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NZ618926B2 - Pesticidal compositions and processes related thereto - Google Patents
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NZ618926B2 - Pesticidal compositions and processes related thereto - Google Patents

Pesticidal compositions and processes related thereto Download PDF

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Publication number
NZ618926B2
NZ618926B2 NZ618926A NZ61892612A NZ618926B2 NZ 618926 B2 NZ618926 B2 NZ 618926B2 NZ 618926 A NZ618926 A NZ 618926A NZ 61892612 A NZ61892612 A NZ 61892612A NZ 618926 B2 NZ618926 B2 NZ 618926B2
Authority
NZ
New Zealand
Prior art keywords
alkyl
halo
methyl
alkoxy
ethyl
Prior art date
Application number
NZ618926A
Other versions
NZ618926A (en
Inventor
William K Brewster
Debra L Camper
Rambabu Gundla
Gary D Gustafson
James E Hunter
Pravin S Iyer
Hemant Joshi
William C Lo
Beth Lorsbach
Michael R Loso
Original Assignee
Dow Agrosciences Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dow Agrosciences Llc filed Critical Dow Agrosciences Llc
Priority claimed from PCT/US2012/043418 external-priority patent/WO2012177813A1/en
Publication of NZ618926A publication Critical patent/NZ618926A/en
Publication of NZ618926B2 publication Critical patent/NZ618926B2/en

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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
    • 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
    • A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
    • A01N33/16—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds containing nitrogen-to-oxygen bonds
    • A01N33/24—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds containing nitrogen-to-oxygen bonds only one oxygen atom attached to the nitrogen atom
    • 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
    • A01N35/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical
    • A01N35/06—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical containing keto or thioketo groups as part of a ring, e.g. cyclohexanone, quinone; Derivatives thereof, e.g. ketals
    • 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
    • A01N35/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical
    • A01N35/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical at least one of the bonds to hetero atoms is to nitrogen
    • A01N35/10—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical at least one of the bonds to hetero atoms is to nitrogen containing a carbon-to-nitrogen double bond
    • A—HUMAN NECESSITIES
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    • 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
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    • 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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    • A01N37/18—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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    • A01N37/28—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 containing the group; Thio analogues thereof
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    • 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
    • A01N37/30—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 containing the groups —CO—N< and, both being directly attached by their carbon atoms to the same carbon skeleton, e.g. H2N—NH—CO—C6H4—COOCH3; Thio-analogues 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
    • A01N37/32—Cyclic imides of polybasic carboxylic acids or thio analogues thereof
    • A—HUMAN NECESSITIES
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    • 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
    • A01N37/34—Nitriles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01N37/36—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 singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic 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
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    • A01N37/36—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 singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic acids
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    • A01N37/40—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 singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic acids having at least one oxygen or sulfur atom attached to an aromatic ring system having at least one carboxylic group or a thio analogue, or a derivative thereof, and one oxygen or sulfur atom attached to the same aromatic ring system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • 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
    • A—HUMAN NECESSITIES
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    • A01N41/10—Sulfones; Sulfoxides
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    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
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Abstract

Disclosed are compounds of formula one where the substituents are as defined herein. The compounds are intended for use in pest control in both animals and plants. The compounds may be combined with other known agricultural active agents to create compositions useful for the same purposes. Also disclosed are processes for the application of compounds and compositions of the invention to control pests. Examples of the compounds of formula one include (E)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)benzoic acid and (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. losed are processes for the application of compounds and compositions of the invention to control pests. Examples of the compounds of formula one include (E)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)benzoic acid and (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.

Description

PESTICIDAL COMPOSITIONS AND PROCESSES RELATED THERETO CROSS REFERENCES TO RELATED APPLICATIONS This Application claims priority from U.S. provisional application 611500,685 filed on June 24, 2011 the entire content of this provisional application is hereby incorporated by reference into this Application. This Application also claims priority from U.S. provisional ation 611540,056 filed on September 28, 2011 the entire content of this ional ation is also hereby incorporated by reference into this ation. This Application also claims priority from U.S. provisional application 611601,077 filed on February 21, 2012 the entire content of this provisional application is also hereby incorporated by reference into this Application. This Application also claims priority from U.S. provisional ation 611645,267 filed on May 10, 2012 the entire content of this provisional application is also hereby incorporated by reference into this Application.
FIELD OF THE DISCLOSURE The ion 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.
OUND 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 ltural 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 ns 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. s 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 ant 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. wo 2012/177813 Therefore, for many reasons, including the above reasons, a need exists for new pesticides.
TIONS The examples given in the definitions are lly non-exhaustive and must not be construed as limiting the ion 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 double bond), branched or unbranched, substituent consisting of carbon and hydrogen, for example, vinyl, allyl, butenyl, pentenyl, and hexenyl.
"Alkenyloxy" means an l further consisting of a carbon-oxygen single bond, for example, allyloxy, loxy, pentenyloxy, hexenyloxy.
"Alkoxy" means an alkyl further ting of a carbon-oxygen single bond, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and tert-butoxy. " 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 utyl.
"Alkynyl" means an acyclic, rated (at least one carbon-carbon triple bond), branched or unbranched, substituent consisting of carbon and hydrogen, for example, l, propargyl, butynyl, and pentynyl.
"Alkynyloxy" means an alkynyl further ting 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- , isopropyl, n-butyl, sec-butyl, yl, 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. wo 2012/177813 "Cycloalkenyloxy" means a lkenyl further consisting of a carbon-oxygen single bond, for example, cyclobutenyloxy, cyclopentenyloxy, norbornenyloxy, and bicyclo[2.2.2]octenyloxy.
"Cycloalkyl" means a monocyclic or clic, 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 o[2.2.2]octyloxy.
"Halo" means , 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 etrafluoroethyl.
"Heterocyclyl" means a cyclic substituent that may be fully saturated, partially unsaturated, or fully unsaturated, where the cyclic structure ns at least one carbon and at least one heteroatom, where said heteroatom is nitrogen, , or oxygen. In the case of sulfur, that atom can be in other oxidation states such as a sulfoxide and sulfone. es 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 e, but are not limited to, zinyl, dinyl, morpholinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl and tetrahydropyranyl. Examples of partially unsaturated heterocyclyls include, but are not d to, 1,2,3,4-tetrahydroquinolinyl, hydro-oxazolyl, 4,5- dihydro-1H-pyrazolyl, 4,5-dihydro-isoxazolyl, and 2,3-dihydro-[1,3,4]-oxadiazolyl.
Additional examples e the following wo 2012/177813 2012/043418 0 6 b=O ~0 II thietanyl thietanyl-oxide thietany1-dioxide.
DETAILED DESCRIPTION OF THE DISCLOSURE This document discloses molecules having the following a ("Formula One"): R5 R6 R7 R8 X3XR10 X2 ~ R3 'xr RII Formula One wherein: (a) R1 is selected from (1) H, F, Cl, Br, I, CN, N02, (C1-Cs)alkyl, halo(C1-Cs)alkyl, (C1- Cs)alkoxy, 1-Cs)alkoxy, S(C1-Cs)alkyl, S(halo(C1-Cs)alkyl), S(O)(C1-Cs)alkyl, S(O)(halo(C1-Cs)alkyl), S(Oh(C1-Cs)alkyl, S(Oh(halo(C1-Cs)alkyl), N(Rl4)(R15), (2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and N02, (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1- C8)alkyl, has one or more substituents selected from CN and N02, (4) substituted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more tuents selected from CN and N02, and (5) substituted halo(CrC8)alkoxy, wherein said substituted halo(Cr C8)alkoxy has one or more substituents selected from CN and N02; (b) R2 is selected from (1) H, F, Cl, Br, I, CN, N02, (CrC8)alkyl, halo(CrC8)alkyl, (Cr Cs)alkoxy, halo(C1-Cs)alkoxy, s)alky1, (C1-Cs)alky1), S(0 )(C1-Cs)alky1, S(O)(halo(C1-Cs)alkyl), S(Oh(C1-Cs)alkyl, S(Oh(halo(C1-Cs)alkyl), N(Rl4)(R15), wo 2012/177813 (2) substituted (C1-C8)alkyl, n said substituted (C1-C8)alkyl has one or more substituents ed from CN and N02, (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1- C8)alkyl, has one or more substituents selected from CN and N02, (4) tuted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more substituents selected from CN and N02, and (5) substituted halo(CrC8)alkoxy, wherein said substituted halo(Cr C8)alkoxy has one or more substituents selected from CN and N02; (c) R3 is selected from (1) H, F, Cl, Br, I, CN, N02, (CI-Cs)alkyl, halo(CI-Cs)alkyl, (C1- Cs)alkoxy, I-Cs)alkoxy, S(CI-Cs)alkyl, S(halo(CI-Cs)alkyl), S(O)(CI-Cs)alkyl, alo(CI-Cs)alkyl), S(0)2(C1-Cs)alkyl, halo(CI-Cs)alkyl), N(R14)(R15), (2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and N02, (3) substituted halo(C1-C8)alkyl, n said substituted halo(C1- C8)alkyl, has one or more substituents selected from CN and N02, (4) substituted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more substituents selected from CN and N02, and (5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C1- C8)alkoxy has one or more tuents selected from CN and N02; (d) R4 is selected from (1) H, F, Cl, Br, I, CN, N02, (CrC8)alkyl, halo(CrC8)alkyl, (Cr Cs)alkoxy, halo(CI-Cs)alkoxy, S(CI-Cs)alkyl, S(halo(CI-Cs)alkyl), S(O)(CI-Cs)alkyl, S(O)(halo(CI-Cs)alkyl), S(0)2(C1-Cs)alkyl, S(0)2(halo(CI-Cs)alkyl), N(R14)(R15), (2) substituted (CrC8)alkyl, wherein said substituted (CrC8)alkyl has one or more substituents selected from CN and N02, (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1- C8)alkyl, has one or more substituents selected from CN and N02, (4) substituted (C1-C8)alkoxy, n said substituted (C1-C8)alkoxy has one or more substituents selected from CN and N02, and (5) substituted halo(C1-C8)alkoxy, wherein said tuted 1- C8)alkoxy has one or more substituents selected from CN and N02; (e) R5 is selected from wo 2012/177813 (1) H, F, Cl, Br, I, CN, N02, (CI-Cs)alkyl, I-Cs)alkyl, (C1- oxy, halo(CI-Cs)alkoxy, S(CI-Cs)alkyl, S(halo(CI-Cs)alkyl), S(O)(CI-Cs)alkyl, S(O)(halo(CI-Cs)alkyl), S(0)2(C1-Cs)alkyl, S(0)2(halo(CI-Cs)alkyl), N(R14)(R15), (2) substituted )alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and N02, (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1- C8)alkyl, has one or more substituents selected from CN and N02, (4) substituted (CrC8)alkoxy, wherein said substituted (CrC8)alkoxy has one or more substituents selected from CN and N02, and (5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C1- C8)alkoxy has one or more substituents selected from CN and N02; (f) R6 is a (C1-C8)haloalkyl; (g) R7 is selected from H, F, Cl, Br, I, OH, (C1-C8)alkoxy, and halo(C1- Cs)alkoxy; (h) R8 is selected from H, (C1-C8)alkyl, halo(C1-C8)alkyl, OR14, and N(Rl4)(R15); (i) R9 is ed from H, F, Cl, Br, I, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1- C8)alkoxy, halo(C1-C8)alkoxy, OR14, and N(Rl4)(R15); (j) R10 is ed from (1) (u), H, F, Cl, Br, I, CN, N02, )alkyl, halo(CI-Cs)alkyl, (C1- Cs)alkoxy, halo(CI-Cs)alkoxy, cyclo(C3-C6)alkyl, S(CI-Cs)alkyl, S(halo(CI-Cs)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(0)2(C1-C8)alkyl, S(0)2(halo(C1-C8)alkyl), NR14R15, C(=O)H, C(=O)N(Rl4)(R15), CN(Rl4)(R15)(=NOH), (C=O)O(C1-C8)alkyl, (C=O)OH, heterocyclyl, (C2-Cs)alkenyl, 2-Cs)alkenyl, (C2-Cs)alkynyl, (2) substituted (CrC8)alkyl, wherein said substituted (CrC8)alkyl has one or more substituents selected from OH, (C1-C8)alkoxy, S(C1-C8)alkyl, S(O)(C1-C8)alkyl, S(0)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 )alkoxy, S(C1-C8)alkyl, S(O)(C1- Cs)alkyl, S(0)2(C1-Cs)alkyl, and N(Rl4)(R15); (k) Rll is selected from (u), substituted (C1-C8)alkyl, C(=O)OH, C(=O)O(C1- C8)alkyl, substituted- )alkyl), C(=O)O(substituted )alkyl), C(=0)N(R14)(R15), C(=O)heterocyclyl, substituted heterocyclyl), C(=S)N(Rl4)(R15), C(=S)heterocyclyl, C(=S)(substituted heterocyclyl), (C1- wo 2012/177813 C8)alkylN(Rlla)(C(=Xll)Rllb), N(lla)(lld), ON(llc)(lld), halo(C1-C8)alkyl, (C1- Cs)alkyl, (CI-Cs)alkylN(H)(heterocyclyl), (CI-Cs)alkyl(N(R15))(C=O)O(CI-Cs)alkyl, (CIC8 )alkyl(Rl4)(Rl5), N(H)N(H)(heterocyclyl), B(OH)2, (C1-C8)alkylN(Rlla)(C(=Xll)Rl4), (C1-C8)alkylN(Rlla)(C(=Xll)N(Rl4)(Rl5)), (C1-C8)alkylN(Rlla)(C(=Xll)OR14), substituted or unsubstituted heterocyclyl, (Rl4)(N(Rl6)(Rl7), C(=O)N(Rl4)((C1- C8)alkylC(=O)N(Rl4)N(Rl4)(Rl5)), C(=O)N(Rl4)((C1-C8)alkylC(=O)N(Rl4)(Rl5)), C(=S)N(Rl4)((C1-C8)alkylC(=S)N(Rl4)(Rl5)), C(=S)N(Rl4)((C1- C8)alkylC(=O)N(Rl4)(Rl5)), C(=O)N(Rl4)((C1-C8)alkylC(=S)N(Rl4)(Rl5)), C(=O)N(R14)((C1-Cs)alkylC(=0)(Rl5), (1) wherein each said substituted (C1-C8)alkyl has one or more tuents selected from F, Cl, Br, I, CN, N02, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, wherein each said substituted aryl has one or more substituents selected from F, Cl, Br, I, CN, N02, (CI-Cs)alkyl, halo(CI-Cs)alkyl, (CI-Cs)alkoxy, halo(CICs )alkoxy, S(CI-Cs)alkyl, S(halo(CI-Cs)alkyl), Cs)alkylh (wherein each (CI-Cs)alkyl is independently selected), and oxo, (2) wherein each said substituted cyclyl has one or more substituents selected from F, Cl, Br, I, CN, N02, (CI-Cs)alkyl, halo(CI-Cs)alkyl, (CI-Cs)alkoxy, halo(CICs )alkoxy, s)alkyl, S(halo(CI-Cs)alkyl), Cs)alkylh (wherein each (CI-Cs)alkyl is independently selected), C(=O)(CI-Cs)alkyl, C(=0)(C3-C6)cycloalkyl, S(=OMCI-Cs)alkyl, NR14R15, and