compound (DI42) was prepared and carried on as crude intermediate.
    • 1-(1-Bromo-2,2,2-trifluoroethyl)-4-methylbenzene (DI44)
  • Figure US20170088507A1-20170330-C00242
  • 2,2,2-Trifluoro-1-(p-tolyl)ethanol (DI43) was isolated as colorless oil (5.0 g, 99%): 15 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 5.02 (m, 1H), 2.46 (m, 1H), 2.37 (s, 3H); ESIMS m/z 190 ([M]+). The title compound (DI44) was isolated (3.0 g, 45%).
    • 1-(1-Bromo-2,2,2-trifluoroethyl)-3-fluorobenzene (DI46)
  • Figure US20170088507A1-20170330-C00243
  • 2,2,2-Trifluoro-1-(3-fluorophenyl)ethanol (DI45) was isolated as a colorless viscous oil (2.8 g, 93%): 1H NMR (400 MHz, CDCl3) δ 7.41 (m, 1H), 7.25 (m, 2H), 7.14 (m, 1H), 5.06 (m, 1H), 2.60 (s, 1H); ESIMS m/z 194 ([M]+). The title compound (DI46) was isolated (2.0 g, 61%).
    • 1-(1-Bromo-2,2,2-trifluoroethyl)-2-fluorobenzene (DI48)
  • Figure US20170088507A1-20170330-C00244
  • 2,2,2-Trifluoro-1-(2-fluorophenyl)ethanol (DI47) was isolated as a colorless oil (2.5 g, 99%): 1H NMR (400 MHz, CDCl3) δ 7.40 (m, 1H), 7.43 (m, 1H), 7.24 (m, 1H), 7.13 (m, 1H), 5.42 (m, 1H), 2.65 (s, 1H); ESIMS m/z 194 ([M]+). The title compound (DI48) was isolated (2.0 g, 61%): 1H NMR (400 MHz, CDCl3) δ 7.61 (m, 1H), 7.40 (m, 1H), 7.23 (m, 1H), 7.10 (m, 1H), 5.40 (m, 1H); GCMS m/z 255 ([M−H]−).
    • Example 91: Preparation of 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI5)
  • Figure US20170088507A1-20170330-C00245
  • To a stirring solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K2CO3 (13.3 g, 96.7 mmol) and 1,2,4-triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120° C. for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with water and extracted with EtOAc (3×100 mL). The combined EtOAc layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65%): mp 145-149° C.: 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]+).
  • The following compound was made in accordance with the procedures disclosed in Example 91.
    • 5-Formyl-2-(1H-1,2,4-triazol-1-yl)benzonitrile (DI49)
  • Figure US20170088507A1-20170330-C00246
  • The title compound was isolated (2.8 g, 60%); 1H NMR (400 MHz, CDCl3) δ 10.10 (s, 1H), 8.98 (s, 1H), 8.35 (s, 1H), 8.30 (d, 1H), 8.22 (s, 1H), 8.07 (d, 1H); IR (thin film) 3433, 3120, 1702, 1599, 1510 cm−1.
    • 2-Chloro-4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI50)
  • Figure US20170088507A1-20170330-C00247
  • The title compound was isolated as an off white solid (3.0 g, 40%): mp 149-151° C.; 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 8.74 (s, 1H), 8.17 (s, 1H), 8.10 (s, 1H), 7.90 (m, 2H); ESIMS m/z 208.10 ([M+H]+).
    • 5-Methyl-4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI51)
  • Figure US20170088507A1-20170330-C00248
  • The title compound was isolated as a white solid (0.5 g, 74%): mp 109-111° C.; 1H NMR (400 MHz, D6-DMSO) δ 10.06 (s, 1H), 9.00 (s, 1H), 8.30 (s, 1H), 7.99 (s, 1H), 7.92 (d, J=9.2 Hz, 1H), 7.69 (d, J=9.2 Hz, 1H), 2.30 (s, 3H); ESIMS m/z 188.13 ([M+H]+).
    • Example 92: Preparation of 5-Formyl-2-(3-nitro-1H-1,2,4-triazol-1-yl)benzonitrile (DI52)
  • Figure US20170088507A1-20170330-C00249
  • To a stirring solution of 2-fluoro-5-formylbenzonitrile (0.5 g, 3.3 mmol) in DMF (25 mL) were added K2CO3 (0.68 g, 4.95 mmol) and 3-nitro-1,2,4 triazole (0.45 g, 4.2 mmol) and the resultant reaction mixture was stirred at ambient temperature for 14 h. After completion of reaction (TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined EtOAc layer was washed with water and brine then dried over Na2SO4 and concentrated under reduced pressure to afforded the title compound as a pale yellow solid (0.36 g, 45%): mp 170-172° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.12 (s, 1H), 9.61 (s, 1H), 8.69 (s, 1H), 8.45 (d, J=9.3 Hz, 1H), 8.23 (d, J=9.3 Hz, 1H); ESIMS m/z 242.3 ([M−H]−); IR (thin film) 2238, 1705, 1551, 1314 cm−1.
    • Example 93: Preparation of 4-(3-Methyl-1H-1,2,4-triazol-1-yl)benzaldehyde (DI53)
  • Figure US20170088507A1-20170330-C00250
  • To a stirring solution of 4-fluorobenzaldehyde (5.0 g, 40.32 mmol) in DMF (50 mL), were added K2CO3 (3.34 g, 40.32 mmol) and 3-methyl-1,2,4-trizole (3.34 g, 40.32 mmol) and the resultant reaction mixture was stirred at ambient temperature for 4 h. After completion of the reaction (TLC), the reaction mixture was diluted with water and extracted with EtOAc (3×). The combined EtOAc layer was washed with water and brine then dried over Na2SO4 and concentrated under reduced pressure to afforded the title compound as a white solid (4.1 g, 60%): mp 125-128° C.; 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 8.76 (s, 1H), 8.02 (d, 2H), 7.85 (d, 2H), 2.50 (s, 3H); ESIMS m/z 188.04 ([M+H]+).
  • The following compound was made in accordance with the procedures disclosed in Example 93.
    • 4-(1H-1,2,4-triazol-1-yl)-3-(trifluoromethyl)benzaldehyde (DI54)
  • Figure US20170088507A1-20170330-C00251
  • The title compound was isolated as white solid (1.05 g, 60%): mp 81-83° C.; 1H NMR (400 MHz, CDCl3) δ 10.15 (s, 1H), 8.43 (s, 1H), 8.37 (s, 1H), 8.25 (d, J=7.2 Hz, 1H), 8.18 (s, 1H), 7.79 (d, J=7.2 Hz, 1H); ESIMS m/z 241.0 ([M]+).
    • 4-(3-Nitro-1H-1,2,4-triazol-1-yl)benzaldehyde (DI55)
  • Figure US20170088507A1-20170330-C00252
  • The title compound was isolated as pale yellow solid (0.10 g, 23%): mp 159-161° C.; 1H NMR (400 MHz, CDCl3) δ 10.10 (s, 1H), 8.89 (s, 1H), 8.15 (m, 2H), 8.00 (m, 2H); ESIMS m/z 217.11 ([M−H]−).
    • 3-Bromo-4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI56)
  • Figure US20170088507A1-20170330-C00253
  • The title compound was isolated as white solid (3.2 g, 51%): mp 126-128° C.; 1H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 8.69 (s, 1H), 8.27 (M, 1H, 8.18 (s, 1H) 7.99 (d, J=9.2 Hz, 1H), 7.76 (d, J=9.2 Hz, 1H); ESIMS m/z 250.9 ([M]+).
    • 5-Formyl-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzonitrile (DI57)
  • Figure US20170088507A1-20170330-C00254
  • The title compound was isolated as white solid (0.13 g, 30%): mp 147-149° C.; 1H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H), 8.89 (s, 1H), 8.32 (d, J=1.8 Hz, 1H), 8.24 (dd, J=8.6, 1.3 Hz, 1H), 8.06 (d, J=8.6 Hz, 1H), 2.54 (s, 3H); ESIMS m/z 213.09 ([M+H]+); IR (thin film) 2239, 1697 cm−1.
    • 3-Nitro-4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI58)
  • Figure US20170088507A1-20170330-C00255
  • The title compound was isolated as pale yellow solid (3.0 g, 60%): mp 116-118° C.; 1H NMR (400 MHz, CDCl3) δ 10.15 (s, 1H), 8.48 (s, 1H), 8.46 (s, 1H), 8.26 (d, J=6.9 Hz, 1H), 8.16 (s, 1H), 7.83 (d, J=6.9 Hz, 1H); ESIMS m/z 219.00 ([M+H]+).
    • Example 94: Preparation of 1-(4-Vinylphenyl)-1H-1,2,4-triazole (DI59)
  • Figure US20170088507A1-20170330-C00256
  • To a stirred solution of 4-[1,2,4]triazol-1-yl-benzaldehyde (9.0 g, 52 mmol) in 1,4-dioxane (100 mL), were added K2CO3 (10.76 g, 78 mmol) and methyl triphenyl phosphonium bromide (22.2 g, 62.4 mmol) at ambient temperature. The resultant reaction mixture was heated to 70° C. for 18 h. After completion of the reaction (TLC), the reaction mixture was cooled to ambient temperature and filtered and the obtained filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) to afforded the title compound as a white solid (5.6 g, 63%): ESIMS m/z 172.09 ([M+H]+).
  • The following compound was made in accordance with the procedures disclosed in Example 94.
    • 1-(2-Methyl-4-vinylphenyl)-1H-1,2,4-triazole (DI60)
  • Figure US20170088507A1-20170330-C00257
  • The title compound was isolated as an off white solid (1.5 g, 76%): 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 8.11 (s, 1H), 7.35 (m, 2H), 7.27 (d, J=8.7 Hz, 1H), 6.74 (m, 1H), 5.82 (d, J=17.3 Hz, 1H), 5.36 (d, J=10.0 Hz, 1H), 2.25 (s, 3H); ESIMS m/z 186.14 ([M+H]+).
    • 2-(1H-1,2,4-Triazol-1-yl)-5-vinylbenzonitrile (DI61)
  • Figure US20170088507A1-20170330-C00258
  • The title compound was isolated as an off-white solid (1.40 g, 71%): mp 126-129° C.; 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 8.18 (s, 1H), 7.82-7.84 (m, 1H), 7.72-7.80 (m, 2H), 6.70-6.80 (dd, J=17.6, 10.8 Hz, 1H), 5.90-5.95 (d, J=17.6 Hz, 1H), 5.50-5.70 (d, J=10.8 Hz, 1H); ESIMS m/z 197.03 ([M+H]+).
    • Example 95: Preparation of 2-(3-Nitro-1H-1,2,4-triazol-1-yl)-5-vinylbenzonitrile (DI62)
  • Figure US20170088507A1-20170330-C00259
  • To a stirred solution of 5-formyl-2-(3-nitro-1H-1,2,4-triazol-1-yl)benzonitrile (0.36 g, 1.49 mmol) in 1,4-dioxane (25 mL), were added K2CO3 (0.3 g, 2.2 mmol) and methyl triphenyl phosphonium bromide (0.63 g, 1.79 mmol). The resultant reaction mixture was heated to 100° C. for 18 h. After completion of the reaction (TLC), the reaction mixture was cooled to ambient temperature and filtered and the obtained filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) to afford the title compound as a solid (0.25 g, 70%): mp 103-105° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.34 (m, 1H), 7.98 (d, J=7.8 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 6.87 (m, 1H), 6.20 (d, J=15.7 Hz, 1H), 5.56 (d, J=11.8 Hz, 1H); ESIMS m/z 240.27 ([M−H]−); IR (thin film) 2240, 1514, 1312 cm−1.
  • The following compound was made in accordance with the procedures disclosed in Example 95.
    • 1-(3-Chloro-4-vinylphenyl)-1H-1,2,4-triazole (DI63)
  • Figure US20170088507A1-20170330-C00260
  • The title compound was isolated as an off-white solid (2.3 g, 80%): mp 134-137° C.; 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.11 (s, 1H), 7.76 (s, 1H), 7.70 (d, J=9.0 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 7.10 (m, 1H), 5.80 (d, J=17.2 Hz, 1H), 5.47 (d, J=12.4 Hz, 1H); ESIMS m/z 206.04 ([M+H]+.
    • 3-Methyl-1-(4-vinylphenyl)-1H-1,2,4-triazole (DI64)
  • Figure US20170088507A1-20170330-C00261
  • The title compound was isolated as a white solid (0.6 g, 60%): mp 109-111° C.; 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.40-7.60 (m, 4H), 6.70-7.00 (dd, J=17.6, 10.8 Hz, 1H), 5.80 (d, J=17.6 Hz, 1H), 5.30 (d, J=17.6 Hz, 1H), 2.50 (s, 3H); ESIMS m/z 186.20 ([M+H]+).
    • 1-(2-(Trifluoromethyl)-4-vinylphenyl)-1H-1,2,4-triazole (DI65)
  • Figure US20170088507A1-20170330-C00262
  • The title compound was isolated as a colorless oil (0.6 g, 60%): 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 8.14 (s, 1H), 7.84 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.50 (d, J=7.6 Hz, 1H), 6.70-6.90 (dd, J=17.6, 10.8 Hz, 1H), 5.90-6.00 (d, J=17.6 Hz, 1H), 5.50-5.80 (d, J=10.8 Hz 1H); ESIMS m/z 240.16 ([M+H]+).
    • 3-Nitro-1-(4-vinylphenyl)-1H-1,2,4-triazole (DI66)
  • Figure US20170088507A1-20170330-C00263
  • The title compound was isolated as a pale yellow solid (61 mg, 20%): mp 137-139° C.; 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.68 (d, J=7.7 Hz, 2H), 7.60 (d, J=8.3 Hz, 2H), 6.77 (dd, J=17.7, 10.8, 1H), 5.87 (d, J=17.7 Hz, 1H), 5.42 (d, J=10.8 Hz, 1H); ESIMS m/z 217.28 ([M+H]+).
    • 1-(2-Bromo-4-vinylphenyl)-1H-1,2,4-triazole (DI67)
  • Figure US20170088507A1-20170330-C00264
  • The title compound was isolated as a white solid (1.2 g, 40%): mp 75-77° C.; 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 8.12 (s, 1H), 7.75 (s, 1H) 7.42 (s, 2H), 6.70 (m, 1H), 5.83 (d, J=18 Hz, 1H), 5.42 (d, J=12 Hz, 1H); ESIMS m/z 249.1 ([M]+).
    • 2-(3-Methyl-1H-1,2,4-triazol-1-yl)-5-vinylbenzonitrile (DI68)
  • Figure US20170088507A1-20170330-C00265
  • The title compound was isolated as an off-white solid (0.6 g, 60%): mp 96-97° C.; 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 7.80 (s, 1H), 7.74 (m, 2H), 6.73 (dd, J=17.6 Hz, 10.8 Hz, 1H), 5.88 (d, J=17.6 Hz, 1H), 5.49 (d, J=10.8 Hz, 1H), 2.52 (s, 3H); ESIMS m/z 211.10 ([M+H]+); IR (thin film) 2229 cm−1.
    • 1-(2-Nitro-4-vinylphenyl)-1H-1,2,4-triazole (DI69)
  • Figure US20170088507A1-20170330-C00266
  • The title compound was isolated as a yellow solid (1.78 g, 60%): mp 102-104° C.; 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.12 (s, 1H), 8.02 (s, 1H), 7.72-7.76 (d, J=8.0 Hz, 1H), 7.52-7.56 (d, J=17.6 Hz, 1H), 6.70-6.82 (dd, J=17.6, 10.8 Hz, 1H), 5.85-6.00 (d, J=17.6 Hz, 1H), 5.50-5.60 (d, J=10.8, Hz 1H); ESIMS m/z 217.0 ([M+H]+).
    • Example 96: Preparation of 3-Methyl-2-(1H-1,2,4-triazol-1-yl)-5-vinylbenzonitrile (DI70)
  • Figure US20170088507A1-20170330-C00267
    • Step 1. 5-Bromo-2-fluoro-3-methylbenzaldehyde
  • To a stirred solution of di-isopropyl amine (4.01 g, 39.88 mmol) in THF (20 mL) was added n-butyl lithium (1.6 M in hexane) (19.9 mL, 31.91 mmol) at −78° C. slowly dropwise over the period of 10 min, the reaction mixture was stirred at −78° C. for 30 min. A solution of 4-bromo-1-fluoro-2-methylbenzene (5.0 g, 26.6 mmol) in THF (30.0 mL) was added at −78° C., and the reaction mixture was stirred for 1 h at the same temperature. DMF (5.0 mL) was added and stirred at −78° C. for another 30 min. The reaction was monitored by TLC; then the reaction mixture was quenched with 1N HCl solution (aq) at 0° C. The aqueous layer was extracted with diethyl ether, washed with water and saturated brine solution. The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude compound purified by flash column chromatography (SiO2, 100-200 mesh; eluting with 5% ethyl acetate/pet ether) to afford the title compound as a white solid (3.6 g, 64%); mp 48-50° C.: 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 8.22 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 6.75 (dd, J=17.6, 10.8 Hz, 1H), 5.92 (dd, J=17.6, 10.8 Hz, 1H), 5.52 (d, J=17.6 Hz, 1H), 2.21 (s, 3H); ESIMS m/z 211.35 ([M−H]−).
    • Step 2. ((E)-5-Bromo-2-fluoro-3-methylbenzaldehyde oxime
  • To a stirred solution of 5-bromo-2-fluoro-3-methylbenzaldehyde (3.5 g, 16.2 mmol) in ethanol (50.0 mL) were added sodium acetate (2.0 g, 24.3 mmol) and hydroxylamine hydrochloride (1.69 g, 24.3 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was concentrated on rotavapour to obtain crude compound, which was washed with water filtered and dried under vacuum to afford the title compound as a white solid: mp 126-127° C.; 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.51 (s, 1H), 7.34 (d, J=2.4 Hz, 1H), 2.25 (s, 3H); ESIMS m/z 232.10 ([M+H]+).
    • Step 3. 5-Bromo-2-fluoro-3-methylbenzonitrile
  • A stirred solution of (E)-5-bromo-2-fluoro-3-methylbenzaldehyde oxime (0.5 g, 2.2 mmol) in acetic anhydride (5.0 mL) was heated to reflux for 18 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined ethyl acetate layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound as a light brown gummy material (0.4 g, crude): ESIMS m/z 213.82 ([M+H]+).
    • Step 4. 5-Bromo-3-methyl-2-(1H-1,2,4-triazol-1-yl)benzonitrile (DI71)
  • To a stirred solution of 5-bromo-2-fluoro-3-methylbenzonitrile (1.0 g, 47.716 mmol), in DMF (10.0 mL) was added potassium carbonate (1.95 g, 14.14 mmol) followed by 1H-1,2,4-triazole (0.811 g, 9.433 mmol) at ambient temperature. The reaction mixture was heated to 140° C. for 18 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with ethyl acetate (2×100 mL). The combined ethyl acetate layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound purified by flash column chromatography (SiO2, 100-200 mesh; eluting with 30% ethyl acetate/pet ether) to afford the title compound as a pink solid (0.6 g, 49%): 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.23 (s, 1H), 7.91 (d, J=2.4 Hz, 2H), 2.21 (s, 3H), ESIMS m/z 262.57 ([M+H]+); IR (thin film) 2231, 554 cm−1.
    • Step 5. 3-Methyl-2-(1H-1,2,4-triazol-1-yl)-5-vinylbenzonitrile (DI70)
  • A mixture of 5-bromo-3-methyl-2-(1H-1,2,4-triazol-1-yl)benzonitrile (0.6 g, 2.3 mmol), potassium carbonate (0.95 g, 6.87 mmol), vinyl boronic anhydride (0.82 g, 3.43 mmol) and triphenylphosphine (0.13 g, 0.114 mmol) in toluene (20.0 mL) were stirred and degassed with argon for 30 min. The reaction mixture was heated to reflux for 18 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with ethyl acetate (2×100 mL). The combined ethyl acetate layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound that was purified by flash column chromatography (SiO2, 100-200 mesh; eluting with 30% ethyl acetate/pet ether) to afford the title compound as a pink solid (0.25 g, 52%): 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 8.22 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 6.75 (dd, J=17.6, 10.8 Hz, 1H), 5.92 (d, J=17.6, 1H), 5.52 (d, J=10.8 Hz, 1H), 2.21 (s, 3H), ESIMS m/z 211.35 ([M+H]+); IR (thin film) 2236, 1511 cm−1.
  • The following compound was made in accordance with the procedures disclosed in Steps 4 and 5 of Example 96.
    • 1-(2-Fluoro-4-vinylphenyl)-1H-1,2,4-triazole (DI72)
  • Figure US20170088507A1-20170330-C00268
  • 1-(4-Bromo-2-fluorophenyl)-1H-1,2,4-triazole (DI73) was isolated as a pale yellow solid (3.0 g, 75%): mp 113-116° C.; 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.13 (m, 2H), 7.50 (m, 1H), 7.21 (m, 1H); ESIMS m/z 241.93 ([M]+). The title compound (DI72) was isolated as a yellow solid (1.0 g, 71%): mp 67-70° C.; 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.13 (s, 1H), 7.94 (m, 1H), 7.41 (m, 1H), 7.24 (s, 1H), 6.75 (dd, J=17.6, 10.8 Hz, 1H), 5.81 (d, J=17.6 Hz, 1H), 5.37 (d, J=10.8 Hz, 1H); ESIMS m/z 190.00 ([M+H]+).
    • Example 119: Preparation of 1-(1-(4-Vinylphenyl)-1H-1,2,4-triazol-5-yl)ethanone (DI78)
  • Figure US20170088507A1-20170330-C00269
  • To a stirred solution of 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (1 g, 5.8 mmol) in 25 mL of THF, was added n-BuLi (0.37 g, 5.8 mmol) at −78° C. and stirred for 30 min. To this N-methoxy-N-methyl acetamide in THF (0.66 g, 6.4 mmol) was added and the resultant reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (3×50 mL). The combined EtOAc layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in Pet ether) to afford the title compound as an off white solid (280 mg, 23%): mp 97-98° C.; 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.50 (d, 2H), 7.38 (d, 2H), 6.68 (dd, 1H), 5.85 (d, 1H), 5.38 (d, 1H), 2.75 (s, 3H); ESIMS m/z 214.14 ([M+H]+).
    • Example 120: Preparation of Cyclopropyl(1-(4-vinylphenyl)-1H-1,2,4-triazol-5-yl)methanone (DI79)
  • Figure US20170088507A1-20170330-C00270
  • To a stirred solution of 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (1 g, 5.8 mmol) in 25 mL of THF, was added n-BuLi (0.37 g, 5.8 mmol) at −78° C. and stirred for 30 min. To this N-methoxy N-methylcyclopropoxide in THF (0.82 g, 6.4 mmol) was added and the resultant reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (3×25 mL). The combined EtOAc layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in Pet ether) to afford the title compound as an off white solid (420 mg, 30%): mp 90-91° C.; 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.50 (d, J=7.8 Hz, 2H), 7.38 (d, J=7.8 Hz, 2H), 6.75 (dd, J=16.3, 10.7 Hz, 1H), 5.81 (d, J=16.3 Hz, 1H), 5.35 (d, J=10.7 Hz, 1H), 3.22 (m, 1H), 1.27 (m, 2H), 1.18 (m, 2H); ESIMS m/z 240.18 ([M+H]+); IR (thin film) 2922, 1630 cm−1.
    • Example 121: Preparation of 5-(Methylthio)-1-(4-vinylphenyl)-1H-1,2,4-triazole (DI80)
  • Figure US20170088507A1-20170330-C00271
  • To a stirred solution of 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (1 g, 5.8 mmol) in 50 mL of THF, was added n-BuLi (0.41 g, 6.4 mmol) at −78° C. and stirred for 30 min. To this dimethyldisulfide in THF (0.6 g, 6.43 mmol) was added and the resultant reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (3×25 mL). The combined EtOAc layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in Pet ether) to afford the title compound as an off white solid (0.6 g, 48%): mp 68-70° C.; 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.05 (m, 4H), 6.75 (dd, J=16.4, 10.7 Hz, 1H), 5.81 (d, J=16.4 Hz, 1H), 5.35 (d, J=10.7 Hz, 1H), 2.73 (s, 3H); ESIMS m/z 218.09 ([M+H]+).
    • Example 122: Preparation of 5-Methyl-1-(4-vinylphenyl)-1H-1,2,4-triazole (DI81)
  • Figure US20170088507A1-20170330-C00272
  • To a stirred solution of 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (0.5 g, 2.9 mmol) in 10 mL of THF, was added n-BuLi (0.22 g, 3.5 mmol) at −78° C. and stirred for 30 min. To this methyl iodide in THF (0.50 g, 3.5 mmol) was added and the resultant reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (3×25 mL). The combined EtOAc layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in Pet ether) afford the title compound as a pale brown liquid (250 mg, 46%): 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.55 (d, J=9 Hz, 2H), 7.42 (d, J=9 Hz, 2H), 6.76 (dd, J=18, 11 Hz, 1H), 5.83 (d, J=18 Hz, 1H), 5.38 (d, J=11 Hz, 1H), 2.55 (s, 3H); ESIMS m/z 186.13 ([M+H]+); IR (thin film) 1517, 1386, 1182, 847 cm−1.
    • Example 97: Preparation of (E)-1-(4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)-1H-1,2,4-triazole (DC1)
  • Figure US20170088507A1-20170330-C00273
  • To a stirred solution of 1-(1-bromo-2,2,2-trifluoro-ethyl)-3,5-dichloro-benzene (2.0 g, 6.51 mmol) in 1,2-dichlorobenzene (25 mL), were added 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (2.22 g, 13.0 mmol), CuCl (64 mg, 0.65 mmol) and 2,2-bipyridyl (0.2 g, 1.3 mmol). The resultant reaction mixture was degassed with argon for 30 min, then stirred at 180° C. for 24 h. After completion of reaction (TLC), the reaction mixture was cooled to ambient temperature and filtered and the filtrate concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) afforded the title compound as an off-white solid (0.8 g, 32%): mp 93-97° C.; 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 8.11 (s, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.38 (t, J=1.8 Hz, 1H), 7.29 (s, 2H), 6.62 (d, J=15.6 Hz, 1H), 6.42 (dd, J=15.6, 8.2 Hz, 1H), 4.15 (m, 1H); ESIMS m/z 398.05 ([M+H]+).
  • Compounds DC2-DC37, DC44, DC45, DC47-49, DC50, DC51, DC54, DC58, DC60, DC62, and DC63-DC67 in Table 1 were made in accordance with the procedures disclosed in Example 97.
    • Example 98: Preparation of (E)-2-(3-Nitro-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzonitrile (DC40)
  • Figure US20170088507A1-20170330-C00274
  • To a stirred solution of 2-(3-nitro-1H-1,2,4-triazol-1-yl)-5-vinylbenzonitrile (0.9 g, 3.7 mmol) in 1,2-dichlorobenzene (10 mL), were added 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (2.5 g, 7.5 mmol), CuCl (73 mg, 0.74 mmol) and 2,2-bipyridyl (0.23 g, 1.49 mmol) and the resultant reaction mixture was degassed with argon for 30 min and then stirred at 180° C. for 14 h. After completion of the reaction (TLC), the reaction mixture was cooled to ambient temperature and filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh, 25-30% EtOAc in Pet ether) afforded the title compound as a off white solid (0.9 g, 50%): mp 70-73° C.; 1H NMR (300 MHz, CDCl3) δ 8.86 (s, 1H), 7.88 (m, 3H), 7.44 (s, 2H), 6.67 (d, J=16.0 Hz, 1H), 6.56 (dd, J=16.0, 7.6 Hz, 1H), 4.19 (m, 1H); ESIMS m/z 436.11 ([M-2H]−).
    • Example 99: Preparation of (E)-2-(3-Amino-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzonitrile (DC41)
  • Figure US20170088507A1-20170330-C00275
  • To a stirred solution of (E)-2-(3-nitro-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzonitrile (0.6 g, 1.2 mmol) in MeOH (10 mL), were added Zn dust (0.39 g, 5.98 mmol) and sat. aq NH4Cl solution (5 mL) and the resultant reaction mixture was stirred at ambient temperature for 2 h. After completion of the reaction (TLC), the reaction mass was concentrated under reduced pressure. The reaction mass was diluted with CH2Cl2, filtered through a celite bed, and the obtained filtrate concentrated under reduced pressure to afford the title compound as a solid (0.5 g, 89%): mp 72-75° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.26 (s, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.91 (s, 2H), 7.77 (d, J=8.4 Hz, 1H), 6.42 (dd, J=15.6, 9.2 Hz, 1H), 6.83 (d, J=15.6 Hz, 1H), 5.87 (s, 2H), 4.89 (m, 1H); ESIMS m/z 469.95 ([M−H]−).
  • Compound DC38 in Table 1 was made in accordance with the procedures disclosed in Example 99. Also, compound DC55 in Table 1 was made from compound DC54 in accordance with the procedures disclosed in Example 99, with the exception of using ammonium formate in place of ammonium chloride.
    • Example 100: Preparation of (E)-N-(1-(2-Cyano-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)-1H-1,2,4-triazol-3-yl)-N-(cyclopropanecarbonyl)cyclopropanecarboxamide (DC42)
  • Figure US20170088507A1-20170330-C00276
  • To a stirred solution of (E)-2-(3-amino-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzonitrile (0.1 g, 0.21 mmol) in CH2Cl2 at ambient temperature, was added cyclopropylcarbonyl chloride (0.045 g, 0.42 mmol) and the reaction mixture was stirred for 2 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 and washed with water and brine and dried over Na2SO4. Concentration under reduced pressure and purification by preparative HPLC afforded the title compound as a solid (0.09 g, 79%): mp 104-107° C.; 1H NMR (300 MHz, CDCl3) δ 8.78 (s, 2H), 7.83 (s, 1H), 7.80 (m, 2H), 7.42 (s, 2H), 6.65 (d, J=16.4 Hz, 1H), 6.51 (dd, J=7.6, 8.0 Hz, 1H), 4.17 (m, 1H), 2.16 (m, 2H), 1.25 (m, 4H), 1.00 (m, 4H); ESIMS m/z 609.98 ([M+H]+); IR (thin film) 2234, 1714, 1114, 807 cm−1.
    • Example 101: Preparation of (E)-N-(1-(2-Cyano-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)-1H-1,2,4-triazol-3-yl)cyclopropanecarboxamide (DC43)
  • Figure US20170088507A1-20170330-C00277
  • To a stirred solution of (E)-2-(3-amino-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzonitrile (0.15 g, 0.31 mmol) in CH2Cl2 at 0° C., were added TEA (0.1 g, 1 mmol) and cyclopropylcarbonyl chloride (0.04 g, 0.38 mmol) and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2 and washed with water and brine and dried over Na2SO4. Concentration under reduced pressure and purification by column chromatography (SiO2, 100-200 mesh) afforded the title compound as a solid (66 mg, 34%): mp 109-112° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.94 (br s, 1H), 8.36 (s, 1H), 8.08 (m, J=8.4 Hz, 1H), 7.91 (s, 2H), 7.84 (d, J=8.4 Hz, 1H), 7.13 (dd, J=15.6, 9.2 Hz, 1H), 6.87 (d, J=15.6 Hz, 1H), 4.92 (m, 1H), 1.99 (br s, 1H), 0.82 (s, 4H); ESIMS m/z 540.04 ([M+H]+); IR (thin film) 3233, 2233, 1699, 1114, 807 cm−1.
  • Compound DC39 in Table 1 was made in accordance with the procedures disclosed in Example 101.
    • Example 102: Preparation of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)ethanone (DI74)
  • Figure US20170088507A1-20170330-C00278
  • To a stirred solution of 4-bromoacetophenone (10 g, 50 mmol) in DMF (100 mL), were added 1,2,4-triazole (5 g, 75 mmol), Cs2CO3 (32.6 g, 100.5 mmol) and CuI (1.4 g, 10.1 mmol) and the resultant reaction mixture was refluxed for 48 h. After completion of the reaction (by TLC), the reaction mixture was cooled to ambient temperature and diluted with water (200 mL) and extracted with EtOAc. The combined organic layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure. Purification by washing with diethyl ether afforded the title compound as a solid (5 g, 96%): 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.16, (s, 1H), 8.13 (d, J=8.6 Hz, 2H), 7.83 (d, J=8.6 Hz, 2H), 2.66 (s, 3H); ESIMS m/z 186.02 ([M−H]−).
    • Example 103: Preparation of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobutan-1-one (DI75)
  • Figure US20170088507A1-20170330-C00279
    • Step 1. 1-(4-(1-(Trimethylsilyloxy)vinyl)phenyl)-1H-1,2,4-triazole (DI76)
  • To a stirred solution of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)ethanone (4.5 g, 24.0 mmol) in CH2Cl2 at 0° C., were added TEA (3.7 g, 36.1 mmol) and trimethylsilyl triflluoromethanesulfonate (8 g, 36 mmol) and the resultant reaction mixture was stirred for 1 h. The reaction mixture was quenched with a mixture of sat aq sodium bicarbonate solution and ether. The ether layer and was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound (5.5 g) which was taken directly to next step.
    • Step 2. 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobutan-1-one (DI75)
  • To a stirred solution of 1-(4-(1-(trimethylsilyloxy)vinyl)phenyl)-1H-1,2,4-triazole (6 g, 23 mmol) and 1-(1-bromo-2,2,2-trifluoro-ethyl)-3,5-dichlorobenzene (7.1 g, 34.7 mmol) in 1,2-dichlorobenzene (30 mL) was degassed with argon. To this CuCl (0.23 g, 2.31 mmol) and 2,2-bipyridyl (0.73 g, 4.63 mmol) was added to the above reaction mixture and the resultant reaction mixture was heated to 180° C. for 18 h. After completion of the reaction (by TLC), the reaction mixture was absorbed onto silica gel and purified by column chromatography (SiO2; 10% EtOAc in petroleum ether) to afford title compound as a solid (3 g, 31%): 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.15 (s, 1H), 8.10 (d, J=8.3 Hz, 2H), 7.82 (d, J=8.3 Hz, 2H), 7.33 (m, 1H), 7.30 (m, 2H), 4.20 (m, 1H), 3.63 (m, 2H); ESIMS m/z 412.14 ([M−H]−).
    • Example 104: Preparation of 2-(4-(1H-1,2,4-triazol-1-yl)phenyl)-4-(3,5-dichlorophenyl)-5,5,5-trifluoropentan-2-ol (DI77)
  • Figure US20170088507A1-20170330-C00280
  • To a solution of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobutan-1-one (300 mg, 0.726 mmol) in THF cooled to 0° C. was added methylmagnesium bromide (450 mg, 5 mmol) drop wise. The reaction was stirred for 3 h at 0° C., then the reaction mixture was quenched with sat aq NH4Cl solution and extracted with ethyl acetate. The combined EtOAc layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 20%-25% EtOAc in petroleum ether) afforded the title compound as a solid (100 mg, 32%): 1H NMR (400 MHz, CDCl3) δ two diastereoisomers 8.58 (s, 1H, minor), 8.48 (s, 1H, major), 8.13 (s, 1H, minor), 8.09 (s, 1H, major), 7.70 (d, J=9.0 Hz, 2H, minor), 7.53 (d, J=9.0 Hz, 2H, minor), 7.40 (d, J=9.0 Hz, 2H, major), 7.31 (m, 1H, minor), 7.27 (d, J=9.0 Hz, 2H, major), 7.20 (m, 2H, minor), 7.01 (m, 1H, major), 6.75 (m, 2H, major), 350 (m, 1H), 2.50 (m, 2H), 1.56 (s, 3H, major), 1.54 (s, 3H, minor); ESIMS m/z 430.05 ([M+H]+).
    • Example 105: Preparation of (E)-1-(4-(4-(3,5-Dichlorophenyl)-5,5,5-trifluoropent-2-en-2-yl)phenyl)-1H-1,2,4-triazole (DC68)
  • Figure US20170088507A1-20170330-C00281
  • To a solution of 2-(4-(1H-1,2,4-triazol-1-yl)phenyl)-4-(3,5-dichlorophenyl)-5,5,5-trifluoropentan-2-ol (100 mg, 0.233 mmol) in toluene was added a catalytic amount of p-toluenesulfonic acid (PTSA) and the water was removed by azeotropic distillation over the course of 12 h. The reaction mixture was cooled to ambient temperature and dissolved in ethyl acetate. The solution was washed with sat aq NaHCO3 solution and brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 20%-25% EtOAc in petroleum ether) afforded the title compound as a solid (30 mg, 31%).
    • Example 123: Preparation of (E)-5-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)benzaldehyde (DC52)
  • Figure US20170088507A1-20170330-C00282
  • To a stirred solution of (E)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile (0.3 g, 0.71 mmol) in toluene (10 mL) at −78° C. was added dropwise diisobutylaluminum hydride (DIBAL-H, 1.0 M solution in toluene; 0.85 mL), and the reaction mixture was stirred at −78° C. for 20 min. The reaction mixture was quenched with the addition of 1 N HCl solution, then the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2; 50% EtOAc/Pet ether) to afford the title compound as a yellow oil.
  • Compound DC53 in Table 1 was made in accordance with the procedures disclosed in Example 123.
    • Example 124: Preparation of (E)-5-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N-methyl-2-(1H-1,2,4-triazol-1-yl)aniline (DC57)
  • Figure US20170088507A1-20170330-C00283
  • To a stirred solution of (E)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)aniline (0.3 g, 0.7 mmol) in CH2Cl2 (10 mL) was added TEA (0.155 mL, 1.09 mmol) and methyl iodide (0.124 g, 0.873 mmol). The reaction was stirred at ambient temperature for 18 h. The CH2Cl2 layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2; 50% EtOAc/Pet ether) to afford the title compound as a yellow semi-solid (0.07 g, 70%).
    • Example 125: Preparation of (E)-5-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)benzoic acid (DC61)
  • Figure US20170088507A1-20170330-C00284
  • A solution of (E)-ethyl 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)benzoate (0.2 g, 0.4 mmol) in 6 N HCl (10 mL) was stirred at 100° C. for 18 h. The reaction was cooled to ambient temperature, resulting in a white solid precipitate. The precipitate was filtered to afford the title compound as a white solid (0.12 g, 60%).
    • Example 126: Preparation of (Z)-5-((E)-3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N′-hydroxy-2-(1H-1,2,4-triazol-1-yl)benzimidamide (DC59
  • Figure US20170088507A1-20170330-C00285
  • A solution of (E)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile (0.3 g, 0.71 mmol), sodium acetate (0.087 g, 1.065 mmol) and hydroxylammonium chloride (0.072 g, 1.065 mmol) in 9:1 ethanol/water mixture (10 mL) was stirred at 70° C. for 8 h. The reaction was cooled to ambient temperature, and the ethanol was evaporated. The residue was dissolved in water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off white solid.
    • Example 127: Preparation of (E)-1-(4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluoro-3-methoxybut-1-en-1-yl)phenyl)-1H-1,2,4-triazole (DC70)
  • Figure US20170088507A1-20170330-C00286
    • Step 1. (E)-3-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1-(3,5-dichlorophenyl)prop-2-en-1-one
  • To a solution of 1-(3,5-dichlorophenyl)ethanone (0.5 g, 2.6 mmol) in ethanol (20 mL) was added 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (0.46 g, 2.65 mmol) and the reaction was cooled to 0° C. Sodium hydroxide (0.22 g, 5.29 mmol) in water (10 mL) was then added and the reaction was allowed to stir for 2 h at 0° C. The reaction was extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford the title compound (0.149 g, 17%): ESIMS m/z 430.05 ([M+H]+) 344.08
    • Step 2. (E)-4-(4-(1H-1,2,4-triazol-1-yl)phenyl)-2-(3,5-dichlorophenyl)-1,1,1-trifluorobut-3-en-2-ol (DC69)
  • To a solution of (E)-3-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1-(3,5-dichlorophenyl)prop-2-en-1-one (1 g, 3 mmol) in THF (150 mL) was added trifluoromethyltrimethylsilane (0.517 g, 3.644 mmol) and tetra-n-butylammonium fluoride (TBAF) (1.0 M, 1 mL) at 0° C. The reaction was slowly warmed to ambient temperature and allowed to stir for 2 h. The reaction was then cooled to 0° C. and 5 M HCl solution was added and the reaction was stirred for an additional 4 h at ambient temperature. The reaction was extracted with CH2Cl2 and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2; 25% EtOAc/hexanes) to afford the title compound as an off-white solid (0.3 g, 25%).
    • Step 3. (E)-1-(4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluoro-3-methoxybut-1-en-1-yl)phenyl)-1H-1,2,4-triazole (DC70)
  • To a solution of (E)-4-(4-(1H-1,2,4-triazol-1-yl)phenyl)-2-(3,5-dichlorophenyl)-1,1,1-trifluorobut-3-en-2-ol (0.15 g, 0.36 mmol) in THF (5 mL) was added NaH (60%, 10 mg, 0.44 mmol) at 0° C. The reaction was allowed to stir at 0° C. for 30 min, then methyl iodide (61 mg, 0.44 mmol) was added slowly and the reaction was warmed to ambient temperature and allowed to stir for 4 h. The reaction was quenched with aq NH4Cl solution and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (55 mg, 35%).
    • Prophetic Example F11: Preparation of (E)-2-Bromo-N′-methyl-N′-propionyl-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzohydrazide (F11)
  • Figure US20170088507A1-20170330-C00287
  • Prophetically, (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid can be reacted with N-methylpropionohydrazide in the presence of N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (EDC.HCl) and DMAP in 1,2-dichloroethane (DCE) to furnish the title molecule (Org. Lett. 2004, 6, 929-931).
    • Example 128: Preparation of (E)-2-Bromo-N′-methyl-N′-propionyl-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzohydrazide (F11)
  • Figure US20170088507A1-20170330-C00288
  • To a stirred solution of (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl) but-1-enyl) benzoic acid (200 mg, 0.41 mmol) in 1,2-dichloroethane (DCE) (10 mL) was added N-methylpropionohydrazide (WO 2009110510) (50 mg, 0.49 mmol), DMAP (55 mg, 0.45 mmol), EDC.HCl (60 mg, 0.41 mmol) and DIPEA (0.20 mL, 1.1 mmol). The reaction mixture was stirred at 25° C. for 12 h, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh) eluting with 30% EtOAc in hexane afforded the title compound as an off white solid (86 mg, 34%).
    • Example 129: Preparation of (E)-N-(2-Aminoethyl)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide
  • Figure US20170088507A1-20170330-C00289
    • Step 1. (E)-tert-Butyl 2-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamido)ethylcarbamate
  • PyBOP (420 mg, 0.82 mmol) and DIPEA (0.410 mL, 2.46 mmol) were added to a stirred solution of (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (400 mg, 0.82 mmol) and tert-butyl 2-aminoethylcarbamate (130 mg, 0.82 mmol) in CH2Cl2 (10 mL) and the reaction mixture was stirred at ambient temperature for 18 h. Water was added to the reaction mixture and extracted with CH2Cl2 (25 mL). The organic layer was washed with 2N HCl followed by saturated NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered, concentrated and the residue was purified by column chromatography on silica (100-200 mesh) eluting with 40% EtOAc in petroleum ether to afford the title compound as a brown solid (200 mg, 39%): 1H NMR (400 MHz, DMSO-d6) δ 8.38 (t, J=5.2 Hz, 1H), 7.91-7.89 (m, 3H), 7.58 (d, J=6.8 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 6.99 (dd, J=15.6, 9.2 Hz, 1H), 6.84 (t, J=6.0 Hz, 1H), 6.76 (t, J=15.6 Hz, 1H), 4.84-4.80 (m, 1H), 3.24-3.20 (m, 2H), 3.11-3.08 (m, 2H), 1.30 (s, 9H); ESIMS m/z 628.80 ([M+H]+); IR (thin film) 3365, 1701, 1167, 699, 555 cm+1.
    • Step 2. (E)-N-(2-Aminoethyl)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide
  • TFA (0.5 mL) was added to a stirred solution of (E)-tert-butyl 2-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamido)ethylcarbamate (200 mg, 0.31 mmol) in CH2Cl2 (10 mL) at 0° C. and the reaction mixture was then stirred at ambient temperature for 18 h. The volatiles were evaporated under reduced pressure; water was added to the residue and extracted with CH2Cl2. The organic layer was washed with brine dried (Na2SO4), filtered, concentrated and the residue was purified by column chromatography on silica (100-200 mesh) eluting with 1-5% MeOH in CH2Cl2 to afford the title compound as a brown solid (50 mg, 31%): 1H NMR (400 MHz, DMSO-d6) δ 8.56 (bs, 1H), 7.70 (bs, 2H), 7.94-7.91 (m, 3H), 7.62-7.59 (m, 1H), 7.50 (d, J=7.6 Hz, 1H), 7.00 (dd, J=15.6, 9.2 Hz, 1H), 6.77 (d, J=15.6 Hz, 1H), 4.84-4.81 (m, 1H), 3.46-3.41 (m, 2H), 2.95-2.92 (m, 2H); ESIMS m/z 528.72 ([M+H]+); IR (thin film) 3435, 1671, 1113, 722, 555 cm−1.
  • The following prophetic molecules could be made in accordance with the procedures disclosed in Prophetic Example F11:
  • Compound
    Number Structure
    F1 
    Figure US20170088507A1-20170330-C00290
    F2 
    Figure US20170088507A1-20170330-C00291
    F3 
    Figure US20170088507A1-20170330-C00292
    F4 
    Figure US20170088507A1-20170330-C00293
    F5 
    Figure US20170088507A1-20170330-C00294
    F6 
    Figure US20170088507A1-20170330-C00295
    F7 
    Figure US20170088507A1-20170330-C00296
    F8 
    Figure US20170088507A1-20170330-C00297
    F9 
    Figure US20170088507A1-20170330-C00298
    F10
    Figure US20170088507A1-20170330-C00299
    F11
    Figure US20170088507A1-20170330-C00300
    F12
    Figure US20170088507A1-20170330-C00301
    F13
    Figure US20170088507A1-20170330-C00302
    F14
    Figure US20170088507A1-20170330-C00303
    F15
    Figure US20170088507A1-20170330-C00304
    F16
    Figure US20170088507A1-20170330-C00305
    F17
    Figure US20170088507A1-20170330-C00306
    F18
    Figure US20170088507A1-20170330-C00307
    F19
    Figure US20170088507A1-20170330-C00308
    F20
    Figure US20170088507A1-20170330-C00309
    F21
    Figure US20170088507A1-20170330-C00310
    F22
    Figure US20170088507A1-20170330-C00311
    F23
    Figure US20170088507A1-20170330-C00312
    F24
    Figure US20170088507A1-20170330-C00313
    F25
    Figure US20170088507A1-20170330-C00314
    F26
    Figure US20170088507A1-20170330-C00315
    F27
    Figure US20170088507A1-20170330-C00316
    F28
    Figure US20170088507A1-20170330-C00317
    F29
    Figure US20170088507A1-20170330-C00318
    F30
    Figure US20170088507A1-20170330-C00319
    F31
    Figure US20170088507A1-20170330-C00320
    F32
    Figure US20170088507A1-20170330-C00321
    F33
    Figure US20170088507A1-20170330-C00322
    F34
    Figure US20170088507A1-20170330-C00323
    F35
    Figure US20170088507A1-20170330-C00324
    F36
    Figure US20170088507A1-20170330-C00325
    F37
    Figure US20170088507A1-20170330-C00326
    F38
    Figure US20170088507A1-20170330-C00327
    F39
    Figure US20170088507A1-20170330-C00328
    F40
    Figure US20170088507A1-20170330-C00329
    F41
    Figure US20170088507A1-20170330-C00330
  • The following prophetic molecules could be made in accordance with the procedures disclosed in this application:
  • Figure US20170088507A1-20170330-C00331
    Compound
    Number R1 R2 R3 R4 R10 R11a X5 R11b
    F42 F F F H Br H O CH2CF3
    F43 F F F H Cl H O CH2CF3
    F44 F F F H CF3 H O CH2CF3
    F45 F F F H CH3 H O CH2CF3
    F46 F F F H Br H O cyclopropyl
    F47 F F F H Cl H O cyclopropyl
    F48 F F F H CF3 H O cyclopropyl
    F49 F F F H CH3 H O cyclopropyl
    F50 F F F H Br H O CH2CH3
    F51 F F F H Cl H O CH2CH3
    F52 F F F H CF3 H O CH2CH3
    F53 F F F H CH3 H O CH2CH3
    F54 F F F H Br H S CH2CH3
    F55 F F F H Cl H S CH2CH3
    F56 F F F H CF3 H S CH2CH3
    F57 F F F H CH3 H S CH2CH3
    F58 F F F H Br CH3 S CH2CH3
    F59 F F F H Cl CH3 S CH2CH3
    F60 F F F H CF3 CH3 S CH2CH3
    F61 F F F H CH3 CH3 S CH2CH3
    F62 F F F H Br CH3 O CH2CH3
    F63 F F F H Cl CH3 O CH2CH3
    F64 F F F H CF3 CH3 O CH2CH3
    F65 F F F H CH3 CH3 O CH2CH3
    F66 F F F H Br CH3 O CH2CN
    F67 F F F H Cl CH3 O CH2CN
    F68 F F F H CF3 CH3 O CH2CN
    F69 F F F H CH3 CH3 O CH2CN
    F70 F F F H Br CH3 S cyclopropyl
    F71 F F F H Cl CH3 S cyclopropyl
    F72 F F F H CF3 CH3 S cyclopropyl
    F73 F F F H CH3 CH3 S cyclopropyl
    F74 Cl Cl H Cl Br H O CH2CF3
    F75 Cl Cl H Cl Cl H O CH2CF3
    F76 Cl Cl H Cl CF3 H O CH2CF3
    F77 Cl Cl H Cl CH3 H O CH2CF3
    F78 Cl Cl H Cl Br H O cyclopropyl
    F79 Cl Cl H Cl Cl H O cyclopropyl
    F80 Cl Cl H Cl CF3 H O cyclopropyl
    F81 Cl Cl H Cl CH3 H O cyclopropyl
    F82 Cl Cl H Cl Br H O CH2CH3
    F83 Cl Cl H Cl Cl H O CH2CH3
    F84 Cl Cl H Cl CF3 H O CH2CH3
    F85 Cl Cl H Cl CH3 H O CH2CH3
    F86 Cl Cl H Cl Br H S CH2CH3
    F87 Cl Cl H Cl Cl H S CH2CH3
    F88 Cl Cl H Cl CF3 H S CH2CH3
    F89 Cl Cl H Cl CH3 H S CH2CH3
    F90 Cl Cl H Cl Br CH3 S CH2CH3
    F91 Cl Cl H Cl Cl CH3 S CH2CH3
    F92 Cl Cl H Cl CF3 CH3 S CH2CH3
    F93 Cl Cl H Cl CH3 CH3 S CH2CH3
    F94 Cl Cl H Cl Br CH3 O CH2CH3
    F95 Cl Cl H Cl Cl CH3 O CH2CH3
    F96 Cl Cl H Cl CF3 CH3 O CH2CH3
    F97 Cl Cl H Cl CH3 CH3 O CH2CH3
    F98 Cl Cl H Cl Br CH3 O CH2CN
    F99 Cl Cl H Cl Cl CH3 O CH2CN
    F100 Cl Cl H Cl CF3 CH3 O CH2CN
    F101 Cl Cl H Cl CH3 CH3 O CH2CN
    F102 Cl Cl H Cl Br CH3 S cyclopropyl
    F103 Cl Cl H Cl Cl CH3 S cyclopropyl
    F104 Cl Cl H Cl CF3 CH3 S cyclopropyl
    F105 Cl Cl H Cl CH3 CH3 S cyclopropyl
    F106 H H H OCF3 Br H O CH2CF3
    F107 H H H OCF3 Cl H O CH2CF3
    F108 H H H OCF3 CF3 H O CH2CF3
    F109 H H H OCF3 CH3 H O CH2CF3
    F110 H H H OCF3 Br H O cyclopropyl
    F111 H H H OCF3 Cl H O cyclopropyl
    F112 H H H OCF3 CF3 H O cyclopropyl
    F113 H H H OCF3 CH3 H O cyclopropyl
    F114 H H H OCF3 Br H O CH2CH3
    F115 H H H OCF3 Cl H O CH2CH3
    F116 H H H OCF3 CF3 H O CH2CH3
    F117 H H H OCF3 CH3 H O CH2CH3
    F118 H H H OCF3 Br H S CH2CH3
    F119 H H H OCF3 Cl H S CH2CH3
    F120 H H H OCF3 CF3 H S CH2CH3
    F121 H H H OCF3 CH3 H S CH2CH3
    F122 H H H OCF3 Br CH3 S CH2CH3
    F123 H H H OCF3 Cl CH3 S CH2CH3
    F124 H H H OCF3 CF3 CH3 S CH2CH3
    F125 H H H OCF3 CH3 CH3 S CH2CH3
    F126 H H H OCF3 Br CH3 O CH2CH3
    F127 H H H OCF3 Cl CH3 O CH2CH3
    F128 H H H OCF3 CF3 CH3 O CH2CH3
    F129 H H H OCF3 CH3 CH3 O CH2CH3
    F130 H H H OCF3 Br CH3 O CH2CN
    F131 H H H OCF3 Cl CH3 O CH2CN
    F132 H H H OCF3 CF3 CH3 O CH2CN
    F133 H H H OCF3 CH3 CH3 O CH2CN
    F134 H H H OCF3 Br CH3 S cyclopropyl
    F135 H H H OCF3 Cl CH3 S cyclopropyl
    F136 H H H OCF3 CF3 CH3 S cyclopropyl
    F137 H H H OCF3 CH3 CH3 S cyclopropyl
    F138 H F H Br Br H O CH2CF3
    F139 H F H Br Cl H O CH2CF3
    F140 H F H Br CF3 H O CH2CF3
    F141 H F H Br CH3 H O CH2CF3
    F142 H F H Br Br H O cyclopropyl
    F143 H F H Br Cl H O cyclopropyl
    F144 H F H Br CF3 H O cyclopropyl
    F145 H F H Br CH3 H O cyclopropyl
    F146 H F H Br Br H O CH2CH3
    F147 H F H Br Cl H O CH2CH3
    F148 H F H Br CF3 H O CH2CH3
    F149 H F H Br CH3 H O CH2CH3
    F150 H F H Br Br H S CH2CH3
    F151 H F H Br Cl H S CH2CH3
    F152 H F H Br CF3 H S CH2CH3
    F153 H F H Br CH3 H S CH2CH3
    F154 H F H Br Br CH3 S CH2CH3
    F155 H F H Br Cl CH3 S CH2CH3
    F156 H F H Br CF3 CH3 S CH2CH3
    F157 H F H Br CH3 CH3 S CH2CH3
    F158 H F H Br Br CH3 O CH2CH3
    F159 H F H Br Cl CH3 O CH2CH3
    F160 H F H Br CF3 CH3 O CH2CH3
    F161 H F H Br CH3 CH3 O CH2CH3
    F162 H F H Br Br CH3 O CH2CN
    F163 H F H Br Cl CH3 O CH2CN
    F164 H F H Br CF3 CH3 O CH2CN
    F165 H F H Br CH3 CH3 O CH2CN
    F166 H F H Br Br CH3 S cyclopropyl
    F167 H F H Br Cl CH3 S cyclopropyl
    F168 H F H Br CF3 CH3 S cyclopropyl
    F169 H F H Br CH3 CH3 S cyclopropyl
    F170 H CH3 Cl H Br H O CH2CF3
    F171 H CH3 Cl H Cl H O CH2CF3
    F172 H CH3 Cl H CF3 H O CH2CF3
    F173 H CH3 Cl H CH3 H O CH2CF3
    F174 H CH3 Cl H Br H O cyclopropyl
    F175 H CH3 Cl H Cl H O cyclopropyl
    F176 H CH3 Cl H CF3 H O cyclopropyl
    F177 H CH3 Cl H CH3 H O cyclopropyl
    F178 H CH3 Cl H Br H O CH2CH3
    F179 H CH3 Cl H Cl H O CH2CH3
    F180 H CH3 Cl H CF3 H O CH2CH3
    F181 H CH3 Cl H CH3 H O CH2CH3
    F182 H CH3 Cl H Br H S CH2CH3
    F183 H CH3 Cl H Cl H S CH2CH3
    F184 H CH3 Cl H CF3 H S CH2CH3
    F185 H CH3 Cl H CH3 H S CH2CH3
    F186 H CH3 Cl H Br CH3 S CH2CH3
    F187 H CH3 Cl H Cl CH3 S CH2CH3
    F188 H CH3 Cl H CF3 CH3 S CH2CH3
    F189 H CH3 Cl H CH3 CH3 S CH2CH3
    F190 H CH3 Cl H Br CH3 O CH2CH3
    F191 H CH3 Cl H Cl CH3 O CH2CH3
    F192 H CH3 Cl H CF3 CH3 O CH2CH3
    F193 H CH3 Cl H CH3 CH3 O CH2CH3
    F194 H CH3 Cl H Br CH3 O CH2CN
    F195 H CH3 Cl H Cl CH3 O CH2CN
    F196 H CH3 Cl H CF3 CH3 O CH2CN
    F197 H CH3 Cl H CH3 CH3 O CH2CN
    F198 H CH3 Cl H Br CH3 S cyclopropyl
    F199 H CH3 Cl H Cl CH3 S cyclopropyl
    F200 H CH3 Cl H CF3 CH3 S cyclopropyl
    F201 H CH3 Cl H CH3 CH3 S cyclopropyl
    F202 H Cl CH3 H Br H O CH2CF3
    F203 H Cl CH3 H Cl H O CH2CF3
    F204 H Cl CH3 H CF3 H O CH2CF3
    F205 H Cl CH3 H CH3 H O CH2CF3
    F206 H Cl CH3 H Br H O cyclopropyl
    F207 H Cl CH3 H Cl H O cyclopropyl
    F208 H Cl CH3 H CF3 H O cyclopropyl
    F209 H Cl CH3 H CH3 H O cyclopropyl
    F210 H Cl CH3 H Br H O CH2CH3
    F211 H Cl CH3 H Cl H O CH2CH3
    F212 H Cl CH3 H CF3 H O CH2CH3
    F213 H Cl CH3 H CH3 H O CH2CH3
    F214 H Cl CH3 H Br H S CH2CH3
    F215 H Cl CH3 H Cl H S CH2CH3
    F216 H Cl CH3 H CF3 H S CH2CH3
    F217 H Cl CH3 H CH3 H S CH2CH3
    F218 H Cl CH3 H Br CH3 S CH2CH3
    F219 H Cl CH3 H Cl CH3 S CH2CH3
    F220 H Cl CH3 H CF3 CH3 S CH2CH3
    F221 H Cl CH3 H CH3 CH3 S CH2CH3
    F222 H Cl CH3 H Br CH3 O CH2CH3
    F223 H Cl CH3 H Cl CH3 O CH2CH3
    F224 H Cl CH3 H CF3 CH3 O CH2CH3
    F225 H Cl CH3 H CH3 CH3 O CH2CH3
    F226 H Cl CH3 H Br CH3 O CH2CN
    F227 H Cl CH3 H Cl CH3 O CH2CN
    F228 H Cl CH3 H CF3 CH3 O CH2CN
    F229 H Cl CH3 H CH3 CH3 O CH2CN
    F230 H Cl CH3 H Br CH3 S cyclopropyl
    F231 H Cl CH3 H Cl CH3 S cyclopropyl
    F232 H Cl CH3 H CF3 CH3 S cyclopropyl
    F233 H Cl CH3 H CH3 CH3 S cyclopropyl
    F234 H CH3 F CH3 Br H O CH2CF3
    F235 H CH3 F CH3 Cl H O CH2CF3
    F236 H CH3 F CH3 CF3 H O CH2CF3
    F237 H CH3 F CH3 CH3 H O CH2CF3
    F238 H CH3 F CH3 Br H O cyclopropyl
    F239 H CH3 F CH3 Cl H O cyclopropyl
    F240 H CH3 F CH3 CF3 H O cyclopropyl
    F241 H CH3 F CH3 CH3 H O cyclopropyl
    F242 H CH3 F CH3 Br H O CH2CH3
    F243 H CH3 F CH3 Cl H O CH2CH3
    F244 H CH3 F CH3 CF3 H O CH2CH3
    F245 H CH3 F CH3 CH3 H O CH2CH3
    F246 H CH3 F CH3 Br H S CH2CH3
    F247 H CH3 F CH3 Cl H S CH2CH3
    F248 H CH3 F CH3 CF3 H S CH2CH3
    F249 H CH3 F CH3 CH3 H S CH2CH3
    F250 H CH3 F CH3 Br CH3 S CH2CH3
    F251 H CH3 F CH3 Cl CH3 S CH2CH3
    F252 H CH3 F CH3 CF3 CH3 S CH2CH3
    F253 H CH3 F CH3 CH3 CH3 S CH2CH3
    F254 H CH3 F CH3 Br CH3 O CH2CH3
    F255 H CH3 F CH3 Cl CH3 O CH2CH3
    F256 H CH3 F CH3 CF3 CH3 O CH2CH3
    F257 H CH3 F CH3 CH3 CH3 O CH2CH3
    F258 H CH3 F CH3 Br CH3 O CH2CN
    F259 H CH3 F CH3 Cl CH3 O CH2CN
    F260 H CH3 F CH3 CF3 CH3 O CH2CN
    F261 H CH3 F CH3 CH3 CH3 O CH2CN
    F262 H CH3 F CH3 Br CH3 S cyclopropyl
    F263 H CH3 F CH3 Cl CH3 S cyclopropyl
    F264 H CH3 F CH3 CF3 CH3 S cyclopropyl
    F265 H CH3 F CH3 CH3 CH3 S cyclopropyl
    F266 H Cl H Br Br H O CH2CF3
    F267 H Cl H Br Cl H O CH2CF3
    F268 H Cl H Br CF3 H O CH2CF3
    F269 H Cl H Br CH3 H O CH2CF3
    F270 H Cl H Br Br H O cyclopropyl
    F271 H Cl H Br Cl H O cyclopropyl
    F272 H Cl H Br CF3 H O cyclopropyl
    F273 H Cl H Br CH3 H O cyclopropyl
    F274 H Cl H Br Br H O CH2CH3
    F275 H Cl H Br Cl H O CH2CH3
    F276 H Cl H Br CF3 H O CH2CH3
    F277 H Cl H Br CH3 H O CH2CH3
    F278 H Cl H Br Br H S CH2CH3
    F279 H Cl H Br Cl H S CH2CH3
    F280 H Cl H Br CF3 H S CH2CH3
    F281 H Cl H Br CH3 H S CH2CH3
    F282 H Cl H Br Br CH3 S CH2CH3
    F283 H Cl H Br Cl CH3 S CH2CH3
    F284 H Cl H Br CF3 CH3 S CH2CH3
    F285 H Cl H Br CH3 CH3 S CH2CH3
    F286 H Cl H Br Br CH3 O CH2CH3
    F287 H Cl H Br Cl CH3 O CH2CH3
    F288 H Cl H Br CF3 CH3 O CH2CH3
    F289 H Cl H Br CH3 CH3 O CH2CH3
    F290 H Cl H Br Br CH3 O CH2CN
    F291 H Cl H Br Cl CH3 O CH2CN
    F292 H Cl H Br CF3 CH3 O CH2CN
    F293 H Cl H Br CH3 CH3 O CH2CN
    F294 H Cl H Br Br CH3 S cyclopropyl
    F295 H Cl H Br Cl CH3 S cyclopropyl
    F296 H Cl H Br CF3 CH3 S cyclopropyl
    F297 H Cl H Br CH3 CH3 S cyclopropyl
    F298 H H Br Br Br H O CH2CF3
    F299 H H Br Br Cl H O CH2CF3
    F300 H H Br Br CF3 H O CH2CF3
    F301 H H Br Br CH3 H O CH2CF3
    F302 H H Br Br Br H O cyclopropyl
    F303 H H Br Br Cl H O cyclopropyl
    F304 H H Br Br CF3 H O cyclopropyl
    F305 H H Br Br CH3 H O cyclopropyl
    F306 H H Br Br Br H O CH2CH3
    F307 H H Br Br Cl H O CH2CH3
    F308 H H Br Br CF3 H O CH2CH3
    F309 H H Br Br CH3 H O CH2CH3
    F310 H H Br Br Br H S CH2CH3
    F311 H H Br Br Cl H S CH2CH3
    F312 H H Br Br CF3 H S CH2CH3
    F313 H H Br Br CH3 H S CH2CH3
    F314 H H Br Br Br CH3 S CH2CH3
    F315 H H Br Br Cl CH3 S CH2CH3
    F316 H H Br Br CF3 CH3 S CH2CH3
    F317 H H Br Br CH3 CH3 S CH2CH3
    F318 H H Br Br Br CH3 O CH2CH3
    F319 H H Br Br Cl CH3 O CH2CH3
    F320 H H Br Br CF3 CH3 O CH2CH3
    F321 H H Br Br CH3 CH3 O CH2CH3
    F322 H H Br Br Br CH3 O CH2CN
    F323 H H Br Br Cl CH3 O CH2CN
    F324 H H Br Br CF3 CH3 O CH2CN
    F325 H H Br Br CH3 CH3 O CH2CN
    F326 H H Br Br Br CH3 S cyclopropyl
    F327 H H Br Br Cl CH3 S cyclopropyl
    F328 H H Br Br CF3 CH3 S cyclopropyl
    F329 H H Br Br CH3 CH3 S cyclopropyl
    F330 H H Cl NO2 Br H O CH2CF3
    F331 H H Cl NO2 Cl H O CH2CF3
    F332 H H Cl NO2 CF3 H O CH2CF3
    F333 H H Cl NO2 CH3 H O CH2CF3
    F334 H H Cl NO2 Br H O cyclopropyl
    F335 H H Cl NO2 Cl H O cyclopropyl
    F336 H H Cl NO2 CF3 H O cyclopropyl
    F337 H H Cl NO2 CH3 H O cyclopropyl
    F338 H H Cl NO2 Br H O CH2CH3
    F339 H H Cl NO2 Cl H O CH2CH3
    F340 H H Cl NO2 CF3 H O CH2CH3
    F341 H H Cl NO2 CH3 H O CH2CH3
    F342 H H Cl NO2 Br H S CH2CH3
    F343 H H Cl NO2 Cl H S CH2CH3
    F344 H H Cl NO2 CF3 H S CH2CH3
    F345 H H Cl NO2 CH3 H S CH2CH3
    F346 H H Cl NO2 Br CH3 S CH2CH3
    F347 H H Cl NO2 Cl CH3 S CH2CH3
    F348 H H Cl NO2 CF3 CH3 S CH2CH3
    F349 H H Cl NO2 CH3 CH3 S CH2CH3
    F350 H H Cl NO2 Br CH3 O CH2CH3
    F351 H H Cl NO2 Cl CH3 O CH2CH3
    F352 H H Cl NO2 CF3 CH3 O CH2CH3
    F353 H H Cl NO2 CH3 CH3 O CH2CH3
    F354 H H Cl NO2 Br CH3 O CH2CN
    F355 H H Cl NO2 Cl CH3 O CH2CN
    F356 H H Cl NO2 CF3 CH3 O CH2CN
    F357 H H Cl NO2 CH3 CH3 O CH2CN
    F358 H H Cl NO2 Br CH3 S cyclopropyl
    F359 H H Cl NO2 Cl CH3 S cyclopropyl
    F360 H H Cl NO2 CF3 CH3 S cyclopropyl
    F361 H H Cl NO2 CH3 CH3 S cyclopropyl
    F362 H H F CN Br H O CH2CF3
    F363 H H F CN Cl H O CH2CF3
    F364 H H F CN CF3 H O CH2CF3
    F365 H H F CN CH3 H O CH2CF3
    F366 H H F CN Br H O cyclopropyl
    F367 H H F CN Cl H O cyclopropyl
    F368 H H F CN CF3 H O cyclopropyl
    F369 H H F CN CH3 H O cyclopropyl
    F370 H H F CN Br H O CH2CH3
    F371 H H F CN Cl H O CH2CH3
    F372 H H F CN CF3 H O CH2CH3
    F373 H H F CN CH3 H O CH2CH3
    F374 H H F CN Br H S CH2CH3
    F375 H H F CN Cl H S CH2CH3
    F376 H H F CN CF3 H S CH2CH3
    F377 H H F CN CH3 H S CH2CH3
    F378 H H F CN Br CH3 S CH2CH3
    F379 H H F CN Cl CH3 S CH2CH3
    F380 H H F CN CF3 CH3 S CH2CH3
    F381 H H F CN CH3 CH3 S CH2CH3
    F382 H H F CN Br CH3 O CH2CH3
    F383 H H F CN Cl CH3 O CH2CH3
    F384 H H F CN CF3 CH3 O CH2CH3
    F385 H H F CN CH3 CH3 O CH2CH3
    F386 H H F CN Br CH3 O CH2CN
    F387 H H F CN Cl CH3 O CH2CN
    F388 H H F CN CF3 CH3 O CH2CN
    F389 H H F CN CH3 CH3 O CH2CN
    F390 H H F CN Br CH3 S cyclopropyl
    F391 H H F CN Cl CH3 S cyclopropyl
    F392 H H F CN CF3 CH3 S cyclopropyl
    F393 H H F CN CH3 CH3 S cyclopropyl
    F394 H Cl OCF3 Cl Br H O CH2CF3
    F395 H Cl OCF3 Cl Cl H O CH2CF3
    F396 H Cl OCF3 Cl CF3 H O CH2CF3
    F397 H Cl OCF3 Cl CH3 H O CH2CF3
    F398 H Cl OCF3 Cl Br H O cyclopropyl
    F399 H Cl OCF3 Cl Cl H O cyclopropyl
    F400 H Cl OCF3 Cl CF3 H O cyclopropyl
    F401 H Cl OCF3 Cl CH3 H O cyclopropyl
    F402 H Cl OCF3 Cl Br H O CH2CH3
    F403 H Cl OCF3 Cl Cl H O CH2CH3
    F404 H Cl OCF3 Cl CF3 H O CH2CH3
    F405 H Cl OCF3 Cl CH3 H O CH2CH3
    F406 H Cl OCF3 Cl Br H S CH2CH3
    F407 H Cl OCF3 Cl Cl H S CH2CH3
    F408 H Cl OCF3 Cl CF3 H S CH2CH3
    F409 H Cl OCF3 Cl CH3 H S CH2CH3
    F410 H Cl OCF3 Cl Br CH3 S CH2CH3
    F411 H Cl OCF3 Cl Cl CH3 S CH2CH3
    F412 H Cl OCF3 Cl CF3 CH3 S CH2CH3
    F413 H Cl OCF3 Cl CH3 CH3 S CH2CH3
    F414 H Cl OCF3 Cl Br CH3 O CH2CH3
    F415 H Cl OCF3 Cl Cl CH3 O CH2CH3
    F416 H Cl OCF3 Cl CF3 CH3 O CH2CH3
    F417 H Cl OCF3 Cl CH3 CH3 O CH2CH3
    F418 H Cl OCF3 Cl Br CH3 O CH2CN
    F419 H Cl OCF3 Cl Cl CH3 O CH2CN
    F420 H Cl OCF3 Cl CF3 CH3 O CH2CN
    F421 H Cl OCF3 Cl CH3 CH3 O CH2CN
    F422 H Cl OCF3 Cl Br CH3 S cyclopropyl
    F423 H Cl OCF3 Cl Cl CH3 S cyclopropyl
    F424 H Cl OCF3 Cl CF3 CH3 S cyclopropyl
    F425 H Cl OCF3 Cl CH3 CH3 S cyclopropyl
    F426 H Cl CN Cl Br H O CH2CF3
    F427 H Cl CN Cl Cl H O CH2CF3
    F428 H Cl CN Cl CF3 H O CH2CF3
    F429 H Cl CN Cl CH3 H O CH2CF3
    F430 H Cl CN Cl Br H O cyclopropyl
    F431 H Cl CN Cl Cl H O cyclopropyl
    F432 H Cl CN Cl CF3 H O cyclopropyl
    F433 H Cl CN Cl CH3 H O cyclopropyl
    F434 H Cl CN Cl Br H O CH2CH3
    F435 H Cl CN Cl Cl H O CH2CH3
    F436 H Cl CN Cl CF3 H O CH2CH3
    F437 H Cl CN Cl CH3 H O CH2CH3
    F438 H Cl CN Cl Br H S CH2CH3
    F439 H Cl CN Cl Cl H S CH2CH3
    F440 H Cl CN Cl CF3 H S CH2CH3
    F441 H Cl CN Cl CH3 H S CH2CH3
    F442 H Cl CN Cl Br CH3 S CH2CH3
    F443 H Cl CN Cl Cl CH3 S CH2CH3
    F444 H Cl CN Cl CF3 CH3 S CH2CH3
    F445 H Cl CN Cl CH3 CH3 S CH2CH3
    F446 H Cl CN Cl Br CH3 O CH2CH3
    F447 H Cl CN Cl Cl CH3 O CH2CH3
    F448 H Cl CN Cl CF3 CH3 O CH2CH3
    F449 H Cl CN Cl CH3 CH3 O CH2CH3
    F450 H Cl CN Cl Br CH3 O CH2CN
    F451 H Cl CN Cl Cl CH3 O CH2CN
    F452 H Cl CN Cl CF3 CH3 O CH2CN
    F453 H Cl CN Cl CH3 CH3 O CH2CN
    F454 H Cl CN Cl Br CH3 S cyclopropyl
    F455 H Cl CN Cl Cl CH3 S cyclopropyl
    F456 H Cl CN Cl CF3 CH3 S cyclopropyl
    F457 H Cl CN Cl CH3 CH3 S cyclopropyl
    F458 H CH3 H Br Br H O CH2CF3
    F459 H CH3 H Br Cl H O CH2CF3
    F460 H CH3 H Br CF3 H O CH2CF3
    F461 H CH3 H Br CH3 H O CH2CF3
    F462 H CH3 H Br Br H O cyclopropyl
    F463 H CH3 H Br Cl H O cyclopropyl
    F464 H CH3 H Br CF3 H O cyclopropyl
    F465 H CH3 H Br CH3 H O cyclopropyl
    F466 H CH3 H Br Br H O CH2CH3
    F467 H CH3 H Br Cl H O CH2CH3
    F468 H CH3 H Br CF3 H O CH2CH3
    F469 H CH3 H Br CH3 H O CH2CH3
    F470 H CH3 H Br Br H S CH2CH3
    F471 H CH3 H Br Cl H S CH2CH3
    F472 H CH3 H Br CF3 H S CH2CH3
    F473 H CH3 H Br CH3 H S CH2CH3
    F474 H CH3 H Br Br CH3 S CH2CH3
    F475 H CH3 H Br Cl CH3 S CH2CH3
    F476 H CH3 H Br CF3 CH3 S CH2CH3
    F477 H CH3 H Br CH3 CH3 S CH2CH3
    F478 H CH3 H Br Br CH3 O CH2CH3
    F479 H CH3 H Br Cl CH3 O CH2CH3
    F480 H CH3 H Br CF3 CH3 O CH2CH3
    F481 H CH3 H Br CH3 CH3 O CH2CH3
    F482 H CH3 H Br Br CH3 O CH2CN
    F483 H CH3 H Br Cl CH3 O CH2CN
    F484 H CH3 H Br CF3 CH3 O CH2CN
    F485 H CH3 H Br CH3 CH3 O CH2CN
    F486 H CH3 H Br Br CH3 S cyclopropyl
    F487 H CH3 H Br Cl CH3 S cyclopropyl
    F488 H CH3 H Br CF3 CH3 S cyclopropyl
    F489 H CH3 H Br CH3 CH3 S cyclopropyl
    F490 H H F CH3 Br H O CH2CF3
    F491 H H F CH3 Cl H O CH2CF3
    F492 H H F CH3 CF3 H O CH2CF3
    F493 H H F CH3 CH3 H O CH2CF3
    F494 H H F CH3 Br H O cyclopropyl
    F495 H H F CH3 Cl H O cyclopropyl
    F496 H H F CH3 CF3 H O cyclopropyl
    F497 H H F CH3 CH3 H O cyclopropyl
    F498 H H F CH3 Br H O CH2CH3
    F499 H H F CH3 Cl H O CH2CH3
    F500 H H F CH3 CF3 H O CH2CH3
    F501 H H F CH3 CH3 H O CH2CH3
    F502 H H F CH3 Br H S CH2CH3
    F503 H H F CH3 Cl H S CH2CH3
    F504 H H F CH3 CF3 H S CH2CH3
    F505 H H F CH3 CH3 H S CH2CH3
    F506 H H F CH3 Br CH3 S CH2CH3
    F507 H H F CH3 Cl CH3 S CH2CH3
    F508 H H F CH3 CF3 CH3 S CH2CH3
    F509 H H F CH3 CH3 CH3 S CH2CH3
    F510 H H F CH3 Br CH3 O CH2CH3
    F511 H H F CH3 Cl CH3 O CH2CH3
    F512 H H F CH3 CF3 CH3 O CH2CH3
    F513 H H F CH3 CH3 CH3 O CH2CH3
    F514 H H F CH3 Br CH3 O CH2CN
    F515 H H F CH3 Cl CH3 O CH2CN
    F516 H H F CH3 CF3 CH3 O CH2CN
    F517 H H F CH3 CH3 CH3 O CH2CN
    F518 H H F CH3 Br CH3 S cyclopropyl
    F519 H H F CH3 Cl CH3 S cyclopropyl
    F520 H H F CH3 CF3 CH3 S cyclopropyl
    F521 H H F CH3 CH3 CH3 S cyclopropyl
    F522 H H F Cl Br H O CH2CF3
    F523 H H F Cl Cl H O CH2CF3
    F524 H H F Cl CF3 H O CH2CF3
    F525 H H F Cl CH3 H O CH2CF3
    F526 H H F Cl Br H O cyclopropyl
    F527 H H F Cl Cl H O cyclopropyl
    F528 H H F Cl CF3 H O cyclopropyl
    F529 H H F Cl CH3 H O cyclopropyl
    F530 H H F Cl Br H O CH2CH3
    F531 H H F Cl Cl H O CH2CH3
    F532 H H F Cl CF3 H O CH2CH3
    F533 H H F Cl CH3 H O CH2CH3
    F534 H H F Cl Br H S CH2CH3
    F535 H H F Cl Cl H S CH2CH3
    F536 H H F Cl CF3 H S CH2CH3
    F537 H H F Cl CH3 H S CH2CH3
    F538 H H F Cl Br CH3 S CH2CH3
    F539 H H F Cl Cl CH3 S CH2CH3
    F540 H H F Cl CF3 CH3 S CH2CH3
    F541 H H F Cl CH3 CH3 S CH2CH3
    F542 H H F Cl Br CH3 O CH2CH3
    F543 H H F Cl Cl CH3 O CH2CH3
    F544 H H F Cl CF3 CH3 O CH2CH3
    F545 H H F Cl CH3 CH3 O CH2CH3
    F546 H H F Cl Br CH3 O CH2CN
    F547 H H F Cl Cl CH3 O CH2CN
    F548 H H F Cl CF3 CH3 O CH2CN
    F549 H H F Cl CH3 CH3 O CH2CN
    F550 H H F Cl Br CH3 S cyclopropyl
    F551 H H F Cl Cl CH3 S cyclopropyl
    F552 H H F Cl CF3 CH3 S cyclopropyl
    F553 H H F Cl CH3 CH3 S cyclopropyl
    F554 H F F F Br H O CH2CF3
    F555 H F F F Cl H O CH2CF3
    F556 H F F F CF3 H O CH2CF3
    F557 H F F F CH3 H O CH2CF3
    F558 H F F F Br H O cyclopropyl
    F559 H F F F Cl H O cyclopropyl
    F560 H F F F CF3 H O cyclopropyl
    F561 H F F F CH3 H O cyclopropyl
    F562 H F F F Br H O CH2CH3
    F563 H F F F Cl H O CH2CH3
    F564 H F F F CF3 H O CH2CH3
    F565 H F F F CH3 H O CH2CH3
    F566 H F F F Br H S CH2CH3
    F567 H F F F Cl H S CH2CH3
    F568 H F F F CF3 H S CH2CH3
    F569 H F F F CH3 H S CH2CH3
    F570 H F F F Br CH3 S CH2CH3
    F571 H F F F Cl CH3 S CH2CH3
    F572 H F F F CF3 CH3 S CH2CH3
    F573 H F F F CH3 CH3 S CH2CH3
    F574 H F F F Br CH3 O CH2CH3
    F575 H F F F Cl CH3 O CH2CH3
    F576 H F F F CF3 CH3 O CH2CH3
    F577 H F F F CH3 CH3 O CH2CH3
    F578 H F F F Br CH3 O CH2CN
    F579 H F F F Cl CH3 O CH2CN
    F580 H F F F CF3 CH3 O CH2CN
    F581 H F F F CH3 CH3 O CH2CN
    F582 H F F F Br CH3 S cyclopropyl
    F583 H F F F Cl CH3 S cyclopropyl
    F584 H F F F CF3 CH3 S cyclopropyl
    F585 H F F F CH3 CH3 S cyclopropyl
    F586 H CF3 H CF3 Br H O CH2CF3
    F587 H CF3 H CF3 Cl H O CH2CF3
    F588 H CF3 H CF3 CF3 H O CH2CF3
    F589 H CF3 H CF3 CH3 H O CH2CF3
    F590 H CF3 H CF3 Br H O cyclopropyl
    F591 H CF3 H CF3 Cl H O cyclopropyl
    F592 H CF3 H CF3 CF3 H O cyclopropyl
    F593 H CF3 H CF3 CH3 H O cyclopropyl
    F594 H CF3 H CF3 Br H O CH2CH3
    F595 H CF3 H CF3 Cl H O CH2CH3
    F596 H CF3 H CF3 CF3 H O CH2CH3
    F597 H CF3 H CF3 CH3 H O CH2CH3
    F598 H CF3 H CF3 Br H S CH2CH3
    F599 H CF3 H CF3 Cl H S CH2CH3
    F600 H CF3 H CF3 CF3 H S CH2CH3
    F601 H CF3 H CF3 CH3 H S CH2CH3
    F602 H CF3 H CF3 Br CH3 S CH2CH3
    F603 H CF3 H CF3 Cl CH3 S CH2CH3
    F604 H CF3 H CF3 CF3 CH3 S CH2CH3
    F605 H CF3 H CF3 CH3 CH3 S CH2CH3
    F606 H CF3 H CF3 Br CH3 O CH2CH3
    F607 H CF3 H CF3 Cl CH3 O CH2CH3
    F608 H CF3 H CF3 CF3 CH3 O CH2CH3
    F609 H CF3 H CF3 CH3 CH3 O CH2CH3
    F610 H CF3 H CF3 Br CH3 O CH2CN
    F611 H CF3 H CF3 Cl CH3 O CH2CN
    F612 H CF3 H CF3 CF3 CH3 O CH2CN
    F613 H CF3 H CF3 CH3 CH3 O CH2CN
    F614 H CF3 H CF3 Br CH3 S cyclopropyl
    F615 H CF3 H CF3 Cl CH3 S cyclopropyl
    F616 H CF3 H CF3 CF3 CH3 S cyclopropyl
    F617 H CF3 H CF3 CH3 CH3 S cyclopropyl
    F618 H F H CF3 Br H O CH2CF3
    F619 H F H CF3 Cl H O CH2CF3
    F620 H F H CF3 CF3 H O CH2CF3
    F621 H F H CF3 CH3 H O CH2CF3
    F622 H F H CF3 Br H O cyclopropyl
    F623 H F H CF3 Cl H O cyclopropyl
    F624 H F H CF3 CF3 H O cyclopropyl
    F625 H F H CF3 CH3 H O cyclopropyl
    F626 H F H CF3 Br H O CH2CH3
    F627 H F H CF3 Cl H O CH2CH3
    F628 H F H CF3 CF3 H O CH2CH3
    F629 H F H CF3 CH3 H O CH2CH3
    F630 H F H CF3 Br H S CH2CH3
    F631 H F H CF3 Cl H S CH2CH3
    F632 H F H CF3 CF3 H S CH2CH3
    F633 H F H CF3 CH3 H S CH2CH3
    F634 H F H CF3 Br CH3 S CH2CH3
    F635 H F H CF3 Cl CH3 S CH2CH3
    F636 H F H CF3 CF3 CH3 S CH2CH3
    F637 H F H CF3 CH3 CH3 S CH2CH3
    F638 H F H CF3 Br CH3 O CH2CH3
    F639 H F H CF3 Cl CH3 O CH2CH3
    F640 H F H CF3 CF3 CH3 O CH2CH3
    F641 H F H CF3 CH3 CH3 O CH2CH3
    F642 H F H CF3 Br CH3 O CH2CN
    F643 H F H CF3 Cl CH3 O CH2CN
    F644 H F H CF3 CF3 CH3 O CH2CN
    F645 H F H CF3 CH3 CH3 O CH2CN
    F646 H F H CF3 Br CH3 S cyclopropyl
    F647 H F H CF3 Cl CH3 S cyclopropyl
    F648 H F H CF3 CF3 CH3 S cyclopropyl
    F649 H F H CF3 CH3 CH3 S cyclopropyl
    F650 H Cl H CF3 Br H O CH2CF3
    F651 H Cl H CF3 Cl H O CH2CF3
    F652 H Cl H CF3 CF3 H O CH2CF3
    F653 H Cl H CF3 CH3 H O CH2CF3
    F654 H Cl H CF3 Br H O cyclopropyl
    F655 H Cl H CF3 Cl H O cyclopropyl
    F656 H Cl H CF3 CF3 H O cyclopropyl
    F657 H Cl H CF3 CH3 H O cyclopropyl
    F658 H Cl H CF3 Br H O CH2CH3
    F659 H Cl H CF3 Cl H O CH2CH3
    F660 H Cl H CF3 CF3 H O CH2CH3
    F661 H Cl H CF3 CH3 H O CH2CH3
    F662 H Cl H CF3 Br H S CH2CH3
    F663 H Cl H CF3 Cl H S CH2CH3
    F664 H Cl H CF3 CF3 H S CH2CH3
    F665 H Cl H CF3 CH3 H S CH2CH3
    F666 H Cl H CF3 Br CH3 S CH2CH3
    F667 H Cl H CF3 Cl CH3 S CH2CH3
    F668 H Cl H CF3 CF3 CH3 S CH2CH3
    F669 H Cl H CF3 CH3 CH3 S CH2CH3
    F670 H Cl H CF3 Br CH3 O CH2CH3
    F671 H Cl H CF3 Cl CH3 O CH2CH3
    F672 H Cl H CF3 CF3 CH3 O CH2CH3
    F673 H Cl H CF3 CH3 CH3 O CH2CH3
    F674 H Cl H CF3 Br CH3 O CH2CN
    F675 H Cl H CF3 Cl CH3 O CH2CN
    F676 H Cl H CF3 CF3 CH3 O CH2CN
    F677 H Cl H CF3 CH3 CH3 O CH2CN
    F678 H Cl H CF3 Br CH3 S cyclopropyl
    F679 H Cl H CF3 Cl CH3 S cyclopropyl
    F680 H Cl H CF3 CF3 CH3 S cyclopropyl
    F681 H Cl H CF3 CH3 CH3 S cyclopropyl
    F682 H H F CF3 Br H O CH2CF3
    F683 H H F CF3 Cl H O CH2CF3
    F684 H H F CF3 CF3 H O CH2CF3
    F685 H H F CF3 CH3 H O CH2CF3
    F686 H H F CF3 Br H O cyclopropyl
    F687 H H F CF3 Cl H O cyclopropyl
    F688 H H F CF3 CF3 H O cyclopropyl
    F689 H H F CF3 CH3 H O cyclopropyl
    F690 H H F CF3 Br H O CH2CH3
    F691 H H F CF3 Cl H O CH2CH3
    F692 H H F CF3 CF3 H O CH2CH3
    F693 H H F CF3 CH3 H O CH2CH3
    F694 H H F CF3 Br H S CH2CH3
    F695 H H F CF3 Cl H S CH2CH3
    F696 H H F CF3 CF3 H S CH2CH3
    F697 H H F CF3 CH3 H S CH2CH3
    F698 H H F CF3 Br CH3 S CH2CH3
    F699 H H F CF3 Cl CH3 S CH2CH3
    F700 H H F CF3 CF3 CH3 S CH2CH3
    F701 H H F CF3 CH3 CH3 S CH2CH3
    F702 H H F CF3 Br CH3 O CH2CH3
    F703 H H F CF3 Cl CH3 O CH2CH3
    F704 H H F CF3 CF3 CH3 O CH2CH3
    F705 H H F CF3 CH3 CH3 O CH2CH3
    F706 H H F CF3 Br CH3 O CH2CN
    F707 H H F CF3 Cl CH3 O CH2CN
    F708 H H F CF3 CF3 CH3 O CH2CN
    F709 H H F CF3 CH3 CH3 O CH2CN
    F710 H H F CF3 Br CH3 S cyclopropyl
    F711 H H F CF3 Cl CH3 S cyclopropyl
    F712 H H F CF3 CF3 CH3 S cyclopropyl
    F713 H H F CF3 CH3 CH3 S cyclopropyl
    F714 H Cl Cl Cl Cl H O cyclopropyl
    F715 H Cl Cl Cl CF3 H O cyclopropyl
    F716 H Cl Cl Cl CH3 H O cyclopropyl
    F717 H Cl Cl Cl Cl H O CH2CH3
    F718 H Cl Cl Cl CF3 H O CH2CH3
    F719 H Cl Cl Cl CH3 H O CH2CH3
    F720 H Cl Cl Cl Cl H S CH2CH3
    F721 H Cl Cl Cl CF3 H S CH2CH3
    F722 H Cl Cl Cl CH3 H S CH2CH3
    F723 H Cl Cl Cl Cl CH3 S CH2CH3
    F724 H Cl Cl Cl CF3 CH3 S CH2CH3
    F725 H Cl Cl Cl CH3 CH3 S CH2CH3
    F726 H Cl Cl Cl Cl CH3 O CH2CH3
    F727 H Cl Cl Cl CF3 CH3 O CH2CH3
    F728 H Cl Cl Cl CH3 CH3 O CH2CH3
    F729 H Cl Cl Cl Cl CH3 O CH2CN
    F730 H Cl Cl Cl CF3 CH3 O CH2CN
    F731 H Cl Cl Cl CH3 CH3 O CH2CN
    F732 H Cl Cl Cl Cl CH3 S cyclopropyl
    F733 H Cl Cl Cl CF3 CH3 S cyclopropyl
    F734 H Cl Cl Cl CH3 CH3 S cyclopropyl
    F735 H Cl H Cl Br H O CH2CF3
    F736 H Cl H Cl Cl H O CH2CF3
    F737 H Cl H Cl CF3 H O CH2CF3
    F738 H Cl H Cl CH3 H O CH2CF3
    F739 H Cl H Cl Br H O cyclopropyl
    F740 H Cl H Cl Cl H O cyclopropyl
    F741 H Cl H Cl CF3 H O cyclopropyl
    F742 H Cl H Cl CH3 H O cyclopropyl
    F743 H Cl H Cl Br H O CH2CH3
    F744 H Cl H Cl Cl H O CH2CH3
    F745 H Cl H Cl CF3 H O CH2CH3
    F746 H Cl H Cl CH3 H O CH2CH3
    F747 H Cl H Cl Br H S CH2CH3
    F748 H Cl H Cl Cl H S CH2CH3
    F749 H Cl H Cl CF3 H S CH2CH3
    F750 H Cl H Cl CH3 H S CH2CH3
    F751 H Cl H Cl Br CH3 S CH2CH3
    F752 H Cl H Cl Cl CH3 S CH2CH3
    F753 H Cl H Cl CF3 CH3 S CH2CH3
    F754 H Cl H Cl CH3 CH3 S CH2CH3
    F755 H Cl H Cl Br CH3 O CH2CH3
    F756 H Cl H Cl Cl CH3 O CH2CH3
    F757 H Cl H Cl CF3 CH3 O CH2CH3
    F758 H Cl H Cl CH3 CH3 O CH2CH3
    F759 H Cl H Cl Br CH3 O CH2CN
    F760 H Cl H Cl Cl CH3 O CH2CN
    F761 H Cl H Cl CF3 CH3 O CH2CN
    F762 H Cl H Cl CH3 CH3 O CH2CN
    F763 H Cl H Cl Br CH3 S cyclopropyl
    F764 H Cl H Cl Cl CH3 S cyclopropyl
    F765 H Cl H Cl CF3 CH3 S cyclopropyl
    F766 H Cl H Cl CH3 CH3 S cyclopropyl
    F767 H H Cl Cl Br H O CH2CF3
    F768 H H Cl Cl Cl H O CH2CF3
    F769 H H Cl Cl CF3 H O CH2CF3
    F770 H H Cl Cl CH3 H O CH2CF3
    F771 H H Cl Cl Br H O cyclopropyl
    F772 H H Cl Cl Cl H O cyclopropyl
    F773 H H Cl Cl CF3 H O cyclopropyl
    F774 H H Cl Cl CH3 H O cyclopropyl
    F775 H H Cl Cl Br H O CH2CH3
    F776 H H Cl Cl Cl H O CH2CH3