oxo, (3) wherein Rlla is selected from H, (C1-C8)alkyl, and (C1-C8)alkylheterocyclyl , R14, C(Xll)R14, (CrC8)alkylR14 (4) n Rllb is selected from (C1-C8)alkyl, cyclo(C3-C6)alkyl, halo(C1-C8)alkyl, heterocyclyl, substituted-heterocyclyl (where said substituents are one or more ofF, Cl, Br, I, CN, N02, (CrC8)alkyl, rC8)alkyl, alkoxy, halo(Cr Cs)alkoxy, S(CI-Cs)alkyl, S(halo(CI-Cs)alkyl), N((CI-Cs)alkylh (wherein each (CI-Cs)alkyl is independently selected), and oxo), (C1-C8)alkylS(C1-C8)alkyl, (C1-C8)alkylS(O)(C1- Cs)alkyl, )alkylS(0)2(CI-Cs)alkyl, N(Rllc)(Rlld), O(CI-Cs)alkyl, Oheterocyclyl, 0- substituted-heterocyclyl (where said substituents are one or more ofF, Cl, Br, I, CN, N02, (CI-Cs)alkyl, halo(CI-Cs)alkyl, )alkoxy, halo(CI-Cs)alkoxy, S(CI-Cs)alkyl, S(halo(CIC8 ), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo), C(=O)ORlld, C(=O)N(Rllc)(Rlld), C(=O)(Rlld)aryl, substituted aryl (where said substituents are one or more ofF, Cl, Br, I, CN, N02,(C1-C8)alkyl, halo(C1-C8)alkyl, (C1- wo 2012/177813 Cs)alkoxy, halo(CI-Cs)alkoxy, S(CI-Cs)alkyl, (CI-Cs)alkyl), N((C1-Cs)alkyl)2 (wherein each (C1-C8)alkyl is ndently selected), (5) n XII is 0 or S, (6) wherein R 11 c is selected from H, (7) wherein Rlld is selected from H, (C1-C8)alkyl, (C1-C8)alkenyl, halo(C1-C8)alkyl, heterocyclyl, substituted-heterocyclyl (where said substituents are one or more ofF, Cl, Br, I, CN, N02, (CrC8)alkyl, halo(CrC8)alkyl, (CrC8)alkoxy, halo(Cr C8)alkoxy, S(CrC8)alkyl, S(halo(CrC8)alkyl), N((CrC8)alkylh (wherein each alkyl is independently selected), and oxo), N(H)(C(=O)cyclo(C3-C6)alkyl), N(H)(C(=O)halo(C1- Cs)alkyl), (8) wherein optionally R11c and R11d along with N form a 5, 6, 7, or 8 membered ring that may optionally further contain 1, 2, or 3, additional heteroatoms selected from 0, N, or S, in the ring; (I) R12 is selected from (v), H, F, Cl, Br, I, CN, (C1-C8)alkyl, halo(C1-C8)alkyl, (CI-Cs)alkoxy, halo(CI-Cs)alkoxy, and cyclo(C3-C6)alkyl; (m) Rl3 is selected from (v), H, F, Cl, Br, I, CN, (C1-C8)alkyl, halo(C1-C8)alkyl, (CI-Cs)alkoxy, and halo(CI-Cs)alkoxy; (n) each R14 is independently ed from H, (C1-C8)alkyl, (C1-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), cyclyl, substituted-heterocyclyl, (C1-C8)alkyl-heterocyclyl, (C1-C8)alky1-(substituted-heterocyclyl), O-(C1-C8)alky1- cyclyl, O-(C1-C8)alkyl-(substituted-heterocyclyl), N(R16)(R17), (C1-C8)alkyl- (R16)(R17), C(=O)(CI-Cs)alkyl, C(=O)(halo(CI-Cs)alkyl),C(=O)(C3-C6)cycloalkyl, (C1-C8)alkyl-C(=0)0(C1-C8)alkyl, C(=O)H wherein each said substituted (C1-C8)alkyl has one or more substituents selected from CN, and N02, wherein each said substituted halo(C1-C8)alkyl), has one or more substituents selected from CN, and N02, wherein each said substituted-aryl has one or more tuents selected from F, Cl, Br, I, CN, N02, (CI-Cs)alkyl, halo(CI-Cs)alkyl, (CI-Cs)alkoxy, halo(CI-Cs)alkoxy, S(CI-Cs)alkyl, S(halo(CI-Cs)alkyl), N((CI-Cs)alkylh (wherein each )alkyl is independently selected), and oxo, and wo 2012/177813 wherein each said substituted-heterocyclyl has one or more substituents ed from F, Cl, Br, I, CN, N02, (C1-Cs)alkyl, halo(C1-Cs)alkyl, (C1-Cs)alkoxy, halo(C1- Cs)alkoxy, )cycloalkyl S(C1-Cs)alkyl, S(halo(C1-Cs)alkyl), N((C1-Cs)alkylh (wherein each (C1-C8)alkyl is independently selected), heterocyclyl, C(=O)(C1-C8)alkyl, (C1- C8)alkyl, and oxo, (wherein said alkyl, , and heterocyclyl, may be further substituted with one or more ofF, Cl, Br, I, CN, and N02); (o) each RlS is independently selected from H, (CrC8)alkyl, (CrC8)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), 0- (C1-C8)alkyl-aryl, C8)alkyl-(substituted-aryl), cyclyl, substituted-heterocyclyl, (C1-C8)alkyl-heterocyclyl, (C1-C8)alkyl-(substituted-heterocyclyl), C8)alkylheterocyclyl , O-(C1-C8)alkyl-(substituted-heterocyclyl), N(R16)(R17), (C1-C8)alkyl- C(=O)N(R16)(R17), C1-Cs)alkyl, C(=O)(halo(C1-Cs)alkyl), C(=O)(C3-C6)cycloalkyl, (C1-Cs)alkyl-C(=0)0(C1-Cs)alkyl, C(=O)H wherein each said substituted (C1-C8)alkyl has one or more substituents selected from CN, and N02, wherein each said substituted halo(C1-C8)alkyl), has one or more tuents selected from CN, and N02, wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, N02, (C1-Cs)alkyl, halo(C1-Cs)alkyl, )alkoxy, halo(C1-Cs)alkoxy, S(C1-Cs)alkyl, S(halo(C1-Cs)alkyl), N((C1-Cs)alkylh (wherein each (C1-Cs)alkyl is independently selected), and oxo, and wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, N02, (C1-Cs)alkyl, halo(C1-Cs)alkyl, (C1-Cs)alkoxy, 1- C8)alkoxy, (CrC6)cycloalkyl S(CrC8)alkyl, S(halo(CrC8)alkyl), N((CrC8)alkylh (wherein each (C1-C8)alkyl is independently ed), 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 ofF, Cl, Br, I, CN, and N02); (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, substitutedaryl , (C1-Cs)alkyl-aryl, )alkyl-(substituted-aryl), O-(C1-Cs)alkyl-aryl, O-(C1-Cs)alkyl- (substituted-ary1), heterocycly1, substituted-heterocycly1, ( C1-C8)alky1-heterocycly1, ( C1- C8)alkyl-(substituted-heterocyclyl), O-(C1-C8)alkyl-heterocyclyl, O-(C1-C8)alkyl- (substituted-heterocyclyl), O-(C1-C8)alkyl wo 2012/177813 wherein each said tuted (C1-C8)alkyl has one or more substituents selected from CN, and N02, wherein each said substituted halo(C1-C8)alkyl), has one or more substituents selected from CN, and N02, n each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, N02, (C1-Cs)alkyl, halo(C1-Cs)alkyl, (C1-Cs)alkoxy, halo(C1-Cs)alkoxy, S(CrC8)alkyl, S(halo(CrC8)alkyl), 8)alkylh (wherein each (CrC8)alkyl is independently selected), and oxo, and wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, N02, (C1-Cs)alkyl, halo(C1-Cs)alkyl, (C1-Cs)alkoxy, halo(C1- Cs)alkoxy, S(C1-Cs)alkyl, S(halo(C1-Cs)alkyl), N((C1-Cs)alkylh (wherein each (C1-Cs)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, tuted-halo(C1-C8)alkyl, cyclo(C3-C6)alkyl, aryl, substituted- IS aryl, (C1-Cs)alkyl-aryl, (C1-Cs)alkyl-(substituted-aryl), O-(C1-Cs)alkyl-aryl, O-(C1-Cs)alkyl- (substituted-ary1), cycly1, substituted-heterocycly1, ( alky1-heterocycly1, ( 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 N02, wherein each said substituted halo(C1-C8)alkyl), has one or more substituents selected from CN, and N02, wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, N02, (C1-Cs)alkyl, halo(C1-Cs)alkyl, (C1-Cs)alkoxy, halo(C1-Cs)alkoxy, S(CrC8)alkyl, S(halo(CrC8)alkyl), N((CrC8)alkylh (wherein each (CrC8)alkyl is independently ed), and oxo, and wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, N02, (C1-Cs)alkyl, halo(C1-Cs)alkyl, (C1-Cs)alkoxy, halo(C1- Cs)alkoxy, S(C1-Cs)alkyl, S(halo(C1-Cs)alkyl), Cs)alkylh (wherein each (C1-Cs)alkyl is independently selected), and oxo; (r) Xl is selected from N and CR12; (s) X2 is ed from N, CR9, and CR13; (t) X3 is selected from Nand CR9; wo 2012/177813 (u) RlO and Rll together form a linkage containing 3 to 4 atoms selected from C, N, 0, 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 F, Cl, Br, I, R14, N(Rl4)(R15), N(Rl4)(C(=O)Rl4), (C(=S)Rl4), N(R14)(C(=0)N(Rl4)(R14)), N(Rl4)(C(=S)N(R14)(Rl4)), (C(=0)N(Rl4)((CICs )alkenyl)), N(Rl4)(C(=S)N(Rl4)((C1-C8)alkenyl)), oxo, C(=O)(C1-C8)alkylN(Rl4)(Rl4), (CrC8)alkylC(=O)N(R14)R(15), wherein each R14 is independently selected; and (v) R12 and R13 together form a linkage containing 3 to 4 atoms selected from C, N, 0, and S, wherein said linkage ts back to the ring to form a 5 to 6 member saturated or unsaturated cyclic ring, n said linkage has at least one substituent X4 wherein X4 is selected from R14, N(Rl4)(R15), N(Rl4)(C(=O)Rl4), N(Rl4)(C(=S)Rl4), N(R14)(C(=0)N(Rl4)(R14)), N(Rl4)(C(=S)N(R14)(Rl4)), N(R14)(C(=0)N(Rl4)((CICs yl)), N(Rl4)(C(=S)N(Rl4)((C1-C8)alkenyl)), wherein each R14 is independently selected.
In another embodiment of this invention Rl may be selected from any combination of one or more of the following- H, F, Cl, Br, I, CN, N02, methyl, ethyl, (C3)alkyl, (C4)alkyl, (Cs)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, 4)alkyl, halo(Cs)alkyl, halo(C6)alkyl, halo(C7)alkyl, 8)alkyl, methoxy, ethoxy, koxy, (C4)alkoxy, (Cs)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, hoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(Cs)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.
In another embodiment of this invention R2 may be selected from any ation of one or more of the following- H, F, Cl, Br, I, CN, N02, methyl, ethyl, kyl, (C4)alkyl, (Cs)alkyl, kyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, 3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (Cs)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(Cs)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, N02, methyl, ethyl, (C3)alkyl, (C4)alkyl, (Cs)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(Cs)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (Cs)alkoxy, (C6)alkoxy, (C7)alkoxy, koxy, halomethoxy, haloethoxy, wo 2012/177813 halo(C3)alkoxy, halo(C4)alkoxy, halo(Cs)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.
In another embodiment of this ion R4 may be selected from any combination of one or more of the following- H, F, Cl, Br, I, CN, N02, methyl, ethyl, (C3)alkyl, (C4)alkyl, (Cs)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(Cs)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, hoxy, halo(C3)alkoxy, halo(C4)alkoxy, 5)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 ing- H, F, Cl, Br, I, CN, N02, methyl, ethyl, (C3)alkyl, (C4)alkyl, (Cs)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(Cs)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (Cs)alkoxy, koxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(Cs)alkoxy, halo(C6)alkoxy, 7)alkoxy, and halo(C8)alkoxy.
In another embodiment of this invention R2 and R4 are selected from F, Cl, Br, I, CN, and N02 and Rl, R3, and R5 are H.
In another ment of this invention R2, R3, and R4 are selected from F, Cl, Br, I, CN, and N02 and Rl, and R5 are H.
In another ment of this invention R2, R3, and R4 are independently ed from F and Cl and Rland R5 are H.
In another embodiment of this invention Rl 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 ion 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, 3)alkyl, halo(C4)alkyl, halo(Cs)alkyl, halo(C6)alkyl, halo(C7)alkyl, and 8)alkyl.
In another embodiment of this invention R6 is trifluoromethyl.
In r embodiment of this invention R7 may be ed 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. wo 77813 In another embodiment of this invention R8 may be selected from any combination of one or more of the following- H, , ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(Cs)alkyl, halo(C6)alkyl, 7)alkyl, and 8)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, thyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(Cs)alkyl, halo(C6)alkyl, halo(C7)alkyl, 8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (Cs)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(Cs)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.
In another embodiment of this invention RlO 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, (Cs)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, 3)alkyl, 4)alkyl, halo(Cs)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, koxy, (Cs)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, hoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(Cs)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, halo(C8)alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
In another embodiment of this invention RlO 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 RlO is ed from Br, C(=NOH)NH2, , C(=O)NH2, C(=O)OCH2CH3, C(=O)OH, CF3, CH2CH3, CH20H, CH3, Cl, CN, F, H, NH2, )H, NHCH3, N02, OCH3, OCHF2, and pyridyl.
In another embodiment of this invention Rll may be selected from any combination of one or more of the ing- C(=O)(substituted- (C1-C8)alkyl), C(=O)N(Rl4)(R15), C(=0)heterocycly1, and C(=0)(substituted-heterocycly1).
In another embodiment of this invention Rll is C(=O)morpholinyl.
In another embodiment of this invention Rll may be selected from any combination of CH2N(H)C(=O)CH3, CH2N(H)C(=O)cyclopropyl, CH2N(H)C(=O)CH2CF3, CH2N(H)C(=O)CH2CH3, CH2N(H)C(=O)C(CH3)3, CH2N(H)C(=0)(chloropyridyl), CH2N(H)C(=O)CH2(chloropyridyl), CH2N(H)C(=O)CH2CH2SCH3, N(H)C(=O)(pyridyl), CH2N(CH2pyridy1)C(=0)cyclopropy1, CH2N(H)C(=0)N(H)(CH2CH3), CH2N(H)C(=0)morpholiny1, CH2N(H)C(=0)N(H)(pyridy1), CH2N(H)C(=0)NH2, wo 77813 CH2N(H)C(=O)NH(CH2CH3), CH2N(H)C(=O)NH(CH2CHCH2), CH2N(H)C(=O)OC(CH3)3, CH2N(H)C(=O)O(chlorophenyl), CH2N(H)C(=O)(C=O)OCH3, CH2N(H)C(=0)(C=O)N(H)CH2CF3, CH2N(H)(pyridy1), N(H)N(H)C(=0)cyclopropy1, N(H)N(H)C(=O)CH2CF3, ON(H)C(=O)cyclopropyl, and ON(H)C(=O)CH2CF3.
In another embodiment of this invention R11 may be selected from any combination of triazolyl, 1,2,4-triazolyl-C(=O)cyclopropyl, 1,2,4-triazolyl-C(=0)CH3, 1,2,- methyltriazolyl, 1,2,4-triazolyl-N(C(=0)cyclopropyl)2, 1,2,4- triazolylN(H)(C(=O)cyclopropyl), 1,2,4-triazolylNH2, 1,2,4-triazolyl-N02, 1,2,4- triazolylS(OhCH3, 1,2,4-triazolylSCH3, C(=O)(morpholinyl), C(=O)N(CH3)(CH3), C(=O)N(H)(CH(CH3)chloropyridinyl), C(=O)N(H)(CH2C(=O)N(CH3)(CH2CF3)), C(=O)N(H)(CH2-benzothiazolyl), C(=O)N(H)(CH2C(=O)N(H)(CH2CF3)), C(=O)N(H)(CH2C(=O)N(H)(CH2CH=CH2)), C(=O)N(H)(CH2C(=O)N(H)(cyclopropyl)), C(=O)N(H)(CH2C(=O)N(H)(N(CH3)2)), (H)(CH2C(=O)N(H)(OCH3)), C(=O)N(H)(CH2C(=O)N(H)(thietanyl)), C(=O)N(H)(CH2C(=O)N(H)(thietanyl-dioxide)) C(=O)N(H)(CH2C(=O)OC(CH3)3), (H)(CH2C(=S)N(H)(CH2CF3)), C(=O)N(H)(CH2CF3), C(=O)N(H)(CH2CH2-chloropyridinyl) C(=O)N(H)(CH2-furanyl), C(=O)N(H)(CH2-methylimidazolyl) C(=O)N(H)(CH2-cyclopropyloxadiazolyl), C(=O)N(H)(CH2-phenyl), C(=O)N(H)(CH2- trifluoromethylphenyl), C(=O)N(H)(CH2-fluorophenyl), C(=O)N(H)(CH2-pyrazinyl), C(=O)N(H)(CH2-trifluoromethylpyridinyl), C(=O)N(H)(CH2-chloropyridinyl), C(=O)N(H)(CH2-pyridinyl-N02), (H)(CH2-pyridinyl-OCH3), C(=O)N(H)(CH2- dinyl), C(=O)N(H)(CH2-tetrahydrofuranyl), C(=O)N(H)(CH2-chlorothiazolyl), C(=O)N(H)(CH3), C(=O)NH2, C(=O)N(H)(N(CH3)(fluorophenyl)), C(=O)N(H)(N(H)(fluorophenyl)), C(=O)N(H)(OCH2-chloropyridinyl), C(=O)N(H)(piperidinyl), C(=O)N(H)(piperidinylC(=0)CH2CF3), C(=O)N(H)(piperidinyl-- CH2CN), C(=O)N(H)(piperidinylC(=O)CH3), C(=O)N(H)(piperidinylCH2CH20H), C(=O)N(H)(piperidinyl-oxetanyl), C(=O)N(H)(chloropyridinyl), C(=O)N(H)(CH2- tetrahydropyranyl), C(=O)N(H)(thietanyl), C(=O)N(H)(thietanyl-dioxide), C(=O)N(H)(thietanyl-oxide), C(=O)N(H)(CH2-pyrazinyl) C(=O)pyrrolidinyl-oxo, C(=S)N(H)(CH2C(=O)N(H)(CH2CF3)), C(=S)N(H)(CH2C(=S)N(H)(CH2CF3)), C(=S)N(H)(CH2-chloropyridinyl), H2- nyl)(C(=0)-cyclopropyl), CH2N(H)(C(=O)C(=O)N(H)(CH2CF3), CH2N(H)(C(=O)C(=O)OCH3), CH2N(H)(C(=O)C(CH3)3), CH2N(H)(C(=O)-CH2- wo 2012/177813 chloropyridinyl), CH2N(H)(C(=O)CH2CF3), CH2N(H)(C(=O)CH2CH2S(0)2CH3), CH2N(H)(C(=O)CH2CH2SCH3), CH2N(H)(C(=O)CH2CH3), CH2N(H)(C(=O)-cyclopropyl), CH2N(H)(C(=O)morpholinyl), CH2N(H)(C(=O)N(CH3)2, CH2N(H)(C(=O)N(H)(CH2CH3)), CH2N(H)(C(=0)N(H)(pyridiny1)), CH2N(H)(C(=0)OC(CH3 )3), )(C(=0)0- chloropheny1), CH2N(H)(C(=0)-pyridiny1), CH2N(H)(C(=0)-chloropyridiny1), )(C(=S)cyclopropyl), CH2N(H)(C(=S)N(H)(CH2CH=CH2)), CH2N(H)(C(=S)N(H)(CH2CH3)), CH2N(H)(pyridinyl), N(H)(N(H)(C(=O)CH2CF3), N(H)(N(H)(C(=O)cyclopropyl), ON(H)(C(=O)CH2CF3), and ON(H)(C(=O)cyclopropyl).
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, , ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(Cs)alkyl, 6)alkyl, halo(C7)alkyl, halo(C8)alkyl, halomethoxy, hoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(Cs)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and 8)alkoxy.
In another embodiment of this invention R12 is ed from CH3, and H.
In another embodiment of this invention R13 may be selected from any combination of one or more of the ing- H, F, Cl, Br, I, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, hyl, halo(C3)alkyl, halo(C4)alkyl, halo(Cs)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(Cs)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 r embodiment of this invention R12-R13 are a hydrocarbyllinkage containing CH=CHCH=CH.