    F777 H H Cl Cl CF3 H O CH2CH3
    F778 H H Cl Cl CH3 H O CH2CH3
    F779 H H Cl Cl Br H S CH2CH3
    F780 H H Cl Cl Cl H S CH2CH3
    F781 H H Cl Cl CF3 H S CH2CH3
    F782 H H Cl Cl CH3 H S CH2CH3
    F783 H H Cl Cl Br CH3 S CH2CH3
    F784 H H Cl Cl Cl CH3 S CH2CH3
    F785 H H Cl Cl CF3 CH3 S CH2CH3
    F786 H H Cl Cl CH3 CH3 S CH2CH3
    F787 H H Cl Cl Br CH3 O CH2CH3
    F788 H H Cl Cl Cl CH3 O CH2CH3
    F789 H H Cl Cl CF3 CH3 O CH2CH3
    F790 H H Cl Cl CH3 CH3 O CH2CH3
    F791 H H Cl Cl Br CH3 O CH2CN
    F792 H H Cl Cl Cl CH3 O CH2CN
    F793 H H Cl Cl CF3 CH3 O CH2CN
    F794 H H Cl Cl CH3 CH3 O CH2CN
    F795 H H Cl Cl Br CH3 S cyclopropyl
    F796 H H Cl Cl Cl CH3 S cyclopropyl
    F797 H H Cl Cl CF3 CH3 S cyclopropyl
    F798 H H Cl Cl CH3 CH3 S cyclopropyl
    F799 H Cl F Cl Cl H O CH2CF3
    F800 H Cl F Cl CF3 H O CH2CF3
    F801 H Cl F Cl CH3 H O CH2CF3
    F802 H Cl F Cl Br H O cyclopropyl
    F803 H Cl F Cl Cl H O cyclopropyl
    F804 H Cl F Cl CF3 H O cyclopropyl
    F805 H Cl F Cl CH3 H O cyclopropyl
    F806 H Cl F Cl Br H O CH2CH3
    F807 H Cl F Cl Cl H O CH2CH3
    F808 H Cl F Cl CF3 H O CH2CH3
    F809 H Cl F Cl CH3 H O CH2CH3
    F810 H Cl F Cl Br H S CH2CH3
    F811 H Cl F Cl Cl H S CH2CH3
    F812 H Cl F Cl CF3 H S CH2CH3
    F813 H Cl F Cl CH3 H S CH2CH3
    F814 H Cl F Cl Br CH3 S CH2CH3
    F815 H Cl F Cl Cl CH3 S CH2CH3
    F816 H Cl F Cl CF3 CH3 S CH2CH3
    F817 H Cl F Cl CH3 CH3 S CH2CH3
    F818 H Cl F Cl Br CH3 O CH2CH3
    F819 H Cl F Cl Cl CH3 O CH2CH3
    F820 H Cl F Cl CF3 CH3 O CH2CH3
    F821 H Cl F Cl CH3 CH3 O CH2CH3
    F822 H Cl F Cl Br CH3 O CH2CN
    F823 H Cl F Cl Cl CH3 O CH2CN
    F824 H Cl F Cl CF3 CH3 O CH2CN
    F825 H Cl F Cl CH3 CH3 O CH2CN
    F826 H Cl F Cl Br CH3 S cyclopropyl
    F827 H Cl F Cl Cl CH3 S cyclopropyl
    F828 H Cl F Cl CF3 CH3 S cyclopropyl
    F829 H Cl F Cl CH3 CH3 S cyclopropyl
    F830 H Br H Br Cl H O CH2CF3
    F831 H Br H Br CF3 H O CH2CF3
    F832 H Br H Br CH3 H O CH2CF3
    F833 H Br H Br Br H O cyclopropyl
    F834 H Br H Br Cl H O cyclopropyl
    F835 H Br H Br CF3 H O cyclopropyl
    F836 H Br H Br CH3 H O cyclopropyl
    F837 H Br H Br Br H O CH2CH3
    F838 H Br H Br Cl H O CH2CH3
    F839 H Br H Br CF3 H O CH2CH3
    F840 H Br H Br CH3 H O CH2CH3
    F841 H Br H Br Br H S CH2CH3
    F842 H Br H Br Cl H S CH2CH3
    F843 H Br H Br CF3 H S CH2CH3
    F844 H Br H Br CH3 H S CH2CH3
    F845 H Br H Br Br CH3 S CH2CH3
    F846 H Br H Br Cl CH3 S CH2CH3
    F847 H Br H Br CF3 CH3 S CH2CH3
    F848 H Br H Br CH3 CH3 S CH2CH3
    F849 H Br H Br Br CH3 O CH2CH3
    F850 H Br H Br Cl CH3 O CH2CH3
    F851 H Br H Br CF3 CH3 O CH2CH3
    F852 H Br H Br CH3 CH3 O CH2CH3
    F853 H Br H Br Br CH3 O CH2CN
    F854 H Br H Br Cl CH3 O CH2CN
    F855 H Br H Br CF3 CH3 O CH2CN
    F856 H Br H Br CH3 CH3 O CH2CN
    F857 H Br H Br Br CH3 S cyclopropyl
    F858 H Br H Br Cl CH3 S cyclopropyl
    F859 H Br H Br CF3 CH3 S cyclopropyl
    F860 H Br H Br CH3 CH3 S cyclopropyl
    • Example A: Bioassays on Beet Armyworm (“BAW”) and Corn Earworm (“CEW”) and Cabbage Looper (“CL”)
  • BAW has few effective parasites, diseases, or predators to lower its population. BAW infests many weeds, trees, grasses, legumes, and field crops. In various places, it is of economic concern upon asparagus, cotton, corn, soybeans, tobacco, alfalfa, sugar beets, peppers, tomatoes, potatoes, onions, peas, sunflowers, and citrus, among other plants. CEW is known to attack corn and tomatoes, but it also attacks artichoke, asparagus, cabbage, cantaloupe, collards, cowpeas, cucumbers, eggplant, lettuce, lima beans, melon, okra, peas, peppers, potatoes, pumpkin, snap beans, spinach, squash, sweet potatoes, and watermelon, among other plants. CEW is also known to be resistant to certain insecticides. CL feeds on a wide variety of cultivated plants and weeds. It feeds readily on crucifers, and has been reported damaging broccoli, cabbage, cauliflower, Chinese cabbage, collards, kale, mustard, radish, rutabaga, turnip, and watercress. Other vegetable crops injured include beet, cantaloupe, celery, cucumber, lima bean, lettuce, parsnip, pea, pepper, potato, snap bean, spinach, squash, sweet potato, tomato, and watermelon. CL is also known to be resistant to certain insecticides. Consequently, because of the above factors control of these pests is important. Furthermore, molecules that control these pests are useful in controlling other pests.
  • Certain molecules disclosed in this document were tested against BAW and CEW and CL using procedures described in the following examples. In the reporting of the results, the “BAW & CEW & CL Rating Table” was used (See Table Section).
  • Bioassays on BAW (Spodoptera exigua)
  • Bioassays on BAW 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 ag/cm2 of the test compound (dissolved in 50 μL 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, 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 was then averaged. The results are indicated in the table entitled “Table 3: Assay Results” (See Table Section).
  • Bioassays on CEW (Helicoverpa zea)
  • Bioassays on CEW were conducted using a 128-well diet tray assay. one to five second instar CEW 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 ag/cm2 of the test compound (dissolved in 50 μL 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, 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 was then averaged. The results are indicated in the table entitled “Table 3: Assay Results” (See Table Section).
    • Bioassays on CL (Trichoplusia ni)
  • Bioassays on CL 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 μg/cm2 of the test compound (dissolved in 50 μL 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, 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 was then averaged. The results are indicated in the table entitled “Table 3A: Assay Results” (See Table Section).
    • Example B: Bioassays on Green Peach Aphid (“GPA”) (Myzus persicae)
  • 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 plants. GPA also attacks many ornamental crops such as carnation, chrysanthemum, flowering white cabbage, poinsettia, and roses. GPA has developed resistance to many pesticides.
  • 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 Rating Table” was used (See Table Section).
  • Cabbage seedlings grown in 3-inch pots, with 2-3 small (3-5 cm) true 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 compounds (2 mg) were dissolved in 2 mL of acetone/MeOH (1:1) solvent, forming stock solutions of 1000 ppm test compound. The stock solutions were diluted 5× with 0.025% Tween 20 in water to obtain the solution at 200 ppm test compound. 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 acetone/MeOH (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 by 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 3: Assay Results” (See Table Section).
    • Pesticidally Acceptable Acid Addition Salts, Salt Derivatives, Solvates, Ester Derivatives, Polymorphs, Isotopes and Radionuclides
  • Molecules of Formula One may be formulated into pesticidally acceptable acid addition salts. By way of a 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 a 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, and magnesium.
  • Molecules of Formula One may be formulated into salt derivatives. By way of a non-limiting example, a salt derivative can be prepared by contacting a free base with a sufficient amount of the desired acid to produce a salt. A free base may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide (NaOH), potassium carbonate, ammonia, and sodium bicarbonate. As an example, in many cases, a pesticide, such as 2,4-D, is made more water-soluble by converting it to its dimethylamine salt.
  • Molecules of Formula One may be formulated into stable complexes with a solvent, such that the complex remains intact after the non-complexed solvent is removed. These complexes are often referred to as “solvates.” However, it is particularly desirable to form stable hydrates with water as the solvent.
  • Molecules of Formula One may be made into ester derivatives. These ester derivatives can then be applied in the same manner as the invention disclosed in this document is applied.
  • Molecules of Formula One may be made as various crystal polymorphs. Polymorphism is important in the development of agrochemicals since different crystal polymorphs or structures of the same molecule can have vastly different physical properties and biological performances.
  • Molecules of Formula One may be made with different isotopes. Of particular importance are molecules having 2H (also known as deuterium) in place of 1H.
  • Molecules of Formula One may be made with different radionuclides. Of particular importance are molecules having 14C.
    • Stereoisomers
  • Molecules of Formula One may exist as one or more stereoisomers. Thus, certain molecules can be produced as racemic mixtures. It will be appreciated by those skilled in the art that one stereoisomer may be more active than the other stereoisomers. Individual stereoisomers may be obtained by known selective synthetic procedures, by conventional synthetic procedures using resolved starting materials, or by conventional resolution procedures. Certain molecules disclosed in this document can exist as two or more isomers. The various isomers include geometric isomers, diastereomers, and enantiomers. Thus, the molecules disclosed in this document include geometric isomers, racemic mixtures, individual stereoisomers, and optically active mixtures. It will be appreciated by those skilled in the art that one isomer may be more active than the others. The structures disclosed in the present disclosure are drawn in only one geometric form for clarity, but are intended to represent all geometric forms of the molecule.
    • Combinations
  • Molecules of Formula One may also be used in combination (such as, in a compositional mixture, or a simultaneous or sequential application) with one or more compounds having acaricidal, algicidal, avicidal, bactericidal, fungicidal, herbicidal, insecticidal, molluscicidal, nematicidal, rodenticidal, or virucidal properties. Additionally, the molecules of Formula One may also be used in combination (such as, in a compositional mixture, or a simultaneous or sequential application) with compounds that are antifeedants, bird repellents, chemosterilants, herbicide safeners, insect attractants, insect repellents, mammal repellents, mating disrupters, plant activators, plant growth regulators, or synergists. Examples of such compounds in the above groups that may be used with the Molecules of Formula One are—(3-ethoxypropyl)mercury bromide, 1,2-dichloropropane, 1,3-dichloropropene, 1-methylcyclopropene, 1-naphthol, 2-(octylthio)ethanol, 2,3,5-tri-iodobenzoic acid, 2,3,6-TBA, 2,3,6-TBA-dimethylammonium, 2,3,6-TBA-lithium, 2,3,6-TBA-potassium, 2,3,6-TBA-sodium, 2,4,5-T, 2,4,5-T-2-butoxypropyl, 2,4,5-T-2-ethylhexyl, 2,4,5-T-3-butoxypropyl, 2,4,5-TB, 2,4,5-T-butometyl, 2,4,5-T-butotyl, 2,4,5-T-butyl, 2,4,5-T-isobutyl, 2,4,5-T-isoctyl, 2,4,5-T-isopropyl, 2,4,5-T-methyl, 2,4,5-T-pentyl, 2,4,5-T-sodium, 2,4,5-T-triethylammonium, 2,4,5-T-trolamine, 2,4-D, 2,4-D-2-butoxypropyl, 2,4-D-2-ethylhexyl, 2,4-D-3-butoxypropyl, 2,4-D-ammonium, 2,4-DB, 2,4-DB-butyl, 2,4-DB-dimethylammonium, 2,4-DB-isoctyl, 2,4-DB-potassium, 2,4-DB-sodium, 2,4-D-butotyl, 2,4-D-butyl, 2,4-D-diethylammonium, 2,4-D-dimethylammonium, 2,4-D-diolamine, 2,4-D-dodecylammonium, 2,4-DEB, 2,4-DEP, 2,4-D-ethyl, 2,4-D-heptylammonium, 2,4-D-isobutyl, 2,4-D-isoctyl, 2,4-D-isopropyl, 2,4-D-isopropylammonium, 2,4-D-lithium, 2,4-D-meptyl, 2,4-D-methyl, 2,4-D-octyl, 2,4-D-pentyl, 2,4-D-potassium, 2,4-D-propyl, 2,4-D-sodium, 2,4-D-tefuryl, 2,4-D-tetradecylammonium, 2,4-D-triethylammonium, 2,4-D-tris(2-hydroxypropyl)ammonium, 2,4-D-trolamine, 2iP, 2-methoxyethylmercury chloride, 2-phenylphenol, 3,4-DA, 3,4-DB, 3,4-DP, 4-aminopyridine, 4-CPA, 4-CPA-potassium, 4-CPA-sodium, 4-CPB, 4-CPP, 4-hydroxyphenethyl alcohol, 8-hydroxyquinoline sulfate, 8-phenylmercurioxyquinoline, abamectin, abscisic acid, ACC, acephate, acequinocyl, acetamiprid, acethion, acetochlor, acetophos, acetoprole, acibenzolar, acibenzolar-S-methyl, acifluorfen, acifluorfen-methyl, acifluorfen-sodium, aclonifen, acrep, acrinathrin, acrolein, acrylonitrile, acypetacs, acypetacs-copper, acypetacs-zinc, alachlor, alanycarb, albendazole, aldicarb, aldimorph, aldoxycarb, aldrin, allethrin, allicin, allidochlor, allosamidin, alloxydim, alloxydim-sodium, allyl alcohol, allyxycarb, alorac, alpha-cypermethrin, alpha-endosulfan, ametoctradin, ametridione, ametryn, amibuzin, amicarbazone, amicarthiazol, amidithion, amidoflumet, amidosulfuron, aminocarb, aminocyclopyrachlor, aminocyclopyrachlor-methyl, aminocyclopyrachlor-potassium, aminopyralid, aminopyralid-potassium, aminopyralid-tris(2-hydroxypropyl)ammonium, amiprofos-methyl, amiprophos, amisulbrom, amiton, amiton oxalate, amitraz, amitrole, ammonium sulfamate, ammonium α-naphthaleneacetate, amobam, ampropylfos, anabasine, ancymidol, anilazine, anilofos, anisuron, anthraquinone, antu, apholate, aramite, arsenous oxide, asomate, aspirin, asulam, asulam-potassium, asulam-sodium, athidathion, atraton, atrazine, aureofungin, aviglycine, aviglycine hydrochloride, azaconazole, azadirachtin, azafenidin, azamethiphos, azimsulfuron, azinphos-ethyl, azinphos-methyl, aziprotryne, azithiram, azobenzene, azocyclotin, azothoate, azoxystrobin, bachmedesh, barban, barium hexafluorosilicate, barium polysulfide, barthrin, BCPC, beflubutamid, benalaxyl, benalaxyl-M, benazolin, benazolin-dimethylammonium, benazolin-ethyl, benazolin-potassium, bencarbazone, benclothiaz, bendiocarb, benfluralin, benfuracarb, benfuresate, benodanil, benomyl, benoxacor, benoxafos, benquinox, bensulfuron, bensulfuron-methyl, bensulide, bensultap, bentaluron, bentazone, bentazone-sodium, benthiavalicarb, benthiavalicarb-isopropyl, benthiazole, bentranil, benzadox, benzadox-ammonium, benzalkonium chloride, benzamacril, benzamacril-isobutyl, benzamorf, benzfendizone, benzipram, benzobicyclon, benzofenap, benzofluor, benzohydroxamic acid, benzoximate, benzoylprop, benzoylprop-ethyl, benzthiazuron, benzyl benzoate, benzyladenine, berberine, berberine chloride, beta-cyfluthrin, beta-cypermethrin, bethoxazin, bicyclopyrone, bifenazate, bifenox, bifenthrin, bifujunzhi, bilanafos, bilanafos-sodium, binapacryl, bingqingxiao, bioallethrin, bioethanomethrin, biopermethrin, bioresmethrin, biphenyl, bisazir, bismerthiazol, bispyribac, bispyribac-sodium, bistrifluron, bitertanol, bithionol, bixafen, blasticidin-S, borax, Bordeaux mixture, boric acid, boscalid, brassinolide, brassinolide-ethyl, brevicomin, brodifacoum, brofenvalerate, brofluthrinate, bromacil, bromacil-lithium, bromacil-sodium, bromadiolone, bromethalin, bromethrin, bromfenvinfos, bromoacetamide, bromobonil, bromobutide, bromocyclen, bromo-DDT, bromofenoxim, bromophos, bromophos-ethyl, bromopropylate, bromothalonil, bromoxynil, bromoxynil butyrate, bromoxynil heptanoate, bromoxynil octanoate, bromoxynil-potassium, brompyrazon, bromuconazole, bronopol, bucarpolate, bufencarb, buminafos, bupirimate, buprofezin, Burgundy mixture, busulfan, butacarb, butachlor, butafenacil, butamifos, butathiofos, butenachlor, butethrin, buthidazole, buthiobate, buthiuron, butocarboxim, butonate, butopyronoxyl, butoxycarboxim, butralin, butroxydim, buturon, butylamine, butylate, cacodylic acid, cadusafos, cafenstrole, calcium arsenate, calcium chlorate, calcium cyanamide, calcium polysulfide, calvinphos, cambendichlor, camphechlor, camphor, captafol, captan, carbamorph, carbanolate, carbaryl, carbasulam, carbendazim, carbendazim benzenesulfonate, carbendazim sulfite, carbetamide, carbofuran, carbon disulfide, carbon tetrachloride, carbophenothion, carbosulfan, carboxazole, carboxide, carboxin, carfentrazone, carfentrazone-ethyl, carpropamid, cartap, cartap hydrochloride, carvacrol, carvone, CDEA, cellocidin, CEPC, ceralure, Cheshunt mixture, chinomethionat, chitosan, chlobenthiazone, chlomethoxyfen, chloralose, chloramben, chloramben-ammonium, chloramben-diolamine, chloramben-methyl, chloramben-methylammonium, chloramben-sodium, chloramine phosphorus, chloramphenicol, chloraniformethan, chloranil, chloranocryl, chlorantraniliprole, chlorazifop, chlorazifop-propargyl, chlorazine, chlorbenside, chlorbenzuron, chlorbicyclen, chlorbromuron, chlorbufam, chlordane, chlordecone, chlordimeform, chlordimeform hydrochloride, chlorempenthrin, chlorethoxyfos, chloreturon, chlorfenac, chlorfenac-ammonium, chlorfenac-sodium, chlorfenapyr, chlorfenazole, chlorfenethol, chlorfenprop, chlorfenson, chlorfensulphide, chlorfenvinphos, chlorfluazuron, chlorflurazole, chlorfluren, chlorfluren-methyl, chlorflurenol, chlorflurenol-methyl, chloridazon, chlorimuron, chlorimuron-ethyl, chlormephos, chlormequat, chlormequat chloride, chlornidine, chlornitrofen, chlorobenzilate, chlorodinitronaphthalenes, chloroform, chloromebuform, chloromethiuron, chloroneb, chlorophacinone, chlorophacinone-sodium, chloropicrin, chloropon, chloropropylate, chlorothalonil, chlorotoluron, chloroxuron, chloroxynil, chlorphonium, chlorphonium chloride, chlorphoxim, chlorprazophos, chlorprocarb, chlorpropham, chlorpyrifos, chlorpyrifos-methyl, chlorquinox, chlorsulfuron, chlorthal, chlorthal-dimethyl, chlorthal-monomethyl, chlorthiamid, chlorthiophos, chlozolinate, choline chloride, chromafenozide, cinerin I, cinerin II, cinerins, cinidon-ethyl, cinmethylin, cinosulfuron, ciobutide, cisanilide, cismethrin, clethodim, climbazole, cliodinate, clodinafop, clodinafop-propargyl, cloethocarb, clofencet, clofencet-potassium, clofentezine, clofibric acid, clofop, clofop-isobutyl, clomazone, clomeprop, cloprop, cloproxydim, clopyralid, clopyralid-methyl, clopyralid-olamine, clopyralid-potassium, clopyralid-tris(2-hydroxypropyl)ammonium, cloquintocet, cloquintocet-mexyl, cloransulam, cloransulam-methyl, closantel, clothianidin, clotrimazole, cloxyfonac, cloxyfonac-sodium, CMA, codlelure, colophonate, copper acetate, copper acetoarsenite, copper arsenate, copper carbonate, basic, copper hydroxide, copper naphthenate, copper oleate, copper oxychloride, copper silicate, copper sulfate, copper zinc chromate, coumachlor, coumafuryl, coumaphos, coumatetralyl, coumithoate, coumoxystrobin, CPMC, CPMF, CPPC, credazine, cresol, crimidine, crotamiton, crotoxyphos, crufomate, cryolite, cue-lure, cufraneb, cumyluron, cuprobam, cuprous oxide, curcumenol, cyanamide, cyanatryn, cyanazine, cyanofenphos, cyanophos, cyanthoate, cyantraniliprole, cyazofamid, cybutryne, cyclafuramid, cyclanilide, cyclethrin, cycloate, cycloheximide, cycloprate, cycloprothrin, cyclosulfamuron, cycloxaprid, cycloxydim, cycluron, cyenopyrafen, cyflufenamid, cyflumetofen, cyfluthrin, cyhalofop, cyhalofop-butyl, cyhalothrin, cyhexatin, cymiazole, cymiazole hydrochloride, cymoxanil, cyometrinil, cypendazole, cypermethrin, cyperquat, cyperquat chloride, cyphenothrin, cyprazine, cyprazole, cyproconazole, cyprodinil, cyprofuram, cypromid, cyprosulfamide, cyromazine, cythioate, daimuron, dalapon, dalapon-calcium, dalapon-magnesium, dalapon-sodium, daminozide, dayoutong, dazomet, dazomet-sodium, DBCP, d-camphor, DCIP, DCPTA, DDT, debacarb, decafentin, decarbofuran, dehydroacetic acid, delachlor, deltamethrin, demephion, demephion-O, demephion-S, demeton, demeton-methyl, demeton-O, demeton-O-methyl, demeton-S, demeton-S-methyl, demeton-S-methylsulphon, desmedipham, desmetryn, d-fanshiluquebingjuzhi, diafenthiuron, dialifos, di-allate, diamidafos, diatomaceous earth, diazinon, dibutyl phthalate, dibutyl succinate, dicamba, dicamba-diglycolamine, dicamba-dimethylammonium, dicamba-diolamine, dicamba-isopropylammonium, dicamba-methyl, dicamba-olamine, dicamba-potassium, dicamba-sodium, dicamba-trolamine, dicapthon, dichlobenil, dichlofenthion, dichlofluanid, dichlone, dichloralurea, dichlorbenzuron, dichlorflurenol, dichlorflurenol-methyl, dichlormate, dichlormid, dichlorophen, dichlorprop, dichlorprop-2-ethylhexyl, dichlorprop-butotyl, dichlorprop-dimethylammonium, dichlorprop-ethylammonium, dichlorprop-isoctyl, dichlorprop-methyl, dichlorprop-P, dichlorprop-P-2-ethylhexyl, dichlorprop-P-dimethylammonium, dichlorprop-potassium, dichlorprop-sodium, dichlorvos, dichlozoline, diclobutrazol, diclocymet, diclofop, diclofop-methyl, diclomezine, diclomezine-sodium, dicloran, diclosulam, dicofol, dicoumarol, dicresyl, dicrotophos, dicyclanil, dicyclonon, dieldrin, dienochlor, diethamquat, diethamquat dichloride, diethatyl, diethatyl-ethyl, diethofencarb, dietholate, diethyl pyrocarbonate, diethyltoluamide, difenacoum, difenoconazole, difenopenten, difenopenten-ethyl, difenoxuron, difenzoquat, difenzoquat metilsulfate, difethialone, diflovidazin, diflubenzuron, diflufenican, diflufenzopyr, diflufenzopyr-sodium, diflumetorim, dikegulac, dikegulac-sodium, dilor, dimatif, dimefluthrin, dimefox, dimefuron, dimepiperate, dimetachlone, dimetan, dimethacarb, dimethachlor, dimethametryn, dimethenamid, dimethenamid-P, dimethipin, dimethirimol, dimethoate, dimethomorph, dimethrin, dimethyl carbate, dimethyl phthalate, dimethylvinphos, dimetilan, dimexano, dimidazon, dimoxystrobin, dinex, dinex-diclexine, dingjunezuo, diniconazole, diniconazole-M, dinitramine, dinobuton, dinocap, dinocap-4, dinocap-6, dinocton, dinofenate, dinopenton, dinoprop, dinosam, dinoseb, dinoseb acetate, dinoseb-ammonium, dinoseb-diolamine, dinoseb-sodium, dinoseb-trolamine, dinosulfon, dinotefuran, dinoterb, dinoterb acetate, dinoterbon, diofenolan, dioxabenzofos, dioxacarb, dioxathion, diphacinone, diphacinone-sodium, diphenamid, diphenyl sulfone, diphenylamine, dipropalin, dipropetryn, dipyrithione, diquat, diquat dibromide, disparlure, disul, disulfiram, disulfoton, disul-sodium, ditalimfos, dithianon, dithicrofos, dithioether, dithiopyr, diuron, d-limonene, DMPA, DNOC, DNOC-ammonium, DNOC-potassium, DNOC-sodium, dodemorph, dodemorph acetate, dodemorph benzoate, dodicin, dodicin hydrochloride, dodicin-sodium, dodine, dofenapyn, dominicalure, doramectin, drazoxolon, DSMA, dufulin, EBEP, EBP, ecdysterone, edifenphos, eglinazine, eglinazine-ethyl, emamectin, emamectin benzoate, EMPC, empenthrin, endosulfan, endothal, endothal-diammonium, endothal-dipotassium, endothal-disodium, endothion, endrin, enestroburin, EPN, epocholeone, epofenonane, epoxiconazole, eprinomectin, epronaz, EPTC, erbon, ergocalciferol, erlujixiancaoan, esdepallethrine, esfenvalerate, esprocarb, etacelasil, etaconazole, etaphos, etem, ethaboxam, ethachlor, ethalfluralin, ethametsulfuron, ethametsulfuron-methyl, ethaprochlor, ethephon, ethidimuron, ethiofencarb, ethiolate, ethion, ethiozin, ethiprole, ethirimol, ethoate-methyl, ethofumesate, ethohexadiol, ethoprophos, ethoxyfen, ethoxyfen-ethyl, ethoxyquin, ethoxysulfuron, ethychlozate, ethyl formate, ethyl α-naphthaleneacetate, ethyl-DDD, ethylene, ethylene dibromide, ethylene dichloride, ethylene oxide, ethylicin, ethylmercury 2,3-dihydroxypropyl mercaptide, ethylmercury acetate, ethylmercury bromide, ethylmercury chloride, ethylmercury phosphate, etinofen, etnipromid, etobenzanid, etofenprox, etoxazole, etridiazole, etrimfos, eugenol, EXD, famoxadone, famphur, fenamidone, fenaminosulf, fenamiphos, fenapanil, fenarimol, fenasulam, fenazaflor, fenazaquin, fenbuconazole, fenbutatin oxide, fenchlorazole, fenchlorazole-ethyl, fenchlorphos, fenclorim, fenethacarb, fenfluthrin, fenfuram, fenhexamid, fenitropan, fenitrothion, fenjuntong, fenobucarb, fenoprop, fenoprop-3-butoxypropyl, fenoprop-butometyl, fenoprop-butotyl, fenoprop-butyl, fenoprop-isoctyl, fenoprop-methyl, fenoprop-potassium, fenothiocarb, fenoxacrim, fenoxanil, fenoxaprop, fenoxaprop-ethyl, fenoxaprop-P, fenoxaprop-P-ethyl, fenoxasulfone, fenoxycarb, fenpiclonil, fenpirithrin, fenpropathrin, fenpropidin, fenpropimorph, fenpyrazamine, fenpyroximate, fenridazon, fenridazon-potassium, fenridazon-propyl, fenson, fensulfothion, fenteracol, fenthiaprop, fenthiaprop-ethyl, fenthion, fenthion-ethyl, fentin, fentin acetate, fentin chloride, fentin hydroxide, fentrazamide, fentrifanil, fenuron, fenuron TCA, fenvalerate, ferbam, ferimzone, ferrous sulfate, fipronil, flamprop, flamprop-isopropyl, flamprop-M, flamprop-methyl, flamprop-M-isopropyl, flamprop-M-methyl, flazasulfuron, flocoumafen, flometoquin, flonicamid, florasulam, fluacrypyrim, fluazifop, fluazifop-butyl, fluazifop-methyl, fluazifop-P, fluazifop-P-butyl, fluazinam, fluazolate, fluazuron, flubendiamide, flubenzimine, flucarbazone, flucarbazone-sodium, flucetosulfuron, fluchloralin, flucofuron, flucycloxuron, flucythrinate, fludioxonil, fluenetil, fluensulfone, flufenacet, flufenerim, flufenican, flufenoxuron, flufenprox, flufenpyr, flufenpyr-ethyl, flufiprole, flumethrin, flumetover, flumetralin, flumetsulam, flumezin, flumiclorac, flumiclorac-pentyl, flumioxazin, flumipropyn, flumorph, fluometuron, fluopicolide, fluopyram, fluorbenside, fluoridamid, fluoroacetamide, fluorodifen, fluoroglycofen, fluoroglycofen-ethyl, fluoroimide, fluoromidine, fluoronitrofen, fluothiuron, fluotrimazole, fluoxastrobin, flupoxam, flupropacil, flupropadine, flupropanate, flupropanate-sodium, flupyradifurone, flupyrsulfuron, flupyrsulfuron-methyl, flupyrsulfuron-methyl-sodium, fluquinconazole, flurazole, flurenol, flurenol-butyl, flurenol-methyl, fluridone, flurochloridone, fluroxypyr, fluroxypyr-butometyl, fluroxypyr-meptyl, flurprimidol, flursulamid, flurtamone, flusilazole, flusulfamide, fluthiacet, fluthiacet-methyl, flutianil, flutolanil, flutriafol, fluvalinate, fluxapyroxad, fluxofenim, folpet, fomesafen, fomesafen-sodium, fonofos, foramsulfuron, forchlorfenuron, formaldehyde, formetanate, formetanate hydrochloride, formothion, formparanate, formparanate hydrochloride, fosamine, fosamine-ammonium, fosetyl, fosetyl-aluminium, fosmethilan, fospirate, fosthiazate, fosthietan, frontalin, fuberidazole, fucaojing, fucaomi, funaihecaoling, fuphenthiourea, furalane, furalaxyl, furamethrin, furametpyr, furathiocarb, furcarbanil, furconazole, furconazole-cis, furethrin, furfural, furilazole, furmecyclox, furophanate, furyloxyfen, gamma-cyhalothrin, gamma-HCH, genit, gibberellic acid, gibberellins, gliftor, glufosinate, glufosinate-ammonium, glufosinate-P, glufosinate-P-ammonium, glufosinate-P-sodium, glyodin, glyoxime, glyphosate, glyphosate-diammonium, glyphosate-dimethylammonium, glyphosate-isopropylammonium, glyphosate-monoammonium, glyphosate-potassium, glyphosate-sesquisodium, glyphosate-trimesium, glyphosine, gossyplure, grandlure, griseofulvin, guazatine, guazatine acetates, halacrinate, halfenprox, halofenozide, halosafen, halosulfuron, halosulfuron-methyl, haloxydine, haloxyfop, haloxyfop-etotyl, haloxyfop-methyl, haloxyfop-P, haloxyfop-P-etotyl, haloxyfop-P-methyl, haloxyfop-sodium, HCH, hemel, hempa, HEOD, heptachlor, heptenophos, heptopargil, heterophos, hexachloroacetone, hexachlorobenzene, hexachlorobutadiene, hexachlorophene, hexaconazole, hexaflumuron, hexaflurate, hexalure, hexamide, hexazinone, hexylthiofos, hexythiazox, HHDN, holosulf, huancaiwo, huangcaoling, huanjunzuo, hydramethylnon, hydrargaphen, hydrated lime, hydrogen cyanide, hydroprene, hymexazol, hyquincarb, IAA, IBA, icaridin, imazalil, imazalil nitrate, imazalil sulfate, imazamethabenz, imazamethabenz-methyl, imazamox, imazamox-ammonium, imazapic, imazapic-ammonium, imazapyr, imazapyr-isopropylammonium, imazaquin, imazaquin-ammonium, imazaquin-methyl, imazaquin-sodium, imazethapyr, imazethapyr-ammonium, imazosulfuron, imibenconazole, imicyafos, imidacloprid, imidaclothiz, iminoctadine, iminoctadine triacetate, iminoctadine trialbesilate, imiprothrin, inabenfide, indanofan, indaziflam, indoxacarb, inezin, iodobonil, iodocarb, iodomethane, iodosulfuron, iodosulfuron-methyl, iodosulfuron-methyl-sodium, iofensulfuron, iofensulfuron-sodium, ioxynil, ioxynil octanoate, ioxynil-lithium, ioxynil-sodium, ipazine, ipconazole, ipfencarbazone, iprobenfos, iprodione, iprovalicarb, iprymidam, ipsdienol, ipsenol, IPSP, isamidofos, isazofos, isobenzan, isocarbamid, isocarbophos, isocil, isodrin, isofenphos, isofenphos-methyl, isolan, isomethiozin, isonoruron, isopolinate, isoprocarb, isopropalin, isoprothiolane, isoproturon, isopyrazam, isopyrimol, isothioate, isotianil, isouron, isovaledione, isoxaben, isoxachlortole, isoxadifen, isoxadifen-ethyl, isoxaflutole, isoxapyrifop, isoxathion, ivermectin, izopamfos, japonilure, japothrins, jasmolin I, jasmolin II, jasmonic acid, jiahuangchongzong, jiajizengxiaolin, jiaxiangjunzhi, jiecaowan, jiecaoxi, jodfenphos, juvenile hormone I, juvenile hormone II, juvenile hormone III, kadethrin, karbutilate, karetazan, karetazan-potassium, kasugamycin, kasugamycin hydrochloride, kejunlin, kelevan, ketospiradox, ketospiradox-potassium, kinetin, kinoprene, kresoxim-methyl, kuicaoxi, lactofen, lambda-cyhalothrin, latilure, lead arsenate, lenacil, lepimectin, leptophos, lindane, lineatin, linuron, lirimfos, litlure, looplure, lufenuron, lvdingjunzhi, lvxiancaolin, lythidathion, MAA, malathion, maleic hydrazide, malonoben, maltodextrin, MAMA, mancopper, mancozeb, mandipropamid, maneb, matrine, mazidox, MCPA, MCPA-2-ethylhexyl, MCPA-butotyl, MCPA-butyl, MCPA-dimethylammonium, MCPA-diolamine, MCPA-ethyl, MCPA-isobutyl, MCPA-isoctyl, MCPA-isopropyl, MCPA-methyl, MCPA-olamine, MCPA-potassium, MCPA-sodium, MCPA-thioethyl, MCPA-trolamine, MCPB, MCPB-ethyl, MCPB-methyl, MCPB-sodium, mebenil, mecarbam, mecarbinzid, mecarphon, mecoprop, mecoprop-2-ethylhexyl, mecoprop-dimethylammonium, mecoprop-diolamine, mecoprop-ethadyl, mecoprop-isoctyl, mecoprop-methyl, mecoprop-P, mecoprop-P-2-ethylhexyl, mecoprop-P-dimethylammonium, mecoprop-P-isobutyl, mecoprop-potassium, mecoprop-P-potassium, mecoprop-sodium, mecoprop-trolamine, medimeform, medinoterb, medinoterb acetate, medlure, mefenacet, mefenpyr, mefenpyr-diethyl, mefluidide, mefluidide-diolamine, mefluidide-potassium, megatomoic acid, menazon, mepanipyrim, meperfluthrin, mephenate, mephosfolan, mepiquat, mepiquat chloride, mepiquat pentaborate, mepronil, meptyldinocap, mercuric chloride, mercuric oxide, mercurous chloride, merphos, mesoprazine, mesosulfuron, mesosulfuron-methyl, mesotrione, mesulfen, mesulfenfos, metaflumizone, metalaxyl, metalaxyl-M, metaldehyde, metam, metam-ammonium, metamifop, metamitron, metam-potassium, metam-sodium, metazachlor, metazosulfuron, metazoxolon, metconazole, metepa, metflurazon, methabenzthiazuron, methacrifos, methalpropalin, methamidophos, methasulfocarb, methazole, methfuroxam, methidathion, methiobencarb, methiocarb, methiopyrisulfuron, methiotepa, methiozolin, methiuron, methocrotophos, methometon, methomyl, methoprene, methoprotryne, methoquin-butyl, methothrin, methoxychlor, methoxyfenozide, methoxyphenone, methyl apholate, methyl bromide, methyl eugenol, methyl iodide, methyl isothiocyanate, methylacetophos, methylchloroform, methyldymron, methylene chloride, methylmercury benzoate, methylmercury dicyandiamide, methylmercury pentachlorophenoxide, methylneodecanamide, metiram, metobenzuron, metobromuron, metofluthrin, metolachlor, metolcarb, metominostrobin, metosulam, metoxadiazone, metoxuron, metrafenone, metribuzin, metsulfovax, metsulfuron, metsulfuron-methyl, mevinphos, mexacarbate, mieshuan, milbemectin, milbemycin oxime, milneb, mipafox, mirex, MNAF, moguchun, molinate, molosultap, monalide, monisouron, monochloroacetic acid, monocrotophos, monolinuron, monosulfuron, monosulfuron-ester, monuron, monuron TCA, morfamquat, morfamquat dichloride, moroxydine, moroxydine hydrochloride, morphothion, morzid, moxidectin, MSMA, muscalure, myclobutanil, myclozolin, N-(ethylmercury)-p-toluenesulphonanilide, nabam, naftalofos, naled, naphthalene, naphthaleneacetamide, naphthalic anhydride, naphthoxyacetic acids, naproanilide, napropamide, naptalam, naptalam-sodium, natamycin, neburon, niclosamide, niclosamide-olamine, nicosulfuron, nicotine, nifluridide, nipyraclofen, nitenpyram, nithiazine, nitralin, nitrapyrin, nitrilacarb, nitrofen, nitrofluorfen, nitrostyrene, nitrothal-isopropyl, norbormide, norflurazon, nornicotine, noruron, novaluron, noviflumuron, nuarimol, OCH, octachlorodipropyl ether, octhilinone, ofurace, omethoate, orbencarb, orfralure, ortho-dichlorobenzene, orthosulfamuron, oryctalure, orysastrobin, oryzalin, osthol, ostramone, oxabetrinil, oxadiargyl, oxadiazon, oxadixyl, oxamate, oxamyl, oxapyrazon, oxapyrazon-dimolamine, oxapyrazon-sodium, oxasulfuron, oxaziclomefone, oxine-copper, oxolinic acid, oxpoconazole, oxpoconazole fumarate, oxycarboxin, oxydemeton-methyl, oxydeprofos, oxydisulfoton, oxyfluorfen, oxymatrine, oxytetracycline, oxytetracycline hydrochloride, paclobutrazol, paichongding, para-dichlorobenzene, parafluron, paraquat, paraquat dichloride, paraquat dimetilsulfate, parathion, parathion-methyl, parinol, pebulate, pefurazoate, pelargonic acid, penconazole, pencycuron, pendimethalin, penflufen, penfluron, penoxsulam, pentachlorophenol, pentanochlor, penthiopyrad, pentmethrin, pentoxazone, perfluidone, permethrin, pethoxamid, phenamacril, phenazine oxide, phenisopham, phenkapton, phenmedipham, phenmedipham-ethyl, phenobenzuron, phenothrin, phenproxide, phenthoate, phenylmercuriurea, phenylmercury acetate, phenylmercury chloride, phenylmercury derivative of pyrocatechol, phenylmercury nitrate, phenylmercury salicylate, phorate, phosacetim, phosalone, phosdiphen, phosfolan, phosfolan-methyl, phosglycin, phosmet, phosnichlor, phosphamidon, phosphine, phosphocarb, phosphorus, phostin, phoxim, phoxim-methyl, phthalide, picloram, picloram-2-ethylhexyl, picloram-isoctyl, picloram-methyl, picloram-olamine, picloram-potassium, picloram-triethylammonium, picloram-tris(2-hydroxypropyl)ammonium, picolinafen, picoxystrobin, pindone, pindone-sodium, pinoxaden, piperalin, piperonyl butoxide, piperonyl cyclonene, piperophos, piproctanyl, piproctanyl bromide, piprotal, pirimetaphos, pirimicarb, pirimioxyphos, pirimiphos-ethyl, pirimiphos-methyl, plifenate, polycarbamate, polyoxins, polyoxorim, polyoxorim-zinc, polythialan, potassium arsenite, potassium azide, potassium cyanate, potassium gibberellate, potassium naphthenate, potassium polysulfide, potassium thiocyanate, potassium α-naphthaleneacetate, pp′-DDT, prallethrin, precocene I, precocene II, precocene III, pretilachlor, primidophos, primisulfuron, primisulfuron-methyl, probenazole, prochloraz, prochloraz-manganese, proclonol, procyazine, procymidone, prodiamine, profenofos, profluazol, profluralin, profluthrin, profoxydim, proglinazine, proglinazine-ethyl, prohexadione, prohexadione-calcium, prohydrojasmon, promacyl, promecarb, prometon, prometryn, promurit, propachlor, propamidine, propamidine dihydrochloride, propamocarb, propamocarb hydrochloride, propanil, propaphos, propaquizafop, propargite, proparthrin, propazine, propetamphos, propham, propiconazole, propineb, propisochlor, propoxur, propoxycarbazone, propoxycarbazone-sodium, propyl isome, propyrisulfuron, propyzamide, proquinazid, prosuler, prosulfalin, prosulfocarb, prosulfuron, prothidathion, prothiocarb, prothiocarb hydrochloride, prothioconazole, prothiofos, prothoate, protrifenbute, proxan, proxan-sodium, prynachlor, pydanon, pymetrozine, pyracarbolid, pyraclofos, pyraclonil, pyraclostrobin, pyraflufen, pyraflufen-ethyl, pyrafluprole, pyramat, pyrametostrobin, pyraoxystrobin, pyrasulfotole, pyrazolynate, pyrazophos, pyrazosulfuron, pyrazosulfuron-ethyl, pyrazothion, pyrazoxyfen, pyresmethrin, pyrethrin I, pyrethrin II, pyrethrins, pyribambenz-isopropyl, pyribambenz-propyl, pyribencarb, pyribenzoxim, pyributicarb, pyriclor, pyridaben, pyridafol, pyridalyl, pyridaphenthion, pyridate, pyridinitril, pyrifenox, pyrifluquinazon, pyriftalid, pyrimethanil, pyrimidifen, pyriminobac, pyriminobac-methyl, pyrimisulfan, pyrimitate, pyrinuron, pyriofenone, pyriprole, pyripropanol, pyriproxyfen, pyrithiobac, pyrithiobac-sodium, pyrolan, pyroquilon, pyroxasulfone, pyroxsulam, pyroxychlor, pyroxyfur, quassia, quinacetol, quinacetol sulfate, quinalphos, quinalphos-methyl, quinazamid, quinclorac, quinconazole, quinmerac, quinoclamine, quinonamid, quinothion, quinoxyfen, quintiofos, quintozene, quizalofop, quizalofop-ethyl, quizalofop-P, quizalofop-P-ethyl, quizalofop-P-tefuryl, quwenzhi, quyingding, rabenzazole, rafoxanide, rebemide, resmethrin, rhodethanil, rhodojaponin-III, ribavirin, rimsulfuron, rotenone, ryania, saflufenacil, saijunmao, saisentong, salicylanilide, sanguinarine, santonin, schradan, scilliroside, sebuthylazine, secbumeton, sedaxane, selamectin, semiamitraz, semiamitraz chloride, sesamex, sesamolin, sethoxydim, shuangjiaancaolin, siduron, siglure, silafluofen, silatrane, silica gel, silthiofam, simazine, simeconazole, simeton, simetryn, sintofen, SMA, S-metolachlor, sodium arsenite, sodium azide, sodium chlorate, sodium fluoride, sodium fluoroacetate, sodium hexafluorosilicate, sodium naphthenate, sodium orthophenylphenoxide, sodium pentachlorophenoxide, sodium polysulfide, sodium thiocyanate, sodium α-naphthaleneacetate, sophamide, spinetoram, spinosad, spirodiclofen, spiromesifen, spirotetramat, spiroxamine, streptomycin, streptomycin sesquisulfate, strychnine, sulcatol, sulcofuron, sulcofuron-sodium, sulcotrione, sulfallate, sulfentrazone, sulfiram, sulfluramid, sulfometuron, sulfometuron-methyl, sulfosulfuron, sulfotep, sulfoxaflor, sulfoxide, sulfoxime, sulfur, sulfuric acid, sulfuryl fluoride, sulglycapin, sulprofos, sultropen, swep, tau-fluvalinate, tavron, tazimcarb, TCA, TCA-ammonium, TCA-calcium, TCA-ethadyl, TCA-magnesium, TCA-sodium, TDE, tebuconazole, tebufenozide, tebufenpyrad, tebufloquin, tebupirimfos, tebutam, tebuthiuron, tecloftalam, tecnazene, tecoram, teflubenzuron, tefluthrin, tefuryltrione, tembotrione, temephos, tepa, TEPP, tepraloxydim, terallethrin, terbacil, terbucarb, terbuchlor, terbufos, terbumeton, terbuthylazine, terbutryn, tetcyclacis, tetrachloroethane, tetrachlorvinphos, tetraconazole, tetradifon, tetrafluron, tetramethrin, tetramethylfluthrin, tetramine, tetranactin, tetrasul, thallium sulfate, thenylchlor, theta-cypermethrin, thiabendazole, thiacloprid, thiadifluor, thiamethoxam, thiapronil, thiazafluron, thiazopyr, thicrofos, thicyofen, thidiazimin, thidiazuron, thiencarbazone, thiencarbazone-methyl, thifensulfuron, thifensulfuron-methyl, thifluzamide, thiobencarb, thiocarboxime, thiochlorfenphim, thiocyclam, thiocyclam hydrochloride, thiocyclam oxalate, thiodiazole-copper, thiodicarb, thiofanox, thiofluoximate, thiohempa, thiomersal, thiometon, thionazin, thiophanate, thiophanate-methyl, thioquinox, thiosemicarbazide, thiosultap, thiosultap-diammonium, thiosultap-disodium, thiosultap-monosodium, thiotepa, thiram, thuringiensin, tiadinil, tiaojiean, tiocarbazil, tioclorim, tioxymid, tirpate, tolclofos-methyl, tolfenpyrad, tolylfluanid, tolylmercury acetate, topramezone, tralkoxydim, tralocythrin, tralomethrin, tralopyril, transfluthrin, transpermethrin, tretamine, triacontanol, triadimefon, triadimenol, triafamone, tri-allate, triamiphos, triapenthenol, triarathene, triarimol, triasulfuron, triazamate, triazbutil, triaziflam, triazophos, triazoxide, tribenuron, tribenuron-methyl, tribufos, tributyltin oxide, tricamba, trichlamide, trichlorfon, trichlormetaphos-3, trichloronat, triclopyr, triclopyr-butotyl, triclopyr-ethyl, triclopyr-triethylammonium, tricyclazole, tridemorph, tridiphane, trietazine, trifenmorph, trifenofos, trifloxystrobin, trifloxysulfuron, trifloxysulfuron-sodium, triflumizole, triflumuron, trifluralin, triflusulfuron, triflusulfuron-methyl, trifop, trifop-methyl, trifopsime, triforine, trihydroxytriazine, trimedlure, trimethacarb, trimeturon, trinexapac, trinexapac-ethyl, triprene, tripropindan, triptolide, tritac, triticonazole, tritosulfuron, trunc-call, uniconazole, uniconazole-P, urbacide, uredepa, valerate, validamycin, valifenalate, valone, vamidothion, vangard, vaniliprole, vernolate, vinclozolin, warfarin, warfarin-potassium, warfarin-sodium, xiaochongliulin, xinjunan, xiwojunan, XMC, xylachlor, xylenols, xylylcarb, yishijing, zarilamid, zeatin, zengxiaoan, zeta-cypermethrin, zinc naphthenate, zinc phosphide, zinc thiazole, zineb, ziram, zolaprofos, zoxamide, zuomihuanglong, α-chlorohydrin, α-ecdysone, α-multistriatin, and α-naphthaleneacetic acid. For more information consult the “COMPENDIUM OF PESTICIDE COMMON NAMES” located at http://www.alanwood.net/pesticides/index.html. Also consult “THE PESTICIDE MANUAL” 14th Edition, edited by C D S Tomlin, copyright 2006 by British Crop Production Council, or its prior or more recent editions.
    • Biopesticides
  • Molecules of Formula One may also be used in combination (such as in a compositional mixture, or a simultaneous or sequential application) with one or more biopesticides. The term “biopesticide” is used for microbial biological pest control agents that are applied in a similar manner to chemical pesticides. Commonly these are bacterial, but there are also examples of fungal control agents, including Trichoderma spp. and Ampelomyces quisqualis (a control agent for grape powdery mildew). Bacillus subtilis are used to control plant pathogens. Weeds and rodents have also been controlled with microbial agents. One well-known insecticide example is Bacillus thuringiensis, a bacterial disease of Lepidoptera, Coleoptera, and Diptera. Because it has little effect on other organisms, it is considered more environmentally friendly than synthetic pesticides. Biological insecticides include products based on:
  • 1. entomopathogenic fungi (e.g. Metarhizium anisopliae);
  • 2. entomopathogenic nematodes (e.g. Steinernema feltiae); and
  • 3. entomopathogenic viruses (e.g. Cydia pomonella granulovirus).
  • Other examples of entomopathogenic organisms include, but are not limited to, baculoviruses, bacteria and other prokaryotic organisms, fungi, protozoa and Microsproridia. Biologically derived insecticides include, but not limited to, rotenone, veratridine, as well as microbial toxins; insect tolerant or resistant plant varieties; and organisms modified by recombinant DNA technology to either produce insecticides or to convey an insect resistant property to the genetically modified organism. In one embodiment, the molecules of Formula One may be used with one or more biopesticides in the area of seed treatments and soil amendments. The Manual of Biocontrol Agents gives a review of the available biological insecticide (and other biology-based control) products. Copping L. G. (ed.) (2004). The Manual of Biocontrol Agents (formerly the Biopesticide Manual) 3rd Edition. British Crop Production Council (BCPC), Farnham, Surrey UK.
    • Other Active Compounds
  • Molecules of Formula One may also be used in combination (such as in a compositional mixture, or a simultaneous or sequential application) with one or more of the following:
    • 1. 3-(4-chloro-2,6-dimethylphenyl)-4-hydroxy-8-oxa-1-azaspiro[4,5]dec-3-en-2-one;
    • 2. 3-(4′-chloro-2,4-dimethyl[1,1′-biphenyl]-3-yl)-4-hydroxy-8-oxa-1-azaspiro[4,5]dec-3-en-2-one;
    • 3. 4-[[(6-chloro-3-pyridinyl)methyl]methylamino]-2(5H)-furanone;
    • 4. 4-[[(6-chloro-3-pyridinyl)methyl]cyclopropylamino]-2(5H)-furanone;
    • 5. 3-chloro-N2-[(1S)-1-methyl-2-(methylsulfonyl)ethyl]-N1-[2-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]-1,2-benzenedicarboxamide;
    • 6. 2-cyano-N-ethyl-4-fluoro-3-methoxy-benenesulfonamide;
    • 7. 2-cyano-N-ethyl-3-methoxy-benzenesulfonamide;
    • 8. 2-cyano-3-difluoromethoxy-N-ethyl-4-fluoro-benzenesulfonamide;
    • 9. 2-cyano-3-fluoromethoxy-N-ethyl-benzenesulfonamide;
    • 10. 2-cyano-6-fluoro-3-methoxy-N,N-dimethyl-benzenesulfonamide;
    • 11. 2-cyano-N-ethyl-6-fluoro-3-methoxy-N-methyl-benzenesulfonamide;
    • 12. 2-cyano-3-difluoromethoxy-N,N-dimethylbenzenesulfon-amide;
    • 13. 3-(difluoromethyl)-N-[2-(3,3-dimethylbutyl)phenyl]-1-methyl-1H-pyrazole-4-carboxamide;
    • 14. N-ethyl-2,2-dimethylpropionamide-2-(2,6-dichloro-α,α,α-trifluoro-p-tolyl) hydrazone;
    • 15. N-ethyl-2,2-dichloro-1-methylcyclopropane-carboxamide-2-(2,6-dichloro-α,α,α-trifluoro-p-tolyl) hydrazone nicotine;
    • 16. O-{(E-)-[2-(4-chloro-phenyl)-2-cyano-1-(2-trifluoromethylphenyl)-vinyl]} S-methyl thiocarbonate;
    • 17. (E)-N1-[(2-chloro-1,3-thiazol-5-ylmethyl)]-N2-cyano-N1-methylacetamidine;
    • 18. 1-(6-chloropyridin-3-ylmethyl)-7-methyl-8-nitro-1,2,3,5,6,7-hexahydro-imidazo[1,2-a]pyridin-5-ol;
    • 19. 4-[4-chlorophenyl-(2-butylidine-hydrazono)methyl)]phenyl mesylate; and
    • 20. N-Ethyl-2,2-dichloro-1-methylcyclopropanecarboxamide-2-(2,6-dichloro-alpha, alpha, alpha-trifluoro-p-tolyl)hydrazone.
    Synergistic Mixtures
  • Molecules of Formula One may be used with certain active compounds to form synergistic mixtures where the mode of action of such compounds compared to the mode of action of the molecules of Formula One are the same, similar, or different. Examples of modes of action include, but are not limited to: acetylcholinesterase inhibitor; sodium channel modulator; chitin biosynthesis inhibitor; GABA and glutamate-gated chloride channel antagonist; GABA and glutamate-gated chloride channel agonist; acetylcholine receptor agonist; acetylcholine receptor antagonist; MET I inhibitor; Mg-stimulated ATPase inhibitor; nicotinic acetylcholine receptor; Midgut membrane disrupter; oxidative phosphorylation disrupter, and ryanodine receptor (RyRs). Generally, weight ratios of the molecules of Formula One in a synergistic mixture with another compound are from about 10:1 to about 1:10, in another embodiment from about 5:1 to about 1:5, and in another embodiment from about 3:1, and in another embodiment about 1:1.
    • 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, fumigants, 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. For further information on formulation types see “Catalogue of Pesticide Formulation Types and International Coding System” Technical Monograph no 2, 5th Edition by CropLife International (2002).
  • 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 selected 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 non-ionic 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 selected from conventional anionic and non-ionic 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 crushing 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 can be 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 respiratory 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 monolamellar or oligolamellar layer comprising: (1) at least one non-ionic lipophilic surface-active agent, (2) at least one non-ionic 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 Feb. 1, 2007, having patent application Ser. No. 11/495,228. For ease of use, this embodiment will be referred to as “OIWE”.
  • For further information consult “Insect Pest Management” 2nd Edition by D. Dent, copyright CAB International (2000). Additionally, for more detailed information consult “Handbook of Pest Control—The Behavior, Life History, and Control of Household Pests” by Arnold Mallis, 9th Edition, copyright 2004 by GIE Media Inc.
    • Other Formulation Components
  • Generally, when the molecules disclosed in Formula One are 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 functions 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 lauryl sulfate; sodium dioctyl sulfosuccinate; alkyl phenol ethoxylates; and aliphatic alcohol ethoxylates.
  • A dispersing agent is a substance which adsorbs onto the surface of 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, non-ionic, 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. Non-ionics 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 very 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 types of surfactants usually used for solubilization are non-ionics, 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 non-ionics 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, oil-in-water emulsions, suspoemulsions, and 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 C10 aromatic solvents. Chlorinated hydrocarbons are useful as cosolvents to prevent crystallization of pesticides when the formulation is emulsified into water. Alcohols are sometimes used as cosolvents to increase solvent power. Other solvents may include vegetable oils, seed oils, and esters of vegetable and seed oils.
  • 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 not limited to, montmorillonite, 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 can 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-hydroxybenzoic acid sodium salt; methyl p-hydroxybenzoate; and 1,2-benzisothiazolin-3-one (BIT).
  • The presence of surfactants 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 polyglucosides.
  • 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 general, the molecules of Formula One may be used to control pests e.g. beetles, earwigs, cockroaches, flies. aphids, scales, whiteflies, leafhoppers, ants, wasps, termites, moths, butterflies, lice, grasshoppers, locusts, crickets, fleas, thrips, bristletails, mites, ticks, nematodes, and symphylans.
  • In another embodiment, the molecules of Formula One may be used to control pests in the Phyla Nematoda and/or Arthropoda.
  • In another embodiment, the molecules of Formula One may be used to control pests in the Subphyla Chelicerata, Myriapoda, and/or Hexapoda.
  • In another embodiment, the molecules of Formula One may be used to control pests in the Classes of Arachnida, Symphyla, and/or Insecta.
  • In another embodiment, the molecules of Formula One may be used to control pests of the Order Anoplura. A non-exhaustive list of particular genera includes, but is not limited to, Haematopinus spp., Hoplopleura spp., Linognathus spp., Pediculus spp., and Polyplax spp. A non-exhaustive list of particular species includes, but is not limited to, Haematopinus asini, Haematopinus suis, Linognathus setosus, Linognathus ovillus, Pediculus humanus capitis, Pediculus humanus humanus, and Pthirus pubis.
  • In another embodiment, the molecules of Formula One may be used to control pests in the Order Coleoptera. A non-exhaustive list of particular genera includes, but is not limited to, Acanthoscelides spp., Agriotes spp., Anthonomus spp., Apion spp., Apogonia spp., Aulacophora spp., Bruchus spp., Cerosterna spp., Cerotoma spp., Ceutorhynchus spp., Chaetocnema spp., Colaspis spp., Ctenicera spp., Curculio spp., Cyclocephala spp., Diabrotica spp., Hypera spp., Ips spp., Lyctus spp., Megascelis spp., Meligethes spp., Otiorhynchus spp., Pantomorus spp., Phyllophaga spp., Phyllotreta spp., Rhizotrogus spp., Rhynchites spp., Rhynchophorus spp., Scolytus spp., Sphenophorus spp., Sitophilus spp., and Tribolium spp. A non-exhaustive list of particular species includes, but is not limited to, Acanthoscelides obtectus, Agrilus planipennis, Anoplophora glabripennis, Anthonomus grandis, Ataenius spretulus, Atomaria linearis, Bothynoderes punctiventris, Bruchus pisorum, Callosobruchus maculatus, Carpophilus hemipterus, Cassida vittata, Cerotoma trifurcata, Ceutorhynchus assimilis, Ceutorhynchus napi, Conoderus scalaris, Conoderus stigmosus, Conotrachelus nenuphar, Cotinis nitida, Crioceris asparagi, Cryptolestes ferrugineus, Cryptolestes pusillus, Cryptolestes turcicus, Cylindrocopturus adspersus, Deporaus marginatus, Dermestes lardarius, Dermestes maculatus, Epilachna varivestis, Faustinus cubae, Hylobius pales, Hypera postica, Hypothenemus hampei, Lasioderma serricorne, Leptinotarsa decemlineata, Liogenysfuscus, Liogenys suturalis, Lissorhoptrus oryzophilus, Maecolaspis joliveti, Melanotus communis, Meligethes aeneus, Melolontha melolontha, Oberea brevis, Oberea linearis, Oryctes rhinoceros, Oryzaephilus mercator, Oryzaephilus surinamensis, Oulema melanopus, Oulema oryzae, Phyllophaga cuyabana, Popillia japonica, Prostephanus truncatus, Rhyzopertha dominica, Sitona lineatus, Sitophilus granarius, Sitophilus oryzae, Sitophilus zeamais, Stegobium paniceum, Tribolium castaneum, Tribolium confusum, Trogoderma variabile, and Zabrus tenebrioides.
  • In another embodiment, the molecules of Formula One may be used to control pests of the Order Dermaptera.
  • In another embodiment, the molecules of Formula One may be used to control pests of the Order Blattaria. A non-exhaustive list of particular species includes, but is not limited to, Blattella germanica, Blatta orientalis, Parcoblatta pennsylvanica, Periplaneta americana, Periplaneta australasiae, Periplaneta brunnea, Periplaneta fuliginosa, Pycnoscelus surinamensis, and Supella longipalpa.
  • In another embodiment, the molecules of Formula One may be used to control pests of the Order Diptera. A non-exhaustive list of particular genera includes, but is not limited to, Aedes spp., Agromyza spp., Anastrepha spp., Anopheles spp., Bactrocera spp., Ceratitis spp., Chrysops spp., Cochliomyia spp., Contarinia spp., Culex spp., Dasineura spp., Delia spp., Drosophila spp., Fannia spp., Hylemyia spp., Liriomyza spp., Musca spp., Phorbia spp., Tabanus spp., and Tipula spp. A non-exhaustive list of particular species includes, but is not limited to, Agromyza frontella, Anastrepha suspensa, Anastrepha ludens, Anastrepha obliqa, Bactrocera cucurbitae, Bactrocera dorsalis, Bactrocera invadens, Bactrocera zonata, Ceratitis capitata, Dasineura brassicae, Delia platura, Fannia canicularis, Fannia scalaris, Gasterophilus intestinalis, Gracillia perseae, Haematobia irritans, Hypoderma lineatum, Liriomyza brassicae, Melophagus ovinus, Musca autumnalis, Musca domestica, Oestrus ovis, Oscinellafrit, Pegomya betae, Psila rosae, Rhagoletis cerasi, Rhagoletis pomonella, Rhagoletis mendax, Sitodiplosis mosellana, and Stomoxys calcitrans.
  • In another embodiment, the molecules of Formula One may be used to control pests of the Order Hemiptera. A non-exhaustive list of particular genera includes, but is not limited to, Adelges spp., Aulacaspis spp., Aphrophora spp., Aphis spp., Bemisia spp., Ceroplastes spp., Chionaspis spp., Chrysomphalus spp., Coccus spp., Empoasca spp., Lepidosaphes spp., Lagynotomus spp., Lygus spp., Macrosiphum spp., Nephotettix spp., Nezara spp., Philaenus spp., Phytocoris spp., Piezodorus spp., Planococcus spp., Pseudococcus spp., Rhopalosiphum spp., Saissetia spp., Therioaphis spp., Toumeyella spp., Toxoptera spp., Trialeurodes spp., Triatoma spp. and Unaspis spp. A non-exhaustive list of particular species includes, but is not limited to, Acrosternum hilare, Acyrthosiphon pisum, Aleyrodes proletella, Aleurodicus dispersus, Aleurothrixus floccosus, Amrasca biguttula biguttula, Aonidiella aurantii, Aphis gossypii, Aphis glycines, Aphis pomi, Aulacorthum solani, Bemisia argentifolii, Bemisia tabaci, Blissus leucopterus, Brachycorynella asparagi, Brevennia rehi, Brevicoryne brassicae, Calocoris norvegicus, Ceroplastes rubens, Cimex hemipterus, Cimex lectularius, Dagbertusfasciatus, Dichelops furcatus, Diuraphis noxia, Diaphorina citri, Dysaphis plantaginea, Dysdercus suturellus, Edessa meditabunda, Eriosoma lanigerum, Eurygaster maura, Euschistus heros, Euschistus servus, Helopeltis antonii, Helopeltis theivora, Icerya purchasi, Idioscopus nitidulus, Laodelphax striatellus, Leptocorisa oratorius, Leptocorisa varicornis, Lygus hesperus, Maconellicoccus hirsutus, Macrosiphum euphorbiae, Macrosiphum granarium, Macrosiphum rosae, Macrosteles quadrilineatus, Mahanarvafrimbiolata, Metopolophium dirhodum, Mictis longicornis, Myzus persicae, Nephotettix cinctipes, Neurocolpus longirostris, Nezara viridula, Nilaparvata lugens, Parlatoria pergandii, Parlatoria ziziphi, Peregrinus maidis, Phylloxera vitifoliae, Physokermes piceae, Phytocoris californicus, Phytocoris relativus, Piezodorus guildinii, Poecilocapsus lineatus, Psallus vaccinicola, Pseudacysta perseae, Pseudococcus brevipes, Quadraspidiotus perniciosus, Rhopalosiphum maidis, Rhopalosiphum padi, Saissetia oleae, Scaptocoris castanea, Schizaphis graminum, Sitobion avenae, Sogatella furcifera, Trialeurodes vaporariorum, Trialeurodes abutiloneus, Unaspis yanonensis, and Zulia entrerriana.
  • In another embodiment, the molecules of Formula One may be used to control pests of the Order Hymenoptera. A non-exhaustive list of particular genera includes, but is not limited to, Acromyrmex spp., Atta spp., Camponotus spp., Diprion spp., Formica spp., Monomorium spp., Neodiprion spp., Pogonomyrmex spp., Polistes spp., Solenopsis spp., Vespula spp., and Xylocopa spp. A non-exhaustive list of particular species includes, but is not limited to, Athalia rosae, Atta texana, Iridomyrmex humilis, Monomorium minimum, Monomorium pharaonis, Solenopsis invicta, Solenopsis geminata, Solenopsis molesta, Solenopsis richtery, Solenopsis xyloni, and Tapinoma sessile.
  • In another embodiment, the molecules of Formula One may be used to control pests of the Order Isoptera. A non-exhaustive list of particular genera includes, but is not limited to, Coptotermes spp., Cornitermes spp., Cryptotermes spp., Heterotermes spp., Kalotermes spp., Incisitermes spp., Macrotermes spp., Marginitermes spp., Microcerotermes spp., Procornitermes spp., Reticulitermes spp., Schedorhinotermes spp., and Zootermopsis spp. A non-exhaustive list of particular species includes, but is not limited to, Coptotermes curvignathus, Coptotermes frenchi, Coptotermes formosanus, Heterotermes aureus, Microtermes obesi, Reticulitermes banyulensis, Reticulitermes grassei, Reticulitermes flavipes, Reticulitermes hageni, Reticulitermes hesperus, Reticulitermes santonensis, Reticulitermes speratus, Reticulitermes tibialis, and Reticulitermes virginicus.
  • In another embodiment, the molecules of Formula One may be used to control pests of the Order Lepidoptera. A non-exhaustive list of particular genera includes, but is not limited to, Adoxophyes spp., Agrotis spp., Argyrotaenia spp., Cacoecia spp., Caloptilia spp., Chilo spp., Chrysodeixis spp., Colias spp., Crambus spp., Diaphania spp., Diatraea spp., Earias spp., Ephestia spp., Epimecis spp., Feltia spp., Gortyna spp., Helicoverpa spp., Heliothis spp., Indarbela spp., Lithocolletis spp., Loxagrotis spp., Malacosoma spp., Peridroma spp., Phyllonorycter spp., Pseudaletia spp., Sesamia spp., Spodoptera spp., Synanthedon spp., and Yponomeuta spp. A non-exhaustive list of particular species includes, but is not limited to, Achaea janata, Adoxophyes orana, Agrotis ipsilon, Alabama argillacea, Amorbia cuneana, Amyelois transitella, Anacamptodes defectaria, Anarsia lineatella, Anomis sabulifera, Anticarsia gemmatalis, Archips argyrospila, Archips rosana, Argyrotaenia citrana, Autographa gamma, Bonagota cranaodes, Borbo cinnara, Bucculatrix thurberiella, Capua reticulana, Carposina niponensis, Chlumetia transversa, Choristoneura rosaceana, Cnaphalocrocis medinalis, Conopomorpha cramerella, Cossus cossus, Cydia caryana, Cydia funebrana, Cydia molesta, Cydia nigricana, Cydia pomonella, Darna diducta, Diatraea saccharalis, Diatraea grandiosella, Earias insulana, Earias vittella, Ecdytolopha aurantianum, Elasmopalpus lignosellus, Ephestia cautella, Ephestia elutella, Ephestia kuehniella, Epinotia aporema, Epiphyas postvittana, Erionota thrax, Eupoecilia ambiguella, Euxoa auxiliaris, Grapholita molesta, Hedylepta indicata, Helicoverpa armigera, Helicoverpa zea, Heliothis virescens, Hellula undalis, Keiferia lycopersicella, Leucinodes orbonalis, Leucoptera coffeella, Leucoptera malifoliella, Lobesia botrana, Loxagrotis albicosta, Lymantria dispar, Lyonetia clerkella, Mahasena corbetti, Mamestra brassicae, Maruca testulalis, Metisa plana, Mythimna unipuncta, Neoleucinodes elegantalis, Nymphula depunctalis, Operophtera brumata, Ostrinia nubilalis, Oxydia vesulia, Pandemis cerasana, Pandemis heparana, Papilio demodocus, Pectinophora gossypiella, Peridroma saucia, Perileucoptera coffeella, Phthorimaea operculella, Phyllocnistis citrella, Pieris rapae, Plathypena scabra, Plodia interpunctella, Plutella xylostella, Polychrosis viteana, Prays endocarpa, Prays oleae, Pseudaletia unipuncta, Pseudoplusia includens, Rachiplusia nu, Scirpophaga incertulas, Sesamia inferens, Sesamia nonagrioides, Setora nitens, Sitotroga cerealella, Sparganothis pilleriana, Spodoptera exigua, Spodoptera frugiperda, Spodoptera eridania, Thecla basilides, Tineola bisselliella, Trichoplusia ni, Tuta absoluta, Zeuzera coffeae, and Zeuzera pyrina.
  • In another embodiment, the molecules of Formula One may be used to control pests of the Order Mallophaga. A non-exhaustive list of particular genera includes, but is not limited to, Anaticola spp., Bovicola spp., Chelopistes spp., Goniodes spp., Menacanthus spp., and Trichodectes spp. A non-exhaustive list of particular species includes, but is not limited to, Bovicola bovis, Bovicola caprae, Bovicola ovis, Chelopistes meleagridis, Goniodes dissimilis, Goniodes gigas, Menacanthus stramineus, Menopon gallinae, and Trichodectes canis.
  • In another embodiment, the molecules of Formula One may be used to control pests of the Order Orthoptera. A non-exhaustive list of particular genera includes, but is not limited to, Melanoplus spp., and Pterophylla spp. A non-exhaustive list of particular species includes, but is not limited to, Anabrus simplex, Gryllotalpa africana, Gryllotalpa australis, Gryllotalpa brachyptera, Gryllotalpa hexadactyla, Locusta migratoria, Microcentrum retinerve, Schistocerca gregaria, and Scudderia furcata.
  • In another embodiment, the molecules of Formula One may be used to control pests of the Order Siphonaptera. A non-exhaustive list of particular species includes, but is not limited to, Ceratophyllus gallinae, Ceratophyllus niger, Ctenocephalides canis, Ctenocephalides felis, and Pulex irritans.
  • In another embodiment, the molecules of Formula One may be used to control pests of the Order Thysanoptera. A non-exhaustive list of particular genera includes, but is not limited to, Caliothrips spp., Frankliniella spp., Scirtothrips spp., and Thrips spp. A non-exhaustive list of particular sp. includes, but is not limited to, Frankliniella fusca, Frankliniella occidentalis, Frankliniella schultzei, Frankliniella williamsi, Heliothrips haemorrhoidalis, Rhipiphorothrips cruentatus, Scirtothrips citri, Scirtothrips dorsalis, and Taeniothrips rhopalantennalis, Thrips hawaiiensis, Thrips nigropilosus, Thrips orientalis, Thrips tabaci.
  • In another embodiment, the molecules of Formula One may be used to control pests of the Order Thysanura. A non-exhaustive list of particular genera includes, but is not limited to, Lepisma spp. and Thermobia spp.
  • In another embodiment, the molecules of Formula One may be used to control pests of the Order Acarina. A non-exhaustive list of particular genera includes, but is not limited to, Acarus spp., Aculops spp., Boophilus spp., Demodex spp., Dermacentor spp., Epitrimerus spp., Eriophyes spp., Ixodes spp., Oligonychus spp., Panonychus spp., Rhizoglyphus spp., and Tetranychus spp. A non-exhaustive list of particular species includes, but is not limited to, Acarapis woodi, Acarus siro, Aceria mangiferae, Aculops lycopersici, Aculus pelekassi, Aculus schlechtendali, Amblyomma americanum, Brevipalpus obovatus, Brevipalpus phoenicis, Dermacentor variabilis, Dermatophagoides pteronyssinus, Eotetranychus carpini, Notoedres cati, Oligonychus coffeae, Oligonychus ilicis, Panonychus citri, Panonychus ulmi, Phyllocoptruta oleivora, Polyphagotarsonemus latus, Rhipicephalus sanguineus, Sarcoptes scabiei, Tegolophus perseaflorae, Tetranychus urticae, and Varroa destructor.
  • In another embodiment, the molecules of Formula One may be used to control pest of the Order Symphyla. A non-exhaustive list of particular sp. includes, but is not limited to, Scutigerella immaculata.