In another embodiment of this invention R14 rnay be selected from any combination of one or more of the following- H, methyl, ethyl, (C3)alkyl, kyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(Cs)alkyl, halo(C6)alkyl, 7)alkyl, halo(C8)alkyl, methyl-aryl, ethyl-aryl, (C3)alkyl-aryl, (C4)alkylaryl , (Cs)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), (Cs)alkyl- (substituted-aryl), (C6)alkyl-(substituted-aryl), (C7)alkyl-(substituted-aryl), (C8)alkyl- (substituted-aryl), 0-methyl-aryl, 0-ethyl-aryl, O-(C3)alkyl-aryl, O-(C4)alkyl-aryl, 0- (Cs)alkyl-aryl, O-(C6)alkyl-aryl, O-(C7)alkyl-aryl, O-(C8)alkyl-aryl, 0-methyl-(substitutedaryl ), l-(substituted-aryl), O-(C3)alkyl-(substituted-aryl), O-(C4)alkyl-(substituted- wo 2012/177813 aryl), 0-(Cs)alkyl-(substituted-aryl), O-(C6)alkyl-(substituted-aryl), alkyl-(substitutedaryl ), O-(C8)alkyl-(substituted-aryl), methyl-heterocyclyl, heterocyclyl, kylheterocyclyl , (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-(substitutedheterocyclyl ), (Cs)alkyl-(substituted-heterocyclyl), (C6)alkyl-(substituted-heterocyclyl), (C7)alkyl-(substituted-heterocyclyl), (C8)alkyl-(substituted-heterocyclyl), 0-methylheterocycly1 , 0-ethy1-heterocycly1, 0-(C3)alky1-heterocycly1, 0-(C4)alky1-heterocycly1, O- kyl-heterocyclyl, O-(C6)alkyl-heterocyclyl, O-(C7)alkyl-heterocyclyl, O-(C8)alkyl- heterocyclyl, 0-methyl-(substituted-heterocyclyl), 0-ethyl-(substituted-heterocyclyl), O- (C3)alkyl-(substituted-heterocyclyl), O-(C4)alkyl-(substituted-heterocyclyl), 0-(Cs)alkyl- (substituted-heterocycly 1), 0-(C6)alky1-(substituted-heterocycly1), 0-(C7)alky1-(substituted- heterocyclyl), O-(C8)alkyl-(substituted-heterocyclyl), methyl-C(=O)N(Rl6)(Rl7), ethyl- (Rl6)(Rl7), (C3)alkyl-C(=O)N(Rl6)(Rl7), (C4)alkyl-C(=O)N(Rl6)(Rl7), (C5)alkyl- C(=O)N(Rl6)(Rl7), (C6)alkyl-C(=O)N(Rl6)(Rl7), (C7)alkyl-C(=O)N(Rl6)(Rl7), and (C8)alkyl-C(=O)N(Rl6)(Rl7).
In another embodiment of this invention R14 rnay be selected from any combination of one or more of the following- H, CH3, CH2CF3, CH2-halopyridyl, oxo-pyrrolidinyl, halophenyl, thietanyl, CH2-phenyl, ridyl, 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 ment of this invention R15 may be selected from any ation of one or more of the following - H, , ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(Cs)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, -aryl, ethyl-aryl, (C3)alkyl-aryl, (C4)alkylaryl , (Cs)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), (Cs)alkyl- (substituted-aryl), (C6)alkyl-(substituted-aryl), (C7)alkyl-(substituted-aryl), (C8)alkyl- (substituted-aryl), 0-methyl-aryl, 0-ethyl-aryl, O-(C3)alkyl-aryl, O-(C4)alkyl-aryl, 0- (Cs)alkyl-aryl, O-(C6)alkyl-aryl, O-(C7)alkyl-aryl, O-(C8)alkyl-aryl, 0-methyl-(substitutedaryl ), 0-ethyl-(substituted-aryl), O-(C3)alkyl-(substituted-aryl), O-(C4)alkyl-(substitutedaryl ), 0-(Cs)alkyl-(substituted-aryl), O-(C6)alkyl-(substituted-aryl), alkyl-(substitutedaryl ), O-(C8)alkyl-(substituted-aryl), methyl-heterocyclyl, heterocyclyl, (C3)alkylheterocyclyl , (C4)alkyl-heterocyclyl, (C5)alkyl-heterocyclyl, (C6)alkyl-heterocyclyl, wo 2012/177813 (C7)alkyl-heterocyclyl, (C8)alkyl-heterocyclyl, methyl-(substituted-heterocyclyl), ethyl- (substituted-heterocyclyl), (C3)alkyl-(substituted-heterocyclyl), (C4)alkyl-(substitutedheterocyclyl ), (Cs)alkyl-(substituted-heterocyclyl), (C6)alkyl-(substituted-heterocyclyl), (C7)alkyl-(substituted-heterocyclyl), (C8)alkyl-(substituted-heterocyclyl), 0-methyl- heterocyclyl, 0-ethyl-heterocyclyl, O-(C3)alkyl-heterocyclyl, O-(C4)alkyl-heterocyclyl, O- (C5)alkyl-heterocyclyl, alkyl-heterocyclyl, O-(C7)alkyl-heterocyclyl, O-(C8)alkylheterocyclyl , 0-methyl-(substituted-heterocyclyl), 0-ethyl-(substituted-heterocyclyl), O- (C3)alkyl-(substituted-heterocyclyl), O-(C4)alkyl-(substituted-heterocyclyl), O-(C5)alkyl- (substituted-heterocycly 1), 0-(C6)alky1-(substituted-heterocycly1), alky1-(substituted- heterocyclyl), O-(C8)alkyl-(substituted-heterocyclyl), methyl-C(=O)N(Rl6)(Rl7), ethyl- (Rl6)(Rl7), (C3)alkyl-C(=O)N(Rl6)(Rl7), (C4)alkyl-C(=O)N(Rl6)(Rl7), (C5)alkyl- C(=O)N(Rl6)(Rl7), (C6)alkyl-C(=O)N(Rl6)(Rl7), (C7)alkyl-C(=O)N(Rl6)(Rl7), and (C8)alkyl-C(=O)N(Rl6)(Rl7).
In another embodiment of this ion R15 may be selected from any combination of one or more of the following- H, CH3, CH2CF3, CH2-halopyridyl, rrolidinyl, halophenyl, thietanyl, CH2-phenyl, CH2-pyridyl, thietanyl-dioxide, lothiazolyl, C((CH3)2)-pyridy1, N(H)(halopheny1), CH2-pyrimidiny1, CH2-tetrahydrofurany1, CH2-furany1, O-CH2-halopyridyl, and O)N(H)(CH2CF3).
In r embodiment of this invention R16 rnay be ed 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(Cs)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methyl-aryl, ethyl-aryl, (C3)alkyl-aryl, (C4)alkylaryl , (Cs)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), (Cs)alkyl- (substituted-aryl), (C6)alkyl-(substituted-aryl), (C7)alkyl-(substituted-aryl), (C8)alkyl- (substituted-aryl), 0-methyl-aryl, 0-ethyl-aryl, O-(C3)alkyl-aryl, O-(C4)alkyl-aryl, 0- kyl-aryl, O-(C6)alkyl-aryl, O-(C7)alkyl-aryl, O-(C8)alkyl-aryl, 0-methyl-(substitutedaryl ), 0-ethyl-(substituted-aryl), O-(C3)alkyl-(substituted-aryl), O-(C4)alkyl-(substitutedaryl ), 0-(Cs)alkyl-(substituted-aryl), O-(C6)alkyl-(substituted-aryl), O-(C7)alkyl-(substituted- aryl), O-(C8)alkyl-(substituted-aryl), methyl-heterocyclyl, ethyl-heterocyclyl, (C3)alkylheterocyclyl , (C4)alkyl-heterocyclyl, (C5)alkyl-heterocyclyl, kyl-heterocyclyl, (C7)alkyl-heterocyclyl, (C8)alkyl-heterocyclyl, methyl-(substituted-heterocyclyl), ethyl- (substituted-heterocyclyl), (C3)alkyl-(substituted-heterocyclyl), (C4)alkyl-(substitutedheterocyclyl ), kyl-(substituted-heterocyclyl), (C6)alkyl-(substituted-heterocyclyl), wo 2012/177813 (C7)alkyl-(substituted-heterocyclyl), (C8)alkyl-(substituted-heterocyclyl), 0-methylheterocyclyl , 0-ethyl-heterocyclyl, alkyl-heterocyclyl, O-(C4)alkyl-heterocyclyl, O- (C5)alkyl-heterocyclyl, alkyl-heterocyclyl, O-(C7)alkyl-heterocyclyl, O-(C8)alkylheterocyclyl , 0-methyl-(substituted-heterocyclyl), 0-ethyl-(substituted-heterocyclyl), 0- (C3)alkyl-(substituted-heterocyclyl), O-(C4)alkyl-(substituted-heterocyclyl), 0-(Cs)alkyl- (substituted-heterocycly 1), 0-(C6)alky1-(substituted-heterocycly1), 0-(C7)alky1-(substituted- heterocyclyl), and 0-(C8)alkyl-(substituted-heterocyclyl).
In another embodiment of this ion R16 rnay be selected from any combination of one or more of the following- H, CH2CF3, cyclopropyl, thietanyl, thietanyl e, 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, kyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(Cs)alkyl, halo(C6)alkyl, 7)alkyl, halo(C8)alkyl, methyl-aryl, ethyl-aryl, (C3)alkyl-aryl, (C4)alkyl- aryl, (Cs)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), (Cs)alkyl- (substituted-aryl), (C6)alkyl-(substituted-aryl), (C7)alkyl-(substituted-aryl), (C8)alkyl- (substituted-aryl), 0-methyl-aryl, 0-ethyl-aryl, O-(C3)alkyl-aryl, O-(C4)alkyl-aryl, 0- (Cs)alkyl-aryl, O-(C6)alkyl-aryl, alkyl-aryl, O-(C8)alkyl-aryl, 0-methyl-(substituted- aryl), 0-ethyl-(substituted-aryl), O-(C3)alkyl-(substituted-aryl), O-(C4)alkyl-(substitutedaryl ), 0-(Cs)alkyl-(substituted-aryl), O-(C6)alkyl-(substituted-aryl), O-(C7)alkyl-(substitutedaryl ), O-(C8)alkyl-(substituted-aryl), methyl-heterocyclyl, ethyl-heterocyclyl, (C3)alkylheterocyclyl , (C4)alkyl-heterocyclyl, kyl-heterocyclyl, (C6)alkyl-heterocyclyl, (C7)alkyl-heterocyclyl, (C8)alkyl-heterocyclyl, methyl-(substituted-heterocyclyl), ethyl- (substituted-heterocyclyl), (C3)alkyl-(substituted-heterocyclyl), (C4)alkyl-(substitutedheterocyclyl ), (Cs)alkyl-(substituted-heterocyclyl), (C6)alkyl-(substituted-heterocyclyl), (C7)alkyl-(substituted-heterocyclyl), (C8)alkyl-(substituted-heterocyclyl), 0-methylheterocyclyl , 0-ethyl-heterocyclyl, alkyl-heterocyclyl, alkyl-heterocyclyl, O- (C5)alkyl-heterocyclyl, O-(C6)alkyl-heterocyclyl, O-(C7)alkyl-heterocyclyl, O-(C8)alkyl- heterocyclyl, 0-methyl-(substituted-heterocyclyl), 0-ethyl-(substituted-heterocyclyl), O- (C3)alkyl-(substituted-heterocyclyl), O-(C4)alkyl-(substituted-heterocyclyl), 0-(Cs)alkyl- (substituted-heterocycly 1), 0-(C6)alky1-(substituted-heterocycly1), 0-(C7)alky1-(substituted- heterocyclyl), and O-(C8)alkyl-(substituted-heterocyclyl). wo 2012/177813 In another embodiment of this invention R17 may be selected from any combination of one or more of the following- H, CH2CF3, ropyl, 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 when R10 and R11 form a linkage said linkage is selected from (a)- (1). * --0" *~ '-- The molecules of Formula One will generally have a molecular mass of about 100 Daltons to about 1200 s. However, it is generally red if the molecular mass is from about 120 Daltons to about 900 Daltons, and it is even more lly preferred if the molecular mass is from about 140 Daltons to about 600 Daltons. wo 77813 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 ions, such as aqueous sodium hydroxide , in a polar protic solvent, such as methyl alcohol (CH30H) at 0 °C. Alternatively, an aldehyde of a 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 ormed 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 usly disclosed, by reaction with a halogenating reagent, such as N-bromosuccinimide and triethyl phosphite in a non-reactive solvent, such as dichloromethane (CH2Cb) 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.
Scheme I ::=¢(R6 _a__ IT ::~~6 __c__ ::xx.~~ R2 R2 0 IV v I~ R7 b R3 # Rl Formation of the styrene coupling partners can be accomplished as in Schemes II, III IV and V.
In Scheme II, a vinylbenzoic acid of a VI, wherein R11 is (C=O)OH and R8, R9, RlO, R12, R13, X1, X2, and X3 are as usly disclosed, can be converted in two steps to the vinylbenzamide of Formula VIla, wherein R11 is (C=O)N(R14)(R15), and R8, R9, RlO, R12, R13, R14, R15, and X are as previously disclosed. As in step d of Scheme II, wo 2012/177813 the benzoic acid of Formula VI is treated with oxalyl de in the presence of a catalytic amount of N,N-dimethylformamide (DMF) in a non-reactive t such as CH2Ch to form the acid chloride, which is subsequently allowed to react with an amine (HN(R14)(R15)), n R14 and R15 are as previously disclosed, in the presence of a base, such as triethylamine, in a polar aprotic solvent, such as THF, to provide the vinyl benzamide of Formula VIla, n Rll is (C=O)N(R14)(R15), and R8, R9, RlO, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed, as in step e of Scheme II.
Scheme II o R8 l .X3 RIO -;7' II X X2 h X2'xrh 'xt Rll R11 VI VIla In Schemes III and IV, a halobenzoic acid of Formula VIII, wherein R18 is Br or I, R11 is (C=O)OH and R9, RlO, R12, R13, X1, X2, and X3 are as previously disclosed can be converted to a vinylbenzoic acid ester of Formula VIIb1 or a VIIb2, wherein R18 is Br or I, R11 is (C=O)O(C1-C6 alkyl), and R8, R9, RlO, R12, R13, X1, X2, and X3 are as previously disclosed. In stepf of Scheme III, the halobenzoic acid of Formula VIII, wherein R18 is Br, is treated with a base, such as n-butyllithium (n-BuLi), and DMF in a polar, aprotic solvent, such as THF, at a temperature of about -78 oc. The resulting formyl benzoic acid is allowed to react with an acid, such as sulfuric acid (H2S04), 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, RlO, 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 (K2C03), and methyl triphenyl phosphonium bromide in a polar c solvent, such as 1,4-dioxane, at ambient temperature, as in step h of Scheme III. wo 2012/177813 2012/043418 Scheme III H R8 Rl8'(X3XRIO f,g Rlo~ h o X2 ~ X2 ~ X2 ~ 'Xl Rll 'Xl Rll 'Xl Rll VIII IX Vllbl In step i of Scheme IV, the halobenzoic acid of Formula VIII, wherein Rl8 is Br, Rll is (C=O)OH, and R8, R9, RIO, Rl2, Rl3, XI, X2, and X3 are as previously disclosed, is treated with di-tert-butyl dicarbonate in the presence of a base, such as ylamine (Et3N) and a catalytic amount of 4-(dimethylamino)pyridine (DMAP) in a polar aprotic solvent, such as THF, at ambient temperature. The resulting c acid tert-butyl ester is allowed to react with vinyl boronic anhydride ne complex in the presence of a palladium catalyst, such a tetrakis(triphenylphospine)palladium(O) (Pd(PPh3)4), and a base, such as K2C03, in a nonreactive solvent such as toluene at reflux temperature, as in step j, to provide the vinyl IO benzoic acid ester of Formula VIIb2, wherein Rll is (C=O)O(C1-C6 alkyl), and R8, R9, RIO, Rl2, Rl3, XI, X2, and X3 are as previously disclosed.
Scheme IV i,j ~x3XR1o X2 ~ 'XI Rll VIII VIIb2 In step k of Scheme V, the vinyl c acid ester of Formula VIIb2, wherein RIO is Br, Rll is (C=O)O(C1-C6 alkyl), and R8, R9, Rl2, Rl3, XI, X2, and X3 are as previously defined, can be further transformed into the corresponding vinyl benzoic acid ester of Formula VIIb3, wherein RIO is CN, Rll is (C=O)O(C1-C6 alkyl), and R8, R9, Rl2, Rl3, XI, X2, and X3 are as previously disclosed, by reaction with copper(!) cyanide (CuCN) in a polar aprotic solvent, such as DMF, at 140 oc. wo 2012/177813 Scheme V R8 R8 ~x3XRlo k ~x3XRlo X2 ~ X2 ~ 'Xl R11 'Xl Rll Vllb2 Vllb3 Coupling of the compounds of Formula V with the compounds of a VIla, VIIb1, VIIb2 and VIIb3 can be accomplished as in Schemes VI, VII, and VIII. In step I of Scheme VI, a compound of Formula V, wherein Y, Rl, R2, R3, R4, R5, R6, and R7 are as previously sed, and the vinylbenzamide of Formula VIla, n Rll is (C=O)N(Rl4)(Rl5), and R8, R9, RIO, Rl2, Rl3, Rl4, Rl5, Xl, X2, and X3 are as previously disclosed, are allowed to react in the presence of copper(!) chloride (CuCl) and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180 octo provide the molecules of Formula One, wherein Rll is (C=O)N(Rl4)(Rl5), and Rl, R2, R3, IO R4, R5, R6, R7, R8, R9, RIO, Rl2, Rl3, Rl4, Rl5, Xl, X2, and X3 are as previously sed.
Scheme VI R5 y R8 R6 R5 R7 ~X3 RIO R4 + X 1:(X3 R3 X2 ~ X2 ~ 'Xl Rll R3 'Xl R11 R2 R2 v VIla Formula One In step I 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, RIO, 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 octo e the compounds of Formula Xa, wherein R11 is (C=O)O(C1-C6 alkyl), and R1, R2, R3, R4, R5, R6, R7, R8, R9, RIO, R12, R13, X1, X2, and X3 are as previously disclosed. The compounds of Formula Xa are then ted to the molecules of Formula One, n R11 is (C=O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, RIO, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed, by either a two-step process as disclosed in steps m wo 2012/177813 and nor 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 t, such as 1,4-dioxane, at about 100 oc. The acid is subsequently coupled to an amine (HN(R14)(R15)), wherein R14 and R15 are as previously disclosed, with 1-hydroxybenzotriazole hydrate (HOBt•H20) and N-(3- dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (EDC•HCl) in the presence of a base, such as N,N-diisopropylethylamine (DIEA), and in a polar aprotic solvent, such as DMF, to give the molecules of Formula One, n 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 a Xa is allowed to react with an amine (HN(R14)(R15)) in the presence of a on of trimethylaluminum in toluene in a nonreactive solvent, such as CH2Ch, 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.