  • In another embodiment, the molecules of Formula One may be used to control pests of the Phylum Nematoda. A non-exhaustive list of particular genera includes, but is not limited to, Aphelenchoides spp., Belonolaimus spp., Criconemella spp., Ditylenchus spp., Heterodera spp., Hirschmanniella spp., Hoplolaimus spp., Meloidogyne spp., Pratylenchus spp., and Radopholus spp. A non-exhaustive list of particular sp. includes, but is not limited to, Dirofilaria immitis, Heterodera zeae, Meloidogyne incognita, Meloidogyne javanica, Onchocerca volvulus, Radopholus similis, and Rotylenchulus reniformis.
  • For additional information consult “HANDBOOK OF PEST CONTROL—THE BEHAVIOR, LIFE HISTORY, AND CONTROL OF HOUSEHOLD PESTS” by Arnold Mallis, 9th Edition, copyright 2004 by GIE Media Inc.
    • Applications
  • Molecules of Formula One are generally used in amounts from about 0.01 grams per hectare to about 5000 grams per hectare to provide control. Amounts from about 0.1 grams per hectare to about 500 grams per hectare are generally preferred, and amounts from about 1 gram per hectare to about 50 grams per hectare are generally more preferred.
  • The area to which a molecule of Formula One is applied can be any area inhabited (or maybe inhabited, or traversed by) a pest, for example: where crops, trees, fruits, cereals, fodder species, vines, turf and 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 building (such as impregnated wood), and the soil around buildings. Particular crop areas to use a molecule of Formula One include areas where apples, corn, 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.
  • Controlling pests generally means that pest populations, pest activity, or both, are reduced in an area. This can come about when: pest populations are repulsed from an area; when pests are incapacitated in or around an area; or pests are exterminated, in whole, or in part, in or around an area. 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, the area is not in or on a human; consequently, the locus is generally a non-human area.
  • The molecules of Formula One may be used in mixtures, applied simultaneously or sequentially, alone or with other compounds to enhance plant vigor (e.g. to grow a better root system, to better withstand stressful growing conditions). Such other compounds are, for example, compounds that modulate plant ethylene receptors, most notably 1-methylcyclopropene (also known as 1-MCP). Furthermore, such molecules may be used during times when pest activity is low, such as before the plants that are growing begin to produce valuable agricultural commodities. Such times include the early planting season when pest pressure is usually low.
  • The molecules of Formula One can be applied to the foliar and fruiting portions of plants to control pests. The molecules will either come in direct contact with the pest, or the pest will consume the pesticide when eating leaf, fruit mass, or extracting sap, that contains the pesticide. The molecules of Formula One can also be applied to the soil, and when applied in this manner, root and stem feeding pests can be controlled. The roots can absorb a molecule taking it up into the foliar portions of the plant to control above ground chewing and sap feeding pests.
  • Generally, with baits, the baits are placed in the ground where, for example, termites can come into contact with, and/or be attracted to, 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, and/or be attracted to, the bait. Baits can comprise a molecule of Formula One.
  • The molecules of Formula One can be encapsulated inside, or placed on the surface of a capsule. The size of the capsules can range from nanometer size (about 100-900 nanometers in diameter) to micrometer size (about 10-900 microns in diameter).
  • Because of the unique ability of the eggs of some pests to resist certain pesticides, repeated applications of the molecules of Formula One 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 (for example by spraying an area) the molecules of Formula One to a different portion of the plant. For example, control of foliar-feeding insects can be achieved by drip irrigation or furrow application, by treating the soil with for example pre- or post-planting soil drench, or by treating the seeds of a plant before planting.
  • Seed treatment can be applied to all types of seeds, including those from which plants genetically modified 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, nutrition-enhancement, drought resistance, or any other beneficial traits. Furthermore, such seed treatments with the molecules of Formula One may 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. Generally, about 1 gram of the molecules of Formula One to about 500 grams per 100,000 seeds is expected to provide good benefits, amounts from about 10 grams to about 100 grams per 100,000 seeds is expected to provide better benefits, and amounts from about 25 grams to about 75 grams per 100,000 seeds is expected to provide even better benefits.
  • It should be readily apparent that the molecules of Formula One may be used on, in, or around plants genetically modified 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.
  • The molecules of Formula One may be used for controlling endoparasites and ectoparasites in the veterinary medicine sector or in the field of non-human animal keeping. The molecules of Formula One are applied, such as by oral administration in the form of, for example, tablets, capsules, drinks, granules, by dermal application in the form of, for example, dipping, spraying, pouring on, spotting on, and dusting, and by parenteral administration in the form of, for example, an injection.
  • The molecules of Formula One may also be employed advantageously in livestock keeping, for example, cattle, sheep, pigs, chickens, and geese. They may also be employed advantageously in pets such as, horses, dogs, and cats. Particular pests to control would be fleas and ticks that are bothersome to such animals. Suitable formulations are administered orally to the animals with the drinking water or feed. The dosages and formulations that are suitable depend on the species.
  • The molecules of Formula One may also be used for controlling parasitic worms, especially of the intestine, in the animals listed above.
  • The molecules of Formula One may also be employed in therapeutic methods for human health care. Such methods include, but are limited to, oral administration in the form of, for example, tablets, capsules, drinks, granules, and by dermal application.
  • Pests around the world have been migrating to new environments (for such pest) and thereafter becoming a new invasive species in such new environment. The molecules of Formula One may also be used on such new invasive species to control them in such new environment.
  • The molecules of Formula One may also be used in an area where plants, such as crops, are growing (e.g. pre-planting, planting, pre-harvesting) and where there are low levels (even no actual presence) of pests that can commercially damage such plants. The use of such molecules in such area is to benefit the plants being grown in the area. Such benefits, may include, but are not limited to, improving the health of a plant, improving the yield of a plant (e.g. increased biomass and/or increased content of valuable ingredients), improving the vigor of a plant (e.g. improved plant growth and/or greener leaves), improving the quality of a plant (e.g. improved content or composition of certain ingredients), and improving the tolerance to abiotic and/or biotic stress of the plant.
  • Before a pesticide can be used or sold commercially, such pesticide undergoes lengthy evaluation processes by various governmental authorities (local, regional, state, national, and international). Voluminous data requirements are specified by regulatory authorities and must be addressed through data generation and submission by the product registrant or by a third party on the product registrant's behalf, often using a computer with a connection to the World Wide Web. 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.
  • A molecule according to Formula One can be tested to determine its efficacy against pests. Furthermore, mode of action studies can be conducted to determine if said molecule has a different mode of action than other pesticides. Thereafter, such acquired data can be disseminated, such as by the internet, to third parties.
  • The headings in this document are for convenience only and must not be used to interpret any portion hereof.
  • TABLE SECTION
    % Control (or Mortality) Rating
    BAW & CEW & CL Rating Table
    50-100 A
    More than 0-Less than 50 B
    Not Tested C
    No activity noticed in this bioassay D
    GPA Rating Table
    80-100 A
    More than 0-Less than 80 B
    Not Tested C
    No activity noticed in this bioassay D
  • TABLE 1
    Compound
    Number Structure
    AI34
    Figure US20170088507A1-20170330-C00332
    AI36
    Figure US20170088507A1-20170330-C00333
    AI37
    Figure US20170088507A1-20170330-C00334
    AI38
    Figure US20170088507A1-20170330-C00335
    AI39
    Figure US20170088507A1-20170330-C00336
    AI40
    Figure US20170088507A1-20170330-C00337
    AI41
    Figure US20170088507A1-20170330-C00338
    AI44
    Figure US20170088507A1-20170330-C00339
    AI45
    Figure US20170088507A1-20170330-C00340
    AC1
    Figure US20170088507A1-20170330-C00341
    AC2
    Figure US20170088507A1-20170330-C00342
    AC3
    Figure US20170088507A1-20170330-C00343
    AC4
    Figure US20170088507A1-20170330-C00344
    AC5
    Figure US20170088507A1-20170330-C00345
    AC6
    Figure US20170088507A1-20170330-C00346
    AC7
    Figure US20170088507A1-20170330-C00347
    AC8
    Figure US20170088507A1-20170330-C00348
    AC9
    Figure US20170088507A1-20170330-C00349
    AC10
    Figure US20170088507A1-20170330-C00350
    AC11
    Figure US20170088507A1-20170330-C00351
    AC12
    Figure US20170088507A1-20170330-C00352
    AC13
    Figure US20170088507A1-20170330-C00353
    AC14
    Figure US20170088507A1-20170330-C00354
    AC15
    Figure US20170088507A1-20170330-C00355
    AC16
    Figure US20170088507A1-20170330-C00356
    AC17
    Figure US20170088507A1-20170330-C00357
    AC18
    Figure US20170088507A1-20170330-C00358
    AC19
    Figure US20170088507A1-20170330-C00359
    AC20
    Figure US20170088507A1-20170330-C00360
    AC21
    Figure US20170088507A1-20170330-C00361
    AC22
    Figure US20170088507A1-20170330-C00362
    AC23
    Figure US20170088507A1-20170330-C00363
    AC24
    Figure US20170088507A1-20170330-C00364
    AC25
    Figure US20170088507A1-20170330-C00365
    AC26
    Figure US20170088507A1-20170330-C00366
    AC27
    Figure US20170088507A1-20170330-C00367
    AC28
    Figure US20170088507A1-20170330-C00368
    AC29
    Figure US20170088507A1-20170330-C00369
    AC30
    Figure US20170088507A1-20170330-C00370
    AC31
    Figure US20170088507A1-20170330-C00371
    AC32
    Figure US20170088507A1-20170330-C00372
    AC33
    Figure US20170088507A1-20170330-C00373
    AC34
    Figure US20170088507A1-20170330-C00374
    AC35
    Figure US20170088507A1-20170330-C00375
    AC36
    Figure US20170088507A1-20170330-C00376
    AC37
    Figure US20170088507A1-20170330-C00377
    AC38
    Figure US20170088507A1-20170330-C00378
    AC39
    Figure US20170088507A1-20170330-C00379
    AC40
    Figure US20170088507A1-20170330-C00380
    AC41
    Figure US20170088507A1-20170330-C00381
    AC42
    Figure US20170088507A1-20170330-C00382
    AC43
    Figure US20170088507A1-20170330-C00383
    AC44
    Figure US20170088507A1-20170330-C00384
    AC45
    Figure US20170088507A1-20170330-C00385
    AC46
    Figure US20170088507A1-20170330-C00386
    AC47
    Figure US20170088507A1-20170330-C00387
    AC48
    Figure US20170088507A1-20170330-C00388
    AC49
    Figure US20170088507A1-20170330-C00389
    AC50
    Figure US20170088507A1-20170330-C00390
    AC51
    Figure US20170088507A1-20170330-C00391
    AC52
    Figure US20170088507A1-20170330-C00392
    AC53
    Figure US20170088507A1-20170330-C00393
    AC54
    Figure US20170088507A1-20170330-C00394
    AC57
    Figure US20170088507A1-20170330-C00395
    AC58
    Figure US20170088507A1-20170330-C00396
    AC59
    Figure US20170088507A1-20170330-C00397
    AC60
    Figure US20170088507A1-20170330-C00398
    AC61
    Figure US20170088507A1-20170330-C00399
    AC62
    Figure US20170088507A1-20170330-C00400
    AC63
    Figure US20170088507A1-20170330-C00401
    AC64
    Figure US20170088507A1-20170330-C00402
    AC65
    Figure US20170088507A1-20170330-C00403
    AC66
    Figure US20170088507A1-20170330-C00404
    AC67
    Figure US20170088507A1-20170330-C00405
    AC68
    Figure US20170088507A1-20170330-C00406
    AC69
    Figure US20170088507A1-20170330-C00407
    AC70
    Figure US20170088507A1-20170330-C00408
    AC71
    Figure US20170088507A1-20170330-C00409
    AC72
    Figure US20170088507A1-20170330-C00410
    AC75
    Figure US20170088507A1-20170330-C00411
    AC76
    Figure US20170088507A1-20170330-C00412
    AC77
    Figure US20170088507A1-20170330-C00413
    AC78
    Figure US20170088507A1-20170330-C00414
    AC79
    Figure US20170088507A1-20170330-C00415
    AC80
    Figure US20170088507A1-20170330-C00416
    AC81
    Figure US20170088507A1-20170330-C00417
    AC82
    Figure US20170088507A1-20170330-C00418
    AC83
    Figure US20170088507A1-20170330-C00419
    AC84
    Figure US20170088507A1-20170330-C00420
    AC85
    Figure US20170088507A1-20170330-C00421
    AC86
    Figure US20170088507A1-20170330-C00422
    AC87
    Figure US20170088507A1-20170330-C00423
    AC89
    Figure US20170088507A1-20170330-C00424
    AC90
    Figure US20170088507A1-20170330-C00425
    AC91
    Figure US20170088507A1-20170330-C00426
    AC92
    Figure US20170088507A1-20170330-C00427
    AC93
    Figure US20170088507A1-20170330-C00428
    AC94
    Figure US20170088507A1-20170330-C00429
    AC95
    Figure US20170088507A1-20170330-C00430
    AC96
    Figure US20170088507A1-20170330-C00431
    AC97
    Figure US20170088507A1-20170330-C00432
    AC98
    Figure US20170088507A1-20170330-C00433
    AC99
    Figure US20170088507A1-20170330-C00434
    AC100
    Figure US20170088507A1-20170330-C00435
    AC101
    Figure US20170088507A1-20170330-C00436
    AC102
    Figure US20170088507A1-20170330-C00437
    AC103
    Figure US20170088507A1-20170330-C00438
    AC104
    Figure US20170088507A1-20170330-C00439
    AC105
    Figure US20170088507A1-20170330-C00440
    AC106
    Figure US20170088507A1-20170330-C00441
    AC107
    Figure US20170088507A1-20170330-C00442
    AC108
    Figure US20170088507A1-20170330-C00443
    AC109
    Figure US20170088507A1-20170330-C00444
    AC110
    Figure US20170088507A1-20170330-C00445
    AC111
    Figure US20170088507A1-20170330-C00446
    AC112
    Figure US20170088507A1-20170330-C00447
    AC113
    Figure US20170088507A1-20170330-C00448
    AC114
    Figure US20170088507A1-20170330-C00449
    AC115
    Figure US20170088507A1-20170330-C00450
    AC116
    Figure US20170088507A1-20170330-C00451
    AC117
    Figure US20170088507A1-20170330-C00452
    AC118
    Figure US20170088507A1-20170330-C00453
    BC1
    Figure US20170088507A1-20170330-C00454
    BC2
    Figure US20170088507A1-20170330-C00455
    BC3
    Figure US20170088507A1-20170330-C00456
    BC4
    Figure US20170088507A1-20170330-C00457
    BC5
    Figure US20170088507A1-20170330-C00458
    BC6
    Figure US20170088507A1-20170330-C00459
    BC7
    Figure US20170088507A1-20170330-C00460
    BC8
    Figure US20170088507A1-20170330-C00461
    BC9
    Figure US20170088507A1-20170330-C00462
    BC10
    Figure US20170088507A1-20170330-C00463
    BC11
    Figure US20170088507A1-20170330-C00464
    BC12
    Figure US20170088507A1-20170330-C00465
    BC13
    Figure US20170088507A1-20170330-C00466
    BC14
    Figure US20170088507A1-20170330-C00467
    CI4
    Figure US20170088507A1-20170330-C00468
    CI5
    Figure US20170088507A1-20170330-C00469
    CI8
    Figure US20170088507A1-20170330-C00470
    CI9
    Figure US20170088507A1-20170330-C00471
    CI34
    Figure US20170088507A1-20170330-C00472
    CI35
    Figure US20170088507A1-20170330-C00473
    CI36
    Figure US20170088507A1-20170330-C00474
    CI37
    Figure US20170088507A1-20170330-C00475
    CI38
    Figure US20170088507A1-20170330-C00476
    CI39
    Figure US20170088507A1-20170330-C00477
    CI40
    Figure US20170088507A1-20170330-C00478
    CI41
    Figure US20170088507A1-20170330-C00479
    CI49
    Figure US20170088507A1-20170330-C00480
    CI50
    Figure US20170088507A1-20170330-C00481
    CI51
    Figure US20170088507A1-20170330-C00482
    CI52
    Figure US20170088507A1-20170330-C00483
    CI53
    Figure US20170088507A1-20170330-C00484
    CI54
    Figure US20170088507A1-20170330-C00485
    CI55
    Figure US20170088507A1-20170330-C00486
    CI56
    Figure US20170088507A1-20170330-C00487
    CI57
    Figure US20170088507A1-20170330-C00488
    CC1
    Figure US20170088507A1-20170330-C00489
    CC2
    Figure US20170088507A1-20170330-C00490
    CC3
    Figure US20170088507A1-20170330-C00491
    CC4
    Figure US20170088507A1-20170330-C00492
    CC5
    Figure US20170088507A1-20170330-C00493
    CC6
    Figure US20170088507A1-20170330-C00494
    CC7
    Figure US20170088507A1-20170330-C00495
    CC8
    Figure US20170088507A1-20170330-C00496
    CC9
    Figure US20170088507A1-20170330-C00497
    CC10
    Figure US20170088507A1-20170330-C00498
    CC11
    Figure US20170088507A1-20170330-C00499
    CC12
    Figure US20170088507A1-20170330-C00500
    CC13
    Figure US20170088507A1-20170330-C00501
    CC14
    Figure US20170088507A1-20170330-C00502
    CC15
    Figure US20170088507A1-20170330-C00503
    CC16
    Figure US20170088507A1-20170330-C00504
    CC17
    Figure US20170088507A1-20170330-C00505
    CC18
    Figure US20170088507A1-20170330-C00506
    CC19
    Figure US20170088507A1-20170330-C00507
    CC20
    Figure US20170088507A1-20170330-C00508
    CC21
    Figure US20170088507A1-20170330-C00509
    CC22
    Figure US20170088507A1-20170330-C00510
    CC23
    Figure US20170088507A1-20170330-C00511
    CC24
    Figure US20170088507A1-20170330-C00512
    CC25
    Figure US20170088507A1-20170330-C00513
    CC26
    Figure US20170088507A1-20170330-C00514
    CC27
    Figure US20170088507A1-20170330-C00515
    CC28
    Figure US20170088507A1-20170330-C00516
    CC29
    Figure US20170088507A1-20170330-C00517
    CC30
    Figure US20170088507A1-20170330-C00518
    CC31
    Figure US20170088507A1-20170330-C00519
    CC32
    Figure US20170088507A1-20170330-C00520
    CC33
    Figure US20170088507A1-20170330-C00521
    CC34
    Figure US20170088507A1-20170330-C00522
    CC35
    Figure US20170088507A1-20170330-C00523
    CC36
    Figure US20170088507A1-20170330-C00524
    CC37
    Figure US20170088507A1-20170330-C00525
    CC38
    Figure US20170088507A1-20170330-C00526
    CC39
    Figure US20170088507A1-20170330-C00527
    CC40
    Figure US20170088507A1-20170330-C00528
    CC41
    Figure US20170088507A1-20170330-C00529
    CC42
    Figure US20170088507A1-20170330-C00530
    CC43
    Figure US20170088507A1-20170330-C00531
    CC44
    Figure US20170088507A1-20170330-C00532
    CC45
    Figure US20170088507A1-20170330-C00533
    CC46
    Figure US20170088507A1-20170330-C00534
    CC47
    Figure US20170088507A1-20170330-C00535
    CC48
    Figure US20170088507A1-20170330-C00536
    CC49
    Figure US20170088507A1-20170330-C00537
    CC50
    Figure US20170088507A1-20170330-C00538
    CC51
    Figure US20170088507A1-20170330-C00539
    CC52
    Figure US20170088507A1-20170330-C00540
    CC53
    Figure US20170088507A1-20170330-C00541
    CC54
    Figure US20170088507A1-20170330-C00542
    DC1
    Figure US20170088507A1-20170330-C00543
    DC2
    Figure US20170088507A1-20170330-C00544
    DC3
    Figure US20170088507A1-20170330-C00545
    DC4
    Figure US20170088507A1-20170330-C00546
    DC5
    Figure US20170088507A1-20170330-C00547
    DC6
    Figure US20170088507A1-20170330-C00548
    DC7
    Figure US20170088507A1-20170330-C00549
    DC8
    Figure US20170088507A1-20170330-C00550
    DC9
    Figure US20170088507A1-20170330-C00551
    DC10
    Figure US20170088507A1-20170330-C00552
    DC11
    Figure US20170088507A1-20170330-C00553
    DC12
    Figure US20170088507A1-20170330-C00554
    DC13
    Figure US20170088507A1-20170330-C00555
    DC14
    Figure US20170088507A1-20170330-C00556
    DC15
    Figure US20170088507A1-20170330-C00557
    DC16
    Figure US20170088507A1-20170330-C00558
    DC17
    Figure US20170088507A1-20170330-C00559
    DC18
    Figure US20170088507A1-20170330-C00560
    DC19
    Figure US20170088507A1-20170330-C00561
    DC20
    Figure US20170088507A1-20170330-C00562
    DC21
    Figure US20170088507A1-20170330-C00563
    DC22
    Figure US20170088507A1-20170330-C00564
    DC23
    Figure US20170088507A1-20170330-C00565
    DC24
    Figure US20170088507A1-20170330-C00566
    DC25
    Figure US20170088507A1-20170330-C00567
    DC26
    Figure US20170088507A1-20170330-C00568
    DC27
    Figure US20170088507A1-20170330-C00569
    DC28
    Figure US20170088507A1-20170330-C00570
    DC29
    Figure US20170088507A1-20170330-C00571
    DC30
    Figure US20170088507A1-20170330-C00572
    DC31
    Figure US20170088507A1-20170330-C00573
    DC32
    Figure US20170088507A1-20170330-C00574
    DC33
    Figure US20170088507A1-20170330-C00575
    DC34
    Figure US20170088507A1-20170330-C00576
    DC35
    Figure US20170088507A1-20170330-C00577
    DC36
    Figure US20170088507A1-20170330-C00578
    DC37
    Figure US20170088507A1-20170330-C00579
    DC38
    Figure US20170088507A1-20170330-C00580
    DC39
    Figure US20170088507A1-20170330-C00581
    DC40
    Figure US20170088507A1-20170330-C00582
    DC41
    Figure US20170088507A1-20170330-C00583
    DC42
    Figure US20170088507A1-20170330-C00584
    DC43
    Figure US20170088507A1-20170330-C00585
    DC44
    Figure US20170088507A1-20170330-C00586
    DC45
    Figure US20170088507A1-20170330-C00587
    DC46
    Figure US20170088507A1-20170330-C00588
    DC47
    Figure US20170088507A1-20170330-C00589
    DC48
    Figure US20170088507A1-20170330-C00590
    DC49
    Figure US20170088507A1-20170330-C00591
    DC50
    Figure US20170088507A1-20170330-C00592
    DC51
    Figure US20170088507A1-20170330-C00593
    DC52
    Figure US20170088507A1-20170330-C00594
    DC53
    Figure US20170088507A1-20170330-C00595
    DC54
    Figure US20170088507A1-20170330-C00596
    DC55
    Figure US20170088507A1-20170330-C00597
    DC56
    Figure US20170088507A1-20170330-C00598
    DC57
    Figure US20170088507A1-20170330-C00599
    DC58
    Figure US20170088507A1-20170330-C00600
    DC59
    Figure US20170088507A1-20170330-C00601
    DC60
    Figure US20170088507A1-20170330-C00602
    DC61
    Figure US20170088507A1-20170330-C00603
    DC62
    Figure US20170088507A1-20170330-C00604
    DC63
    Figure US20170088507A1-20170330-C00605
    DC64
    Figure US20170088507A1-20170330-C00606
    DC65
    Figure US20170088507A1-20170330-C00607
    DC66
    Figure US20170088507A1-20170330-C00608
    DC67
    Figure US20170088507A1-20170330-C00609
    DC68
    Figure US20170088507A1-20170330-C00610
    DC69
    Figure US20170088507A1-20170330-C00611
    DC70
    Figure US20170088507A1-20170330-C00612
  • TABLE 1A
    Structures of Prophetic F Compounds Subsequently Exemplified
    Prepared
    Compound as in
    Number Structure Apprearance Example:
    F1 
    Figure US20170088507A1-20170330-C00613
         		Brown solid  15
    F8 
    Figure US20170088507A1-20170330-C00614
         		White solid 128
    F11
    Figure US20170088507A1-20170330-C00615
         		Off white solid 128
    F33
    Figure US20170088507A1-20170330-C00616
         		Brown gum  15
  • TABLE 2
    Analytical Data for Compounds in Table 1.
    Compound mp
    Number (° C.) ESIMS 1H NMR (δ)a IR (cm−1)
    AC1 156-161 386.09 7.83 (m, 2H),
    ([M − H]−) 7.68-7.63 (m, 5H), 6.93 (dd,
    J = 15.6, 8.0 Hz, 1H),
    6.81 (d J = 15.6 Hz, 1H,),
    4.15 (m, 1H), 2.80 (s,
    3H)
    AC2 110-112 374 7.80 (d, J = 8.4 Hz, 2H),
    ([M + H]+) 7.48 (d, J = 8.0 Hz, 2H),
    7.38 (m, 1H), 7.30 (s,
    2H), 6.65 (d, J = 16.0 Hz,
    1H), 6.46 (dd, J = 16.0,
    8.0 Hz, 1H),
    4.15 (m, 1H)
    AC3 162-166 402.24 7.42 (m, 4H), 7.37 (t, J = 1.8 Hz,
    ([M + H]+) 1H), 7.28 (s,
    2H), 6.63 (d, J = 16.0 Hz,
    1H), 6.41 (dd, J = 16.0,
    8.4 Hz, 1H),
    4.15 (m, 1H), 3.20 (s, 3H),
    3.00 (s, 3H)
    AC4 122-126 454 7.79 (d, J = 1.2 Hz, 2H),
    ([M − H]−) 7.48 (d, J = 8.4 Hz, 2H),
    7.38 (t, J = 1.8 Hz, 1H),
    7.30 (s, 2H), 6.64 (d, J = 15.6 Hz,
    1H), 6.40 (dd,
    J = 15.6, 8.0 Hz, 1H),
    6.30 (m, 1H), 4.15 (m,
    3H)
    AC5 444.12 7.67 (s, 3H), 7.64 (d, J = 8.0 Hz,
    ([M + H]+) 2H), 7.42 (d, J = 8.0 Hz,
    2H), 6.91 (dd, J = 15.6,
    8.0 Hz, 1H),
    6.80 (d, J = 15.6 Hz,
    1H), 4.80 (m, 1H),
    3.60 (br s, 8H)
    AC6 468.40 7.40 (m, 2H), 7.26 (m, 1657, 1113,
    ([M − H]−) 3H), 6.56 (d, J = 16.0 Hz, 804
    1H), 6.48 (dd, J = 16.0,
    8.0 Hz, 1H),
    5.82 (br s, 1H), 4.08 (m, 3H),
    2.52 (s, 3H)
    AC7 511.02 8.39 (s, 1H), 7.74 (m, 3276, 1645,
    ([M − H]−) 1H), 7.39 (m, 3H), 1111, 801
    7.24 (m, 4H), 6.58 (d, J = 16.0 Hz,
    1H), 6.38 (dd,
    J = 16.0, 8.0 Hz, 1H),
    6.16 (br s, 1H), 4.63 (m,
    2H), 4.12 (m, 1H),
    2.41 (s, 3H)
    AC8 454.11 7.39 (s, 1H), 7.22 (m, 1748, 1112,
    ([M − H]−) 2H), 7.19 (m, 3H), 801
    6.53 (d, J = 16.0 Hz, 1H),
    6.39-6.34 (dd, J = 16.0,
    8.0 Hz, 1H), 4.22 (m,
    1H), 3.95 (t, J = 7.0 Hz,
    2H), 2.62 (t, J = 8.0 Hz,
    2H), 2.30 (s, 3H),
    2.18 (m, 2H)
    AC9 494.02 7.45 (t, J = 7.6 Hz, 1H), 3276, 1645,
    ([M − H]−) 7.36 (m, 2H), 7.21 (m, 1112, 801
    3H), 7.15 (m, 4H),
    6.56 (d, J = 16.0 Hz, 1H),
    6.38 (dd, J = 16.0, 8.4 Hz,
    1H), 6.08 (br s, 1H),
    4.68 (d, J = 5.6 Hz, 2H),
    4.11 (m, 1H), 2.44 (s,
    3H)
    A10 140-143 458.00 7.38 (t, J = 1.6 Hz, 1H),
    ([M − H]−) 7.34 (d, J = 7.6 Hz, 1H),
    7.27 (m, 2H), 7.24 (m,
    2H), 6.57 (d, J = 16.0 Hz,
    1H), 6.40 (dd, J = 16.0,
    8.0 Hz, 1H),
    6.16 (m 1H), 5.44 (m, 1H),
    4.12 (m, 1H), 3.51 (m,
    2H), 3.40 (m, 2H),
    2.44 (s, 3H)
    AC11 476.17 7.39-7.29 (m, 9H), 3287, 1644,
    ([M − H]−) 7.24 (m, 2H), 6.56 (d, J = 16.0 Hz, 1112, 801
    1H), 6.38 (dd,
    J = 16.0, 8.0 Hz, 1H),
    5.99 (br s, 1H), 4.63 (d,
    J = 6.0 Hz, 1H),
    4.11 (m, 1H), 2.47 (s, 3H)
    AC12 479.30 8.63 (d, J = 4.4 Hz, 1H), 3293, 1653,
    ([M + H]+) 7.71 (m, 1H), 7.47 (d, J = 8.4 Hz, 1112, 800
    1H), 7.37 (m,
    2H), 7.32 (m, 2H),
    7.23 (m, 2H), 7.13 (m, 1H),
    6.58 (d, J = 16.0 Hz,
    1H), 6.40 (dd, J = 16.0,
    8.0 Hz, 1H), 4.75 (d, J = 4.8 Hz,
    2H), 4.12 (m,
    1H), 2.49 (s, 3H)
    AC13 75-78 490.04 7.38 (m, 2H), 7.27 (m,
    ([M − H]−) 3H), 7.23 (br s, 1H),
    6.58 (d, J = 16.0 Hz,
    1H), 6.45 (m 1H),
    6.42 (dd, J = 16.0, 8.4 Hz,
    1H), 4.91 (m 1H),
    4.64 (m, 2H), 4.14 (m, 1H),
    4.04 (m, 2H), 2.46 (s,
    3H)
    AC14 480.99 8.63 (s, 2H), 7.76 (d, J = 8.0 Hz, 3293, 1645,
    ([M + 2H]+) 1H), 7.36 (m, 1113, 800
    3H), 7.22 (m, 1H),
    7.13 (m, 2H), 6.57 (d, J = 16.0 Hz,
    1H), 6.39 (dd,
    J = 16.0, 8.0 Hz, 1H),
    6.13 (br s, 1H), 4.66 (d,
    J = 5.6 Hz, 2H),
    4.11 (m, 1H), 2.46 (s, 3H)
    AC15 59-61 516.86 7.45 (s, 1H), 7.37 (m, 3246, 1635,
    ([M − H]−) 1H), 7.34 (m, 1H), 1112, 801
    7.26 (m, 3H), 7.22 (m, 1H),
    6.57 (d, J = 16.0 Hz,
    1H), 6.40 (dd, J = 16.0,
    8.0 Hz, 1H), 6.18 (m,
    1H), 4.71 (d, J = 6.4 Hz,
    2H), 4.11 (m, 1H),
    2.46 (s, 3H)
    AC16 506.93 8.47 (m, 1H), 8.19 (s, 1657, 1113,
    ([M + H]+) 1H), 7.76 (m, 1H), 801
    7.47 (m, 2H), 7.37 (m, 1H),
    7.28 (m, 2H), 7.24 (m,
    1H), 7.21 (m, 1H),
    6.59 (d, J = 16.0 Hz, 1H),
    6.39 (dd, J = 16.0, 8.4 Hz,
    1H), 4.12 (m, 1H),
    2.48 (s, 3H), 1.88 (s,
    6H)
    AC17 70-73 494.98 7.49 (m, 2H), 7.38 (m,
    ([M − H]−) 1H), 7.29 (m, 4H),
    7.08 (m, 3H), 6.91 (m, 1H),
    6.61 (d, J = 16.0 Hz,
    1H), 6.48 (m, 1H),
    6.43 (dd, J = 16.0, 8.0 Hz,
    1H), 4.13 (m, 1H),
    2.49 (s, 3H)
    AC18 155-158 480.44 8.73 (d, J = 4.8 Hz, 2H),
    ([M + H]+) 7.53 (d, J = 8.4 Hz, 1H),
    7.37 (m, 1H), 7.27 (m,
    4H), 7.23 (m, 1H),
    7.11 (m, 1H), 6.60 (d, J = 16.0 Hz,
    1H), 6.41 (dd,
    J = 16.0, 8.0 Hz, 1H),
    4.90 (d, J = 4.8 Hz, 2H),
    4.13 (m, 1H), 2.52 (s,
    3H)
    AC19 55-57 471.66 7.37 (m, 1H), 7.33 (d, J = 7.6 Hz,
    ([M + H]+) 1H), 7.27 (m,
    2H), 7.22 (m, 2H),
    6.57 (d, J = 16.0 Hz, 1H),
    6.39 (dd, J = 16.0, 8.0 Hz,
    1H), 6.10 (brs, 1H),
    4.13 (m, 2H), 3.94 (m,
    1H), 3.79 (m, 2H),
    3.35 (m, 1H), 2.45 (s, 3H),
    2.14 (m, 1H), 1.71 (m,
    2H), 1.65 (m, 1H).