Scheme VII R5 Y R R8 6 R5 R4 R7+~X3XRIO l R4 IXX3 RIO R3 ~ X2 'XI RII ~ R3 'XI RII v VIIbi Xa R4 IXX3 RIO m, nor o X2 ~ R3 'XI Rll Formula One In step I of Scheme VIII, the nd of Formula V, n 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 wo 2012/177813 2012/043418 a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180 octo provide the nds of Formula Xb, wherein Rll is (C=O)OH, and Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO, Rl2, Rl3, Rl4, Rl5, XI, X2, and X3 are as previously disclosed. The compounds of Formula Xb are then converted to the molecules of Formula One, wherein Rll is (C=O)N(Rl4)(Rl5), and Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO, Rl2, Rl3, Rl4, Rl5, XI, X2, and X3 are as previously disclosed, in one step as disclosed in step n. In step n of Scheme VII, the acid of Formula Xb is coupled to an amine (HN(R14)(R15)), wherein R14 and R15 are as previously disclosed, with HOBt•H20 and EDC•HCI in the presence of a base, such as DIEA, and in a polar aprotic solvent, such as DMF, to give the molecules of IO Formula One, n Rll is (C=O)N(Rl4)(R15), and Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO, R12, R13, R14, R15, Xl, X2, and X3 are as previously sed.
Scheme VIII R5 Y R R8 6 R5 R7 ~X3XR10 l R4 RIO + X2 ~ --- IXX3 R3 X2 Rl 'Xl Rll ~ R3 'Xl Rll v Vllb2 or VIIb3 Xb R4 X3 RIO X2IX~ R3 'XI R11 Formula One In stepj of Scheme IX, the halobenzoketone of Formula VIIIb, wherein R18 is Br, RIO and Rll 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, Xl, X2, and X3 are as previously sed, is allowed to react with vinyl boronic anhydride pyridine complex in the presence of a ium catalyst, such as Pd(PPh3) 4, and a base, such as K2C03, in a non-reactive solvent such as toluene at reflux temperature, to provide the vinyl benzoketone of Formula VIIb4, wherein RIO and Rll together form a linkage, having 3-4 wo 2012/177813 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 usly disclosed.
Scheme IX Rl81(X3YR10 j ~X3"'(RIO X2 ~ X2 ~ 'Xl R11 'Xl Rll VIIIb Vllb4 In step I of Scheme X, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the enzoketone of Formula Vllb4 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 ature of about 180 oc to provide the compounds of Formula Xc, wherein RlO 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 sed. The compounds of Formula Xc are then converted to the molecules of Formula Xd, wherein RlO 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 les of a Xd as previously disclosed. wo 2012/177813 Scheme X R5 Y R R8 6 R5 R7 ~XJXRIO l R4 X3 RIO + X2~ --- R3 X2IX 'XI RII ~ R3 'XI RII v VIIb4 Xc R4 X3 RIO X2IX~ R3 'XI RII The compounds of Formula Xc are also converted to the les of Formula Xe, wherein RIO and RII 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 RI, R2, R3, R4, R5, R6, R7, R8, R9, RI2, RI3, XI, X2, and X3 are as usly 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 t, such as CH30H, at a temperature of about 65 °C, to give the molecules of Formula Xe.
Scheme XI R5 R5 R4 X3 RIO R4 X3 RIO X2IX X2IX ~ ~ R3 'XI RII R3 'Xl RII R2 R2 Xc Xe The compounds of Formula Xe are converted to the molecules of Formula One, wherein RIO and RII together form a linkage as previously disclosed in (u), and RI, R2, R3, R4, R5, R6, R7, R8, R9, RI2, RI3, XI, X2, and X3 are as previously, in one step as sed I5 in steps r or s. In step r of Scheme XII, the amine of Formula Xe is allowed to react with an wo 2012/177813 isocyanate in a polar, aprotic solvent such as diethyl ether at ambient temperature to provide the les of Formula One as previously disclosed. In steps of Scheme XII, the amine of Formula Xe is coupled to an acid with HOBt•H20 and EDC•HCI in the presence of a base, such as DIEA, in a non-reactive solvent, such as CH2Ch, to give the molecules of Formula One, as previously disclosed.
Scheme XII R5 R5 R4 IXX3 RlO R4 r ors X3 RIO X2 h X2IX h R3 'Xl Rll R3 'XI R11 R2 R2 Xe Formula One In step t of Scheme XIII, the vinyl benzyl chloride of Formula XIa, wherein R11 is:::.
CH2Cl and R8, R9, RlO, 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, RlO, R12, R13, X1, X2, and X3 are as usly disclosed, by on with potassium phthalimide in a polar aprotic solvent, such as DMF, at 70 oc.
Scheme XIII R8 R8 ~X3"(Rl0 t ~X3"(Rl0 X2 ~ X2 ~ XI Rll XI Rll XI a XIIa In step u of Scheme XIV, the 4-methylbenzonitrile of a XIIIa, wherein R11 is CH3 and R9, RlO, R12, R13, X1, X2, and X3 are as previously defined, can be transformed into the corresponding benzy1bromide of Formula XIVa, wherein R11 is CH2Br and R8, R9, RlO, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with N- bromosuccinimide (NBS) and isobutyronitrile (AIBN) in a non-reactive solvent, such as carbon hloride at 77 °C. The nitrile group (CN) of Formula XIVa can be reduced to the ponding aldehyde of Formula XVa, wherein R11 is CH2Br and R9, RlO, R12, R13, X1, X2, and X3 are as previously defined via reaction with diisobutylaluminum hydride (DIBAL-H) in an aprotic solvent, such as e, at 0 °C, followed by quenching with 1.0 M wo 2012/177813 hydrochloric acid (HCI) 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, RlO, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with ium imide in a polar aprotic solvent, such as DMF, at 60 oc 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, RlO, R12, R13, X1, X2, and X3 are as previously sed, by reaction with methyl triphenyl phosphonium bromide in a polar aprotic solvent, such as 1,4-dioxane, in the ce of a base, such as K2C03, at ambient temperature.
Scheme XIV u v XIIIa XIVa XVa H R8 t 0~X3~Rl0 w ~X3~Rl0 X2 .J___ X2 .J___ XI Rll XI Rll XVIa X lib The de ofFormulaXVa, wherein Rll is CH2Br and R9, RlO, 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 K2C03, at ambient temperature to provide the compound of Formula XVII, wherein Rll is CH2NH(2-pyridine) and R9, RlO, R12, R13, X1, X2, and X3 are as usly disclosed, as in step x of Scheme XV. In step w of Scheme XV, the compound of Formula XVII can be ted to the olefin of Formula XVIII, wherein R11 is CH2NH(2-pyridine) and R8, R9, RlO, R12, R13, X1, X2, and X3 are as previously disclosed.
Scheme XV H H R8 0~X3:CRIO X 0~X3:CRIO w ~X3:CRIO X2 ,. X2 ,. X2 ,.
Xl Rll Xl Rll Xl Rll XVa XVII XVIII wo 2012/177813 In a two-step, one-pot reaction as in steps y and z of Scheme XVI, the compound of Formula XIX can be d with the compounds of Formula XX, wherein RlO and Rll are Cl, Xl is N, and R9, R13, X2, and X3 are as previously disclosed, in the ce of a base, such as sodium e (NaH), and a polar aprotic solvent, such as DMF, at ambient temperature to provide the compounds of Formula XXI, wherein RlO is Cl, Rll is (CH)NH2C02CH2CH3, Xl 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 HCI, at reflux temperature, to afford the compounds of Formula XXII, n RlO is Cl, Rll is CH2NH2•HC1, Xl is N, and R9, R13, X2, and X3 are as previously disclosed, as in step aa in Scheme XVI. The nds of Formula XXII can be further transformed to the corresponding phthalimide-protected benzyl amines of Formula XXIIIa, wherein RlO is Cl, Rll is CH2N(Phthalimide), Xl is N, and R9, R13, Xl, X2, and X3 are as previously disclosed, by on with phthalic anhydride in the ce of a base, such as Et3N, 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 RlO is Cl, Rll is CH2N(Phthalimide), Xl 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 K 2C03, in a non-reactive solvent such as toluene at reflux temperature, as in step ac of Scheme XVI.
Scheme XVI 3"(R10 y, z a a X2 ~ XI Rll XX XXI ab ac XXII XXIIIa XIIc In step u of Scheme XVII, the 4-methylnaphthonitrile of Formula XIIIb, wherein X3 is CR9, RlO and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, Rll is CH3, and R12, R13, Xl and X2 are as wo 2012/177813 2012/043418 previously defined, can be ormed into the corresponding naphthyl bromide of Formula XIVb, wherein X3 is CR9, RlO 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 de of a XVb, wherein X3 is CR9, RlO 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 nonaromatic ring), R11 is CH2Br, and R12, R13, X1 and X2 are as previously defined via reaction with diisobutylaluminum hydride -H) in an aprotic solvent, such as toluene, at 0 °C, followed by quenching with 1.0 M HCI as in step v of Scheme XVII. The compound of a XVb can be further transformed to the corresponding phthalimide-protected benzyl amine of Formula XVIb, wherein X3 is CR9, RlO 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 sed, by reaction with potassium phthalimide in a polar aprotic solvent, such as DMF, at 60 oc 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, RlO and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a ered 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 t, such as 1,4-dioxane, in the presence of a base, such as K2C03, at ambient temperature.
Scheme XVII u v XIIIb XIVb XVb H R8 0~X3-y'Rl0 w ~X3-y'Rl0 X2 .J___ X2 .J___ XI Rll XI Rll XVIb XIId wo 2012/177813 The compound of Formula XXIV, wherein R11 is NHNH2•HC1 and R9, RlO, R12, R13, X1, X2, and X3 are as previously disclosed, can be transformed into the corresponding phthalimide-protected hydrazine of Formula XXV, wherein R 11 is thalimide) and R9, RlO, 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 a XXV can be converted to the olefin of Formula XIIe, n R11 is NHN(Phthalimide) and R8, R9, RlO, R13, X1, X2 and X3 are as previously disclosed, by on with vinyl boronic anhydride pyridine complex in the presence of a palladium catalyst, such as 3) 4, and a base, such as K2C03, in a polar aprotic solvent such as 1,2- dimethoxyethane at 150 oc under microwave conditions, as in step ae of Scheme XVIII.
Scheme XVIII llr11X3:CRIO ad llr11X3:CRIO ae ~X3:CRIO X2 "" X2 "" X2 "" XI Rll XI Rll XI Rll XXIV XXV XIIe In step afof Scheme XIX, the compound of Formula XXVI, wherein R11 is B(OHh, and R8, R9, RlO, 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, RlO, R12, R13, X1, X2, and X3 are as previously disclosed.
Scheme XIX R8 R8 ~X3~R10 af ~X3~R10 X2 .J__ X2 .J__ XI Rll XI Rll XXVI XIIf In step I 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 hthalimide) and R8, R9, RlO, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and pyridyl in a solvent, such as 1,2- robenzene, at a temperature of about 180 oc to e the corresponding compounds of Formula XXVIIa, wherein R11 is CH2N(Phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, RlO, R12, R13, X1, X2, and X3 are as previously disclosed. The phthalimide wo 2012/177813 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 oc to provide the compounds of Formula XXVIIIa, wherein Rll is CH2NH2 and Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO, Rl2, Rl3, XI, 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, RIO, R12, R13, X1, X2, and X3 are as previously disclosed, by acylation with an anhydride, such as acetic anhydride, and a base, such as Et3N, in a active solvent such as CH2Ch at 0 oc as in step ah1 of Scheme XX.
Scheme XX R5 y R6 R5 R6 R8 R4NR7' R4 o X3 RlO l I "'I R3VR1 X2 .J....
R3 Rl Xl Rll R2 R2 v XIIa XXVIIa R5 R6 R8 R5 R6 R8 R7o 11 R7o R4 X3 RIO R4 ag 11X3 RIO 2 2 R3 Rl X Xl Rll R3 Rl X Xl Rll R2 R2 XXVIIIa IO Formula One In step I 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, n Rll is CH2N(Phthalimide) and R8, R9, RIO, R12, R13, X1, X2, and X3 are as previously disclosed, are d to react in the presence of CuCl and pyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180 octo provide the corresponding compounds of Formula XXVIIb, wherein R11 is CH2N(Phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, RIO, R12, R13, X1, X2, and X3 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIIb is d as in step ag of Scheme XXI by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90 octo e the compounds of Formula XXVIIIb, wherein R11 is CH2NH2 and R1, R2, R3, R4, R5, R6, R7, R8, R9, RIO, R12, R13, X1, X2, and X3 are as previously sed. The compounds of Formula XXVIIIb can be transformed into the compounds of a One, wherein R11 is CH2N(C=O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, RIO, R12, R13, wo 2012/177813 Xl, X2, and X3 are as previously sed, by reaction with an acid in the presence of HOBt•H20, EDC•HCl and a base, such as DIEA, 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 Rll is CH2N(C=S)(Rl4) and Rl, R2, R3, R4, R5, R6, R7, R8, R9, RlO, R12, R13, Xl, X2, and X3 are as previously disclosed, by reaction with a thioacid in the presence of HOBt•H20, EDC•HCl and a base, such as DIEA, in a polar aprotic solvent, such as DMF, as in step ah2 of Scheme XXI.
In another embodiment, the compounds of Formula b can be transformed into the compounds of a One, wherein Rll is CH2N(C=O)N(Rl4)(R15) and Rl, R2, R3, R4, R5, R6, R7, R8, R9, RlO, R12, R13, Xl, 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 methyl alcohol, followed by on 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 Et3N, in a non-reactive solvent such as CH2Ch at ambient ature of Scheme XXI.
In r embodiment, the compounds of Formula XXVIIIb can be transformed into the nds of Formula One, wherein Rll is CH2N(C=O)N(Rl4)(R15) and Rl, R2, R3, R4, R5, R6, R7, R8, R9, RlO, R12, R13, Xl, 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 Et3N and in a non-reactive solvent such as CH2Ch at 0 ac.
In another embodiment, the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein Rll is CH2N(C=S)N(Rl4)(R15) and Rl, R2, R3, R4, R5, R6, R7, R8, R9, RlO, R12, R13, Xl, X2, and X3 are as previously disclosed, by reaction with an isothiocyanate in the presence of a base such as Et3N and in a active solvent such as CH2Ch at 0 oc, 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 Rll is =O)O(Rl4) and Rl, R2, R3, R4, R5, R6, R7, R8, R9, RlO, R12, R13, Xl, X2, and X3 are as usly disclosed, by reaction with a dicarbonate, such as di-tert-butyl dicarbonate in the ce of a base such as Et3N and in a non-reactive solvent such as CH2Ch at ambient temperature, as in steps ak of Scheme XXI. wo 2012/177813 In yet another embodiment, the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein Rll is CH2N(C=O)(C=O)O(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, RlO, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with a chlorooxalic acid ester, such as 2-chlorooxoacetate in the presence of a base such as Et3N and in a non-reactive solvent such as CH2Ch at 0 °C, as in steps al of Scheme XXI.
Scheme XXI R5 y R6 R5 R6 R8 R4~R7' R7 R4 o X3 RlO l I~ R3YR1 X2 .J....
R3 Rl Xl Rll R2 R2 v Xlib XXVlib R5 R6 R8 R5 R6 R8 R7o 11 R7o R4 X3 RIO R4 ag 11X3 RIO 2 2 R3 Rl X Xl Rll y R3 Rl X Xl Rll R2 of R2 steps XXVIIIb see sion Formula One In step I 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 a XIIc, wherein RlO is Cl, R11 is hthalimide), 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 octo provide the ponding compounds of Formula XXVIIc, wherein RlO 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 ine hydrate in a polar protic solvent such as EtOH at 90 oc to e the compounds of Formula c, wherein RlO is Cl, Rll 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 RlO 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•H20, EDC•HCI wo 2012/177813 and a base, such as DIEA, in a polar c solvent, such as CH2Ch, as in step ah2b of Scheme XXII.
Scheme XXII R5 y R6 R8 R5 R8 R4~R7 R6R7 ~X31RIO R4 ~ X3 RIO R3 ~ Rl 2 X211...
X Xl Rll R3 Xl Rll R2 R2 v XIIc XXVIIc R5 R8 R6R7 R5 R6 R8 ag ~ 11X3 RIO R4 ah2b ~ 11X3 RIO R3 X Xl Rll 2 R3 X Xl Rll R2 R2 XXVIIIc Formula One In step I 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, n X3 is CR9, RlO and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring (or if d 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 pyridyl in a solvent, such as 1,2- dichlorobenzene, at a temperature of about 180 oc to provide the corresponding compounds of Formula XXVIId, wherein X3 is CR9, RlO 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 sed. 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 oc to provide the compounds of Formula XXVIIId, wherein X3 is CR9, RlO 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 nds of Formula XXVIIId can be transformed into the compounds of Formula One, wherein X3 is CR9, RlO 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 sed, by reaction with an acid in wo 2012/177813 the presence of HOBt•H20, EDC•HCI and a base, such as DIEA, in a polar c solvent, such as CH2Ch, 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, RlO 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, RlO, R12, R13, X1 and X2 are as usly disclosed, by reaction with an isocyanate in the presence of a base such as Et3N and in a non-reactive t such as CH2Ch at 0 oc as in step ai1 of Scheme XXIII.
Scheme XXlll R4~R6 R8 R5 R8 R6R7 I~ R7 ~X31RIO R4 0 11X3 RIO R3 ° Rl 2 X2 " X Xl RII R3 RI XI Rll R2 R2 v XIId XXVlid R5 R8 R8 R6R7 R5 ah2b R6R7 R4 R4 ag o 11X3 RIO or ai1 0 11X3 RIO X2 " 2 R3 Rl XI Rll R3 Rl X Xl RII R2 R2 XXVIIId Formula One In step I 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 a XIIe, n Rll is NHN(Phthalimide) and R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, are d 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 octo provide the corresponding compounds of Formula XXVIIe, wherein R11 is thalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as usly 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 oc 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 wo 2012/177813 previously disclosed, by reaction with an acid in the presence of HOBt•H20, EDC•HCI and a base, such as DIEA, in a polar c solvent, such as CH2Ch, as in step ah2b of Scheme XXIV.
Scheme XXIV R4:¢¢R7R5 y R6 R8 R5 R8 R6R7 ~X3 RIO R4 l .,ij X3 RIO R3 .,ij Rl 2 X Xl1Rll X211-- R3 Rl Xl Rll R2 R2 v XIIe XXVIle R5 R8 R6R7 R5 R6 R8 ag .,ij 11X3 RIO ah2b R4 .,ij X3 RIO X2 _. 112 R3 Rl Xl Rll R3 Rl X Xl Rll R2 R2 XXVIlle Formula One In step I 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 Rll is ON(Phthalimide) and R8, R9, RlO, 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 chlorobenzene, at a temperature of about 180 oc to provide the corresponding compounds of Formula XXVIIf, wherein Rll is ON(Phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, RlO, R12, R13, X1, X2, and X3 are as usly sed. 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 oc to provide the compounds of Formula XXVIIIf, wherein R11 is ONH2 and R1, R2, R3, R4, R5, R6, R7, R8, R9, RlO, R12, R13, X1, X2, and X3 are as usly 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•H20, I and a base, such as DIEA, in a polar c solvent, such as CH2Cb, as in step ah2b of Scheme XXV. wo 77813 Scheme XXV R5 y R6 R8 R5 R6 R8 R4~R7 ~X3r R7 RIO R4 -0 X3 RIO X2 "' ~r R3 -0 RI 2 XI Rll R3 RI X Xl RII R2 R2 v Xllf XXVIIf R5 R6 R8 R5 R6 R8 R7 R7 R4 -0 X3 RIO ah2b R4 ag -0 X3 RIO ~r2 ~r2 R3 RI X Xl RII R3 RI X Xl Rll R2 R2 XXVIIIf Formula One In step I of Scheme XXVI, the compound of Formula V, wherein Y, Rl, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XVIII, wherein Rll is CH2NH(2-pyridine) and R8, R9, RIO, Rl2, Rl3, Xl, X2, and X3 are as usly 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 oc to provide the corresponding compounds of Formula One, wherein Rll is CH2NH(2-pyridine), and Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO, Rl2, Rl3, Xl, X2, and X3 are as previously disclosed.
The compounds of Formula One can be further elaborated by rd s. For IO example, when Rll contains a thioether, the her can be oxidized to the e by treatment with oxone in the presence of an acetone:water mixture at ambient temperature.
When Rll 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 CH2Cb.
Scheme XXVI R5 y R6 R8 R5 R6 R8 R4~R7 ~X3 R7 RIO R4 -0 X3 RIO R3 -0 RI X2 r"' ~r2 XI Rll R3 Rl X Xl RII R2 R2 v XVIII Formula One In Scheme XXVII, a fluorobenzaldehyde of Formula XXIX, wherein RIO, Xl, X2, and X3 are as previously disclosed can be converted to a (1,2,4-triazolyl)benzaldehyde of wo 2012/177813 Formula XXX, wherein Rll is a substituted or tituted 1,2,4-triazolyl group, and RIO, XI, 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 ium carbonate, in a solvent such as DMF as in step aj. In step ak, the (1,2,4-triazolyl)benzaldehyde of Formula XXX is converted to a (1,2,4-triazolyl)vinyl benzene of Formula XXXIa wherein R11 is a substituted or unsubstituted 1,2,4-triazolyl group, and R8, RIO, X1, X2, and X3 are as previously disclosed by reaction with triphenyl phosphonium bromide in the ce of a base, such as potassium carbonate, in an aprotic solvent, such as 1,4-dioxane.
Scheme XXVII H H R8 ~ 10 ~ ~X3:CR10 o"' II ~ aj o"' II ~ ak ~X3:CR10 X2 h X2 h X2 h 'XI F 'XI R11 'X1 R11 XXIX XXX XXXIa In Scheme XXVIII, a bromofluorobenzene of Formula XXXII, wherein RIO, X1, X2, and X3 are as previously sed can be ted to a (1,2,4-triazolyl)vinylbenzene of Formula XXXIb, wherein R11 is a substituted or unsubstituted 1,2,4-triazolyl group, and R8, RIO, X1, X2, and X3 are as previously disclosed in two steps. In step al, the bromofluorobenzene is d 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-triazolyl)bromobenzene. In step cl, the (1,2,4-triazolyl)bromobenzene is reacted with vinyl boronic ide ne 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.
Scheme XXVIII al, cl ~X3:CR10 X2 h 'X1 Rll XXXII XXXIb Coupling of the compounds of Formula V with compounds of Formula XXXIa and XXXIb can be accomplished as in Schemes XXIX. In step /, a compound of Formula V, wo 2012/177813 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-triazolyl group, and R8, R9, RlO, X1, X2, and X3 are as usly disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2- robenzene, at a temperature of about 180 oc to provide the molecules of Formula One, wherein Rll is a substituted or unsubstituted 1,2,4-triazolyl group, and R1, R2, R3, R4, R5, R6, R7, R8, RlO, X1, X2, and X3 are as previously disclosed.
Scheme XXIX R5 y R8 R6 R5 R7 Jyx3 RIO R4 X3 RIO R3 X2 hX X2IXh 'XI RII R3 'XI Rll R2 R2 v XXXIa or XXXIb Formula One In Scheme XXX, compounds of Formula XXXIII wherein R11 is a 3-nitro-1,2,4- triazolyl group, and R1, R2, R3, R4, R5, R6, R7, R8, RlO, 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-triazolyl group, and R1, R2, R3, R4, R5, R6, R7, R8, RlO, X1, X2, and X3 are as previously disclosed by a two step process. In step am, the 3-nitro-1,2,4-triazolyl group is reduced to a o-1,2,4-triazolyl group in the presence of zinc dust and ammonium chloride in a protic solvent, such as methanol. In step an, the o-1,2,4- triazolyl group is acylated with an acid chloride, such as cyclopropylcarbonyl chloride or acetyl de, in the presence of a base, such as ylamine, in a solvent such as dichloromethane.
Scheme XXX R5 R5 R4 IXX3 RIO R4 X3 am, an X2 h X2 IXRIO R3 'XI Rll h R3 'XI Rll R2 R2 XXXIII Formula One In step ao of Scheme XXXI, a bromophenyl methyl ketone of a XXXIV wherein RlO, X1, X2, and X3 are as previously disclosed is converted to an phenyl methyl wo 2012/177813 ketone of the Formula XXXV wherein Rll is a 1,2,4-triazolyl group, and RIO, XI, 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 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 triethylamine, in an aprotic solvent, such as dichloromethane.
In step aq, the silyl enol ether is d with a compound of a V, wherein Y is Br, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed in the ce of CuCl and 2,2- bipyridyl in a solvent, such as 1,2-dichlorobenzene at a temperature of about 180 octo IO generate a ketone of the Formula XXXVII, wherein Rll is a 1,2,4-triazolyl group, and R1, R2, R3, R4, R5, R6, R7, RIO, X1, X2, and X3 are as previously disclosed. In step ar, the ketone of the Formula XXXVII is treated with magnesium bromide in an c solvent, such as THF to generate the tertiary alcohol. The tertiary alcohol then undergoes an elimination reaction when treated with a catalytic amount ofp-toluenesulfonic acid in a solvent, such as toluene, when heated to a ature to allow azeotropic removal of water to produce compounds of Formula One wherein R11 is a 1,2,4-triazolyl group, R8 is methyl, and R1, R2, R3, R4, R5, R6, R7, RIO, X1, X2, and X3 are as previously disclosed, as in step as. wo 2012/177813 Scheme :XXXI l X3:cRIO l ao X3 RIO ~ X3 RIO 0~ o~x ap Si9~x X2 h X2 h /I' X2 h 'XI Br 'XI Rll 'XI Rll XXXIV XXXV XXXVI R4«R5y R6 R7 --- R4 RIO X3 X2IX h R3 R3 'XI RII R2 R2 XXXVI v XXXVII ar, as X3 RIO X2IX h R3 'XI RII Formula One In Scheme XXXII, a nd of Formula I, 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 Rl, R2, R3, R4, R5, R6, R7, R8, XI, X2, and X3 are as previously disclosed is converted to a molecule of a One, wherein RIO and Rll 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 Rl, R2, R3, R4, R5, R6, R7, R8, XI, 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. wo 2012/177813 Scheme XXXII R5 R5 R4 IXX3 RIO R4 X3 RIO X2 ~ X2IX~ R3 'XI RII R3 'XI RII R2 R2 XXXVIII Formula One In Scheme XXXIII, a nd of Formula XXXIX, wherein Xl, X2, and X3 are as previously disclosed is converted to a molecule of Formula XL, wherein Xl, X2, and X3 are as previously sed, 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 on 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 a XLI, wherein R8, Xl, X2 and X3 are as previously disclosed, by reaction with potassium vinyl oroborate in the presence of a palladium catalyst, such as PdCb(dppf), and a base, such as K2C03, in a polar aprotic solvent such as DMSO at 100 oc, as in step aw.
Scheme XXXIII Br'Y.-"X3DII ~ '\ au Br~~X3:0 av,aw ~_...X3 X2 ~ N ~ lf :0 'Xl , X2 ~ N 'Xl , X2.Xl N H H \ XXXIX XL XLI In Scheme XXXIV, a compound of a XXXIX, wherein Xl, X2, and X3 are as previously disclosed is converted to a molecule of Formula XLII, wherein Xl, X2, and X3 are as previously sed 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 PdCb, and a ligand, such as triphenylphosphine, and a base, such as Cs2C03, in a solvent mixture such as THF/H20. In step ay, the nitrogen atom is protected with a tert- butyloxycarbonyl (BOC) group by reaction with di-tert-butyl onate in the presence of a catalyst, such as DMAP, in a solvent, such as acetonitrile. wo 2012/177813 2012/043418 Scheme XXXIV Br~X3D II ax,ay ">: \ X2 ~ N XXXIX XLII In step I of Scheme XXXV, the compound of Formula V, wherein Y, Rl, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the nds of Formula XLI or XLII, wherein R8, XI, 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 octo provide the corresponding compounds of Formula XLIIIa or XLIIIb, wherein Rl, R2, R3, R4, R5, R6, R7, R8, XI, X2, and X3 are as previously disclosed.
Scheme XXXV y R5 1_,X3'>:D\- I R4 X3 X2 ~ N I '>:D\ 'Xl , X2 ~ N 'Xl , Boc R3 v XLI or XLII XLIIIa or XLIIIb In Scheme XXXVI, a compound of Formula XLIIIa, wherein Rl, R2, R3, R4, R5, R6, R7, R8, XI, X2, and X3 are as previously disclosed is converted to a molecule of Formula XLIV, n Rl, R2, R3, R4, R5, R6, R7, R8, XI, X2, and X3 are as previously disclosed by treatment with trifluoroacetic acid, in a solvent such as dichloromethane, as in step az.
Compounds of the Formula XLIV can then be transformed into compounds of the Formula XLV wherein Rl, R2, R3, R4, R5, R6, R7, R8, XI, X2, and X3 are as previously disclosed, in two steps. In step ba, the indoline is treated with sodium nitrite (NaN02), in an acid, such as concentrated HCI, at a temperature around 5 °C, to form the nitrosoindole. In step bb, the nitrosoindole is d with ammonium chloride in the presence of zinc powder in a protic solvent, such as methanol. In step be, compounds of the Formula XLV are transformed into compounds of the a XLVI, wherein X4 is N(Rl4)(C(=O)Rl4) and Rl, R2, R3, R4, R5, R6, R7, R8, XI, X2, and X3 are as previously sed, by treatment with and acid, such wo 2012/177813 as 3,3,3-trifluoropropanoic acid, PyBOP, and a base, such as DIEA, in a polar aprotic solvent, such as romethane.
Scheme XXXVI R5 R5 R6 R8 R4 IDX3 R7 az R4 # IX3D~ ba, bb R3 X2.Xl N X2 ..,; I R3 Rl 'Xl N Boc H R2 R2 XLII Ia XLIV R4 IDX3 be R4 IDX3 R3 X2.Xl N I R3 X2.Xl N R2 I R2 X4 XLVI In Scheme XXXVII, a nd 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 oroacetic acid, in a solvent such as dichloromethane, 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((tert-butoxycarbonyl)amino)acetate in the presence of potassium fluoride and a crown ether, such as 18-crownether, in a solvent, such as acetonitrile, as in step be. nds 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 usly disclosed in two steps. In step bf, the Boc group is removed by treatment with trifluoroacetic acid, in a solvent such as dichloromethane. In step bg, the amine is treated with 3,3,3-trifluoropropanoic acid, PyBOP, and a base, such as DIEA, in a polar aprotic solvent, such as dichloromethane. wo 2012/177813 Scheme XXXVII R5 R5 R6 R8 R4 IDX3 R7 bd ...:? IDX3 R3 X2.Xl N R3 X2.Xl N Boc H R2 R2 XLIIIb XLVII R5 R5 R4 IDX3 bf,bg R4 IDX3 R3 X2_xI ?=o -\' R3 X2_xl ?=o R2 R2 XLVIII HN-(0 XLIX HN-rCF3 0 0 In Scheme XXXVIII, a compound of Formula L, wherein Xl, X2, and X3 are as previously disclosed is converted to a compound of the Formula LI, wherein Xl, 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 Xl, X2, and X3 are as previously sed, 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 Xl, 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 PdCb(dppf), and a base, such as K2C03, in a solvent mixture such as DMSO. Compounds of the Formula LIV, wherein Xl, X2, and X3 are as usly sed, can be formed from compounds of the a LIII by reaction with ethyl bromoacetate, in the presence of a base, such as , in a solvent, such as DMF. wo 2012/177813 Scheme I 0 OH n,1X3~ n, x3:Q n,1 x3x:;: I bh NH 1I bi NH I ~ ~ X2 h X2 h X2 h NH 'Xl 'Xl 'Xl 0 0 0 L LI LII bj J: '7 II~X3x:;:~ N J:II~X3x:;: bk '7 ~ '<::::N 0 X2 h hH 'Xl X2 h h II ............
'Xl ~0' "' 0 0 LIII LIV In step I 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 oc to provide the corresponding compound of Formula LV, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as usly 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 ature of about 100 oc. In step bm, the acid is treated with an amine, such as 2,2,2-trifluoroethylamine, PyBOP, and a base, such as DIEA, in a polar c solvent, such as dichloromethane. wo 2012/177813 Scheme XXXIX R5 y R6 RS R7 /yx:c;"' ~N 0 I R3 X2 ~ ~0 ~ 'Xl 0 R2 0 v LIV R5 R6 RS # I XJ:c;"' N 0 bl, bm X2 ~ ~0 ~ R3 'Xl 0 R2 0 In step bn of Scheme XL, carboxylic acids of the Formula LVII, wherein Rll is C(=O)OH and R8, RlO, Xl, X2, and X3 are as previously disclosed and compounds of the a V, wherein Y is Brand Rl, R2, R3, R4, R5, R6, and R7 are as previously disclosed are allowed to react in the presence of CuCl and pyridyl in a solvent, such as N-methyl pyrrolidine, at a temperature of about 150 octo afford compounds of Formula LVIII, wherein Rll is (C=O)OH and Rl, R2, R3, R4, R5, R6, R7, R8, R9, RlO, Xl, X2, and X3 are as previously disclosed. nds of the Formula LVIII can be further transformed to the corresponding benzamides of Formula LIX, n Rll is (C=O)N(Rl4)(R15), and Rl, R2, R3, R4, R5, R6, R7, R8, R9, RlO, Xl, 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 DIEA, in a polar aprotic solvent, such as dichloromethane, as in step bo. wo 2012/177813 Scheme XL R5 y R8 R6 R5 R7 )yx3XRIO R4 bn IXX3 RlO R3 X2 ~ X2 'Xl Rll ~ R3 'Xl Rll v LVII LVIII bo R4 IXX3 RlO X2 ~ R3 'Xl Rll EXAMPLES The examples are for illustration purposes and are not to be construed as limiting the invention sed 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 h and were used as received. Melting points were ed on a Thomas Hoover Unimelt ary g 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 (o) and were recorded at 300, 400, or 600 MHz, and 13C NMR spectral data are in ppm (o) and were recorded at 75, 100, or 150 MHz, unless otherwise stated.
Example 1: Preparation of romo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (All)c'Vcr, 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; wo 2012/177813 .0 grams (g), 20.5 millimoles (mmol)) in methyl alcohol (CH30H; 100 milliliters (mL)) at 0 oc 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 oc and stirred for 2 hours (h). After the reaction was deemed complete by thin layer chromatography (TLC), saturated (satd) aqueous (aq) ammonium chloride ) solution was added to the reaction mixture, and the mixture was trated under reduced pressure. The residue was diluted with diethyl ether (Et20) and washed with water (H20; 3 x 50 mL). The organic layer was dried over sodium sulfate (Na2S04) and concentrated under reduced pressure to afford the title compound as a liquid (4.0 g, 79%): 1H NMR (400 MHz, CDCb) o7.41 (m, 3H), 5.00 (m, 2H), 2.74 (s, lH); ESIMS m/z 242.97 ([M-HD.
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 tetrahydrofuran (THF; 250 mL) were added trifluoromethyltrimethylsilane (9.79 g, 69.2 mmol) and a catalytic amount of utylammonium fluoride (TBAF). The reaction mixture was d at 25 oc for 8 h.
After the reaction was deemed complete by TLC, the reaction e was diluted with 3 N hloric acid (HCl) and then was stirred for 16 h. The reaction mixture was diluted with H20 and was extracted with ethyl acetate (EtOAc; 3 x). The combined organic ts were washed with brine, dried over Na2S04, 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(3,4,5-trichlorophenyl)ethanol (AI3) CI~CF3 The product was ed as a pale yellow liquid (500 mg, 65%): 1H NMR (400 MHz, CDCb) o7.45 (s, 2H), 5.00 (m, 1H), 2.80 (s, 1H); ESIMS m/z 278 ([M+Ht); IR (thin film) 3420, 1133, 718 cm-1. 1-(3,5-Dichlorofluorophenyl)-2,2,2-trifluoroethanol (AI4) Cl~CF3Fy wo 2012/177813 The t was isolated as a pale yellow liquid (500 mg, 65%): 1H NMR (400 MHz, CDCb) o7.41 (s, 2H), 5.00 (m, lH), 2.80 (s, lH); ESlMS m/z 262 ([M+Ht); lR (thin film) 3420, 1133, 718 cm-1. 1-(3,4-Dichlorophenyl)-2,2,2-trifluoroethanol (AI5) Cly0cF3 ClN The product was isolated as a pale yellow liquid (500 mg, 65%): 1H NMR (400 MHz, CDCb) o7.60 (s, 1H), 7.51 (m, 1H), 7.35 (m, 1H), 5.01 (m, 1H), 2.60 (s, 1H); ElMS m/z 244 ([Mt).