    AC20 467.68 7.37 (m, 2H), 7.27 (m, 3437, 1664,
    ([M + H]+) 2H), 7.23 (m, 2H), 1265, 1114,
    6.57 (d, J = 16.0 Hz, 1H), 746
    6.38 (m, 3H), 6.01 (m,
    1H), 4.63 (d, J = 5.6 Hz,
    2H), 4.13 (m, 1H),
    2.45 (s, 3H)
    AC21 61-64 528.78 8.44 (s, 1H), 8.18 (s,
    ([M + H]+) 1H), 7.83 (br s, 1H),
    7.38 (m, 2H), 7.27 (m,
    2H), 7.25 (m, 2H),
    7.21 (m, 1H), 6.57 (d, J = 16.0 Hz,
    1H), 6.40 (dd,
    J = 16.0, 8.0 Hz, 1H),
    5.01 (s, 2H), 4.11 (m,
    1H), 2.43 (s, 3H)
    AC22 545.08 8.39 (s, 1H), 7.73 (m, 3270, 1642,
    ([M − H]−) 1H), 7.40 (s, 1H), 1111, 809
    7.35 (m, 2H), 7.22 (m, 3H),
    6.57 (d, J = 16.0 Hz,
    1H), 6.38 (dd, J = 16.0,
    7.6 Hz, 1H), 6.14 (br s,
    1H), 4.62 (d, J = 6.0 Hz,
    2H), 4.13 (m, 1H),
    2.45 (s, 3H)
    AC23 492.35 7.42 (s, 2H), 7.36 (m, 3273, 1641,
    ([M − H]−) 1H), 7.24 (m, 2H), 1250, 1113,
    6.59 (d, J = 16.0 Hz, 1H), 807
    6.40 (dd, J = 16.0, 8.0 Hz,
    1H), 6.20 (br s, 1H),
    5.46 (m, 1H), 4.15 (m,
    1H), 3.52 (m, 2H),
    3.41 (m, 2H), 2.45 (s, 3H)
    AC24 129-132 526.98 7.40 (m, 2H), 7.27 (m, 3298, 1664,
    ([M + H]+) 2H), 7.25 (m, 2H), 1113, 803
    6.92 (br s, 2H), 6.60 (m, 1H),
    6.48 (dd, J = 16.0, 8.0 Hz,
    1H), 4.19 (d, J = 5.2,
    2H), 4.08 (m, 1H),
    3.99 (m, 2H), 2.46 (s,
    3H)
    AC25 542.24 7.41 (m, 3H), 7.27 (m, 3257, 1652,
    ([M − H]−) 2H), 6.58 (d, J = 15.6 Hz, 1316, 1109,
    1H), 6.42 (m, 2H), 807
    4.92 (m, 1H), 4.65 (m,
    2H), 4.14 (m, 1H),
    4.09 (m, 2H), 2.46 (s, 3H)
    AC26 550.69 7.45 (s, 1H), 7.40 (s, 3255, 1638,
    ([M − H]−) 2H), 7.34 (d, J = 8.0 Hz, 1113, 809
    1H), 7.22 (m, 2H),
    6.54 (d, J = 16.0 Hz, 1H),
    6.38 (dd, J = 16.0, 8.0 Hz,
    1H), 4.71 (d, J = 6.0 Hz,
    2H), 4.11 (m, 1H),
    2.46 (s, 3H)
    AC27 541.00 8.46 (d, J = 4.0 Hz, 1H), 1653, 1113,
    ([M − H]−) 8.20 (s, 1H), 7.76 (m, 809
    1H), 7.47 (m, 2H),
    7.41 (s, 2H), 7.23 (m, 2H),
    7.21 (m, 1H), 6.59 (d, J = 16.0 Hz,
    1H),
    6.37 (dd, J = 16.0, 8.4 Hz,
    1H), 4.11 (m, 1H),
    2.48 (s, 3H), 1.88 (s, 6H)
    AC28 65-67 564.84 8.40 (s, 1H), 7.74 (m, 3267, 1650,
    ([M − H]−) 2H), 7.42 (m, 3H), 1112, 809
    7.36 (m, 2H), 6.72 (br s, 1H),
    6.52 (d, J = 16.0 Hz,
    1H), 6.43 (dd, J = 16.0,
    8.0 Hz, 1H), 4.66 (d, J = 6.4 Hz,
    2H), 4.12 (m,
    1H)
    AC29 75-78 511.78 7.71 (d, J = 8.4 Hz, 1H),
    ([M − H]−) 7.42 (m, 3H), 7.35 (m,
    1H), 6.75 (br s, 1H),
    6.56 (d, J = 16.0 Hz,
    1H), 6.43 (dd, J = 16.0,
    8.0 Hz, 1H), 5.49 (m,
    1H), 4.14 (m, 1H),
    3.50 (m, 4H)
    AC30 110-113 543.72 7.42 (d, J = 8.4 Hz, 1H),
    ([M − H]−) 7.44 (s, 1H), 7.40 (s,
    1H), 7.38 (m, 1H),
    7.06 (br s, 1H), 6.58 (d, J = 15.6 Hz,
    1H), 6.45 (dd,
    J = 15.6, 8.0 Hz, 1H),
    4.93 (m, 1H), 4.65 (m,
    2H), 4.13 (m, 3H)
    AC31 68-70 610.73 8.42 (s, 1H), 7.76 (m,
    ([M + H]+) 1H), 7.61 (m, 2H),
    7.39 (m, 4H), 6.54-6.39 (m,
    3H), 4.66 (d, J = 6.0 Hz,
    2H), 4.12 (m, 1H)
    AC32 78-80 555.89 7.61 (m, 2H), 7.40 (m,
    ([M − H]−) 3H), 6.54 (m, 2H),
    6.40 (dd, J = 16.0, 8.0 Hz,
    1H), 5.46 (m, 1H),
    4.14 (m, 1H), 3.50 (m, 4H)
    AC33 182-184 587.68 7.62 (s, 1H), 7.58 (d, J = 8.0 Hz,
    ([M − H]−) 1H), 7.40 (m,
    3H), 6.84 (br s, 1H),
    6.55 (d, J = 15.6 Hz,
    1H), 6.45 (dd, J = 15.6,
    7.6 Hz, 1H), 4.93 (m
    1H), 4.65 (m, 2H),
    4.13 (m, 4H)
    AC34 151-153 545.83 7.67 (s, 1H), 7.61 (d, J = 6.0 Hz,
    ([M − H]−) 1H), 7.53 (m,
    1H), 7.41 (s, 2H),
    6.64 (d, J = 16.0 Hz, 1H),
    6.40 (dd, J = 16.0, 8.0 Hz,
    1H), 6.18 (br s, 1H),
    5.44 (m, 1H), 4.14 (m,
    1H), 3.50 (m, 2H),
    3.40 (m, 2H)
    AC35 100-102 577.71 7.70 (s, 1H), 7.63 (m, 3257, 1655,
    ([M − H]−) 1H), 7.53 (d, J = 7.6 Hz, 1113, 808
    1H), 7.41 (s, 2H),
    6.53 (d, J = 16.0 Hz, 1H),
    6.49 (m, 2H), 4.93 (m,
    1H), 4.64 (m, 2H),
    4.13 (m, 1H), 4.03 (m, 2H)
    AC36 81-83 600.83 8.40 (s, 1H), 7.73 (m,
    ([M + H]+) 2H), 7.61 (d, J = 8.4 Hz,
    1H), 7.52 (d, J = 8.0 Hz,
    1H), 7.40 (s, 2H),
    7.35 (d, J = 8.0 Hz, 1H),
    6.63 (d, J = 16.0 Hz, 1H),
    6.46 (dd, J = 16.0, 7.6 Hz,
    1H), 6.14 (m, 1H),
    4.63 (d, J = 6.0 Hz, 2H),
    4.14 (m, 1H)
    AC37 512.68 8.39 (s, 1H), 7.73 (m, 3268, 1644,
    ([M + H]+) 1H), 7.48 (m, 2H), 1109, 820
    7.34 (d, J = 7.6 Hz, 1H),
    7.24 (m, 3H), 6.55 (d, J = 16.0 Hz,
    1H), 6.41 (dd,
    J = 16.0, 7.6 Hz, 1H),
    6.12 (m, 1H), 4.62 (d, J = 6.0 Hz,
    2H), 4.13 (m,
    1H), 2.45 (s, 3H)
    AC38 79-80 528.85 8.46 (m, 1H), 7.73 (m,
    ([M − H]−) 1H), 7.35 (m, 4H),
    7.22 (m, 2H), 6.56 (d, J = 16.0 Hz,
    1H), 6.38 (dd,
    J = 16.0, 8.0 Hz, 1H),
    4.62 (d, J = 6.0 Hz, 2H),
    4.10 (m, 1H), 2.45 (s,
    3H)
    AC39 141-144 477.83 9.19 (s, 1H), 8.79 (s,
    ([M − H]−) 2H), 7.37 (m, 2H),
    7.23 (m, 2H), 7.21 (m, 1H),
    6.57 (d, J = 16.0 Hz,
    1H), 6.40 (dd, J = 16.0,
    7.6 Hz 1H), 6.21 (m,
    1H), 4.65 (s, 2H),
    4.11 (m, 1H), 2.46 (s, 3H)
    AC40 69-72 484.67 8.33 (t, J = 5.6 Hz, 1H),
    ([M + H]+) 8.61 (m, 1H), 7.68 (m,
    3H), 7.48 (m, 2H),
    6.86 (dd, J = 15.6, 8.2 Hz
    1H), 6.74 (d, J = 15.6 Hz,
    1H), 4.44 (m, 1H),
    3.76 (d, J = 6.0 Hz, 2H),
    2.54 (m, 1H), 2.67 (s,
    3H), 0.59 (m, 2H),
    0.54 (m, 2H)
    AC41 196-199 515.00 8.66 (d, J = 7.6 Hz,
    ([M − H]−) 1H), 8.39 (t, J = 5.6 Hz,
    1H), 7.65 (s, 3H),
    7.45 (m, 3H), 6.86 (dd, J = 15.6,
    8.8 Hz, 1H),
    6.74 (d, J = 15.6 Hz, 1H),
    5.01 (m, 1H), 4.99 (m,
    1H), 3.78 (d, J = 6.0 Hz,
    2H), 3.40 (m, 2H),
    3.22 (m, 2H), 2.37 (m,
    3H)
    AC42 79-82 534.72 7.99 (d, J = 8.0 Hz,
    ([M + H]+) 1H), 7.89 (d, J = 8.0 Hz,
    1H), 7.51 (m, 2H),
    7.44 (m, 2H), 7.27 (m,
    4H), 6.71 (t, J = 5.2 Hz,
    1H), 6.59 (d, J = 16.0 Hz,
    1H), 6.41 (dd, J = 16.0,
    8.0 Hz, 1H),
    5.05 (d, J = 1.6 Hz, 2H),
    4.12 (m, 1H), 2.52 (m,
    3H)
    AC43 481.75 8.69 (s, 1H), 8.52 (s, 1663,
    ([M + H]+) 2H), 7.45 (d, J = 7.6 Hz, 1608, 1168,
    1H), 7.37 (d, J = 2.0 Hz, 1114, 801
    1H), 7.26 (m, 2H),
    7.21 (m, 1H), 6.83 (s, 1H),
    6.58 (d, J = 16.0 Hz,
    1H), 6.40 (dd, J = 16.0,
    8.4 Hz, 1H), 4.81 (d, J = 5.6 Hz,
    2H), 4.12 (t, J = 8.4 Hz
    1H), 2.45 (s, 3H)
    AC44 528.01 8.44 (d, J = 2.4 Hz, 1H), 1640, 1166,
    ([M + H]+) 7.69 (d, J = 2.4 Hz, 1112, 800
    1H), 7.37 (m, 1H),
    7.33 (s, 1H), 7.31 (s, 1H),
    7.26 (m, 1H), 7.24 (m,
    3H), 6.57 (d, J = 16.0 Hz,
    1H), 6.39 (dd, J = 16.0,
    8.0 Hz, 1H),
    5.96 (d, J = 7.2 Hz, 1H),
    5.32 (t, J = 7.2 Hz, 1H),
    4.11 (t, J = 8.4 Hz, 1H),
    2.41 (s, 3H), 1.61 (d, J = 7.2 Hz,
    3H)
    AC45 512.88 7.66 (s, 1H), 7.37 (d, J = 6.8 Hz, 1657, 1167,
    ([M + H]+) 2H), 7.26 (m, 1106, 800
    3H), 7.18 (m, 1H),
    7.11 (m, 2H), 6.99 (m, 1H),
    6.57 (d, J = 15.6 Hz,
    1H), 6.39 (dd, J = 15.6,
    8.0 Hz, 1H), 4.11 (t, J = 8.4 Hz,
    1H), 3.36 (s,
    3H), 2.43 (s, 3H)
    AC46 61-64 575.93 8.42 (d, J = 2.0 Hz, 1H),
    ([M + H]+) 7.76 (d, J = 2.4 Hz, 1H),
    7.61 (m, 2H), 7.39 (m,
    3H), 7.26 (s, 2H),
    6.54 (d, J = 16.0 Hz, 1H),
    6.42 (dd, J = 16.0, 7.6 Hz,
    1H), 4.65 (d, J = 6.0 Hz,
    2H), 4.14 (m, 1H)
    AC47 525.89 10.02 (s, 1H), 9.87 (s, 3280, 1640
    ([M − H]−) 1H), 8.47 (t, J = 6.0 Hz,
    1H), 7.66 (s, 3H),
    7.44 (s, 1H), 7.40 (d, J = 3.6 Hz,
    2H), 6.86 (dd, J = 15.6,
    9.2 Hz, 1H),
    6.74 (d, J = 15.6 Hz, 1H),
    4.82 (t, J = 9.6 Hz, 2H),
    3.88 (d, J = 6.0 Hz, 2H),
    2.36 (s, 3H), 1.63 (m,
    1H), 0.76 (m, 4H)
    AC48 509.96 7.37 (m, 7H), 7.34 (m, 3275, 1642
    ([M − H]−) 3H),, 6.57 (d, J = 16.0 Hz,
    1H), 6.39 (dd, J = 16.0,
    8.0 Hz, 1H),
    6.01 (m, 1H), 4.60 (d, J = 6.0 Hz,
    2H), 4.13 (m, 1H),
    2.46 (s, 3H)
    AC49 518.85 8.39 (d, J = 2.0 Hz, 1H), 1658, 1112,
    ([M + H]+) 8.11 (m, 1H), 7.71 (d, J = 2.4 Hz, 1025, 2219
    1H), 7.41 (m,
    3H), 7.17 (m, 3H),
    6.59 (d, J = 16.0 Hz, 1H),
    6.47 (dd, J = 16.0, 8.0 Hz,
    1H), 4.66 (d, J = 5.6 Hz,
    2H), 4.14 (m,
    1H)
    AC50 481.88 8.72 (m, 1H), 7.67 (s, 1654, 1112,
    ([M + H]+) 3H), 7.46 (s, 1H), 800, 3069
    7.40 (m, 2H), 7.08 (s, 1H),
    6.82 (m, 2H), 6.55 (d, J = 7.6 Hz,
    1H), 4.82 (m,
    1H), 4.48 (s, 2H),
    3.65 (s, 3H), 2.38 (s, 3H)
    AC51 540.83 7.45 (d, J = 7.6 Hz, 1H), 1652, 1571,
    ([M + H]+) 7.38 (m, 1H), 7.27 (m, 802, 1114,
    2H), 7.22 (m, 2H), 2926
    6.85 (m, 1H), 6.58 (d, J = 16.0 Hz,
    1H), 6.40 (dd,
    J = 16.0, 8.0 Hz, 1H),
    4.33 (m, 2H), 4.14 (m,
    3H), 3.18 (s, 3H),
    2.48 (s, 3H)
    AC52 488.29 7.33 (m, 2H), 7.25 (m, 1635, 11134,
    ([M − H]−) 3H), 6.56 (d, J = 15.6 Hz, 813, 2927
    1H), 6.37 (dd, J = 15.6,
    8.0 Hz, 1H),
    5.61 (d, J = 8.0 Hz, 1H),
    4.21 (m, 1H), 4.01 (m, 1H),
    4.08 (m, 2H), 3.56 (t, J = 10.0 Hz,
    2H), 2.48 (m,
    2H), 2.08 (m, 2H),
    1.5 (m, 3H)
    AC53 532.92 8.49 (d, J = 2.0 Hz, 1H), 1651, 3027,
    ([M + H]+) 7.69 (d, J = 2.4 Hz, 1H), 815, 1113
    7.43 (d, J = 8.0 Hz, 1H),
    7.34 (m, 3H), 7.26 (m,
    2H), 6.95 (m, 1H),
    6.58 (d, J = 16.0 Hz, 1H),
    6.38 (dd, J = 16.0, 8.0 Hz,
    1H), 4.72 (d, J = 5.2 Hz,
    2H), 4.09 (m, 1H),
    2.47 (s, 3H)
    AC54 529.06 8.37 (d, J = 5.2 Hz, 1H), 1654, 3434,
    ([M − H]−) 7.41 (d, J = 8.0 Hz, 1H), 814, 1112
    7.36 (m, 3H), 7.31 (m,
    1H), 7.26 (m, 2H),
    6.58 (d, J = 16.0 Hz, 1H),
    6.40 (dd, J = 16.0, 7.6 Hz,
    1H), 5.20 (t, J = 5.6 Hz,
    1H), 4.63 (d, J = 6.0 Hz,
    2H), 4.13 (m, 1H),
    2.18 (s, 3H)
    AC57 464.96 8.69 (t, J = 6.0 Hz, 1H), 3417, 1658,
    ([M + H]+) 8.58 (t, J = 6.0 Hz, 1H), 1165, 817
    7.92 (s, 1H), 7.87 (d, J = 6.4 Hz,
    2H), 7.62 (d, J = 8.4 Hz,
    1H), 7.45 (d, J = 8.4 Hz,
    1H), 7.0 (m,
    1H), 6.76 (d, J = 15.6 Hz,
    1H), 6.76 (dd, J = 15.6,
    8.0 Hz, 1H),
    4.01 (m, J = 8.0 Hz, 1H),
    3.71 (m, 2H), 3.49 (m,
    2H)
    AC58 124.4-126.9 599.76 7.62 (m, 2H), 7.40 (s,
    ([M + H]+) 2H), 7.37 (d, J = 1.6 Hz,
    1H), 6.61 (t, J = 4.8 Hz,
    1H), 6.55 (d, J = 16.0 Hz,
    1H), 6.41 (dd, J = 16.0,
    7.6 Hz, 1H),
    4.16 (d, J = 6.0 Hz, 2H),
    4.01 (m, 1H), 1.56 (s, 9H)
    AC59 80-83 497.40 8.42 (d, J = 2.1 Hz, 1H),
    ([M − H]−) 8.29 (d, J = 7.5 Hz, 1H),
    7.51 (m, 2H), 7.39 (m,
    1H), 7.36 (m, 4H),
    7.28 (m, 1H), 6.61 (d, J = 15.9 Hz,
    1H), 6.45 (dd,
    J = 15.9, 7.8 Hz 1H),
    4.14 (t, J = 8.4 Hz, 1H),
    2.51 (s, 3H)
    AC60 515.09 8.52 (s, 1H), 8.39 (d, J = 1.8 Hz, 1668, 1589,
    ([M + H]−) 2H), 7.70 (d, J = 2.1 Hz, 1167, 1113,
    1H), 7.62 (s, 802
    1H), 7.43 (s, 1H),
    7.35 (m, 3H), 6.62 (d, J = 16.2 Hz,
    1H), 6.52 (dd,
    J = 16.2, 7.5 Hz, 1H),
    4.62 (d, J = 6.3 Hz,
    2H), 4.19 (m, 1H),
    2.76 (s, 3H)
    AC61 461.90 8.07 (t, J = 8.0 Hz, 1H), 1658, 1114,
    ([M − H]−) 7.39 (t, J = 2.0 Hz, 1H), 801
    7.28 (d, J = 1.2 Hz, 3H),
    7.17 (d, J = 1.6 Hz, 1H),
    7.11 (m, 1H), 6.59 (d, J = 15.6 Hz,
    1H),
    6.47 (dd, J = 15.6, 7.6 Hz,
    1H), 5.49 (m, 1H),
    4.14 (t, J = 8.4 Hz, 1H),
    3.48 (m, 4H)
    AC62 105-108 528.88 8.62 (t, J = 6.4 Hz, 1H),
    ([M − H]−) 8.46 (m, 1H), 7.73 (m,
    5H), 7.48 (d, J = 7.6 Hz,
    1H), 7.03 (dd, J = 15.6,
    9.2 Hz, 1H), 6.81 (d, J = 15.6 Hz,
    1H), 4.86 (m,
    1H), 3.97 (m, 4H)
    AC63 77-80 594.67 8.43 (s, 1H), 7.76 (d, J = 2.4 Hz, 3257, 1653
    ([M + H]+) 1H), 7.60 (m,
    2H), 7.38 (d, J = 7.6 Hz,
    1H), 7.33 (d, J = 6.4 Hz,
    3H), 6.54 (d, J = 16.0 Hz,
    1H), 6.46 (m, 1H),
    6.41 (dd, J = 16.0 8.0 Hz,
    1H), 4.65 (d, J = 6.0 Hz,
    2H), 4.15 (m, 1H)
    AC64 83-85 580.72 7.72 (d, J = 8.0 Hz, 1H),
    ([M − H]−) 7.44 (s, 1H), 7.40 (s,
    2H), 7.36 (d, J = 6.8 Hz,
    1H), 7.05 (t, J = 5.2 Hz,
    1H), 6.70 (t, J = 5.2 Hz,
    1H), 6.57 (d, J = 15.6 Hz,
    1H), 6.44 (dd, J = 15.6,
    8.0 Hz, 1H),
    4.23 (d, J = 5.6 Hz, 2H),
    4.15 (m, 1H), 4.01 (m, 2H)
    AC65 534.72 8.39 (d, J = 2.0 Hz, 1658, 1113,
    ([M − H]−) 1H), 8.12 (t, J = 8.4 Hz, 817, 2925
    1H), 7.71 (d, J = 2.4 Hz,
    1H), 7.34 (m, 3H),
    7.26 (m, 1H), 7.11 (m, 2H),
    6.59 (d, J = 16.0 Hz,
    1H), 6.46 (dd, J = 16.0,
    8.0 Hz, 1H), 4.66 (d, J = 5.2 Hz,
    2H), 4.13 (m,
    1H)
    AC66 73-75 624.61 7.88 (s, 1H), 7.63 (d, J = 1.6 Hz,
    ([M − H]−) 1H), 7.57 (d, J = 8.0 Hz,
    1H), 7.40 (m,
    2H), 6.80 (t, J = 5.6 Hz,
    1H), 6.70 (t, J = 5.6 Hz,
    1H), 6.56 (d, J = 16.0 Hz,
    1H), 6.44 (dd, J = 16.0,
    8.0 Hz, 1H),
    4.22 (m, 2H), 4.12 (m, 1H),
    4.01 (m, 2H)
    AC67 479.82 8.07 (t, J = 8.0 Hz, 1H), 3272, 1644
    ([M − H]−) 7.34 (d, J = 6.0 Hz, 2H),
    7.28 (s, 1H), 7.17 (s,
    2H), 6.59 (d, J = 15.6 Hz,
    1H), 6.46 (dd, J = 15.6,
    8.0 Hz, 1H),
    5.49 (m, 1H),, 4.12 (m, 1H),
    3.49 (m, 4H).
    AC68 90-93 546.80 8.6 (t, J = 6.4 Hz, 1H), 3315, 1684
    ([M − H]−) 8.45 (m, 1H), 7.86 (d, J = 6.4 Hz,
    2H), 7.75 (t, J = 8.0 Hz,
    1H), 7.63 (d, J = 12.0 Hz,
    1H), 7.48 (d,
    J = 8.0 Hz, 1H),
    7.03 (dd, J = 15.6, 9.6 Hz,
    1H), 6.80 (d, J = 15.6 Hz,
    1H), 4.88 (m, 1H),
    3.96 (m, 4H)
    AC69 542.82 7.41 (d, J = 8.0 Hz, 1H), 3294, 1685
    ([M − H]−) 7.34 (d, J = 5.6 Hz, 2H),
    7.26 (m, 1H), 7.23 (m,
    1H), 6.81 (s, 1H),
    6.57 (d, J = 15.6 Hz, 1H),
    6.55 (s, 1H), 6.39 (dd, J = 15.6,
    8.0 Hz, 1H),
    4.18 (m, 2H), 4.13 (m,
    1H), 3.97 (m, 2H),
    2.46 (s, 3H)
    AC70 176-178 545.23 8.38 (d, J = 2.4 Hz, 1H),
    ([M − H]−) 8.22 (d, J = 6.8 Hz, 2H),
    7.71 (d, J = 2.4 Hz, 1H),
    7.35 (d, J = 6.0 Hz, 2H),
    7.30 (d, J = 7.6 Hz, 1H),
    7.15 (d, J = 1.6 Hz, 1H),
    6.93 (d, J = 1.2 Hz, 1H),
    6.60 (d, J = 15.6 Hz,
    1H), 6.43 (dd, J = 15.6,
    7.6 Hz, 1H), 4.66 (d, J = 6.0 Hz,
    2H), 4.13 (m,
    1H), 3.98 (s, 3H)
    AC71 492.20 8.24 (d, J = 7.6 Hz, 1H), 1639, 3079,
    ([M − H]−) 8.15 (d, J = 8.4 Hz, 1H), 858
    7.35 (d, J = 6.0 Hz, 2H),
    7.13 (d, J = 1.2 Hz, 1H),
    6.92 (s, 1H), 6.61 (d, J = 16.0 Hz,
    1H), 6.43 (dd,
    J = 16.0, 7.6 Hz, 1H),
    5.48 (m, 1H), 4.13 (m,
    1H), 4.03 (s, 3H),
    3.48 (m, 4H)
    AC72 543.05 8.42 (d, J = 2.4 Hz, 1H), 1642, 3246,
    ([M − H]−) 7.75 (d, J = 2.4 Hz, 1H), 814, 1113
    7.34 (m, 4H), 7.20 (m,
    2H), 6.60 (d, J = 16.0 Hz,
    1H), 6.36 (dd, J = 16.0,
    8.0 Hz, 1H),
    6.12 (t, J = 5.6 Hz, 1H),
    4.62 (d, J = 6.0 Hz, 2H),
    4.20 (m, 1H), 2.82 (m, 2H),
    1.45 (t, J = 5.6 Hz, 3H)
    AC75 644.78 8.72 (s, 1H), 7.97 (d, J = 7.2 Hz, 3431, 1652,
    ([M + H]+) 1H), 7.70 (d, J = 8.4 Hz, 1171, 809
    1H), 7.61 (m,
    2H), 7.40 (m, 2H),
    6.55 (m, 2H), 6.42 (dd, J = 16.0,
    8.0 Hz, 1H),
    4.76 (d, J = 6.0 Hz, 2H),
    4.12 (m, 1H)
    AC76 531.34 8.87 (t, J = 6.0 Hz, 1H), 3120, 1708,
    ([M + H]+) 8.34 (d, J = 2.1 Hz, 1H), 1171
    7.85 (d, J = 6.3 Hz, 3H),
    7.48 (m, 4H), 6.57 (d, J = 15.6 Hz,
    1H),
    6.45 (dd, J = 15.6, 9.0 Hz,
    1H), 4.84 (m, 1H),
    4.49 (d, J = 5.7 Hz, 2H),
    2.82 (m, 2H), 2.36 (t, J = 5.6 Hz,
    3H)
    AC77 531.1 8.87 (t, J = 6.0 Hz, 1H), 3444, 1648,
    ([M + H]+) 8.34 (d, J = 2.1 Hz, 1H), 1114, 814
    7.85 (d, J = 6.3 Hz, 3H),
    7.48 (m, 4H), 6.57 (d, J = 15.6 Hz,
    1H),
    6.45 (dd, J = 15.6, 8.0 Hz,
    1H), 4.84 (m, 1H),
    4.49 (d, J = 5.7 Hz, 2H),
    2.36 (s, 3H)
    AC78 561.06 8.59 (t, J = 6.4 Hz, 1H), 3432, 1631,
    ([M + H]+) 8.47 (t, J = 5.6 Hz, 1H), 1161, 840
    7.89 (s, 2H), 7.45 (m,
    3H), 6.87 (m, 1H),
    6.75 (d, J = 15.6 Hz, 1H),
    4.85 (t, J = 8.0 Hz 1H),
    3.98 (m, 4H), 2.58 (s,
    3H)
    AC79 610.97 8.69 (t, J = 6.0 Hz, 1H), 3303, 1658,
    ([M + H]+) 8.58 (t, J = 6.0 Hz, 1H), 1166, 817
    7.92 (s, 1H), 7.87 (d, J = 6.4 Hz,
    2H), 7.62 (d, J = 8.4 Hz,
    1H), 7.45 (d, J = 8.4 Hz,
    1H), 7.0 (m,
    1H), 6.76 (d, J = 15.6 Hz,
    1H) 4.83 (t, J = 8.0 Hz,
    1H), 3.98 (m, 4H)
    AC80 561.06 7.37 (m, 3H), 7.26 (m, 3412, 1624,
    ([M + H]+) 1H), 7.24 (m, 1H), 1157, 825
    6.59 (d, J = 15.6 Hz, 1H),
    6.39 (dd, J = 15.6, 8.0 Hz,
    1H), 4.24 (m, 4H),
    3.90 (m, 1H), 2.83 (m,
    2H), 1.26 (m, 3H)
    AC81  9-92 546.93 8.73 (d, J = 5.6 Hz,
    ([M − H]−) 1H), 8.45 (t, J = 6.0 Hz,
    1H), 7.76 (s, 3H),
    7.45 (m, 3H), 6.86 (dd, J = 16.0,
    9.2 Hz, 1H),
    4.83 (m, 1H), 4.56 (m, 2H),
    4.51 (m, 1H), 4.10 (m,
    2H), 3.85 (d, J = 6.0 Hz,
    2H), 2.50 (m, 3H)
    AC82 477.69 7.38 (d, J = 1.8 Hz, 1646, 1353,
    ([M + H]+) 2H), 7.33 (s, 1H), 1196, 1112,
    7.27 (s, 3H), 6.58 (d, J = 16.0 Hz, 800
    1H), 6.42 (d, J = 8.1 Hz,
    1H), 6.36 (dd, J = 16.0,
    7.8 Hz, 1H),
    4.71 (m, 1H), 4.23 (m, 3H),
    3.26 (m, 2H), 2.45 (s,
    3H)
    AC83 493.83 8.07 (t, J = 8.4 Hz, 1H), 1527, 1113,
    ([M − H]−) 7.39 (t, J = 1.6 Hz, 1H), 801, 1167,
    7.31 (d, J = 1.2 Hz, 1H), 1321
    7.26 (m, 2H), 7.23 (m,
    1H), 7.19 (d, J = 1.6 Hz,
    1H), 6.60 (d, J = 16.8 Hz,
    1H), 6.49 (dd, J = 16.8,
    7.6 Hz, 1H),
    4.90 (m, 1H), 4.64 (m, 2H),
    4.14 (m, 2H), 4.10 (m,
    1H)
    AC84 511.75 8.07 (t, J = 8.0 Hz, 1H), 1645, 1113,
    ([M − H]−) 7.34 (m, 3H), 7.19 (d, J = 13.2 Hz, 804, 3030,
    1H), 6.60 (d, 1245
    J = 16.4 Hz, 1H),
    6.48 (dd, J = 16.4, 8.0 Hz,
    1H), 4.88 (m, 1H),
    4.62 (m, 2H), 4.12 (m, 3H)
    AC85 523.83 8.60 (d, J = 6.8 Hz, 1H), 1652, 3039,
    ([M − H]−) 8.15 (d, J = 8.4 Hz, 1H), 802, 1114
    7.35 (d, J = 6.0 Hz, 1H),
    7.15 (d, J = 7.2 Hz, 1H),
    6.94 (s, 1H), 6.60 (d, J = 15.6 Hz,
    1H), 6.44 (dd,
    J = 7.6, 7.6 Hz, 1H),
    4.93 (m, 1H), 4.62 (m,
    2H), 4.13 (m, 6H)
    AC86 524.36 7.35 (d, J = 6.3 Hz, 3H), 3333, 1651,
    ([M + H]+) 7.26 (m, 2H), 7.20 (m, 815
    1H), 6.60 (d, J = 15.9 Hz,
    1H), 6.47 (dd, J = 15.9,
    6.6 Hz, 1H),
    4.86 (m, 1H), 4.65 (m, 2H),
    4.13 (m, 3H), 2.84 (q,
    2.8 Hz, 2H), 1.26 (m,
    3H)
    AC87 495.82 8.07 (t, J = 8.0 Hz, 1H), 1623, 1114,
    ([M − H]−) 7.52 (m, 3H), 7.19 (d, J = 13.2 Hz, 816
    1H), 6.59 (d,
    J = 16.4 Hz, 1H),
    6.47 (dd, J = 16.4, 8.0 Hz,
    1H), 4.69 (m, 1H),
    4.23 (m, 3H), 3.29 (m, 2H)
    AC89 509.89 7.43 (m, 2H), 7.27 (m, 1666, 1166,
    ([M + H]+) 2H), 7.23 (m, 2H), 1112, 800
    6.58 (d, J = 16.0 Hz, 1H),
    6.41 (dd, J = 16.0, 7.6 Hz,
    1H), 4.79 (d, J = 5.6 Hz,
    2H), 4.14 (m,
    1H), 2.48 (s, 3H),
    2.18 (m, 1H), 1.16 (m,
    4H)
    AC90 656.9 8.34 (m, 1H), 8.27 (m,
    ([M − H]−) 1H), 7.60 (d, J = 1.6 Hz,
    1H), 7.49 (d, J = 8.0 Hz,
    2H), 7.40 (s, 2H),
    7.36 (dd, J = 8.2, 1.7 Hz,
    1H), 6.53 (d, J = 16.0 Hz,
    1H), 6.38 (dd, J = 15.9,
    7.9 Hz, 1H),
    4.89 (d, J = 8.4 Hz, 2H),
    4.48 (d, J = 9.0 Hz, 2H),
    4.11 (m, 1H)
    AC91 640.9 8.18 (t, J = 5.0 Hz, 1H),
    ([M − H]−) 7.58 (d, J = 1.6 Hz, 1H),
    7.47 (d, J = 8.0 Hz, 1H),
    7.40 (s, 2H), 7.34 (dd, J = 8.1,
    1.6 Hz, 1H),
    6.52 (m, 2H), 6.37 (dd, J = 15.9,
    7.9 Hz, 1H),
    4.54 (d, J = 4.9 Hz, 2H),
    4.12 (m, 1H), 3.99 (qd, J = 8.9,
    6.5 Hz, 2H)
    AC92 640.9 9.16 (d, J = 6.1 Hz, 1H),
    ([M − H]−) 7.65 (d, J = 1.6 Hz, 1H),
    7.57 (d, J = 8.0 Hz, 1H),
    7.41 (m, 3H), 7.21 (t, J = 5.6 Hz,
    1H), 6.55 (d, J = 15.9 Hz,
    1H),
    6.41 (dd, J = 15.9, 7.8 Hz,
    1H), 4.59 (d, J = 5.6 Hz,
    2H), 4.45 (qd, J = 9.0,
    6.0 Hz, 2H), 4.12 (q, J = 7.2 Hz,
    1H)
    AC93 485.5 7.52-7.41 (d, J = 8.2 Hz, 13C NMR (δ)3
    ([M + H]+) 1H), 7.39-7.34 (m, 1H), 169.91,
    7.24-7.17 (d, J = 1.8 Hz, 169.84,
    2H), 7.02-6.92 (m, 2H), 138.23,
    6.90-6.83 (d, J = 11.4 Hz, 137.41,
    1H), 6.71 (br s, 1H), 136.84,
    6.17 (br s, 1H), 134.79,
    6.12-6.01 (dd, J = 11.4, 10.3 Hz, 134.69,
    1H), 4.44-4.38 (d, J = 4.2 Hz, 131.07,
    1H), 128.69,
    4.35-4.27 (m, 1H), 4.10-3.99 (d, J = 5.1 Hz, 127.49,
    2H), 127.43,
    2.78-2.67 (m, 1H), 2.44 (s, 3H), 126.72,
    0.88-0.78 (m, 2H), 126.61 (q, J = 212.10 Hz),
    0.60-0.45 (m, 2H) 125.61,
    123.76,
    47.89 (q, J = 28.28 Hz),
    43.46,
    22.65, 19.97,
    8.21
    AC94 511.6 8.36-8.24 (d, J = 2.4 Hz, 3262, 1607,
    ([M]−) 1H), 7.75-7.64 (m, 1247, 1164,
    1H), 7.38-7.24 (m, 1111
    3H), 7.24-7.09 (d, J = 1.8 Hz,
    2H),
    6.99-6.90 (m, 2H), 6.89-6.74 (d,
    J = 11.4 Hz, 1H),
    6.63-6.43 (m, 1H),
    6.14-5.98 (m, 1H),
    4.69-4.51 (d, J = 6.1 Hz, 2H),
    4.37-4.20 (m, 1H),
    2.46-2.31 (s, 3H)
    AC95 48-61 626.9 7.58 (d, J = 7.9 Hz, 1H),
    ([M + H]+) 7.44-7.29 (m, 3H),
    7.14 (dd, J = 7.9, 1.6 Hz,
    1H), 6.86 (d, J = 11.4 Hz,
    1H), 6.76 (t, J = 5.9 Hz,
    1H), 6.59 (br
    s, 1H), 6.21-6.04 (m,
    1H), 4.23 (d, J = 5.5 Hz,
    1H), 3.98 (qd, J = 9.0,
    6.5 Hz, 2H)
    AC96 619.6 8.83 (s, 1H), 8.06 (br, 1616, 1114
    ([M + H]+) 1H), 7.90 (s, 2H),
    7.63 (d, J = 8.1 Hz, 2H),
    7.53 (m, 1H), 6.94 (m, 1H),
    6.77 (d, J = 15.3 Hz,
    1H), 6.63 (d, J = 9.3 Hz,
    1H), 4.84 (m, 1H),
    4.30 (d, J = 5.6 Hz, 2H),
    2.99 (s, 6H)
    AC97 606.6 8.20 (d, J = 2.1 Hz, 1644, 1113
    ([M + H]+) 1H), 7.73 (d, J = 2.7 Hz,
    1H), 7.60 (m, 2H),
    7.39 (s, 2H), 7.29 (m, 1H),
    6.79 (d, J = 8.4 Hz, 1H),
    6.55 (d, J = 15.9 Hz,
    1H), 6.40 (m, 2H),
    4.60 (d, J = 2.7 Hz, 2H),
    4.13 (m, 1H), 3.95 (s, 3H)
    AC98 577.87 9.04 (t, J = 6.0 Hz, 1H), 1663, 1168
    ([M + H]+) 8.60 (t, J = 6.6 Hz, 1H),
    8.25 (s, 1H), 7.97 (d, J = 8.1 Hz,
    1H), 7.87 (d, J = 6.3 Hz,
    2H), 7.69 (d, J = 7.5 Hz,
    1H), 7.15 (dd,
    J = 15.9, 9.3 Hz, 1H),
    6.89 (d, J = 15.9 Hz,
    1H), 4.86 (m, 1H),
    3.98 (m, 4H).
    AC99 574.81 8.69 (t, J = 6.0 Hz, 1H), 1650, 1164
    ([M + H]+) 8.58 (t, J = 6.6 Hz, 1H),
    7.91 (s, 1H), 7.85 (m,
    1H), 7.61 (m, 2H),
    7.52 (m, 2H), 6.98 (dd, J = 15.3,
    9.0 Hz, 1H),
    6.76 (d, J = 15.3 Hz, 1H),
    4.81 (m, 1H), 4.01 (m,
    4H)
    AC100 673.80 8.29 (s, 1H), 8.22 (d, J = 8.1 Hz, 3403, 1659
    ([M + H]+) 1H), 7.93 (d, J = 7.8 Hz,
    1H), 7.72 (m,
    1H), 7.65 (m, 2H),
    7.40 (s, 2H), 7.18 (br, 1H),
    6.59 (d, J = 16.0 Hz,
    1H), 6.43 (dd, J = 16.0,
    7.6 Hz, 1H), 5.02 (d, J = 1.2 Hz,
    2H), 4.12 (m,
    1H)
    AC101 636.83 7.56 (d, J = 9.0 Hz, 1637, 1113
    ([M + H]+) 1H), 7.39 (d, J = 6.0 Hz,
    2H), 7.26 (m, 2H),
    6.54 (d, J = 15.9 Hz,
    1H), 6.37 (dd, J = 8.0,
    15.9 Hz, 1H), 4.01 (m,
    1H), 3.84 (m, 2H),
    3.33 (m, 2H), 3.04 (m, 2H),
    2.84 (m, 3H), 2.62 (m,
    1H)
    AC102 592.84 7.60 (m, 2H), 7.32 (m, 1668, 1167
    ([M + H]+) 1H), 7.03 (d, J = 7.2 Hz,
    2H), 6.74 (br, 1H),
    6.62 (br, 1H), 6.56 (d, J = 16.2 Hz,
    1H), 6.41 (dd,
    J = 16.2, 7.8 Hz, 1H),
    4.22 (d, J = 5.4 Hz,
    2H), 4.14 (m, 1H),
    4.01 (m, 2H)
    AC103  99.2-105.0 612.7 8.40 (d, J = 8.0 Hz, 1H), 1634, 1113,
    ([M + H]+) 7.92 (d, J = 5.2 Hz, 1H), 809
    7.59 (d, J = 8.0 Hz, 1H),
    7.35 (d, J = 8.0 Hz, 1H),
    6.99 (dd, J = 16.0, 7.6 Hz,
    1H), 6.76 (d, J = 16.0 Hz,
    1H), 4.84 (m,
    1H), 4.23 (d, J = 13.2 Hz,
    1H), 3.97 (m, 1H),
    3.79 (d, J = 13.6 Hz,
    1H), 3.16 (t, J = 11.2 Hz,
    1H), 2.77 (t, J = 11.2 Hz,
    1H), 1.99 (s,
    3H), 1.88 (m, 2H),
    1.45 (m, 2H)
    AC104 680.97 7.60 (m, 2H), 7.40 (m 3437,
    ([M + H]+) 3H), 6.55 (d, J = 15.6 Hz, 1644,
    1H), 6.41 (dd, J = 15.6, 1113,
    7.8 Hz, 1H), 807,
    4.24 (m, 1H), 3.34 (m, 2H), 511
    2.90 (m, 1H), 2.24 (m,
    2H), 1.52 (m, 2H),
    1.34 (m, 4H)
    AC105 609.9 7.59 (s, 1H), 7.55 (m, 3303, 1649,
    ([M + H]+) 1H), 7.50 (m, 1H), 1115, 2242,
    7.40 (m, 2H), 6.54 (d, J = 16.0 Hz, 809, 506
    1H), 6.50 (J = 16.0,
    8.0 Hz, 1H),
    4.14 (m, 2H), 3.08 (m, 4H),
    2.67 (m, 2H), 2.12 (m,
    2H), 1.70 (m, 2H).
    AC106 584.95 7.59 (s, 1H), 7.51 (d, J = 8.4 Hz, 3417,
    ([M + H]+) 1H), 7.40 (s, 1648,
    2H), 7.36 (d, J = 6.8 Hz, 1112,
    1H), 6.54 (d, J = 16.0 Hz, 805, 555
    1H), 6.40 (dd, J = 16.0,
    8.0 Hz, 1H),
    6.03 (d, J = 8.0 Hz, 1H),
    4.11 (m, 2H), 3.10 (m, 2H),
    2.50 (m, 2H), 2.50 (s,
    3H) (m, 2H), 1.94 (m,
    2H)
    AC107 609.9 8.41 (d, J = 7.8 Hz, 1H), 3303,
    ([M + H]+) 7.90 (s, 2H), 7.62 (m, 1645,
    2H), 7.51 (m, 1H), 1115,
    6.92 (dd, J = 15.9, 9.0 Hz, 2243,
    1H), 6.77 (d, J = 15.9 Hz, 810,
    1H), 4.81 (m, 1H), 507
    3.73 (s, 2H), 3.31 (m,
    1H), 3.28 (m, 1H),
    2.82 (t, J = 11.4 Hz, 2H),
    2.82 (m, 2H), 2.30 (m,
    2H), 1.88 (m, 2H),
    1.57 (m, 2H)
    AC108 626.9 7.60 (m, 2H) 7.39 (s, 3420,
    ([M + H]+) 2H), 7.28 (m, 1H), 1649,
    6.56 (d, J = 15.6 Hz, 1H), 1113,
    6.40 (dd, J = 15.6, 7.8 Hz, 809,
    1H), 5.91 (m, 1H), 554
    4.65 (m, 2H), 4.10 (m,
    1H), 4.07 (m, 2H),
    3.59 (m, 1H), 2.74 (m, 2H),
    2.13 (m, 4H), 2.07 (m,
    1H)
    AC109 614.6 7.56 (m, 2H), 7.39 (s, 1647, 1113
    ([M + H]+) 2H), 7.29 (s, 1H),
    6.50 (d, J = 15.9 Hz, 1H),
    6.41 (dd, J = 15.9, 8.0 Hz
    1H), 4.09 (m, 1H),
    3.88 (m, 2H), 3.49 (m,
    2H), 2.92 (m, 2H),
    2.81 (m, 1H), 2.74 (m, 2H),
    2.25 (m, 4H)
    AC110 572.6 11.20 (s, 1H), 8.66 (br, 3412, 1690,
    ([M + H]+) 1H), 7.92 (m, 3H), 1114, 846,
    7.62 (d, J = 8.0 Hz, 1H), 559
    7.45 (d, J = 8.0 Hz, 1H),
    6.77 (dd, J = 15.6, 9.2 Hz,
    1H), 6.77 (d, J = 15.6 Hz,
    1H), 4.85 (m, 1H),
    3.74 (d, J = 5.2 Hz, 2H),
    3.61 (s, 3H)
    AC111 582.79 8.63 (t, J = 6.0 Hz, 1H), 3419, 1659,
    ([M + H]+) 8.04 (t, J = 6.0 Hz, 1H), 843, 557
    7.92 (m, 3H), 7.62 (d, J = 1.2 Hz,
    1H), 7.47 (d, J = 7.6 Hz,
    1H), 7.00 (dd,
    J = 15.6, 8.8 Hz, 1H),
    6.77 (d, J = 15.6 Hz,
    1H), 5.19 (d, J = 1.6 Hz,
    1H), 5.01 (d, J = 1.2 Hz,
    1H), 4.85 (m, 1H),
    3.86 (d, J = 5.6 Hz, 2H),
    3.75 (t, J = 5.6 Hz, 2H)
    AC112 582.79 8.84 (br, 1H), 8.58 (m, 3399, 1662,
    ([M + H]+) 1H), 8.30 (m, 1H), 1114, 807,
    7.91 (s, 2H), 7.61 (d, J = 8.1 Hz, 582
    1H), 7.42 (d, J = 7.8 Hz,
    1H), 7.00 (dd, J = 15.6,
    9.3 Hz, 1H),
    6.77 (d, J = 15.6 Hz, 1H),
    4.85 (m, 1H), 4.11 (d, J = 5.6 Hz,
    1H), 3.73 (d,
    J = 5.6 Hz, 1H), 3.04 (s,
    6H)
    AC113 626.88 8.48 (t, J = 5.2 Hz, 1H), 3431, 1651,
    ([M + H]+) 8.3 (s, 1H), 7.90 (s, 2H), 1113, 808,
    7.79 (dd, J = 2.0, 2.0 Hz 554
    2H), 7.58 (d, J = 8.4 Hz,
    1H) 7.46 (d, J = 7.6 Hz,
    1H) 7.26 (d, J = 7.6 Hz,
    1H), 6.98 (m, 1H),
    6.75 (d, J = 15.6 Hz, 1H),
    4.85 (m, 1H), 3.49 (d, J = 6.4 Hz,
    2H) 2.87 (t, J = 6.4 Hz,
    2H)
    AC114 113.7-117.5 570.7 8.77 (s, 1H), 8.58 (d, J = 7.2 Hz,
    ([M + H]+) 2H), 7.93 (d, J = 7.2 Hz,
    2H), 7.60 (dd, J = 1.2,
    0.8 Hz, 1H),
    7.37 (d, J = 7.6 Hz, 1H),
    6.99 (m, 1H), 6.77 (d, J = 16 Hz,
    1H), 4.85 (m, 1H),
    4.10 (m, 1H) 3.29 (m,
    2H), 3.05 (m, 2H),
    2.0 (m, 2H), 1.76 (m, 2H)
    AC115 529.00 8.43 (s, 1H), 7.79 (d, J = 8.0 Hz, 1589, 3459,
    ([M + H]+) 1H), 7.51 (m, 801, 1110
    1H), 7.36 (d, J = 8.4 Hz,
    3H), 7.21 (m, 3H),
    6.55 (d, J = 15.6 Hz, 1H),
    6.36 (dd, J = 15.6, 8.0 Hz,
    1H), 5.04 (d, J = 5.6 Hz,
    2H), 4.10 (m, 1H),
    2.35 (s, 3H)
    AC116 614.87 7.99 (d, J = 8.4 Hz, 1H), 3424, 1657,
    ([M + H]+) 7.46 (d, J = 1.6 Hz, 1H), 1165
    7.34 (d, J = 6.4 Hz, 2H),
    7.28 (m, 2H), 6.62 (m,
    2H), 6.47 (dd, J = 16.0,
    7.2 Hz, 1H), 4.23 (m,
    2H), 4.12 (m, 1H),
    4.00 (m, 2H)
    AC117 525.42 8.39 (br, 1H), 7.85 (br, 3401, 1636,
    ([M − H]−) 1H), 7.62 (m, 3H), 1113, 750
    7.53 (d, J = 8.0 Hz, 1H),
    7.46 (s, 1H), 7.40 (d, J = 8.0 Hz,
    1H), 7.17 (m, 1H),
    6.78 (dd, J = 16.0, 8.8 Hz,
    1H), 6.70 (m, 1H),
    4.77 (m, 1H), 4.66 (s,
    1H), 4.32 (s, 1H),
    2.97 (s, 3H), 2.16 (s, 3H)
    AC118 471.79 7.36 (d, J = 8.0 Hz, 2H), 3437, 1655,
    ([M + H]+) 7.27 (m, 2H), 7.22 (m, 1262, 1105,
    2H), 6.57 (d, J = 16.0 Hz, 802
    1H), 6.38 (dd, J = 16.0,
    8.0 Hz, 1H),
    6.10 (br, 1H), 4.15 (m, 2H),
    3.89 (m, 1H), 3.80 (m,
    2H), 3.35 (m, 1H),
    2.46 (s, 3H), 2.06 (s, 1H),
    1.96 (m, 2H), 1.65 (m,
    1H)
    BC1 492.17 7.39 (s, 2H), 3211, 1569,
    ([M + H]+) 7.25-7.18 (m, 3H), 6.58 (d, J = 16.0 Hz, 1113, 806
    1H), 6.30 (dd,
    J = 16.0, 8.4 Hz, 1H),
    5.91-5.70 (br, 2H),
    4.05 (m, 1H),
    3.05-2.80 (m, 6H), 2.70 (m,
    1H), 1.81 (m, 1H)
    BC2 506.4 8.80 (s, 1H), 8.20 (s, 2923, 1542,
    ([M + H]+) 1H), 7.82 (m, 3H), 1033, 805
    7.4 (s, 2H), 6.62 (d, J = 16.0 Hz,
    1H), 6.52 (dd, J = 16.0,
    8.0 Hz, 1H),
    4.18 (m, 1H), 3.38 (m,
    2H), 2.98 (m, 2H),
    2.71 (m, 1H), 2.04 (m, 2H),
    1.54 (s, 3H).