Step 2. 1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (All). To a stirred solution of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanol (4.0 g, 16.3 mmol) in romethane (CH2Cb; 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 oc and was concentrated under reduced pressure. Purification by flash column chromatography (Si02, 100-200 mesh; eluting with 100% pentane) afforded the title nd as a liquid (2.0 g, 40%): 1H NMR (400 MHz, CDCb) o7.41 (s, 3H), 5.00 (m, 1H); ElMS m/z 306 ([Mt).
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) CI~CF3 The product was isolated as a ess oil (300 mg, 60%): 1H NMR (400 MHz, CDCb) o7.59 (s, 2H), 5.00 (m, 1H); ElMS m/z 340.00 ([Mt). -(1-Bromo-2,2,2-trifluoroethyl)-1,3-dichlorofluorobenzene (AI7) Cl~CF3FAf Cl wo 77813 The product was isolated as a colorless oil (320 mg, 60%): 1H NMR (400 MHz, CDCb) o7.45 (s, 2H), 5.00 (m, 2H); ElMS m/z 324.00 ([Mt). 4-(1-Bromo-2,2,2-trifluoroethyl)-1,2-dichlorobenzene (AI8) Cl~CF3 Cl)l) The product was isolated as a colorless oil (300 mg, 60%): 1H NMR (400 MHz, CDCb) o7.63 (s, 1H), 7.51 (m, 1H), 7.35 (m, 1H), 5.01 (m, 1H); ElMS m/z 306.00 ([Mt).
Example 2: ation ofN-methylvinylbenzamide (AI9) Step 1. 4-Vinylbenzoyl chloride (AilO). To a stirred solution of 4-vinylbenzoic acid (1 g, 6.75 mmol) in CH2Ch (20 mL) at 0 oc were added a catalytic amount of N,N- dimethylformamide (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 oc for 6 h. After the on was deemed complete by TLC, the reaction mixture was concentrated under reduced pressure to give the crude acid chloride.
Step 2. N-Methylvinylbenzamide (AI9). To 1M N-methylamine in THF (13.5 mL, 13.5 mmol) at 0 oc were added triethylamine (Et3N; 1.34 mL, 10.12 mmol) and the acid de from Step 1 above in THF (10 mL), and the reaction mixture was stirred at 25 oc for 3 h. After the reaction was deemed complete by TLC, the reaction mixture was ed with water and then was extracted with EtOAc (3x). The combined EtOAc layer was washed with brine and dried over Na2S04 and concentrated under reduced pressure to afford the title compound as an off-white solid (650 mg, 60%): 1H NMR (400 MHz, CDCb) o7.76 (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); ESlMS m/z 161.95 ).
The following compounds were made in accordance with the procedures disclosed in accordance with Example 2.
N,N-dimethylvinylbenzamide (AI11) wo 2012/177813 The product was ed as an off-white solid (650 mg, 60%): 1H NMR (400 MHz, CDCb) o7.42 (m, 4H), 6.71 (m, lH), 5.80 (d, J = 17.6 Hz, lH), 5.31 (d, J = 10.8 Hz, lH), 3.05 (s, 3H), 3.00 (s, 3H); ESIMS m/z 176.01 ([M+Ht).
N -(2,2,3-trifluoromethyl)vinylbenzamide (AI12) ~~'-'Cf3 0 The product was isolated as an off-white solid (900 mg, 60%): 1H NMR (400 MHz, CDCb) o7.76 (d, J = 8.0 Hz, 2H), 7.45 ( d, J = 8.0 Hz, 2H), 6.79 (m, 1H), 6.20 (br s, 1H), .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+Ht).
Morpholino(4-vinylphenyl)methanone (Ail3) The product was isolated as a white solid (850 mg, 60%): ESIMS m/z 218.12 ([M+Ht).
Example 3: Preparation of ethyl2-methylvinylbenzoate (AI14) 0 Step 1. 4-Formylmethylbenzoic acid (AilS). To a stirred solution of 4-bromo methylbenzoic acid (10 g, 46.4 mmol) in dry THF (360 mL) at -78 oc was added lithium (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 oc for 1 h then was warmed to 25 oc 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 Na2S04 and concentrated under d pressure. The residue was washed with ne to afford the title compound as a solid (3.0 g, 40%): mp 196-198 oc; 1H NMR (400 MHz, DMSO-d6) o13.32 (br s, 1H), .05 (s, 1H), 7.98 (m, 1H), 7.84 (m, 2H), 2.61 (s, 3H); ESIMS m/z 163.00 .
Step 2. Ethyl4-formylmethylbenzoate . 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 (H2S04, x M; 2 mL), and the reaction mixture was heated at 80 oc for 18 h. The reaction mixture was cooled to 25 oc and concentrated under reduced pressure. The residue was wo 2012/177813 diluted with EtOAc and washed with H20. The ed EtOAc extracts were washed with brine, dried over Na2S04 and concentrated under reduced pressure to afford the title compound as a solid (2.8 g, 80%): 1H NMR (400 MHz, CDCb) o10.05 (s, lH), 8.04 (m, lH), 7.75 (m, 2H), 4.43 (m, 2H), 2.65 (s, 3H), 1.42 (m, 3H).
Step 3. -methylvinylbenzoate (AI14). To a stirred solution of ethyl4- formylmethylbenzoate (2.8 g, 4 mmol) in 1,4-dioxane (20 mL) were added potassium carbonate (K2C03; 3.01 g, 21.87 mmol) and triphenyl phosphonium bromide (7.8 g, 21.87 mmol) at 25 oc. Then the reaction mixture was heated at 100 oc for 18 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to 25 oc and ed, and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash chromatography (Si02, 100-200 mesh; eluting with 25-30% EtOAc inn- Hexane) to afford the title compound as a solid (2.0 g, 72%): 1H NMR (400 MHz, CDCb) o 7.86 (m, lH), 7.27 (m, 2H), 6.68 (dd, J =17.6, 10.8 Hz, lH), 5.84 (d, J = 17.6 Hz, lH), 5.39 (d, J = 10.8 Hz, lH), 4.39 (m, 2H), 2.60 (s, 3H), 1.40 (m, 3H); ESIMS m/z 191.10 ; IR (thin film) 2980, 1716, 1257 cm-1.
Example 4: Preparation oftert-butyl 2-chlorovinylbenzoate (AI17) Step 1. tert-Butyl 4-bromochlorobenzoate (AilS). To a stirred solution of 4- bromochlorobenzoic acid (5 g, 21.37 mmol) in THF (30 mL) was added di-tert-butyl dicarbonate (25.5 g, 25.58 mmol), Et3N (3.2 g, 31.98 mmol) and 4-(dimethylamino)pyridine (DMAP; 0.78 g, 6.398 mmol), and the reaction mixture was stirred at 25 oc for 18 h. The reaction mixture was diluted with EtOAc and washed with H20. The ed organic layer was washed with brine, dried over Na2S04 and concentrated under reduced pressure. The residue was purified by flash chromatography (Si02, 100-200 mesh; eluting with 2-3% EtOAc inn-hexane) to afford the title compound as a liquid (3.2 g, 51%): 1H NMR (400 MHz, CDCb) o7.62 (m, 2H), 7.44 (d, J = 8.4 Hz, lH), 1.59 (s, 9H); ESIMS m/z 290.10 ([M+Ht); n film) 1728 cm-1.
The following compounds were made in accordance with the procedures sed in Step 1 of Example 4. tert-Butyl 2-bromoiodobenzoate (AI19) wo 2012/177813 2012/043418 Tu;ot The product was isolated as a colorless oil (1.2 g, 50%): 1H NMR (400 MHz, CDCb) 8 8.01 (s, lH), 7.68 (d, J = 8.4 Hz, lH), 7.41 (d, J = 8.0 Hz, 1H), 1.59 (s, 9H); ESIMS m/z 382.10 ([M+Ht); IR(thin film) 1727 cm-1. tert-Butyl 4-bromo(trifluoromethyl)benzoate(AI20) Dru;~t The product was isolated as a colorless oil (1 g, 52%): 1H NMR (400 MHz, CDCb) 8 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+Ht); IR (thin film) 1725 cm-1.
Step 2. tert-butyl2-chlorovinylbenzoate (AI17). To a stirred solution of tertbutyl4-bromochlorobenzoate (1.6 g, 5.50 mmol) in toluene (20 mL) was added is(triphenylphospine)palladium(O) (Pd(PPh3)4 ; (0.31 mg, 0.27 mmol), K2C03 (2.27 g, 16.5 mmol) and vinylboronic anhydride pyridine complex (2.0 g, 8.3 mmol) and the on mixture was heated to reflux for 16 h. The reaction mixture was filtered, and the filtrate was washed with H20 and brine, dried over Na2S04 and concentrated under reduced pressure.
Purification by flash column chromatography (Si02, 100-200 mesh; eluting with 5-6% EtOAc xane) afforded the title compound as a liquid (0.6 g, 46%): 1H NMR (400 MHz, CDCb) 8 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+Ht); 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. utyl 2-bromovinylbenzoate (AI21) The product was isolated as a colorless oil (1g, 52%): 1H NMR (400 MHz, CDCb) 8 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, wo 2012/177813 lH), 5.39 (d, J = 10.8 Hz, lH), 1.60 (s, 9H); ESIMS m/z 282.10 ([M+Ht); IR (thin film) 2978, 1724, 1130 cm-1. tert-Butyl 2-(trifluoromethyl)vinylbenzoate (AI22) The product was isolated as a colorless oil (1.2 g, 50%): 1H NMR (400 MHz, CDCb) 8 7.71 (d, J =6.4 Hz, 2H), 7.59 (d, J =7.6 Hz, lH), 6.77 (dd, J = 17.6, 10.8 Hz, lH), 5.89 (d, J = 17.6 Hz, lH), 5.44 (d, J = 10.8 Hz, lH), 1.58 (s, 9H); ESIMS m/z 272.20 ([M+Ht); IR (thin film) 2982, 1727, 1159 cm-1.
Example 5: Preparation of tert-butyl2-cyanovinylbenzoate (AI23) To a d solution of tert-butyl2-bromovinylbenzoate (0.5 g, 1.77 mmol) in DMF (20 mL) was added copper(!) cyanide (CuCN; 0.23 g, 2.65 mmol), and the reaction mixture was heated at 140 oc for 3 h. The reaction mixture was cooled to 25 °C, diluted with H20, and extracted with EtOAc. The combined organic layer was washed with brine, dried over , and concentrated under d pressure. The residue was purified by flash chromatography (Si02, 0 mesh; eluting with 15% EtOAc inn-hexane) to afford the title compound as a white solid (0.3 g, 72%): mp 51-53 oc; 1H NMR (400 MHz, CDCb) 8 8.03 (s, lH), 7.77 (s, lH), 7.64 (d, J = 8.4 Hz, lH), 6.75 (dd, J = 17.6, 10.8 Hz, lH), 5.93 (d, J = 17.6 Hz, lH), 5.51 (d, J = 10.8 Hz, lH), 1.65 (s, 9H); ESIMS m/z 229.84 ([M+Ht); IR (thin film) 2370, 1709, 1142 cm-1.
Example 6: Preparation of ethyl oiodobenzoate (AI46) IyyBr To a stirred solution of 4-iodobromobenzoic acid (5 g, 15.29 mmol) in ethyl alcohol (EtOH; 100 mL) was added sulfuric acid (H2S04 ; 5 mL), and the reaction mixture was heated at 80 oc for 18 h. The reaction mixture was cooled to 25 oc and concentrated under reduced pressure. The residue was diluted with EtOAc (2x100 mL) and washed with H20 (100 mL). The combined EtOAc extracts were washed with brine, dried over Na2S04 wo 2012/177813 and concentrated under reduced pressure to afford the compound as a pale yellow solid (5 g, 92%): 1H NMR (400 MHz, DMSO-d6) o8.04 (d, J = 1.2 Hz, lH), 7.71 (d, J =7.6 Hz, lH), 7.51 (d, J = 8.4 Hz, lH), 4.41 (q, J =7.2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H).
The following nds were made in accordance with the procedures disclosed in Example 6.
Ethyl 4-bromochlorobenzoate (AI47) BryyCI ~0'-/" The title compound was isolated as an off-white solid (2.0 g, 80 %): 1H NMR (400 MHz, DMSO-d6) o8.25 (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-bromomethylbenzoate (AI48) Br~0-v' The title compound was isolated as a pale yellow liquid (3.0 g, 83%): 1H NMR (400 MHz, CDCb) o7.79 (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 ); IR (thin film) 1725 cm-1.
Ethyl ofluorolbenzoate (AI49) BryyF ~0'-/" The title compound was isolated as a colorless liquid (9.0 g, 79%): 1H NMR (400 MHz, DMSO-d6) o7.84 (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+Ht), IR (thin film) 1734 cm-1.
Example 7: Preparation of ethyl 4-bromoethylbenzoate (AlSO) ~0'-/" wo 2012/177813 To a stirred solution of ofluorobenzoic 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 ooc and the resultant reaction mixture was stirred at RT for 18h. The reaction mixture was quenched with 2 N HCl and extracted with ethyl acetate. The combined ethyl acetate layer was dried over anhydrous Na2S04 and concentrated under reduced pressure to afford crude 4- bromoethylbenzoic acid as a colorless liquid that was used in the next step without purification (0.4 g): 1H NMR (400 MHz, CDCb) o 7.64 (d, J = 8.4 Hz, lH), 7.47 (m, lH), 7.43 (m, lH), 2.95 (q, J = 4.0 Hz, 2H), 1.32 (t, J = 4.0 Hz, 3H); ESIMS m/z 228.97 ([M+Ht).
The title compound was synthesized from 4-bromoethylbenzoic acid in accordance to the procedure in Example 6, isolated as a colorless liquid (0.15 g, 68%): 1H NMR (400 MHz, DMSO-d6)o 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-HD; IR (thin film) 3443, 1686, 568 cm-1.
Example 8: ation of ethyl 2-bromovinylbenzoate (AISl) ~0'-,/ 0 To a stirred solution of ethyl2-bromoiodobenzoate (5 g, 14.3 mmol) in THF/water (100 mL, 9:1) was added potassium vinyltrifluoroborate (1.89 g, 14.3 mmol), Cs2C03 (18.27 g, 56.07 mmol) and triphenylphosphine (0.22 g, 0.85 mmol) and the reaction e was degassed with argon for 20 min, then charged with PdCb (0.05 g,0.28 mmol). The reaction mixture was heated to reflux for 16 h. The reaction mixture was cooled toRT and ed through a celite bed and washed with ethyl acetate. The filtrate was again ted with ethyl acetate and the ed organic layers washed with water and brine, dried over Na2S04 and concentrated under reduced pressure to afford crude compound. The crude compound was purified by column chromatography (Si02, 100-200 mesh; eluting with 2% ethyl e/ petroleum ether) to afford the title compound as a light brown gummy material (2 g, 56%): 1H NMR (400 MHz, CDCb) o 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 =7.2Hz, 2H), 1.43 (t, J = 3.6 Hz, 3H); ESIMS m/z 255.18 ([M+Ht); IR (thin film) 1729 cm-1.
The following compounds were made in accordance with the ures disclosed in Example 8. wo 2012/177813 Ethyl 2-methylvinylbenzoate (AI52) The title compound was isolated as a colorless liquid (0.8 g, 80 %): 1H NMR (400 MHz, CDCb) o7.89 (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+Ht); IR (thin film) 1717, 1257 cm-1.
Ethyl 2-fluorovinylbenzoate (AI53) The title nd was isolated as a pale yellow liquid (2.0 g, 50%): 1H NMR (400 MHz, 6) o7.87 (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+Ht); IR (thin film) 1728 cm-1.
Example 9: Preparation of ethyl2-chlorovinylbenzoate (AI54) 0 To a stirred solution of ethyl2-chlorobromobenzoate (2 g, 7.63 mmol) in dimethylsulfoxide (20 mL) was added potassium rifluoroborate (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 oc for 1 h. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (2 x 50 mL), washed with brine, dried over Na2S04 and concentrated under reduced pressure to obtain the compound as brown gummy material (1.1 g, 69%): 1H NMR (400 MHz, CDCb) o7.81 (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+Ht); IR (thin film) 1729, 886 cm-1.
The following compounds were made in accordance with the procedures disclosed in Example 9. wo 2012/177813 Ethyl 2-ethylvinylbenzoate (AISS) The title compound was isolated as a color less liquid (1.0 g, 66 %): 1H NMR (300 MHz, CDCb) o7.85 (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+Ht); IR (thin film) 1720, 1607, 1263 cm-1 Methyl 2-methoxyvinylbenzoate (AI56) The title compound was isolated as a pale yellow liquid (1.2 g, 75 %): 1H NMR (400 MHz, CDCb) o7.79 (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+Ht); IR (thin film) 1732 cm-1• Example 10: ation of (E)-ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut enyl)methylbenzoate (AI24) 0--.../ Cl 0 To a stirred solution of ethyl2-methylvinylbenzoate (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), (!) 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 oc for 24 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to 25 oc and filtered, and the filtrate was concentrated under reduced pressure.
Purification by flash chromatography (Si02, 100-200 mesh; eluting with 25-30% EtOAc in eum ether) afforded the title nd as a solid (1.7 g, 40%): 1H NMR (400 MHz, CDCb) o7.91 (d, J = 8.0 Hz, 1H), 7.37 (m, 1H), 7.27-7.24 (m, 4H), 6.59 (d, J = 16.0 Hz, wo 2012/177813 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-HD; IR (thin film) 1717, 1255, 1114 cm-1.
Compounds AI25, AI57-AI68 and AC1-AC5 (Table 1) were made in ance with the procedures disclosed in e 10.
(E)-Ethyl 4-(4,4,4-trifluoro(3,4,5-trichlorophenyl)butenyl)(trifluoromethyl)- benzoic acid (AI25) 0--.._/ Cl 0 The product was isolated as a pale brown gummy liquid (500 mg, 40%): 1H NMR (400 MHz, CDCb) 8 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-HD; IR (thin film) 1730, 1201, 1120, 749 cm-1.
(E)-Ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobutenyl)fluorobenzoate (AI57) 0'-.../' Cl 0 1H NMR (400 MHz, CDCb) o 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-HD; IR (thin film) 1723, 1115, 802 cm-1.
(E)-Ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobutenyl)bromobenzoate (AI58) 0'-.../' Cl 0 1H NMR (400 MHz, CDCb) o7.79 (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-HD; IR (thin film) 1727, 1114, 801, 685 cm-1.
(E)-Ethyl 2-bromo(4,4,4-trifluoro(3,4,5-trichlorophenyl) butenyl)benzoate (AI59) wo 2012/177813 o............,..
Cl 0 1H NMR (400 MHz, CDCb) o7.79 (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-HD; IR (thin film) 1726, 1115, 808, 620 cm-1.
(E)-Ethyl 2-methyl(4,4,4-trifluoro(3,4,5-trichlorophenyl) butenyl)benzoate (AI60) o............,..
Cl 0 The title compound was isolated as a light brown gummy material: 1H NMR (400 MHz, CDCb) o7.90 (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-trifluoro(3,4,5-trichlorophenyl) enyl)benzoate (AI61) o............,..
Cl 0 1H NMR (400 MHz, CDCb) o7.87 (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 ([MHD ; IR (thin film) 1726, 1115, 809, 3072 cm-1.
(E)-Ethyl 4-(4,4,4-trifluoro(3,4,5-trichlorophenyl)butenyl) (trifluoromethyl)benzoate (AI62) o............,..
Cl 0 wo 2012/177813 The title compound was isolated as a pale brown liquid (1.0 g, 46.3 %): 1H NMR (400 MHz, CDCb) o7.79 (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-HD; IR (thin film) 1730, 1202, 1120, 750 cm-1.
(E)-Ethyl 2-chloro(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobutenyl)benzoate (AI63) F 0--..._./ Cl 0 1H NMR (400 MHz, CDCb) o7.85 (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 ); IR (thin film) 1728, 1115,817 cm-1.
(E)-Ethyl 2-fluoro(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobutenyl)benzoate (AI64) 0--..._./ Cl 0 1H NMR (400 MHz, CDCb) o7.93 (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-HD; IR (thin film) 1725 cm-1.
(E)-Ethyl 2-bromo(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobutenyl)benzoate (AI65) 0--..._./ Cl 0 1H NMR (400 MHz, CDCb) o7.94 (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-HD; IR (thin film) 1726, 1114, 820, 623 cm-1. wo 2012/177813 (E)-Ethyl yl(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobut enyl)benzoate (AI66) F 0~ Cl 0 The title compound was isolated as a brown semi-solid: 1H NMR (400 MHz, CDCb) o7.90 (d, J = 8.8 Hz, lH), 7.34 (d, J =6.0 Hz, 2H), 7.25 (d, J =7.2 Hz, 2H), 6.59 (d, J = 16.0 Hz, lH), 6.42 (dd, J = 16.0 Hz, 8.0 Hz, lH), 4.38 (q, J =7.2 Hz, 2H), 4.19 (m, lH), 2.63 (s, 3H), 1.41 (t, J =7.2 Hz, 3H); ESIMS m/z 432.90 ([M-HD; IR (thin film) 1715 cm-1.
(E)-Methyl 2-methoxy(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobut enyl)benzoate (AI67) Cl 0 1H NMR (400 MHz, CDCb) o 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+Ht); IR (thin film) 1724 hyl 2-ethyl(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobutenyl)benzoate (AI68) 1H NMR (400 MHz, CDCb) o 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-HD; IR (thin film) 1715, 1115,817 cm-1.
Example 11: Preparation of (E)(3-(3,5-dichlorophenyl)-4,4,4-trifluorobutenyl) methylbenzoic acid (AI32) wo 2012/177813 To a stirred solution of (E)-ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobutenyl)- 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 oc for 48 h. The reaction mixture was cooled to 25 oc and concentrated under d pressure. The residue was diluted with H20 and extracted with chloroform (CHCb). The combined organic layer was dried over Na2S04 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 3 oc; 1H NMR (400 MHz, DMSO-d6) 8 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-HD; IR (thin film) 3448, 1701, 1109,777 cm-1.
The following compounds were made in ance with the procedures disclosed in Example 11.
(E)Methyl(4,4,4-trifluoro(3,4,5-trichlorophenyl)butenyl)benzoic acid (AI26) 0 The product was ed as a pale brown gummy liquid (1 g, 46%): 1H NMR (400 MHz, CDCb) 8 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-HD.
(E)Chloro(4,4,4-trifluoro(3,4,5-trichlorophenyl)butenyl)benzoic acid (AI27) Cl 0 The t was isolated as an off-white semi-solid (1 g, 45%): 1H NMR (400 MHz, CDCb) 8 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-HD; IR (thin film) 3472, 1704, 1113,808 cm-1. wo 2012/177813 (E)Bromo(4,4,4-trifluoro(3,4,5-trichlorophenyl)butenyl)benzoic acid (AI28) The product was ed as a brown solid (1 g, 45%): mp 70-71 oc; 1H NMR (400 MHz, CDCb) 8 7.99 (d, J = 8.0 Hz, lH), 7.72 (s, lH), 7.40 (m, 3H), 6.58 (d, J = 16.0 Hz, lH), 6.48 (dd, J = 16.0, 8.0 Hz, lH), 4.14 (m, lH); ESIMS m/z 484.75 ([M-HD; IR (thin film) 3468, 1700 cm-1.
(E)Cyano(4,4,4-trifluoro(3,4,5-trichlorophenyl)butenyl)benzoic acid (AI29) The product was isolated as an off-white solid (500 mg, 45%): mp 100-101 oc; 1H NMR (400 MHz, CDCb) 8 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-HD.
E)(3-(3,4-Dichlorophenyl)-4,4,4-trifluorobutenyl)methylbenzoic acid (ABO) Cl .o The product was isolated as a pale brown liquid (500 mg, 46%): 1H NMR (400 MHz, CDCb) 8 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-HD; IR (thin film) 3428, 1690, 1113, 780 cm-1.
(E)(3-(3,5-Dichlorofluorophenyl)-4,4,4-trifluorobutenyl)methylbenzoic acid (AI31) wo 2012/177813 The product was isolated as a white solid (500 mg, 50%): mp C; 1H NMR (400 MHz, CDCb) 8 8.02 (d, J = 8.0 Hz, lH), 7.35 (d, J = 5.6 Hz, lH), 7.30 (m, 3H), 6.61 (d, J = 16.0 Hz, lH), 6.48 (dd, J = 16.0, 8.0 Hz, lH), 4.13 (m, lH), 2.65 (s, 3H); ESIMS m/z 406.87 (E)(4,4,4-Trifluoro(3,4,5-trichlorophenyl)butenyl)(trifluoromethyl)benzoic acid (AI33) The product was isolated as a white solid (500 mg, 45%): mp 142-143 oc; 1H NMR (400 MHz, CDCb) 8 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- (E)Bromo(4,4,4-trifluoro(3,4,5-trichlorophenyl)butenyl)benzoic acid (AI69) Cl Br Cl 0 The title compound was isolated as a brown solid (0.8 g, 28%): 1H NMR (400 MHz, CDCb) o 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-HD; IR (thin film) 3469, 1700 cm-1.
(E)Bromo(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluo robutenyl)benzoic acid (AI70) The title compound was isolated as a yellow liquid (0.3 g, crude): 1H NMR (300 MHz, CDCb) o7.79 (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-HD.
(E)(3-(3,5-Dichlorofluorophenyl)-4,4,4-trifluorobutenyl)ethylbenzoic acid (AI71) wo 2012/177813 Cl 0 The title compound was isolated as a brown gummy material (0.2 g, crude): 1H NMR (300 MHz, DMSO-d6) o12.5 (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-HD.
(E)Chloro(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobutenyl)benzoic acid (AI72) The title compound was isolated as a yellow liquid (0.7 g, 95%): 1H NMR (300 MHz, CDCb) o7.85 (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+Ht); IR (thin film) 1728, 1115,817 cm-1.
(E)(3-(3,5-Dichlorofluorophenyl)-4,4,4-trifluorobutenyl)methylbenzoic acid (AI73) The title compound was isolated as a light brown gummy material (0.7 g, 38%): mp 91-93 oc; 1H NMR (400 MHz, CDCb) o8.02 (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 .
(E)(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobutenyl)fluorobenzoic acid (AI74) wo 2012/177813 The title compound was isolated as a light brown liquid (0.3 g, crude): ESIMS m/z 393.15 ([M-HD.
(E)Bromo(3-(3,5-dichlorophenyl)-4,4,4-trifluorobutenyl)benzoic acid (AI75) The title compound was isolated as a light brown liquid (0.35 g, crude): ESIMS m/z 451.91 ([M-HD.
Prophetically, compounds AI34, I41, AI44-AI45 (Table 1) could be made in accordance with the procedures disclosed in e 10, or Examples 10 and 11.
Example 12: Preparation of (E)(3-(3,5-dichlorophenyl)-4,4,4-trifluorobutenyl) methyl-N-(2,2,2-trifluoroethyl)benzamide (AC6) To a stirred solution of (E)(3-(3,5-dichlorophenyl)-4,4,4-trifluorobutenyl) methylbenzoic acid in DMF was added 2,2,2-trifluoroethylamine, 1-hydroxybenzotriazole hydrate (HOBt•H20), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC•HCl) and N,N-diisopropylethylamine (DIEA), and the reaction mixture was stirred at oc for 18 h. The reaction mixture was d with H20 and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2S04 and concentrated under reduced pressure. Purification by flash column chromatography (Si02, 100-200 mesh; eluting with hexane:EtOAc afforded a white olid (110 mg, 50%): 1H NMR (400 MHz, CDCh) 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-HD; IR (thin film) 1657, 1113, 804 cm-1.
Compounds AC7-AC38, C58, AC110-AC112, AC117, and AC118 (Table 1) were made in accordance with the procedures disclosed in Example 12.
Example 13: Preparation of 4-((E)(3,5-dichlorophenyl)-4,4,4-trifluorobutenyl) methyl-N-((pyrimidinyl)methyl)benzamide (AC39) wo 2012/177813 Cl N H r~ ·11 Cl 0 To a stirred solution of (pyrimidinyl)methanamine (0.15 g, 1.43 mmol) in CH2Cb (10 mL) was added drop wise trimethylaluminum (2M solution in toluene; 0.71 mL, 1.43 mmol), and the reaction mixture was stirred at 25 oc for 30 min. A solution of ethyl4-((E) (3,5-dichlorophenyl)-4,4,4-trifluorobutenyl)methylbenzoate (0.3 g, 0.71 mmol) in CH2Cb was added drop wise to the reaction mixture at 25 oc. The reaction mixture was d at reflux for 18 h, cooled to 25 °C, quenched with 0.5 N HCl solution (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine, dried over Na2S04, and concentrated under reduced pressure. The crude compound was purified by flash chromatography (Si02, 100-200 mesh; eluting with 40% EtOAc innhexane ) to afford the title compound (0.18 g, 55%): mp 141-144 oc; 1H (400 MHz, CDCb) o9.19 (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 .
Example 14: Preparation of chloro-N-(2-oxo((2,2,2-trifluoroethyl)amino)ethyl)- 4-(4,4,4-trifluoro(3,4,5-trichlorophenyl)butenyl)benzamide (A C64) To a d solution of glycine amide (0.15 g, 0.58 mmol) in CH2Cb (5 mL) was added trimethylaluminum (2M solution in toluene; 1.45 mL, 2.91 mmol) dropwise, and the reaction mixture was d at 28 oc for 30 min. A solution of (E)-ethyl2-chloro(4,4,4- trifluoro(3,4,5-trichlorophenyl)butenyl)benzoate (0.3 g, 0.58 mmol) in CH2Cb (5 mL) was added drop wise to the reaction mixture at 28 oc. The reaction mixture was d at reflux for 18 h, cooled to 25 °C, quenched with 1N HCl solution (50 mL) and extracted with CH2Cb (2 x 50 mL). The combined organic extracts were washed with brine, dried over Na2S04, and concentrated under reduced re. The crude compound was purified by flash chromatography (Si02, 100-200 mesh; eluting with 40% EtOAc inn-hexane) to afford the title compound as yellow solid (0.15 g, 50%): mp 83-85 oc; 1H NMR (400 MHz, CDCb) o 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 wo 2012/177813 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-HD.
Compounds AC59-AC75 (Table 1) were made in accordance with the procedures disclosed in Example 14.
Example 15: Preparation of (E)bromo(3-(3,5-dichlorofluorophenyl)-4,4,4- orobutenyl)-N-(2-oxo((2,2,2-trifluoroethyl)amino)ethyl)benzamide (AC79) To a stirred solution of (E)bromo(3-(3,5-dichlorofluorophenyl)-4,4,4- trifluorobutenyl)benzoic acid (300 mg, 0.638 mmol) in DCM (5.0 mL) was added 2- amino-N-(2,2,2-trifluoroethyl)acetamide (172. mg, 0.638 mmol) followed by benzotriazol tripyrrolidinophosphonium hexafluorophosphate (PyBOP) (364.5 mg, 0.701 mmol) and DIPEA (0.32 mL, 1.914 mmol), and the resultant reaction e was stirred at RT for 18 h. The reaction e was diluted with water and ted with DCM. The combined DCM layer was washed with brine, dried over Na2S04 and concentrated under reduced pressure. Purification by flash column chromatography (Si02, 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, CDCb) o8.69 (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+Ht); 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)(3-(3,5-dichlorophenyl)-4,4,4-trifluorobutenyl)- -dioxidothietanyl)fluorobenzamide (AC83) Cl .ij F 0 'Cs::;O,, 0 To a stirred solution of (E)(3-(3,5-dichlorophenyl)-4,4,4-trifluorobutenyl) fluoro-N-(thietanyl)benzamide (100 mg, 0.2159 mmol) in acetone/ water (1:1, 5.0 mL) was added axone (266 mg, 0.4319 mmol) and the resultant reaction mixture was stirred at wo 2012/177813 RT for 4h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined ethyl acetate layer was dried over ous Na2S04 and concentrated under reduced pressure. Purification by flash column chromatography (Si02, 100-200 mesh; g with 30% ethyl acetate/ pet ether) afforded the title compound as a off white solid (70.0 mg, 66 %): 1H NMR (400 MHz, CDCb) o8.07 (t, J = 8.4 Hz, lH), 7.39 (t, J = 1.6 Hz, lH), 7.31 (d, J = 1.2 Hz, lH), 7.26 (m, 2H), 7.23 (m, 2H), 7.19 (d, J = 1.6 Hz, lH), 6.60 (d, J = 16.8 Hz, lH), 6.49 (dd, J = 16.8, 7.6 Hz, lH), 4.90 (m, lH), 4.64 (m, 2H), 4.14 (m, 2H),; ESIMS m/z 493.83 ([M-HD; 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. e 17: Preparation of (E)-N-((5-cyclopropyl-1,3,4-oxadiazolyl)methyl)(3- (3,5-dichlorophenyl)-4,4,4-trifluorobutenyl)methylbenzamide (AC89) A solution of (E)-N-(2-(2-(cyclopropanecarbonyl)hydrazinyl)oxoethyl)(3-(3,5- dichlorophenyl)-4,4,4-trifluorobutenyl)methylbenzamide (200 mg, 0.379 mmol) in POCb (2.0 mL) was stirred at RT for 10 min, then the resultant reaction mixture was heated to 50 oc for 1h. The reaction mixture was quenched with ice water at 0 oc and extracted with ethyl acetate. The combined ethyl acetate layer was washed with saturated NaHC03 solution and brine solution, dried over anhydrous Na2S04, and concentrated under reduced pressure.
Purification by flash column chromatography (Si02, 100-200 mesh; eluting with 50% ethyl acetate/ pet ether) afforded the title nd as a light brown gummy material (70.0 mg, 36 %): 1H NMR (400 MHz, CDCb) o7.43 (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+Ht); IR (thin film) 1666, 1166, 1112, 800 cm-1.
Example 18: ation of (E)bromo-N-(2-thioxo((2,2,2- oroethyl)amino)ethyl)(4,4,4-trifluoro(3,4,5-trichlorophenyl)buten yl)benzothioamide (AC90) wo 2012/177813 Cl Br S Cl N~N~CF H 3 Cl s To a stirred solution of (E)bromo-N-(2-oxo((2,2,2-trifluoroethyl)amino)ethyl)- ,4-trifluoro(3,4,5-trichlorophenyl)butenyl)benzamide (400 mg, 0.638 mmol) in mL of THF at RT was added 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4- disulfide (Lawesson'sreagent) (336 mg, 0.830 mmol) in one portion. The resulting reaction mixture was d for 18 h. TLC showed the reaction was not complete, therefore additional Lawesson'sreagent (168 mg, 0.415 mmol) was added and reaction stirred for 48 h.
After the on was deemed complete by TLC, the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (Si02, 230-400 mesh; eluting with 20% EtOAc in hexanes) afforded the title compound as a yellow glassy oil (188 mg, 1H NMR (400 MHz, CDCb) o8.34 (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-HD.
Example 19: Preparation of (E)(2-bromo(4,4,4-trifluoro(3,4,5- trichlorophenyl)butenyl)phenylthioamido)-N-(2,2,2-trifluoroethyl)acetamide (AC91) To a stirred solution of bromo-N-(2-oxo((2,2,2-trifluoroethyl)amino)ethyl)- 4-(4,4,4-trifluoro(3,4,5-trichlorophenyl)butenyl)benzamide (400 mg, 0.638mmol) in mL of THF at RT was added Lawesson'sreagent (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 (Si02, 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, CDCb) o8.18 (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 wo 2012/177813 = 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-HD.
The ing compound was made in accordance with the procedures disclosed in Example 19.
(E)bromo-N-(2-thioxo((2,2,2-trifluoroethyl)amino)ethyl)(4,4,4-trifluoro(3,4,5- trichlorophenyl)butenyl)benzamide (AC92) Cl ~ The product was isolated as a colorless oil (17 .9 mg, 4.36%): 1H NMR (400 MHz, CDCb) o9.16 (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 = .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-HD.