    BC3 518.04 7.40 (s, 2H), 3120, 1592,
    ([M − H]−) 7.33-7.22 (m, 3H), 6.61 (d, J = 16.0 Hz, 1146, 895
    1H),
    6.34-6.28 (dd, J = 16.0, 8.0 Hz,
    1H), 5.96-5.80 (m,
    3H), 5.22 (m, 4H),
    4.01 (m, 2H), 2.84-2.99 (m,
    2H), 2.71 (m, 1H),
    1.86 (m, 1H)
    BC4 529.02 7.39 (s, 2H), 3283, 1652,
    ([M + H]+) 7.25-7.20 (m, 3H), 6.34 (d, J = 16.0 Hz, 1241, 811
    1H), 6.30 (dd, J = 16.0,
    8.0 Hz, 1H),
    5.81 (br, 1H), 5.48 (m,
    1H), 4.10 (m, 1H),
    3.10 (m, 2H), 2.86-3.07 (m,
    2H), 2.86 (m, 1H),
    1.81 (m, 1H);
    BC5 544.25 7.40 (s, 2H), 7.21 (s, 3489, 3291,
    ([M − H]−) 1H), 7.12 (m, 1H), 1655, 1112,
    6.56 (d, J = 16.0 Hz, 1H), 808
    6.32 (dd, J = 16.0, 8.4 Hz,
    1H), 5.85 (br s, 1H),
    5.23 (br s, 1H), 4.12 (m,
    1H), 3.18 (m, 3H),
    2.80 (m, 3H), 2.08 (m, 2H),
    1.83 (m, 5H), 1.25 (m,
    2H), 1.01 (m, 3H),
    0.78 (m, 2H)
    BC6 485.96 7.40 (s, 2H), 3429, 1114,
    ([M − H]−) 7.31-7.18 (m, 3H), 6.58 (d, J = 16.0 Hz, 804
    1H),
    6.24-6.28 (dd, J = 16.0, 8.0 Hz,
    1H), 5.40 (br, 1H),
    4.01 (m, 2H),
    2.78-3.01 (m, 2H), 2.51 (s,
    1H), 1.86 (m, 1H),
    1.20 (m, 2H), 1.01 (m, 2H),
    0.78 (m, 2H)
    BC7 500.01 7.40 (s, 2H), 7.31 (s, 3296, 1115,
    ([M − H]−) 1H), 7.18 (m, 1H), 806
    7.18 (s, 1H), 6.58 (d, J = 16.0 Hz,
    1H), 6.32 (dd, J = 16.0,
    8.0 Hz, 1H),
    5.78 (br s, 1H), 5.21 (br s,
    1H), 4.01 (m, 1H),
    2.78 (m, 2H), 2.01 (m, 1H),
    1.86 (m, 4H), 1.25 (m,
    2H), 1.01 (m, 3H),
    0.78 (m, 2H)
    BC8 511.88 7.38-7.20 (m, 5H), 1657, 1113,
    ([M − H]−) 6.62 (d, J = 16.0 Hz, 1H), 855
    6.34 (dd, J = 16.0, 8.0 Hz,
    1H), 5.83 (br, 1H),
    5.52 (m, 1H), 4.12 (m,
    1H), 3.12 (m, 2H),
    3.06-2.82 (m, 2H), 2.75 (m,
    1H), 1.85 (m, 1H)
    BC9 179-181 556.83 8.30 (s, 1H), 7.68 (d, J = 6.4 Hz,
    ([M − H]−) 1H),
    7.38-7.20 (m, 5H), 6.60 (d, J = 16.0 Hz,
    1H), 6.34 (dd,
    J = 16.0, 8.0 Hz, 1H),
    5.63 (br, 1H), 5.52 (m,
    1H), 4.12 (m, 1H),
    3.56 (s, 2H), 3.06-2.82 (m,
    2H), 2.70 (m, 1H),
    1.82 (m, 1H)
    BC10 497.98 7.38-7.20 (m, 5H), 3027, 1654,
    ([M − H]−) 6.62 (d, J = 16.0 Hz, 1H), 815
    6.34 (dd, J = 16.0, 8.0 Hz,
    1H), 5.83 (br, 1H),
    5.52 (m, 1H), 4.12 (m,
    1H), 3.02 (m, 3H),
    2.82 (m, 1H), 2.50 (m, 3H),
    1.82 (m, 1H), 1.42 (m,
    1H)
    BC11 530.09 7.80 (m, 1H), 7.48 (m, 1715, 1113,
    ([M − H]−) 2H), 7.32 6.65 (d, J = 16.0 Hz, 816
    1H), 6.54 (dd,
    J = 16.0, 8.0 Hz, 1H),
    5.38 (m, 1H), 4.18 (m,
    1H), 3.62 (m, 1H),
    3.32 (m, 1H), 2.86 (m, 1H),
    1.81 (m, 1H)
    BC12 514.86 7.32, (d, J = 6.0 Hz, 2H) 3428, 1112,
    ([M + H]+) 7.28 (m, 1H), 7.20 (d, J = 8.0, 857
    1H), 7.14 (d, J = 8.8,
    1H), 6.70 (d, J = 8.0 Hz,
    1H), 6.60 (m,
    2H), 4.15 (m, 1H),
    3.85 (m, 1H), 3.65 (m, 1H),
    3.46 (m, 2H), 3.19 (m,
    2H);
    BC13 121-126 553.06 8.33 (br, 1H), 7.59 (s,
    ([M − H]−) 1H), 7.45 (m, 3H),
    6.72 (d, J = 3.6, 1H),
    6.39 (m, 1H), 4.71 (t, J = 7.2 Hz,
    2H), 4.15 (m, 2H)
    BC14 172-175 554.0 8.83 (t, J = 6.6 Hz, 1H),
    ([M − H]−) 8.42 (t, J = 14.7 Hz,
    1H), 8.22 (d, J = 8.1 Hz,
    1H), 8.13 (t, J = 6.3 Hz,
    1H), 7.98-7.86 (m,
    2H), 7.16-7.07 (m,
    1H), 7.01-6.93 (m,
    1H), 4.96-4.81 (m,
    3H), 4.00-3.88 (m, 2H)
    CC1 107-109 402.00 7.37 (m, 3H), 7.28 (m,
    ([M + H]+) 4H), 6.60 (d, J = 16.0 Hz,
    1H), 6.36 (dd, J = 16.0,
    8.0 Hz, 1H),
    5.75 (br s, 1H), 4.46 (d, J = 6 Hz,
    2H), 4.01 (m, 1H),
    2.11 (s, 3H)
    CC2 118-120 428.11 7.37 (m, 3H), 7.28 (m,
    ([M + H]+) 4H), 6.60 (d, J = 16.0 Hz,
    1H), 6.35 (dd, J = 16.0,
    8.0 Hz, 1H),
    5.83 (br s, 1H), 4.46 (d, J = 6.0 Hz,
    2H), 4.11 (m,
    1H), 1.40 (m, 1H),
    1.02 (m, 2H), 0.77 (m, 2H)
    CC3 119-122 468.20 7.38 (m, 3H), 7.27 (m,
    ([M − H]−) 3H), 6.60 (d, J = 16.0 Hz,
    1H), 6.36 (dd, J = 16.0,
    8.4 Hz, 1H),
    5.00 (br s, 1H), 4.48 (d, J = 5.6 Hz,
    2H), 4.11 (m,
    1H), 3.15 (q, J = 10.4 Hz,
    2H)
    CC4 414.16 7.37 (m, 3H), 7.28 (m,
    ([M − H]−) 3H), 6.60 (d, J = 16.0 Hz,
    1H), 6.35 (dd, J = 16.0,
    8.0 Hz, 1H),
    5.69 (br s, 1H), 4.46 (d, J = 6.0 Hz,
    2H), 4.21 (m,
    1H), 2.29 (q, J = 5.8 Hz,
    2H), 1.30 (t, J = 7.2 Hz,
    3H)
    CC5 460.28 7.40 (m, 3H), 7.28 (m,
    ([M − H]−) 2H), 6.60 (d, J = 15.6 Hz,
    1H), 6.33 (dd, J = 15.6,
    8.0 Hz, 1H),
    5.84 (br s, 1H), 4.46 (d, J = 5.6 Hz,
    2H), 4.10 (m,
    1H), 1.36 (m, 1H),
    1.02 (m, 2H), 0.77 (m, 2H)
    CC6 106-108 504.08 7.40 (m, 3H), 7.26 (m,
    ([M − H]−) 1H), 6.60 (d, J = 16.0 Hz,
    1H), 6.34 (dd, J = 16.0,
    8.0 Hz, 1H),
    5.96 (br s, 1H), 4.49 (d, J = 5.6 Hz,
    2H), 4.10 (m,
    1H), 3.15 (q, J = 10.8 Hz,
    2H)
    CC7 127-128 436.03 7.42 (m, 4H), 7.24 (m,
    ([M + H]+) 2H), 6.53 (d, J = 16.0 Hz,
    1H), 6.36 (dd, J = 16.0,
    8.0 Hz, 1H),
    5.86 (br s, 1H), 4.51 (d, J = 6.0 Hz,
    2H), 4.05 (m,
    1H), 2.02 (s, 3H)
    CC8 129-131 462.15 8.58 (t, J = 5.6 Hz, 1H),
    ([M + H]+) 7.72 (m, 1H), 7.66 (m,
    3H), 7.49 (d, J = 8.0 Hz,
    1H), 7.30 (d, J = 8.0 Hz,
    1H), 6.90 (dd, J = 16.0,
    8.0 Hz, 1H), 6.73 (d, J = 16 Hz,
    1H), 4.81 (m,
    1H), 4.33 (d, J = 6.0 Hz,
    1H), 1.64 (m, 1H),
    0.68 (m, 4H)
    CC9 132-134 504.25 7.41 (m, 3H), 7.26 (m,
    ([M + H]+) 3H), 6.54 (d, J = 16.0 Hz,
    1H), 6.37 (dd, J = 16.0,
    8.0 Hz, 1H),
    6.13 (br s, 1H), 4.56 (d, J = 6.0 Hz,
    2H), 4.11 (m,
    1H), 3.13 (m, 2H)
    CC10 538.03 7.38 (m, 4H), 6.56 (d, J = 16.0 Hz, 1651, 1112,
    ([M + 2H]+) 1H), 807
    6.38 (dd, J = 16.0, 8.0 Hz,
    1H), 6.18 (m, 1H),
    4.58 (m, 2H), 4.08 (m, 1H),
    3.08 (m, 2H)
    CC11 111-112 494.12 7.42 (m, 3H), 7.24 (m,
    ([M − H]−) 1H), 6.54 (d, J = 15.6 Hz,
    1H), 6.34 (dd, J = 16.0,
    8.0 Hz, 1H),
    6.03 (m, 1H), 4.53 (d, J = 6.0 Hz,
    1H), 4.10 (m, 1H),
    1.39 (m, 1H), 1.00 (m,
    2H), 0.77 (m, 2H)
    CC12 76-78 510.07 7.39 (s, 4H), 7.34 (d, J = 8.0 Hz,
    ([M − H]−) 1H), 7.26 (m,
    1H), 6.57 (d, J = 16.0 Hz,
    1H), 6.35 (dd, J = 16.0,
    8.0 Hz, 1H),
    6.10 (br s, 1H), 4.49 (d, J = 6.0 Hz,
    2H), 4.10 (m,
    1H), 1.20 (s, 9H)
    CC13 73-76 563.37 8.51 (d, J = 5.2 Hz, 1H),
    ([M − H]−) 7.63 (s, 1H), 7.51 (m,
    1H), 7.45 (m, 2H),
    7.39 (s, 2H), 7.28 (m, 1H),
    6.58 (m, 2H), 6.37 (dd, J = 16.0,
    8.0 Hz, 1H),
    4.71 (d, J = 6.0 Hz, 1H),
    4.11 (m, 1H)
    CC14 581.45 8.51 (m, 1H), 8.30 (d, J = 2.4 Hz, 3430, 1656,
    ([M + 1H]+) 1H), 7.73 (m, 1109, 806
    1H), 7.61 (s, 2H),
    7.51 (s, 1H), 7.32 (m, 3H),
    6.66 (d, J = 16.0 Hz,
    1H), 6.56 (dd, J = 16.0,
    8.4 Hz, 1H), 4.50 (m,
    1H), 4.45 (d, J = 5.6 Hz,
    1H), 3.56 (s, 2H)
    CC15 480.24 7.40 (m, 3H), 7.33 (m, 3293, 1651,
    ([M + H]+) 1H), 7.22 (m, 2H), 1543, 1114,
    6.54 (d, J = 15.6 Hz, 1H), 812
    6.34 (dd, J = 16.0, 8.0 Hz,
    1H), 6.03 (br s, 1H),
    4.53 (d, J = 6.0 Hz, 2H),
    4.13 (m, 1H), 1.41 (m,
    1H), 1.00 (m, 2H),
    0.77 (m, 2H)
    CC16 520.33 7.42 (s, 1H), 7.37 (m, 3307, 1665,
    ([M − H]−) 3H), 7.22 (m, 1H), 1114, 813
    6.54 (d, J = 16.0 Hz, 1H),
    6.36 (dd, J = 16.0, 8.0 Hz,
    1H), 6.19 (br s, 1H),
    4.51 (d, J = 6.0 Hz, 2H),
    4.21 (m, 1H), 3.33 (m,
    2H)
    CC17 117-119 459.83 7.51 (m, 2H), 7.39 (m, 3293, 1633,
    ([M − H]−) 2H), 7.24 (m, 2H), 1110, 820
    6.52 (d, J = 15.6 Hz, 1H),
    6.38 (dd, J = 15.6, 7.6 Hz,
    1H), 6.02 (br s, 1H),
    4.53 (d, J = 6.0 Hz, 2H),
    4.14 (m, 1H), 1.38 (m,
    1H)), 1.00 (m, 2H),
    0.77 (m, 2H)
    CC18 119-123 501.88 7.48 (m, 2H), 7.41 (s, 3435, 1644,
    ([M − H]−) 1H), 7.36 (d, J = 8.0 Hz, 1111, 817
    1H), 7.23 (m, 2H),
    6.52 (d, J = 16.0 Hz, 1H),
    6.39 (dd, J = 16.0, 8.0 Hz,
    1H), 6.13 (br s, 1H),
    4.56 (d, J = 6.0 Hz, 2H),
    4.15 (m, 1H), 3.13 (m,
    2H)
    CC19 530 7.41 (m, 2H), 7.24 (m, 3435, 1644,
    ([M + H]+) 1H), 6.53 (d, J = 16.0 Hz, 1111, 817
    1H), 6.35 (dd, J = 16.0,
    8.0 Hz, 1H),
    4.53 (m, 2H), 4.10 (m, 1H),
    3.42 (m, 2H), 2.97 (s,
    3H), 2.78 (m, 2H)
    CC20 512 7.42 (m, 3H), 7.24 (m, 3293, 1633,
    ([M + H]+) 1H), 6.54 (d, J = 15.6 Hz, 1110, 820
    1H), 6.34 (dd, J = 15.6,
    8.0 Hz, 1H),
    6.03 (m 1H), 4.53 (d, J = 6.0 Hz,
    1H), 4.10 (m, 1H),
    1.19 (m, 1H), 1.00 (m,
    2H), 0.77 (m, 2H)
    CC21 55-58 493.99 (DMSO-d6) 8.62 (m,
    ([M − H]−) 1H), 7.95 (s, 1H),
    7.85 (m, 1H), 7.66 (m, 3H),
    7.47 (d, J = 8.0 Hz, 1H),
    6.98 (dd, J = 16.0, 8.0 Hz,
    1H), 6.84 (d, J = 16.0 Hz,
    1H), 4.83 (m,
    1H), 4.44 (s, 2H),
    1.68 (m, 1H), 0.71 (m, 4H)
    CC22 67-69 530.01 8.62 (m, 1H), 7.90 (s,
    ([M + H]+) 3H), 7.82 (m, 1H),
    7.45 (m, 1H), 6.98 (m, 1H),
    6.84 (d, J = 16.0 Hz,
    1H), 4.82 (m, 1H),
    4.4 (s, 2H), 1.66 (m, 1H),
    0.72 (m, 4H)
    CC23 69-71 564.99 9.02 (br s, 1H), 8.54 (br
    ([M − H]−) s, 1H), 8.26 (br s, 1H),
    7.48-7.54 (m, 3H),
    7.22-7.42 (m, 3H),
    6.59-6.62 (m, 2H),
    6.38-6.42 (m, 1H),
    4.82 (m, 2H), 4.19 (s,
    1H)
    CC24 125-127 570.26 7.64 (s, 1H), 7.54 (s,
    ([M − H]−) 2H), 7.46 (s, 2H),
    6.62 (d, J = 16.0 Hz, 1H),
    6.41 (dd, J = 16.0, 8.4 Hz,
    1H), 6.03 (m, 1H),
    4.65 (d, J = 6.4 Hz, 2H),
    4.14 (m, 1H,), 3.13 (q, J = 10.6 Hz,
    2H)
    CC25 579.86 7.60 (s, 1H), 7.40 (s, 3297, 1663,
    ([M − H]−) 2H), 7.37 (d, J = 8.0 Hz, 1114, 809
    1H), 7.31 (d, J = 8.0 Hz,
    1H), 6.53 (d, 1H, J = 16.0 Hz),
    6.35 (dd, J = 16.0,
    8.0 Hz, 1H),
    6.17 (br s, 1H), 4.56 (d, J = 6.4 Hz,
    2H), 4.12 (m,
    1H), 3.15 (q, J = 10.6 Hz,
    2H)
    CC26 129-131 539.89 7.59 (s, 1H), 7.39 (m,
    ([M + H]+) 2H), 7.30 (s, 1H),
    6.53 (d, J = 16.0 Hz, 1H),
    6.35 (dd, J = 16.0, 8.0 Hz,
    1H), 6.06 (br s, 1H),
    4.42 (d, J = 4.4 Hz, 2H),
    4.12 (m, 1H), 1.35 (br s,
    1H), 0.95 (br s, 2H),
    0.75 (m, 2H)
    CC27 519.95 7.39 (s, 2H), 7.33 (t, J = 7.6 Hz, 3306, 1786
    ([M − H]−) 1H), 7.14 (m,
    2H), 6.56 (d, J = 16.0 Hz,
    1H), 6.35 (dd, J = 16.0,
    7.6 Hz, 1H),
    6.06 (br s, 1H), 4.52 (d, J = 16.0 Hz,
    2H), 4.08 (m,
    1H), 3.90 (s, 2H),
    3.13 (m, 2H)
    CC28 477.93 7.39 (s, 2H), 7.35 (m, 3625, 1747
    ([M − H]−) 1H), 7.14 (m, 2H),
    6.55 (d, J = 15.6 Hz, 1H),
    6.33 (dd, J = 15.6, 8.0 Hz,
    1H), 5.93 (br s, 1H),
    4.49 (d, J = 16.0 Hz,
    2H), 4.10 (m, 1H),
    1.36 (m, 1H), 1.00 (m, 2H),
    0.77 (m, 2H)
    CC29 620.86 8.58 (d, J = 4.6 Hz, 1H), 1645, 1115,
    ([M − H]−) 7.74 (m, 1H), 7.62 (m, 808
    2H), 7.52 (m, 1H),
    7.4 (s, 2H), 7.3 (m, 1H),
    7.2 (m, 2H), 6.60 (d, J = 16.0 Hz,
    1H), 6.38 (dd,
    J = 16.0, 8.0 Hz, 1H),
    5.02 (s, 1H), 4.8 (s, 1H),
    4.8 (d, J = 10 Hz, 2H),
    4.10 (m, 1H), 1.8 (m,
    1H), 1.2 (m, 2H),
    0.6 (m, 2H)
    CC30 101-104 559.75 7.41 (m, 4H), 7.24 (m,
    ([M − H]−) 1H), 6.53 (d, J = 16.0 Hz,
    1H), 6.35 (dd, J = 16.0,
    8.0 Hz, 1H),
    6.12 (br s, 1H), 4.53 (m, 2H),
    4.10 (m, 1H), 3.42 (m,
    2H), 2.91 (s, 3H),
    2.78 (m, 2H)
    CC31 177-178 463 7.58 (m, 2H), 7.41 (m,
    ([M − H]−) 3H), 7.24 (m, 1H),
    6.53 (d, J = 16.0 Hz, 1H),
    6.35 (dd, J = 16.0, 8.0 Hz,
    1H), 4.70 (br s, 1H),
    4.43 (s, 2H), 4.08 (m,
    1H), 3.21 (m, 2H),
    1.25 (m, 3H);
    CC32 141-142 532.99 7.66 (m, 2H), 7.54 (m,
    ([M + H]+) 1H), 7.41 (s, 2H),
    6.62 (d, J = 16.0 Hz, 1H),
    6.40 (dd, J = 16.0, 8.0 Hz,
    1H), 4.59 (s, 3H),
    4.19 (m, 1H), 3.25 (m,
    2H), 1.15 (m, 2H)
    CC33 540.88 7.57 (s, 1H), 7.40 (m, 3338, 1631,
    ([M − H]−) 2H), 7.30 (s, 1H), 1578, 1114,
    7.20 (br s, 1H), 6.53 (d, J = 16.0 Hz, 809
    1H), 6.33 (dd,
    J = 16.0, 8.0 Hz, 1H),
    6.06 (br s, 1H), 4.75 (br
    s, 1H), 4.42 (s, 2H),
    4.20 (br s, 1H), 4.15 (m, 2H),
    3.20 (m, 2H), 1.15 (m,
    3H)
    CC34 118-120 541.40 7.42 (m, 3H), 7.28 (m,
    ([M + H]+) 2H), 6.54 (d, J = 16.0 Hz,
    1H), 6.36 (dd, J = 16.0,
    8.0 Hz, 1H),
    4.96 (m, 1H), 4.51 (d, J = 5.6 Hz,
    2H), 4.12 (m, 1H),
    3.69 (t, J = 4.8 Hz, 4H),
    3.35 (t, J = 4.8 Hz, 1H)
    CC35 78-79 547.82 9.95 (br s, 1H), 8.17 (d,
    ([M + H]+) J = 4.8 Hz, 1H), 7.61 (d,
    J = 6.4 Hz), 7.43 (m,
    3H), 7.24 (m, 2H),
    6.90 (t, J = 5.6 Hz, 1H),
    6.66 (d, J = 8.4 Hz, 1H),
    6.54 (d, J = 16.0 Hz, 1H),
    6.33 (dd, J = 16.0, 8.0 Hz,
    1H), 4.65 (d, J = 6.0 Hz,
    1H), 4.09 (m, 1H)
    CC36 497 7.39 (m, 4H), 7.28 (m, 3350, 1705,
    ([M − H]−) 1H), 6.54 (d, J = 16.0 Hz, 1114, 808
    1H), 6.34 (dd, J = 16.0,
    8.0 Hz, 1H),
    4.97 (br s, 1H), 4.38 (d, J = 6.0 Hz,
    2H), 4.10 (m,
    1H), 2.9 (s, 3H), 2.7 (s,
    3H)
    CC37 88-91 515.01 7.49 (d, J = 8 Hz, 1H),
    ([M + H]+) 7.41 (d, J = 7.2 Hz, 2H),
    7.26 (m, 2H), 6.50 (d, J = 16 Hz,
    1H), 6.35 (dd,
    J = 16.0, 8.0 Hz, 1H),
    6.0 (brs, 1H), 5.73 (br s,
    1H), 4.80 (br s, 2H),
    4.09 (m, 1H), 1.23 (m,
    3H)
    CC38 63-66 526.97 7.48 (d, J = 8 Hz, 1H),
    ([M + H]+) 7.39 (m, 3H), 7.27 (m,
    1H), 6.54 (d, J = 16 Hz,
    1H), 6.33 (dd, J = 6.0,
    8.0 Hz, 1H), 6.17 (br s,
    1H), 5.92 (br s, 1H),
    5.83 (m, 2H), 5.29 (t, J = 15.4 Hz,
    2H), 4.80 (br
    s, 2H), 4.12 (m, 1H),
    4.02 (br s, 2H)
    CC39 526.09 7.39 (m, 4H), 7.28 (m, 3350, 1705,
    ([M − H]−) 1H), 6.54 (d, J = 16.0 Hz, 1114, 808
    1H), 6.34 (dd, J = 16.0,
    8.0 Hz, 1H),
    4.97 (br s, 1H), 4.38 (d, J = 6.0 Hz,
    2H), 4.10 (m,
    1H), 1.53 (s, 9H)
    CC40 159-160 580.25 7.46 (m, 5H), 7.29 (m,
    ([M − H]−) 1H), 7.20 (m, 3H),
    6.55 (d, J = 16.0 Hz, 1H),
    6.37 (dd, J = 16.0, 8.0 Hz,
    1H), 5.62 (br s, 1H),
    4.55 (d, J = 6.4 Hz, 2H),
    4.11 (m, 1H)
    CC41 512.22 7.48 (m, 1H), 7.43 (m, 1740, 1701,
    ([M − H]−) 3H), 7.38 (m, 1H), 1114, 808
    7.23 (s, 1H), 6.55 (d, J = 16.0 Hz,
    1H), 6.36 (d, J = 16.0 Hz,
    1H), 4.60 (d,
    2H), 4.18 (m, 1H),
    3.85 (s, 3H)
    CC42 161-163 578.96 (DMSO-d6) 9.45 (br s,
    ([M − H]−) 2H), 7.90 (s, 2H),
    7.75 (s, 1H), 7.46 (br s, 1H),
    7.28 (br s, 1H), 6.93 (m,
    1H), 6.75 (br s, 1H),
    4.80 (m, 1H), 4.40 (br s,
    2H), 3.90 (br s, 2H)
    CC43 140-142 505.39 8.11 (d, J = 4.0 Hz, 1H),
    ([M + H]+) 7.40 (m, 5H), 7.22 (m,
    1H), 6.61 (m, 2H),
    6.35 (m, 2H), 4.94 (br s, 1H)
    4.61 (d, J = 6.4 Hz, 2H),
    4.11 (m, 1H)
    CC44 536.88 8.41 (s, 1H), 7.77 (s, 3320, 1674,
    ([M − H]−) 1H), 7.47 (br s, 1H), 1114, 808
    7.40 (s, 2H), 6.58 (d, J = 16.0 Hz,
    1H), 6.45 (dd,
    J = 16.0, 8.0 Hz, 1H),
    4.68 (d, J = 4.0 Hz, 2H),
    4.14 (m, 1H), 3.24 (q, J = 10.8 Hz,
    2H)
    CC45 494.88 8.41 (s, 1H), 7.76 (s, 3309, 1659,
    ([M − H]−) 1H), 7.40 (s, 2H), 1115, 808
    7.15 (br s, 1H), 6.58 (d, J = 16.0 Hz,
    1H), 6.44 (dd,
    J = 16.0, 8.0 Hz, 1H),
    4.67 (d, J = 4.4 Hz, 2H),
    4.16 (m, 1H), 1.57 (m,
    1H), 1.04 (m, 2H),
    0.87 (m, 2H)
    CC46 151-153 554.04 8.06 (m, 1H), 7.61 (m,
    ([M − H]−) 4H), 7.48 (s, 2H),
    7.44 (d, J = 8.0 Hz, 1H),
    7.38 (m, 1H), 6.42 (m, 1H),
    5.92 (br s, 1H), 4.92 (m,
    2H), 4.24 (m, 1H),
    3.12 (m, 2H)
    CC47 478.09 8.06 (m, 2H), 7.61 (m, 3309, 1659,
    ([M + H]+) 4H), 7.48 (s, 2H), 1115, 808
    7.44 (d, J = 8.0 Hz, 1H),
    7.38 (m, 2H), 6.42 (m, 1H),
    4.92 (s, 2H), 1.36 (m,
    1H), 1.00 (m, 2H),
    0.77 (m, 2H)
    CC48 511.05 8.06 (m, 2H), 7.61 (m, 3309, 1659,
    ([M + H]+) 3H), 7.48 (s, 2H), 1115, 808
    7.44 (d, J = 8.0 Hz, 1H),
    7.38 (m, 2H), 6.42 (m, 1H),
    4.92 (s, 2H), 1.36 (m,
    1H), 1.00 (m, 2H),
    0.77 (m, 2H)
    CC49 84-87 515.33 8.06 (m, 1H), 7.98 (m,
    ([M + H]+). 1H), 7.61 (m, 3H),
    7.48 (s, 2H), 7.44 (d, J = 8.0 Hz,
    1H), 7.38 (m, 2H),
    6.42 (m, 1H), 4.92 (s,
    2H), 4.6 (br s, 1H),
    4.24 (m, 1H), 3.21 (m, 2H),
    1.2 (t, J = 4.6 Hz, 3H)
    CC50 138-140 461.32 9.81 (s, 1H), 7.90 (s,
    ([M − 1H]−) 1H), 7.84 (s, 2H),
    7.34 (d, J = 8.4 Hz, 2H),
    6.65 (d, J = 15.6 Hz, 1H),
    6.61 (m, 1H), 6.57 (s,
    1H), 6.48 (dd, J = 15.6,
    8.8 Hz, 1H), 4.74 (m,
    1H), 1.64 (m, 1H),
    0.75 (m, 4H);
    CC51 149-150 505.31 7.56 (br s, 1H), 7.4 (s,
    ([M − H]−) 3H), 7.3 (m, 3H),
    7.05 (br s, 1H), 6.8 (d, J = 6 Hz,
    2H), 6.57 (m, 2H),
    6.20 (m, 2H), 4.05 (m,
    1H), 3.2 (q, J = 10.4 Hz,
    2H)
    CC52 464.87 7.40 (s, 2H), 7.18 (s, 3309, 1659,
    ([M − H]−) 1H), 7.08 (s, 1H), 1115, 808
    6.85 (m, 1H), 6.45 (m, 1H),
    6.20 (m, 1H),
    5.55 (s, 1H), 4.08 (m, 1H),
    1.30-1.10 (m, 4H),
    1.90 (m, 1H)
    CC53 506 7.40 (s, 2H), 7.18 (s, 3309, 1659,
    ([M + H]+) 1H), 7.08 (s, 1H), 1115, 808
    6.85 (m, 1H), 6.45 (m, 1H),
    6.20 (m, 1H),
    5.55 (s, 1H), 4.08 (m, 1H),
    3.21 (m, 2H)
    CC54 504 7.28 (s, 2H), 7.25 (m,
    ([M + H]+) 2H), 7.10 (d, J = 8.0 Hz,
    2H), 6.89 (d, J = 11.4 Hz,
    1H), 6.07 (br s, 1H),
    6.01 (m, 1H), 4.51 (d, J = 5.8 Hz,
    2H), 4.34 (m,
    1H), 3.12 (q, J = 7.5 Hz,
    2H)
    DC1 93-97 398.05 8.56 (s, 1H), 8.11 (s,
    ([M + H]+) 1H), 7.68 (d, J = 8.4 Hz,
    2H), 7.54 (d, J = 8.4 Hz,
    2H), 7.38 (t, J = 1.8 Hz,
    1H), 7.29 (s, 2H),
    6.62 (d, J = 15.6 Hz, 1H),
    6.42 (dd, J = 15.6, 8.2 Hz,
    1H), 4.15 (m, 1H)
    DC2 363.0746 8.59 (s, 1H), 8.13 (s, 3121, 1524,
    (363.075) 1H), 7.69 (d, J = 8.5 Hz, 1251, 1165,
    2H), 7.55 (d, J = 8.5 Hz, 1119
    2H), 7.41-7.29 (m,
    4H), 6.64 (d, J = 15.7 Hz,
    1H), 6.47 (dd, J = 15.9,
    8.0 Hz, 1H),
    4.17 (m, 1H)
    DC3 329.1144 8.56 (s, 1H), 8.11 (s, 1521, 1246,
    (329.114) 1H), 7.65 (d, J = 8.4 Hz, 1219, 1162,
    2H), 7.52 (d, J = 8.3 Hz, 1152, 1107
    2H), 7.40 (m, 5H),
    6.61 (d, J = 15.8 Hz, 1H),
    6.51 (dd, J = 15.9, 7.7 Hz,
    1H), 4.18 (m, 1H)
    DC4 364.11 8.56 (s, 1H), 8.10 (s, 3147, 1528,
    ([M + H]+) 1H), 7.66 (d, J = 2.0 Hz, 1494, 1246,
    2H), 7.52 (d, J = 8.8 Hz, 1165, 1108
    2H), 7.38 (d, J = 2.4 Hz,
    2H), 7.34 (d, J = 8.4 Hz,
    2H), 6.61 (d, J = 16.0 Hz,
    1H), 6.40 (dd, J = 16.0,
    7.6 Hz, 1H),
    4.15 (m, 1H)
    DC5 344.25 8.54 (s, 1H), 8.10 (s, 3122, 3047,
    ([M + H]+) 1H), 7.62 (d, J = 8.3 Hz, 1523, 1252,
    2H), 7.50 (d, J = 8.4 Hz, 1160, 1107
    2H), 7.25 (d, J = 8.3 Hz,
    2H), 7.20 (d, J = 8.0 Hz,
    2H), 6.60 (d, J = 16.0 Hz,
    1H), 6.51 (dd, J = 16.0,
    8.0 Hz, 1H),
    4.15 (m, 1H), 2.37 (s, 3H)
    DC6 360.28 8.55 (s, 1H), 8.10 (s, 3124, 2936,
    ([M + H]+) 1H), 7.65 (d, J = 8.8 Hz, 1522, 1249,
    2H), 7.52 (d, J = 8.8 Hz, 1160
    2H), 7.32 (d, J = 8.8 Hz,
    2H), 6.95 (d, J = 8.8 Hz,
    2H), 6.60 (d, J = 16.0 Hz,
    1H), 6.56 (dd, J = 16.0,
    7.4 Hz, 1H),
    4.15 (m, 1H), 3.82 (s, 3H)
    DC7 348 8.55 (s, 1H), 8.10 (s, 3141, 1512,
    ([M + H]+) 1H), 7.62 (d, J = 8.8 Hz, 1246, 1118
    2H), 7.5 (d, J = 8.4 Hz,
    2H), 7.38 (m, 2H),
    7.12 (m, 2H), 6.61 (d, J = 16.0 Hz,
    1H), 6.40 (dd,
    J = 16.0, 7.6 Hz, 1H),
    4.15 (m, 1H)
    DC8 366.13 8.57 (s, 1H), 8.11 (s, 3116, 1628,
    ([M + H]+) 1H), 7.65 (d, J = 7.2 Hz, 1524, 1252,
    2H), 7.52 (d, J = 8.0 Hz, 1168, 1118
    2H), 6.95 (m, 2H),
    6.82 (m, 1H), 6.65 (d, J = 16.0 Hz,
    1H), 6.50 (dd,
    J = 16.0, 8.0 Hz, 1H),
    4.15 (m, 1H)
    DC9 348.11 8.71 (s, 1H), 8.20 (s, 3115, 1525,
    ([M + H]+) 1H), 7.70 (d, J = 8.0 Hz, 1248, 1174
    2H), 7.57 (d, J = 8.0 Hz,
    2H), 7.40 (m, 1H),
    7.19 (m, 3H), 6.60 (d, J = 16.0 Hz,
    1H), 6.40 (dd,
    J = 16.0, 8.4 Hz, 1H),
    4.15 (m, 1H)
    DC10 348.11 8.75 (s, 1H), 8.20 (s, 3114, 1526,
    ([M + H]+) 1H), 7.72 (d, J = 8.4 Hz, 1259, 1238,
    2H), 7.6 (d, J = 8.4 Hz, 1193, 1114
    2H), 7.20-7.40 (m,
    4H), 6.60 (d, J = 16.0 Hz,
    1H), 6.40 (dd, J = 16.0,
    8.0 Hz, 1H, ),
    4.60 (m, 1H)
    DC11 75.5-78.5 358.14 8.55 (s, 1H), 8.10 (s,
    ([M + H]+) 1H), 7.65 (d, J = 8.8 Hz,
    2H), 7.52 (d, J = 8.4 Hz,
    2H), 7.01 (s, 3H),
    6.60 (d, J = 16.0 Hz, 1H),
    6.51 (dd, J = 16.0, 7.8 Hz,
    1H), 4.15 (m, 1H),
    2.34 (s, 6H)
    DC12 398.05 8.58 (s, 1H), 8.10 (s, 3055, 2930,
    ([M + H]+) 1H), 7.68 (d, J = 8.4 Hz, 1523, 1250,
    2H), 7.53 (m, 4H), 1165
    7.2 (s, 1H) 6.62 (d, J = 15.6 Hz,
    1H), 6.44 (dd, J = 15.6,
    8.0 Hz, 1H),
    4.15 (m, 1H)
    DC13 396.16 8.58 (s, 1H), 8.10 (s, 3108, 1523,
    ([M + H]+) 1H), 7.62 (d, J = 8.4 Hz, 1249, 1166,
    2H), 7.55 (m, 4H), 1127
    7.25 (m, 1H), 6.64 (d, J = 16.0 Hz,
    1H), 6.40 (dd,
    J = 16.0, 8.0 Hz, 1H),
    4.90 (m, 1H)
    DC14 398.05 8.58 (s, 1H), 8.10 (s, 3117, 2925,
    ([M + H]+) 1H), 7.62 (d, J = 8.4 Hz, 1526, 1246,
    2H), 7.55 (m, 4H), 1172, 1117
    7.25 (m, 1H), 6.67 (d, J = 16.0 Hz,
    1H), 6.40 (dd,
    J = 16.0, 8.0 Hz, 1H),
    5.00 (m, 1H)
    DC15 397.95 8.58 (s, 1H), 8.10 (s, 3120, 1524,
    ([M + H]+) 1H), 7.66 (d, J = 8.0 Hz, 1267, 1176,
    2H), 7.52 (m, 3H), 1112
    7.40 (d, J = 8.0 Hz, 1H),
    7.30 (dd, J = 8.4, 2.9 Hz,
    1H), 6.64 (d, J = 16.0 Hz,
    1H), 6.40 (dd, J = 16.0,
    8.0 Hz, 1H),
    4.90 (m, 1H)
    DC16 466 8.61 (s, 1H), 8.13 (s,
    ([M + H]+) 1H), 7.92 (s, 1H),
    7.86 (s, 2H), 7.70 (d, J = 7.0 Hz,
    2H), 7.54 (d, J = 7.0 Hz,
    2H), 6.67 (d, J = 16.0 Hz,
    1H), 6.46 (dd,
    J = 16.0, 8.0 Hz, 1H),
    4.35 (m, 1H)
    DC17 430.06 8.58 (s, 1H), 8.1 (s, 1H), 3122, 3076,
    ([M + H]+) 7.68 (d, J = 8.4 Hz, 2H), 2929, 1523,
    7.54 (d, J = 8.4 Hz, 2H), 1250, 1168,
    7.51 (s, 1H), 7.42 (s, 1114
    1H), 6.68 (d, J = 16.0 Hz,
    1H), 6.35 (dd, J = 16.0,
    8.0, Hz, 1H),
    4.98 (m, 1H)
    DC18 92-95 429.91 8.57 (s, 1H), 8.11 (s,
    ([M + H]+) 1H), 7.69 (d, J = 8.8 Hz,
    2H), 7.54 (d, J = 8.4 Hz,
    2H), 7.42 (s, 2H),
    6.65 (d, J = 16.0 Hz, 1H),
    6.40 (dd, J = 16.0, 8.0 Hz,
    1H), 4.10 (m, 1H)
    DC19 97-99 430.321 8.58 (s, 1H), 8.12 (s,
    ([M + H]+) 1H), 7.68 (d, J = 8.0 Hz,
    2H), 7.64 (s, 1H),
    7.59 (s, 1H), 7.55 (m, 3H),
    6.60 (d, J = 16.0 Hz,
    1H), 6.40 (dd, J = 16.0,
    8.0 Hz, 1H), 4.22 (m,
    1H)
    DC20 427.0463 8.58 (s, 1H), 8.15 (s, 2937, 1524,
    (427.0466) 1H), 7.70 (d, J = 8.4 Hz, 1482, 1278,
    2H), 7.58 (d, J = 8.4 Hz, 1249, 1166,
    2H), 7.36 (s, 2H), 1112
    6.62 (d, J = 16.0 Hz, 1H),
    6.43 (dd, J = 16.0, 8.0 Hz,
    1H), 4.12 (m, 1H),
    3.88 (s, 3H)
    DC21 412.04 8.42 (s, 1H), 7.60 (d, J = 8.0 Hz, 3108, 1572,
    ([M + H]+) 2H), 7.50 (d, J = 8.0 Hz, 1531, 1242,
    2H), 7.40 (s, 1172, 1104
    1H), 7.22 (s, 2H),
    6.60 (d, J = 16.0 Hz, 1H),
    6.42 (dd, J = 16.0, 8.0 Hz,
    1H), 4.15 (m, 1H),
    2.5 (s, 3H)
    DC22 147-149 441.01 8.62 (s, 1H), 7.78 (d, J = 8.0 Hz,
    ([M − H]−) 2H), 7.60 (d, J = 8.0 Hz,
    2H), 7.40 (s,
    1H), 7.30 (s, 2H),
    6.67 (d, J = 16.0 Hz, 1H),
    6.48 (dd, J = 16.0, 8.0 Hz,
    1H), 4.15 (m, 1H)
    DC23 412.05 7.95 (s, 1H), 7.35 (d, J = 8.0 Hz, 1112, 799
    ([M + H]+) 2H), 7.46 (d, J = 8.0 Hz,
    2H), 7.39 (s,
    1H), 7.29 (s, 2H),
    6.67 (d, J = 16.0 Hz, 1H),
    6.45 (dd, J = 16.0, 8.0 Hz,
    1H), 4.12 (m, 1H),
    2.51 (s, 3H)
    DC24 133-134 440.03 8.10 (s, 1H), 7.52 (d, J = 8.0 Hz,
    ([M + H]+) 2H),
    7.42-7.38 (m, 3H), 7.28 (s, 2H),
    6.67 (d, J = 16.0 Hz,
    1H), 6.45 (dd, J = 16.0,
    8.0 Hz, 1H), 4.16 (m,
    1H), 2.79 (s, 3H)
    DC25 442.02 7.97 (s, 1H), 7.59 (d, J = 8.0 Hz, 1167, 1114,
    ([M − H]−) 2H), 7.53 (d, J = 8.0 Hz, 800
    2H), 7.38 (m,
    1H), 7.29 (s, 2H),
    6.65 (d, J = 16.0 Hz, 1H),
    6.42 (dd, J = 16.0, 8.0 Hz,
    1H), 4.17 (m, 1H),
    2.74 (s, 3H)
    DC26 464.03 8.12 (s, 1H), 7.49 (d, J = 8.0 Hz, 1689, 1253,
    ([M − H]−) 2H), 1166, 1114,
    7.40-7.37 (m 3H), 7.28 (s, 2H), 979, 964
    6.66 (d, J = 16.0 Hz,
    1H), 6.44 (dd, J = 16.0,
    8.0 Hz, 1H), 4.14 (m,
    1H), 3.22 (m, 1H),
    1.09-1.16 (m, 4H)
    DC27 473.94 8.19 (s, 1H), 7.64 (d, J = 7.2 Hz, 1571, 1331,
    ([M − H]−) 2H), 7.55 (d, 7.2 Hz, 1170, 1113,
    2H), 7.39 (s, 1H), 764
    7.30 (s, 2H), 6.62 (d, J = 16.0 Hz,
    1H), 6.42 (dd,
    J = 8.0, 16.0 Hz, 1H),
    4.18 (m, 1H), 3.58 (s,
    3H)
    DC28 421.22 8.79 (s, 1H), 8.18 (s, 3126, 2233,
    ([M + H]+) 1H), 7.80 (m, 3H), 1516, 1250,
    7.52 (m, 2H), 7.24 (m, 1H), 1165, 1109
    6.63 (d, J = 16.0 Hz,
    1H), 6.54 (d, J = 16.0,
    7.6 Hz, 1H), 4.19 (m,
    1H)
    DC29 421.22 8.80 (s, 1H), 8.2 (s, 1H), 3005, 1716,
    ([M + H]+) 7.75-7.82 (m, 3H), 1363, 1223
    7.41 (t, J = 2 Hz, 1H),
    7.26 (m, 2H), 6.65 (d, J = 16.0 Hz,
    1H),
    6.52 (dd, J = 16.0, 7.6 Hz,
    1H), 4.16 (m, 1H)
    DC30 489.17 8.81 (s, 1H), 8.20 (s, 2964, 2234,
    ([M + H]+) 1H), 7.94 (s, 1H), 1289, 1166,
    7.85 (m, 3H), 7.79 (m, 2H), 1136
    6.70 (d, J = 16.0 Hz,
    1H), 6.58 (dd, J = 16.0,
    8.0 Hz, 1H), 4.35 (m,
    1H)
    DC31 117-118 455.27 8.80 (s, 1H), 8.20 (s,
    ([M + H]+) 1H), 7.82 (m, 3H),
    7.4 (s, 2H), 6.62 (d, J = 16.0 Hz,
    1H), 6.52 (dd, J = 16.0,
    8.0 Hz, 1H),
    4.18 (m, 1H)
    DC32 388.0705 8.82 (s, 1H), 8.22 (s, 3126, 2234,
    (388.0703) 1H), 7.82-7.78 (m, 3H), 1520, 1280,
    7.38-7.30 (m, 3H), 1164, 1112
    6.62 (d, J = 16.1 Hz, 1H),
    6.56 (dd, J = 16.1, 6.8 Hz,
    1H), 4.18 (m, 1H)
    DC33 455.22 8.80 (s, 1H), 8.20 (s, 3122, 3086,
    ([M − H]−) 1H), 7.82-7.80 (m, 3H), 2234, 1517,
    7.70-7.50 (m, 3H), 1327, 1168,
    6.65 (d, J = 16.9 Hz, 1H), 1113
    6.54 (dd, J = 16.9, 6.8 Hz,
    1H), 4.25 (m, 1H)
    DC34 452.0412 8.85 (s, 1H), 8.23 (br s, 3122, 2934,
    (452.0419) 1H), 7.83-7.78 (m, 3H), 2231, 1516,
    7.33 (s, 2H), 6.69 (d, J = 14.9 Hz, 1480, 1248,
    1H), 6.50 (dd, 1211, 1165,
    J = 14.9, 7.2 Hz, 1H), 1111
    4.15 (m, 1H), 3.90 (s,
    3H)
    DC35 439.01 8.60 (s, 1H), 8.20 (s, 2233, 1518,
    ([M − H]−) 1H), 7.82 (m, 3H), 1250, 1169,
    7.28 (m, 2H), 6.65 (d, J = 16.0 Hz, 1035, 817
    1H), 6.48 (dd,
    J = 16.0, 8.0 Hz, 1H),
    4.20 (m, 1H)
    DC36 437.25 8.70 (s, 1H), 7.80 (m, 2927, 2233,
    ([M + H]+) 3H), 7.40 (s, 1H), 1572, 1531,
    7.28 (s, 2H), 6.63 (d, J = 16.0 Hz, 1248, 1166,
    1H), 6.50 (dd, J = 16.0, 1112
    8.0 Hz, 1H),
    4.18 (m, 1H), 2.50 (s, 1H)
    DC37 109-111 466.10 8.86 (s, 1H), 7.89 (m,
    ([M − H]−) 3H), 7.40 (s, 1H),
    7.30 (s, 2H), 6.68 (d, J = 16.0 Hz,
    1H), 6.57 (dd, J = 16.0,
    8.0 Hz, 1H),
    4.18 (m, 1H)
    DC38 96-98 436.11 8.58 (s, 1H), 7.75 (m,
    ([M − H]−) 3H), 7.40 (s, 1H),
    7.28 (s, 2H), 6.61 (d, J = 16.0 Hz,
    1H), 6.42 (dd, J = 16.0,
    8.2 Hz, 1H),
    4.40 (br s, 2H), 4.15 (m, 1H)
    DC39 224-226 480.30 8.65 (s, 1H), 8.18 (br s, 3352, 2237,
    ([M + H]+) 1H), 7.80-7.70 (m, 3H), 1707, 1163,
    7.40 (s, 1H), 7.27 (s, 841
    2H), 7.36 (m, 1H),
    7.28 (m, 2H), 6.60 (d, J = 16.8 Hz,
    1H), 6.47 (m,
    1H), 4.16 (m, 1H),
    2.40 (br s, 3H)
    DC40 70-73 436.11 8.86 (s, 1H), 7.88 (m,
    ([M − 2H]−) 3H), 7.44 (s, 2H),
    6.67 (d, J = 16.0 Hz, 1H),
    6.56 (dd, J = 16.0 7.6 Hz,
    1H), 4.19 (m, 1H)
    DC41 72-75 469.95 (DMSO-d6) 8.72 (s,
    ([M − H]−) 1H), 8.26 (s, 1H),
    8.01 (d, J = 8.4 Hz, 1H),
    7.91 (s, 2H), 7.77 (d, J = 8.4 Hz,
    1H), 6.42 (dd, J = 15.6,
    9.2 Hz, 1H),
    6.83 (d, J = 15.6 Hz, 1H),
    5.87 (s, 2H), 4.89 (m,
    1H)
    DC42 104-107 609.98 8.78 (s, 2H), 7.83 (s, 2234, 1714,
    ([M + H]+) 1H), 7.80 (m, 2H), 1114, 807
    7.42 (s, 2H), 6.65 (d, J = 16.4 Hz,
    1H), 6.51 (dd, J = 16.4,
    7.8 Hz, 1H),
    4.17 (m, 1H), 42.16 (m, 2H),
    1.25 (m, 4H), 1.00 (m,
    4H),
    DC43 109-112 540.04 (DMSO-d6) 10.94 (br s, 3233, 2233,
    ([M + H]+) 1H), 8.36 (s, 1H), 1699, 1114,
    8.08 (m, J = 8.4 Hz, 1H), 807
    7.91 (s, 2H), 7.84 (d, J = 8.4 Hz,
    1H), 7.13 (dd, J = 15.6,
    9.2 Hz, 1H),
    6.87 (d, J = 15.6 Hz,
    1H), 4.92 (m, 1H),
    1.99 (br s, 1H), 0.82 (s, 4H)
    DC44 435.26 8.33 (s, 1H), 8.23 (s, 2236, 1510,
    [M − H]− 1H), 7.66 (s, 1H), 1114, 801
    7.60 (s, 1H), 7.41 (m, 1H),
    7.28 (m, 2H), 6.62 (d, J = 16.0 Hz,
    1H),
    6.51 (dd, J = 16.0, 7.8 Hz,
    1H), 4.16 (m, 1H),
    2.20 (s, 3H)
    DC45 75-78 468.87 8.36 (s, 1H), 8.23 (s,
    [M − H]− 1H), 7.66 (s, 1H),
    7.60 (s, 1H), 7.41 (s, 2H),
    6.62 (d, J = 16.4 Hz,
    1H), 6.51 (dd, J = 16.4,
    7.6 Hz, 1H), 4.16 (m,
    1H), 2.20 (s, 3H)
    DC46 411.4 8.83 (s, 1H), 8.21 (s, 13C NMR (δ)3
    ([M]+) 1H), 7.83 (d, J = 8.5 Hz, 155.63,
    1H), 7.61 (d, J = 1.9 Hz, 153.27,
    1H), 7.52 (dd, J = 8.4, 153.12,
    1.9 Hz, 1H), 7.28 (d, J = 3.8 Hz, 143.01,
    2H), 6.93 (d, J = 11.5 Hz, 137.89,
    1H), 136.25,
    6.26-6.20 (m, 1H), 4.22 (m, 134.03,
    1H) 133.88,
    132.23,
    131.23,
    131.18,
    129.20,
    126.17,
    125.04,
    124.99
    DC47 139-141 474.16 8.51 (s, 1H), 8.14 (s,
    ([M − H]−) 1H), 7.75 (s, 1H),
    7.5 (m, 2H), 7.4 (s, 1H),
    7.30 (m, 2H), 6.60 (d, J = 16.0 Hz,
    1H),
    6.50 (dd, J = 16.0, 8.0 Hz,
    1H), 4.15 (m, 1H)
    DC48 124-126 414.05 8.69 (s, 1H), 8.14 (s,
    [M − H]− 1H), 7.96 (d, J = 4.8 Hz,
    1H), 7.39-7.27 (m, 5H),
    6.95 (d, J = 16.0 Hz,
    1H), 6.51 (dd, J = 16.0,
    7.6 Hz, 1H), 4.13 (m,
    1H)
    DC49 81-83 463.96 8.57 (s, 1H), 8.14 (s,
    [M − H]− 1H), 7.60 (m, 2H),
    7.44 (m, 3H), 6.95 (d, J = 16.0 Hz,
    1H), 6.51 (dd,
    J = 16.0, 7.6 Hz, 1H),
    4.13 (m, 1H)
    DC50 140-143 430.07 8.56 (s, 1H), 8.13 (s, 1110, 803
    [M − H]−) 1H), 7.59 (d, J = 1.2 Hz,
    2H), 7.44 (m, 2H),
    7.28 (m, 2H), 6.61 (d, J = 16.0 Hz,
    1H), 6.47 (dd,
    J = 16.0, 8.0 Hz, 1H),
    4.15 (m, 1H)
    DC51 118-121 464.22 8.32 (s, 1H), 8.15 (s,
    ([M − H]−) 1H), 7.82 (s, 1H),
    7.73 (d, J = 8.4 Hz, 1H),
    7.53 (d, J = 8.4 Hz, 1H),
    7.41 (s, 1H), 7.29 (s, 2H),
    6.70 (d, J = 15.6 Hz,
    1H), 6.50 (dd, J = 15.6,
    8.0 Hz, 1H), 4.20 (m,
    1H)
    DC52 9.99 (s, 1H), 8.42 (s, 3123, 3079,
    1H), 8.12 (s, 1H), 2925, 1692,
    8.01 (s, 1H), 7.68 (m, 1H), 1571, 1512,
    7.44 (m, 1H), 7.33 (m, 1253, 1164,
    1H), 7.22 (s, 2H), 1111
    6.62 (d, J = 16.7 Hz, 1H),
    6.45 (dd, J = 16.7, 9.3 Hz,
    1H), 4.10 (m, 1H)
    DC53 8.30 (m, 1H), 8.00 (br s, 3250, 3043,
    1H), 7.75 (m, 1H), 1683, 1116
    7.68 (m, 1H), 7.55 (m, 1H),
    7.36 (m, 1H), 7.28 (m,
    2H), 6.70 (m, 1H),
    6.58 (br s, 1H), 6.33 (m, 1H),
    5.88 (m, 2H), 4.10 (m,
    1H)
    DC54 56-58 441.07 8.40 (s, 1H), 8.13 (s,
    ([M − H]−) 1H), 8.02 (s, 1H),
    7.76 (d, J = 8.4 Hz, 1H),
    7.59 (d, J = 8.0 Hz, 1H),
    7.4 (s, 1H), 7.29 (m, 2H),
    6.69 (d, J = 15.6 Hz,
    1H), 6.57 (dd, J = 15.6,
    7.8 Hz, 1H), 4.15 (m,
    1H)
    DC55 412.97 8.37 (s, 1H), 8.18 (s,
    ([M + H]+) 1H), 7.39 (s, 1H),
    7.30 (m, 2H), 7.19 (d, J = 8.0 Hz,
    1H), 6.90 (m, 2H),
    6.55 (d, J = 15.6 Hz,
    1H), 6.38 (dd, J = 15.6,
    8.2 Hz, 1H), 4.20 (m,
    1H), 2.50 (br s, 2H)
    DC56 175-177 453 9.59 (br s, 1H), 8.55 (s,
    ([M − H]−) 1H), 8.47 (s, 2H),
    8.23 (s, 1H), 7.30 (m, 4H),
    6.62 (d, J = 16.0 Hz,
    1H), 6.40 (dd, J = 16.0,
    8.0 Hz, 1H), 4.15 (m,
    1H), 2.20 (s, 3H)
    DC57 426.0627 8.33 (s, 1H), 8.16 (s, 3342, 3112,
    (426.0626) 1H), 7.38 (s, 1H), 2931, 1606,
    7.29 (s, 2H), 7.15 (d, J = 7.6 Hz, 1583, 1574,
    1H), 6.80 (d, J = 7.6 Hz, 1528, 1153
    1H), 6.74 (m, 1H),
    6.60 (d, J = 15.6 Hz,
    1H), 6.35 (dd, J = 15.6,
    8.4 Hz, 1H), 5.40 (br s,
    1H), 4.15 (m, 1H),
    2.90 (s, 3H)
    DC58 94-97 440.0424 (DMSO-d6) 8.76 (s, 3403, 3304,
    (440.0419) 1H), 8.16 (s, 1H), 3178, 1674,
    7.90 (br s, 1H), 7.83 (s, 1H), 1571, 1169,
    7.70 (d, J = 7.9 Hz, 1H), 1108
    7.71-7.67 (m, 3H),
    7.58 (d, J = 7.9 Hz, 1H),
    7.52 (br s, 1H), 7.00 (dd, J = 15.8,
    8.7 Hz, 1H),
    6.85 (d, J = 15.8 Hz, 1H),
    4.85 (m, 1H)
    DC59 87-90 (DMSO-d6) 9.00 (s,
    1H), 8.63 (s, 1H),
    8.17 (s, 1H), 7.70-7.59 (m,
    5H), 7.00 (dd, J = 16.2,
    9.7 Hz, 1H), 6.85 (d, J = 16.2 Hz,
    1H), 5.90 (br s
    2H), 4.83 (m, 1H)
    DC60 469.0577 8.32 (s, 1H), 8.10 (s, 2987, 1725,
    (469.0572) 1H), 7.97 (s, 1H), 1518, 1275,
    7.65 (d, J = 8.1 Hz, 1H), 1166, 1113
    7.47 (d, J = 8.1 Hz, 1H),
    7.40 (m, 1H), 7.28 (s, 2H),
    6.62 (d, J = 16.5 Hz,
    1H), 6.49 (dd, J = 16.5,
    7.7 Hz, 1H),
    4.23-4.04 (m, 3H), 1.15 (t, J = 8.0 Hz,
    3H)
    DC61 130-132 442.15 (DMSO-d6) 9.90 (s,
    ([M + H]+) 1H), 8.17 (s, 1H),
    8.15 (m, 1H), 7.90 (m, 1H),
    7.71 (m, 2H), 7.67 (m,
    1H), 7.62 (d, J = 7.3 Hz,
    1H), 7.03 (dd, J = 16.5,
    8.3 Hz, 1H), 6.62 (d, J = 16.5 Hz,
    1H), 4.87 (m,
    1H)
    DC62 412.10 8.27 (s, 1H), 8.23 (s, 1513, 1252,
    ([M + H]+) 1H), 7.40 (m, 3H), 1166, 1112,
    7.30 (m, 3H), 6.64 (d, J = 16.0 Hz, 801
    1H), 6.45 (dd,
    J = 16.0, 8.0 Hz, 1H),
    4.19 (m, 1H), 2.21 (s,
    3H)
    DC63 446.01 8.26 (s, 1H), 8.12 (s, 2928,
    ([M + H]+) 1H), 7.42 (s, 2H), 2525, 1249,
    7.18-7.28 (m, 3H), 6.62 (d, J = 15.6 Hz, 1169, 1114,
    1H), 809
    6.39 (dd, J = 15.6, 9.4 Hz,
    1H), 4.10 (m, 1H),
    2.25 (s, 3H)
    DC64 475.03 8.84 (d, J = 5.8 Hz, 2H), 1683, 1167,
    ([M + H]+) 8.33 (s, 1H), 8.20 (s, 650, 479
    1H), 7.75 (m, 1H),
    7.60 (d, J = 28.6 Hz, 1H),
    7.58-7.48 (m, 3H),
    7.42 (m, 1H), 7.28 (s, 2H),
    6.71 (d, J = 16.9 Hz,
    1H), 6.39 (dd, J = 16.9,
    8.2 Hz, 1H), 4.15 (m,
    1H)
    DC65 412.05 8.55 (s, 1H), 8.12 (s, 722, 111
    ([M + H]+) 1H), 7.55 (m, 3H),
    7.39 (m, 1H), 7.30 (d, J = 1.6 Hz,
    1H), 6.85 (d, J = 16.0 Hz,
    1H), 6.41 (dd,
    J = 16.0, 8.0 Hz, 1H),
    4.17 (m, 1H), 2.40 (s,
    3H)
    DC66 60-61 468.26 8.59 (s, 1H), 8.14 (s,
    ([M + H]+) 1H), 7.94 (s, 1H),
    7.70 (d, J = 8.0 Hz, 1H),
    7.61 (d, J = 8.0 Hz, 1H),
    7.43 (s, 2H), 7.23 (d, J = 16.0 Hz,
    1H), 6.41 (dd, J = 16.0,
    8.0 Hz, 1H),
    4.20 (m, 1H)
    DC67 133-134 432.30 8.59 (s, 1H), 8.12 (s, 800, 114
    ([M + H]+) 1H), 7.78 (br s, 1H),
    7.71 (m, 1H), 7.62 (m,
    1H), 7.39 (s, 1H),
    7.32 (s, 2H), 7.03 (d, J = 16.0 Hz,
    1H), 6.43 (dd, J = 16.0,
    8.0 Hz, 1H),
    0.21 (m, 1H)
    DC68 412.03 8.71 (s, 1H), 8.18 (s,
    ([M + H]+) 1H), 7.71 (d, J = 8.0 Hz,
    2H), 7.55 (d, J = 8.0 Hz,
    2H), 7.37 (s, 1H),
    7.28 (m, 2H), 6.08 (d, J = 16.0 Hz,
    1H), 4.26 (m,
    1H), 2.05 (s, 3H)
    DC69 162-168 414.03 8.56 (s, 1H), 8.11 (s,
    ([M + H]+) 1H), 7.70 (d, J = 8.5 Hz,
    2H), 7.56 (d, J = 8.5 Hz,
    2H), 7.54 (m, 2H),
    7.40 (m, 1H), 6.91 (d, J = 16.5 Hz,
    1H), 6.66 (d, J = 16.5 Hz,
    1H)
    DC70  99-103 428.05 8.58 (s, 1H), 8.13 (s,
    ([M + H]+) 1H), 7.73 (d, J = 8.7 Hz,
    2H), 7.60 (d, J = 8.7 Hz,
    2H), 7.46 (m, 2H),
    7.42 (m, 1H), 6.85 (d, J = 16.2 Hz,
    1H), 6.40 (d, J = 16.2 Hz,
    1H), 3.42 (s,
    3H)
    a 1H NMR spectral data were acquired using a 400 MHz instrument in CDCl3 except where noted. HRMS data are noted observed value (theoretical value).
  • TABLE 2A
    Analytical Data for Compounds in Table 1A.
    Compound mp IR (cm−1);
    Number (° C.) ESIMS 1H NMR (δ)a 19F NMR
    F1  132-133 612.9 10.25 (s, 1H), 9.59 (s, 19F NMR
    ([M + H]+) 1H), 7.60 (d, J = 1.6 Hz, (376 MHz,
    1H), 7.54 (d, J = 8.0 Hz, CDCl3) δ
    1H), 7.40 (s, 2H), −62.96,
    7.34 (dd, J = 8.1, 1.7 Hz, −68.57
    1H), 6.51 (d, J = 15.9 Hz,
    1H), 6.40 (dd, J = 15.9,
    7.7 Hz, 1H),
    4.10 (p, J = 8.5 Hz, 1H),
    3.32 (q, J = 10.1 Hz, 2H)
    F8  166-167 558.9 8.85 (d, J = 5.5 Hz, 1H), 19F NMR
    ([M + H]+) 8.37 (d, J = 5.2 Hz, 1H), (376 MHz,
    7.65 (m, 2H), 7.41 (s, CDCl3) δ
    3H), 6.54 (d, J = 15.9 Hz, −68.57
    1H), 6.41 (dd, J = 15.9,
    7.8 Hz, 1H),
    4.11 (p, J = 8.5 Hz, 1H),
    2.38 (q, J = 7.5 Hz, 2H),
    1.25 (t, J = 7.6 Hz, 3H)
    F11 569.0 (400 MHz, DMSO-d6) δ 3431, 1645,
    ([M − H]−) 10.90 (s, 1H), 8.01 (s, 1113, 746,
    1H), 7.91 (s, 2H), 559
    7.66 (d, J = 7.6 Hz, 1H),
    7.51 (d, 7.6 Hz, 1H),
    7.04 (dd, J = 15.6, 9.2 Hz,
    1H), 6.79 (d, J = 15.6 Hz,
    1H), 4.87-4.82 (m,
    1H), 3.09 (s, 3H),
    1.26-1.21 (m, 2H),
    1.22-1.19 (m, 3H)
    F33 624.82 (400 MHz, DMSO-d6) δ 3306, 1717,
    ([M + H]+) 9.44 (bs, 1H), 8.52 (bs, 1164, 723,
    1H), 7.98-7.90 (m, 554
    3H), 7.64-7.59 (m, 1H),
    7.38 (d, J = 8.0 Hz,
    1H), 6.99 (dd, J = 15.6,
    9.2 Hz, 1H), 6.76 (d, J = 15.6 Hz,
    1H),
    4.85-4.81 (m, 1H),
    3.37-3.29 (m, 4H)
    a 1H NMR spectral data were acquired using a 400 MHz instrument in CDCl3 except where noted. HRMS data are noted observed value (theoretical value).
  • TABLE 3
    Assays Results
    Compound BAW CEW GPA
    Number Rating Rating Rating
    AC1 D D B
    AC2 C C C
    AC3 D D B
    AC4 D A B
    AC5 D D B
    AC6 D A B
    AC7 A A B
    AC8 D B B
    AC9 A A B
    AC10 A A B
    AC11 A A D
    AC12 A A D
    AC13 A A B
    AC14 A B D
    AC15 A A B
    AC16 A A C
    AC17 A A B
    AC18 A A B
    AC19 D D B
    AC20 A A C
    AC21 D D C
    AC22 A A D
    AC23 A A B
    AC24 A A D
    AC25 A A D
    AC26 A A B
    AC27 A A B
    AC28 A A B
    AC29 A A B
    AC30 A A B
    AC31 A A B
    AC32 A A B
    AC33 A A B
    AC34 A A B
    AC35 A A C
    AC36 A A B
    AC37 A A B
    AC38 A A C
    AC39 A A C
    AC40 A A D
    AC41 A D D
    AC42 A D D
    AC43 A A B
    AC44 A A B
    AC45 A A D
    AC46 A A D
    AC47 D D B
    AC48 A A B
    AC49 A A B
    AC50 A D B
    AC51 A A B
    AC52 A A B
    AC53 A A B
    AC54 A A B
    AC57 A A B
    AC58 A A B
    AC59 A A B
    AC60 A A B
    AC61 A A B
    AC62 A A D
    AC63 A A B
    AC64 A A B
    AC65 A A B
    AC66 A A B
    AC67 A A B
    AC68 A A D
    AC69 A A A
    AC70 D D B
    AC71 A A B
    AC72 A A B
    AC75 A A B
    AC76 A A D
    AC77 A A B
    AC78 A A A
    AC79 A A A
    AC80 A A B
    AC81 A D D
    AC82 A A B
    AC83 A A B
    AC84 A A D
    AC85 A A B
    AC86 A A D
    AC87 A A B
    AC89 A A B
    AC90 A A C
    AC91 A A C
    AC92 A A C
    AC93 A D C
    AC94 D B B
    AC95 A A C
    AC96 D D C
    AC97 D D C
    AC98 A A C
    AC99 A A C
    AC100 C C C
    AC101 D D C
    AC102 D A C
    AC103 A A D
    AC104 A A B
    AC105 A A D
    AC106 A A B
    AC107 B A D
    AC108 B D D
    AC109 D D C
    AC110 A A C
    AC111 A A C
    AC112 A A C
    AC113 B A D
    AC114 A B D
    AC115 A A D
    AC116 C C C
    AC117 A D B
    AC118 A D D
    BC1 A A D
    BC2 A A D
    BC3 A A D
    BC4 A A B
    BC5 A A B
    BC6 A A D
    BC7 A A D
    BC8 A A B
    BC9 A A D
    BC10 A A B
    BC11 C C C
    BC12 C C C
    BC13 A A D
    BC14 A D D
    CC1 D D D
    CC2 A A B
    CC3 A A D
    CC4 A B B
    CC5 A A B
    CC6 A A B
    CC7 A A B
    CC8 A A D
    CC9 A A B
    CC10 A A B
    CC11 A A B
    CC12 D D B
    CC13 A A B
    CC14 A D D
    CC15 A A B
    CC16 A A B
    CC17 A A B
    CC18 A A B
    CC19 A A B
    CC20 A A D
    CC21 A A D
    CC22 A A B
    CC23 A A B
    CC24 A A D
    CC25 A A B
    CC26 A D B
    CC27 A A D
    CC28 A A D
    CC29 A A B
    CC30 A A D
    CC31 B D C
    CC32 A A B
    CC33 A A B
    CC34 A A B
    CC35 D D D
    CC36 A A D
    CC37 A A D
    CC38 A A D
    CC39 D D B
    CC40 D A D
    CC41 D D B
    CC42 D D D
    CC43 A B B
    CC44 A A B
    CC45 A A D
    CC46 D A C
    CC47 D D C
    CC48 D D C
    CC49 D D D
    CC50 A A D
    CC51 A A D
    CC52 A D D
    CC53 D D B
    CC54 A A C
    DC1 A A D
    DC2 D D C
    DC3 B D C
    DC4 A D C
    DC5 D D C
    DC6 D D C
    DC7 A D C
    DC8 A D C
    DC9 D D C
    DC10 D D C
    DC11 A D C
    DC12 A A B
    DC13 A A C
    DC14 D D C
    DC15 D D C
    DC16 A A C
    DC17 A A C
    DC18 A A C
    DC19 A A C
    DC20 A D C
    DC21 D D C
    DC22 D D C
    DC23 D A C
    DC24 D D C
    DC25 D D C
    DC26 D D C
    DC27 D D C
    DC28 A A B
    DC29 A A C
    DC30 A A C
    DC31 A A B
    DC32 D D C
    DC33 A A C
    DC34 A A B
    DC35 A A B
    DC36 D D C
    DC37 A A C
    DC38 A A C
    DC39 A A C
    DC40 A A C
    DC41 A A C
    DC42 A A C
    DC43 A A C
    DC44 A A C
    DC45 A A C
    DC46 A A C
    DC47 A A C
    DC48 A A C
    DC49 A A C
    DC50 A A C
    DC51 A A C
    DC52 D D C
    DC53 D A C
    DC54 D D C
    DC55 D D C
    DC56 D D C
    DC57 A A C
    DC58 D D C
    DC59 D D C
    DC60 A A C
    DC61 D D C
    DC62 A A C
    DC63 A A C
    DC64 D D C
    DC65 D A C
    DC66 A A C
    DC67 A A C
    DC68 A A C
    DC69 D D C
    DC70 A A C
  • TABLE 3A
    Assays Results
    Compound BAW CL GPA
    Number Rating Rating Rating
    F1  A A C
    F8  A A C
    F11 A A C
    F33 A A B

Claims (20)

We claim:
1. A composition comprising a molecule according to Formula One:
Figure US20170088507A1-20170330-C00617
wherein:
(a) R1 is selected from
(1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), N(R14)(R15),
(2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and NO2,
(3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2,
(4) substituted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more substituents selected from CN and NO2, and
(5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C1-C8)alkoxy has one or more substituents selected from CN and NO2;
(b) R2 is selected from
(1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), N(R14)(R15),
(2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and NO2,
(3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2,
(4) substituted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more substituents selected from CN and NO2, and
(5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C1-C8)alkoxy has one or more substituents selected from CN and NO2;
(c) R3 is selected from
(1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), N(R14)(R15),
(2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and NO2,
(3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2,
(4) substituted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more substituents selected from CN and NO2, and
(5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C1-C8)alkoxy has one or more substituents selected from CN and NO2;
(d) R4 is selected from
(1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), N(R14)(R15),
(2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and NO2,
(3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2,
(4) substituted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more substituents selected from CN and NO2, and
(5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C1-C8)alkoxy has one or more substituents selected from CN and NO2;
(e) R5 is selected from
(1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), N(R14)(R15),
(2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and NO2,
(3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2,
(4) substituted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more substituents selected from CN and NO2, and
(5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C1-C8)alkoxy has one or more substituents selected from CN and NO2;
(f) R6 is a (C1-C8)haloalkyl;
(g) R7 is selected from H, F, Cl, Br, I, OH, (C1-C8)alkoxy, and halo(C1-C8)alkoxy;
(h) R8 is selected from H, (C1-C8)alkyl, halo(C1-C8)alkyl, OR14, and N(R14)(R15);
(i) R9 is selected from H, F, Cl, Br, I, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, OR14, and N(R14)(R15);
(j) R10 is selected from
(1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, cyclo(C3-C6)alkyl, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), NR14R15, C(═O)H, C(═O)N(R14)(R15), CN(R14)(R15)(═NOH), (C═O)O(C1-C8)alkyl, (C═O)OH, heterocyclyl, (C2-C8)alkenyl, halo(C2-C8)alkenyl, (C2-C8)alkynyl,
(2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from OH, (C1-C8)alkoxy, S(C1-C8)alkyl, S(O)(C1-C8)alkyl, S(O)2(C1-C8)alkyl, NR14R15, and
(3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from (C1-C8)alkoxy, S(C1-C8)alkyl, S(O)(C1-C8)alkyl, S(O)2(C1-C8)alkyl, and N(R14)(R15);
(k) R11 is C(═X5)N(H)((C0-C8)alkyl)N(R11a)(C(═X5)(R11b))
wherein each X5 is independently selected from O or S, and
wherein each R11a is independently selected from H, (C1-C8)alkyl, substituted (C1-C8)alkyl, halo(C1-C8)alkyl, substituted halo(C1-C8)alkyl, cyclo(C3-C8)alkyl, and substituted cyclo(C3-C8)alkyl,
wherein each said substituted (C1-C8)alkyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, OC(═O)H, OH, S(C1-C8)alkyl, S(O)(C1-C8)alkyl, S(O)2(C1-C8)alkyl, OS(O)2aryl, N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, wherein each said substituted aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo, wherein each said substituted heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), C(═O)(C1-C8)alkyl, C(═O)(C3-C6)cycloalkyl, S(═O)2(C1-C8)alkyl, NR14R15, and oxo, wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo,
wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2,
wherein said substituted cyclo(C3-C8)alkyl, has one or more substituents selected from CN and NO2
wherein each R11b is independently selected from (C1-C8)alkyl, substituted (C1-C8)alkyl, halo(C1-C8)alkyl, substituted halo(C1-C8)alkyl, cyclo(C3-C8)alkyl, substituted cyclo(C3-C8)alkyl, (C2-C8)alkenyl, and (C2-C8)alkynyl,
wherein each said substituted (C1-C8)alkyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, OC(═O)H, OH, S(C1-C8)alkyl, S(O)(C1-C8)alkyl, S(O)2(C1-C8)alkyl, OS(O)2aryl, N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, wherein each said substituted aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo, wherein each said substituted heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), C(═O)(C1-C8)alkyl, C(═O)(C3-C6)cycloalkyl, S(═O)2(C1-C8)alkyl, NR14R15, and oxo, wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo,
wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2,
wherein said substituted cyclo(C3-C8)alkyl, has one or more substituents selected from CN and NO2;
(l) R12 is selected from (v), H, F, Cl, Br, I, CN, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, and cyclo(C3-C6)alkyl;
(m) R13 is selected from (v), H, F, Cl, Br, I, CN, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, and halo(C1-C8)alkoxy;
(n) each R14 is independently selected from H, (C1-C8)alkyl, (C2-C8)alkenyl, substituted (C1-C8)alkyl, halo(C1-C8)alkyl, substituted halo(C1-C8)alkyl), (C1-C8)alkoxy, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (C1-C8)alkyl-aryl, (C1-C8)alkyl-(substituted-aryl), O—(C1-C8)alkyl-aryl, O—(C1-C8)alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C1-C8)alkyl-heterocyclyl, (C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl-heterocyclyl, O—(C1-C8)alkyl-(substituted-heterocyclyl), N(R16)(R17), (C1-C8)alkyl-C(═O)N(R16)(R17), C(═O)(C1-C8)alkyl, C(═O)(halo(C1-C8)alkyl), C(═O)(C3-C6)cycloalkyl, (C1-C8)alkyl-C(═O)O(C1-C8)alkyl, C(═O)H
wherein each said substituted (C1-C8)alkyl has one or more substituents selected from CN, and NO2,
wherein each said substituted halo(C1-C8)alkyl), has one or more substituents selected from CN, and NO2,
wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo, and
wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, (C3-C6)cycloalkyl S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), heterocyclyl, C(═O)(C1-C8)alkyl, C(═O)O(C1-C8)alkyl, and oxo, (wherein said alkyl, alkoxy, and heterocyclyl, may be further substituted with one or more of F, Cl, Br, I, CN, and NO2);
(o) each R15 is independently selected from H, (C1-C8)alkyl, (C2-C8)alkenyl, substituted (C1-C8)alkyl, halo(C1-C8)alkyl, substituted halo(C1-C8)alkyl), (C1-C8)alkoxy, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (C1-C8)alkyl-aryl, (C1-C8)alkyl-(substituted-aryl), O—(C1-C8)alkyl-aryl, O—(C1-C8)alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C1-C8)alkyl-heterocyclyl, (C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl-heterocyclyl, O—(C1-C8)alkyl-(substituted-heterocyclyl), N(R16)(R17), (C1-C8)alkyl-C(═O)N(R16)(R17), C(═O)(C1-C8)alkyl, C(═O)(halo(C1-C8)alkyl), C(═O)(C3-C6)cycloalkyl, (C1-C8)alkyl-C(═O)O(C1-C8)alkyl, C(═O)H
wherein each said substituted (C1-C8)alkyl has one or more substituents selected from CN, and NO2,
wherein each said substituted halo(C1-C8)alkyl), has one or more substituents selected from CN, and NO2,
wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo, and
wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, (C3-C6)cycloalkyl S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), heterocyclyl, C(═O)(C1-C8)alkyl, C(═O)O(C1-C8)alkyl, and oxo, (wherein said alkyl, alkoxy, and heterocyclyl, may be further substituted with one or more of F, Cl, Br, I, CN, and NO2);
(p) each R16 is independently selected from H, (C1-C8)alkyl, substituted-(C1-C8)alkyl, halo(C1-C8)alkyl, substituted-halo(C1-C8)alkyl, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (C1-C8)alkyl-aryl, (C1-C8)alkyl-(substituted-aryl), O—(C1-C8)alkyl-aryl, O—(C1-C8)alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C1-C8)alkyl-heterocyclyl, (C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl-heterocyclyl, O—(C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl
wherein each said substituted (C1-C8)alkyl has one or more substituents selected from CN, and NO2,
wherein each said substituted halo(C1-C8)alkyl), has one or more substituents selected from CN, and NO2,
wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo, and
wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo;
(q) each R17 is independently selected from H, (C1-C8)alkyl, substituted-(C1-C8)alkyl, halo(C1-C8)alkyl, substituted-halo(C1-C8)alkyl, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (C1-C8)alkyl-aryl, (C1-C8)alkyl-(substituted-aryl), O—(C1-C8)alkyl-aryl, O—(C1-C8)alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C1-C8)alkyl-heterocyclyl, (C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl-heterocyclyl, O—(C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl
wherein each said substituted (C1-C8)alkyl has one or more substituents selected from CN, and NO2,
wherein each said substituted halo(C1-C8)alkyl), has one or more substituents selected from CN, and NO2,
wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo, and
wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo;
(r) X1 is selected from N and CR12;
(s) X2 is selected from N, CR9, and CR13;
(t) X3 is selected from N and CR9; and
(v) R12 and R13 together form a linkage containing 3 to 4 atoms selected from C, N, O, and S, wherein said linkage connects back to the ring to form a 5 to 6 member saturated or unsaturated cyclic ring, wherein said linkage has at least one substituent X4 wherein X4 is selected from R14, N(R14)(R15), N(R14)(C(═O)R14), N(R14)(C(═S)R14), N(R14)(C(═O)N(R14)(R14)), N(R14)(C(═S)N(R14)(R14)), N(R14)(C(═O)N(R14)((C2-C8)alkenyl)), N(R14)(C(═S)N(R14)((C2-C8)alkenyl)), wherein each R14 is independently selected.
2. A molecule according to claim 1 wherein R1 is selected from H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.
3. A molecule according to claim 1 wherein R2 is selected from H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.
4. A molecule according to claim 1 wherein R3 is selected from H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.
5. A molecule according to claim 1 wherein R4 is selected from H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.
6. A molecule according to claim 1 wherein R5 is selected from H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.
7. A molecule according to claim 1 wherein R2 and R4 are selected from F, Cl, Br, I, CN, and NO2 and R1, R3, and R5 are H.
8. A molecule according to claim 1 wherein R2, R3, and R4 are selected from F, Cl, Br, I, CN, and NO2 and R1, and R5 are H.
9. A molecule according to claim 1 wherein R2, R3, and R4 are independently selected from F and Cl and Riand R5 are H.
10. A molecule according to claim 1 wherein R1 is selected from Cl and H.
11. A molecule according to claim 1 wherein R2 is selected from CF3, CH3, Cl, F, and H.
12. A molecule according to claim 1 wherein R3 is selected from OCH3, CH3, F, Cl, or H.
13. A molecule according to claim 1 wherein R4 is selected from CF3, CH3, Cl, F, and H.
14. A molecule according to claim 1 wherein R5 is selected from F, Cl, and H.
15. A molecule according to claim 1 wherein R6 is selected from halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, and halo(C8)alkyl.
16. A molecule according to claim 1 wherein R6 is trifluoromethyl.
17. A molecule according to claim 1 wherein R7 is selected from H, F, Cl, Br, and I.
18. A molecule according to claim 1 wherein R7 is selected from H, OCH3, and OH.
19. A molecule according to claim 1 wherein R8 is selected from H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, and halo(C8)alkyl.
20. A molecule according to claim 1 wherein R8 is selected from CH3 and H.
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