Example 106: Preparation of ethyl (Z) o(4,4,4-trifluoro(3,4,5- trichlorophenyl)butenyl)benzoate (AI76) Cl The title compound was made in accordance with the ure disclosed in Example 88 and was isolated as a yellow viscous oil (416 mg, 23%): 1H NMR (400 MHz, CDCb) o7.80 (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, CDCb) o-69.34 (d, J =8.3 Hz); ElMS m/z 514.10 ([MD; IR (thin film) 2983, 1727, 1247, 1204, 1116 cm-1.
Example 107 : Preparation of (Z)bromo(4,4,4-trifluoro(3,4,5- trichlorophenyl)butenyl)benzoic acid (AI77) wo 2012/177813 To a stirred solution of (Z)-ethyl2-bromo(4,4,4-trifluoro(3,4,5- trichlorophenyl)but-l-en-l-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 CH2Ch and aq. 10 % Na2S20 3. Organic phase was washed once with aq. 10% Na2S20 3 and dried over MgS04 and concentrated in vacuo. Passing the material through a silica plug with 10% EtOAc in hexanes, followed by 20% MeOH in CH2Ch ) as the eluting solvents afforded the title compound as a yellow foam (143 mg, 42%): mp C; 1H NMR (400 MHz, CDCb) o 11.36 (s, lH), 7.99 (d, J = 8.0 Hz, lH), 7.43 (s, lH), 7.30 (s, 2H), 7.14 (d, J =7.9 Hz, lH), 6.85 (d, J = 11.4 Hz, lH), 6.15 (t, J = 10.9 Hz, lH), 4.36- 4.09 (m, F NMR (376 MHz, CDCb) o-69.30.
Example 108: Preparation of (Z)bromo-N-(2-oxo((2,2,2- trifluoroethyl)amino)ethyl)(4,4,4-trifluoro(3,4,5-trichlorophenyl)buten yl)benzamide (AC95) NH 0 \........( CF3 Br HN_; Cl To a stirred solution of (Z)bromo(4,4,4-trifluoro(3,4,5-trichlorophenyl)but enyl)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 oc oil bath for 1.5 h, treated with o- ,2-trifluoroethyl)acetamide hydrochloride (109 mg, .057 mmol) and the resulting mixture heated to reflux for 8 h. After cooling to ambient temperature, the mixture was taken up in Et20 and washed twice with aq. 5% NaHS04 (2X) and once with sat. NaCl (1X).
After dying over MgS04, 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 oc: 1H NMR (400 MHz, CDCb) o7.58 (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, CDCb) o-69.31, -72.3; ElMS m/z 626.9 ([M+1t). wo 2012/177813 Example 109a: Preparation of (E)bromo-N-(piperidinyl)(4,4,4-trifluoro (3,4,5-trichlorophenyl)butenyl)benzamide (AC114) F F F Cl Br oN0NHH Cl (E)-tert-Butyl 4-(2-bromo(4,4,4-trifluoro(3,4,5-trichlorophenyl)but enyl)benzamido)piperidinecarboxylate (0.75 g, 1.11 mmol) was added to eHCl (10 mL) at 0 oc 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-acetylpiperidinyl)bromo(4,4,4-trifluoro- 3-(3,4,5-trichlorophenyl)butenyl)benzamide (AC103) F F F To a stirred solution of bromo-N-(piperidinyl)(4,4,4-trifluoro(3,4,5- trichlorophenyl)butenyl)benzamide (0.1 g, 0.16 mmol) in DCM (10.0 mL) was added triethylamine (0.046 mL, 0.35 mmol) and stirred for 10 min. Then acetyl de (0.014, 0.18 mmol) was added and stirred for 16 hat RT. The reaction mixture was diluted with DCM and washed with saturated NaHC03 on and brine solution. The combined DCM layer was dried over Na2S04 and concentrated under reduced pressure to afford crude compound. The crude compound was washed with 5% diethyl ether In-pentane to afford the title compound as a white solid (0.054 g, 50%).
Example 110: Preparation of (E)bromo(4,4,4-trifluoro(3,4,5- trichlorophenyl)butenyl)-N-(1-(3,3,3-trifluoropropanoyl)piperidinyl)benzamide (AC104) wo 2012/177813 To a stirred solution of 3,3,3-trifluoropropanoic acid (0.02g, 0.16 mmol) in DCM (10.0 mL), (E)bromo-N-(piperidinyl)(4,4,4-trifluoro(3,4,5-trichlorophenyl)but 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 RT. The reaction mixture was stirred at RT for 5 h. The reaction mixture was diluted with DCM. The combined DCM layer was washed with 3N HCl and saturated NaHC03 solution, the separated DCM layer was dried over anhydrous Na2S04 and concentrated under reduced pressure to afford crude nd. The crude compound was ed by column chromatography (Si02, 100-200 mesh; eluting with 2% methanol in DCM) to afford the title compound as a off white gummy material (0.035 g, 29.%).
Example 111: Preparation of (E)bromo(4,4,4-trifluoro(3,4,5- trichlorophenyl)butenyl)-N-(1-(2,2,2-trifluoroethyl)piperidinyl)benzamide (AC105) To a stirred solution of (E)bromo-N-(piperidinyl)(4,4,4-trifluoro(3,4,5- trichlorophenyl)butenyl)benzamide (0.1 g, 0.16 mmol) in THF (5.0 mL) was added triethylamine (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 hat RT. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHC03 on and brine solution. The combined ethyl e layer was dried over Na2S04 and concentrated under reduced pressure to afford the title nd as a brown solid (0.05 g, 44%).
Example 112: Preparation of (E)bromo-N-(1-methylpiperidinyl)(4,4,4-trifluoro- ,5-trichlorophenyl)butenyl)benzamide (AC106) wo 2012/177813 A solution of (E)bromo-N-(piperidinyl)(4,4,4-trifluoro(3,4,5- trichlorophenyl)butenyl)benzamide (0.1 g, 0.16 mmol), formaldehyde (30% in water) (0.1 mL, 0.16 mmol) and acetic acid (0.01 mL) in methanol (5.0 mL) was d at RT for 30 min. After that NaBH3CN (0.01 g, 0.16 mmol) was added at ooc and the on was stirred for 8 hat RT. The solvent was removed under reduced pressure to obtain residue which was diluted with ethyl acetate and washed with saturated aq. NaHC03 solution and brine solution.
The combined ethyl acetate layer was dried over Na2S04 and concentrated under d 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)bromo-N-(1-(cyanomethyl)piperidinyl)(4,4,4- trifluoro(3,4,5-trichlorophenyl)butenyl)benzamide ) To a stirred solution of (E)bromo-N-(piperidinyl)(4,4,4-trifluoro(3,4,5- orophenyl)butenyl)benzamide (0.25 g, 0.43 mmol) in THF (10.0 mL) was added triethylamine (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 hat RT.
The reaction mixture was diluted with ethyl acetate and washed with saturated brine solution.
The combined ethyl acetate layer was dried over Na2S04 and trated under reduced pressure to afford the title compound as an off-white solid (0.125 g, 46.8%).
Example 114: Preparation of (E)bromo-N-(1-(oxetanyl)piperidinyl)(4,4,4- trifluoro(3,4,5-trichlorophenyl)butenyl)benzamide (AC108) wo 2012/177813 A on of (E)bromo-N-(piperidinyl)(4,4,4-trifluoro(3,4,5- orophenyl)butenyl)benzamide (0.2 g, 0.35 mmol), oxetanone (0.027 g, 0.38 mmol) and acetic acid (0.01 mL) in methanol (5.0 mL) was stirred at RT for 30 min. After that NaBH3CN (0.022 g, 0.35 mmol) was added at 0 oc slowly lot wise over the period of 10 min and the reaction was d for 8 hat RT. The t was removed under reduced pressure to obtain a residue which was diluted with ethyl acetate and washed with ted NaHC03 on and brine solution. The combined ethyl acetate layer was dried over Na2S04 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)bromo-N-(1-(2-hydroxyethyl)piperidinyl) (4,4,4-trifluoro(3,4,5-trichlorophenyl)butenyl)benzamide (AC109) To a stirred solution of (E)bromo-N-(piperidinyl)(4,4,4-trifluoro(3,4,5- trichlorophenyl)butenyl)benzamide (0.25 g, 0.43 mmol) in THF (10.0 mL) was added triethylamine (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 hat RT. The reaction mixture was diluted with ethyl acetate and washed with saturated brine solution. The combined ethyl acetate layer was dried over Na2S04 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-bromo(4,4,4-trifluoro(3,4,5- trichlorophenyl)butenyl)benzamido)acetic acid (AI78) wo 2012/177813 To a stirred solution of (E)-tert-butyl2-(2-bromo(4,4,4-trifluoro(3,4,5- trichlorophenyl)butenyl)benzamido)acetate (440 mg, 0.734 mmol) in DCM (36.0 ml), was added TFA (4.0 mL) and the reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure to obtain residue which was washed with ane to afford the title compound as an off-white solid (310 mg, 78%): 1H NMR (400 MHz, CDCb) o13.0 (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+Ht); IR (thin film) 3429, 1635, 1114, 772 em.-1 Example 117: Preparation of (E)-N-((6-chloropyridinyl)methyl)(3-(3,5- dichlorophenyl)-4,4,4-trifluorobutenyl)methylbenzothioamide (AC115) To the stirred on of (E)-N-((6-chloropyridinyl)methyl)(3-(3,5- dichlorophenyl)-4,4,4-trifluorobutenyl)methylbenzamide (0.06 g, 0.117 mmol) in toluene (3 mL) was added Lawesson'sreagent (0.14 g, 0.351 mmol) and the reaction was irradiated at 100 °C for 1 h, then cooled to R T and concentrated under reduced pressure to provide crude compound. The crude product was purified by preparative HPLC to afford the t as yellow color solid (0.03 g, 49%).
Example 118: Preparation of (E)(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobut- 1-enyl)-N-(2-oxo((2,2,2-trifluoroethyl)amino)ethyl) (trifluoromethoxy)benzamide (AC116) wo 2012/177813 Step 1. 2-(Trifluoromethoxy)vinylbenzoic acid (AI79): To a stirred solution of 4-bromo(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 oc for 1 h. The reaction mixture was diluted with water ), extracted with ethyl acetate (2 x 50 mL), washed with brine, and dried over Na2S04. 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, CDCb) o8.05 (d, J = 8.1 Hz, lH), 7.44 (d, J = 1.8 Hz, lH), 7.35 (s, lH), 6.78 (dd, J 1, 11.1 Hz, lH), 5.92 (d, J = 17.4 Hz, lH), .51 (d, J = 10.8 Hz, lH); ESIMS m/z 232.97 ([M+Ht).
Step 2. (E)(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobutenyl) (trifluoromethoxy)benzoic acid (AlSO): To a stirred solution of 2-(trifluoromethoxy) 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), (!) 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 oc for 1 h. After the reaction was complete by TLC, the reaction mixture was diluted with water (100mL) and extracted with ethyl acetate (2X 50 mL). The combined c layers were washed with brine, dried over Na2S04 and concentrated under reduced re to obtain the crude compound which was purified by flash column chromatography to afford the product as pale yellow gummy al (0.3 g, 21%): 1H NMR (400 MHz, CDCb) o8.08 (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-HD.
Step 3. (E)(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobutenyl)-N-(2- oxo(2,2,2-trifluoroethylamino)ethyl)(trifluoromethoxy)benzamide (AC116) : A mixture of (3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobutenyl) (trifluoromethoxy)benzoic acid (0.25 g, 0.52 mmol), o-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 DCM (10.0 mL) were stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with DCM. The combined DCM layer was washed with brine, dried over Na2S04 and concentrated under reduced pressure. Purification by flash column chromatography (Si02, 0 mesh; eluting with 20% ethyl acetate/ pet ether) afforded the title compound as a pale yellow gummy material (0.15 g, 47 %). wo 2012/177813 Example 20: Preparation of l-2,3-dihydro-1H-indenone (Bil) To a stirred solution of 5-bromo-2,3-dihydro-1H-indenone (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), K2C03 (22.88 g, 165.83 mmol). The resultant reaction mixture was heated at reflux for 16 h. The on mixture was cooled to 25 oc and filtered, and the filtrate was concentrated under reduced re. The residue was diluted with EtOAc and washed with H20 and brine. The combined c extracts were dried over anhydrous Na2S04 and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (Si02, 5% EtOAc in petroleum ether) afforded the title nd as a solid (1.8 g, 48%): 1H NMR (400 MHz, CDCb) o7.74 (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+HD.
The following compound was made in accordance with the procedures disclosed in Example 20. 6-Vinyl-3,4-dihydronaphthalen-1(2H)-one (BI2) The t was isolated as an off-white solid (5 g, 48%): 1H NMR (400 MHz, DMSO-d6) o7.85 (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 ([MHD ; IR (thin film) 1681 cm-1.
Example 21: Preparation of (E)(4,4,4-trifluoro(3,4,5-trichlorophenyl)butenyl)- 2,3-dihydro-1H-indenone (BI3) 5-(1-Bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene ( 4 g, 11.7 mmol), 5-vinyl- 2,3-dihydro-1H-indenone (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 oc for 16 wo 2012/177813 h. The reaction mixture was cooled to 25 oc and concentrated under reduced pressure. The residue was ed by flash column chromatography (Si02, 5% EtOAc in petroleum ether) to afford the title compound as a liquid (1.28 g, 25%): 1H NMR (400 MHz, CDCb) o7.76 (d, J =7.4 Hz, lH), 7.52 (m, 3H), 6.68 (d, J =7.4 Hz, lH), 6.52 (m, lH), 4.18 (m, lH), 3.18 (m, 2H), 2.75 (m, 2H); ESIMS m/z 419.14 ([M+HD; IR (thin film) 1708.94, 1113.60,807.77 em.-1 The following nd was made in accordance with the procedures disclosed in e 21.
(E)(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobutenyl)-2,3-dihydro-1H- indenone (BI4) The product was isolated as a brown semi-solid (1.2 g, 16%): 1H NMR (400 MHz, CDCb) o7.76 (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-HD; IR (thin film) 815,1113,1709 cm-1.
(E)(4,4,4-Trifluoro(3,4,5-trichlorophenyl)butenyl)-3,4-dihydronaphthalen- 1(2H)-one (BI5) The product was isolated as a pale yellow semi solid (1.2 g, 30%): 1H NMR (400 MHz, CDCb) o8.20 (d, J = 8.0 Hz, 1H), 7.42 (s, 2H), 7.35 (m, 1H), 7.24 (m, 2H), 6.62 (d, J = 16Hz, 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-HD; IR (thin film) 1680, 1113, 808 cm-1.
Example 22: Preparation of (E)(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobut enyl)fluoro-2,3-dihydro-1H-indenone (BI6) Cl .o- Cl 0 wo 2012/177813 To a stirred solution of (E)(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobut enyl)-2,3-dihydro-lH-indenone (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 room temperature, concentrated under reduced pressure and diluted with DCM. The solution was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude t which was purified by flash column chromatography (Si02, 100-200 mesh; 15% EtOAc in petroleum ether) to afford the title compound as a pale yellow semi solid (O.lg, 24%): 1H NMR (400 MHz, CDCb) o7.80 (m, lH), 7.48 (m, 2H), 7.32 (m, 2H), 6.65 (d, J = 16.0 Hz, lH), 6.54 (dd, J = 16.0, 8.0 Hz, lH), 5.38 (m, lH), 4.18 (m, lH), 3.62 (m, lH), 3.32 (m, lH); ESIMS m/z 419.06 ; IR (thin film) 1728, 1114, 817 cm-1.
Example 23: ation of (E)(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobut enyl)-N-(3,3,3-trifluoropropyl)-2,3-dihydro-1H-indenamine (BC10) Cl NH To a stirred solution of (E)(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobut enyl)-2,3-dihydro-1H-indenone (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 on mixture was stirred at room 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 (Si02, 100-200 mesh; 10-15% EtOAc in petroleum ether) to afford the title compound as a ess gummy material g, 24%): 1H NMR (400 MHz, CDCb) o7.38-7.20 (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-HD; IR (thin film) 3027, 1654, 815 cm-1.
Example 24: Preparation of 6-((E)-4,4,4-trifluoro(3,4,5-trichlorophenyl)butenyl)- 3,4-dihydronaphthalen-1(2H)-one oxime (BI5a) wo 2012/177813 To a stirred solution of -(4,4,4-trifluoro(3,4,5-trichlorophenyl)but-l-enyl)- 3,4-dihydronaphthalen-1(2H)-one (0.4 g, 0.92 mmol) in EtOH (50 mL) were added hydroxylamine hloride (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 trated under reduced pressure, and the residue was diluted with H20 and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure to give the crude compound, which was purified by flash column chromatography (Si02, 100-200 mesh; 10-15% EtOAc in petroleum ether). The title compound was isolated as a solid (0.3 g, 73%): mp 8 oc; 1H NMR (400 MHz, CDCb) o7.89 (d, J = 8.4 Hz, lH), 7.41 (s, 2H), 7.24 (m, lH), 7.17 (m, lH), 6.57 (d, J = 16 Hz, lH), 6.46 (dd, J = 16.0, 8.0 Hz, lH), 4.13 (m, lH), 2.82 (m, 4H), 2.04 (m, 2H); ESIMS mlz 445.95 ([M-HD.
Example 25: ation of (E)(4,4,4-trifluoro(3,4,5-trichlorophenyl)butenyl)- 2,3-dihydro-1H-indenamine (BI5b) To a stirred solution of (E)(4,4,4-trifluoro(3,4,5-trichlorophenyl)butenyl)-2,3- dihydro-1H-indenone (1 g, 2.39 mmol) in CH30H (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 d pressure, and the residue was diluted with H20 and extracted with EtOAc . The ed organic extracts were washed with H20 and saturated aqueous sodium bicarbonate (satd aq NaHC03) solution, dried over anhydrous Na2S04, and concentrated under reduced pressure to afford the title compound as a liquid (500 mg, crude): 1H NMR (400 MHz, DMSO-d6) o7.85 (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+Ht); IR (thin film) 2924, 1552, 1112, 807 cm-1. wo 2012/177813 The following compound was made in accordance with the procedures disclosed in Example 25.
(E)(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobutenyl)-2,3-dihydro-1H- indenamine (BI7) 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-HD.
(E)(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobutenyl)fluoro-2,3- o-1H-indenamine (BI8) 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-HD.
(E)(4,4,4-trifluoro(3,4,5-trichlorophenyl)butenyl)-1,2,3,4-tetrahydronaphthalen- 1-amine (BI9) The product was ed as a pale yellow liquid (500 mg crude). e 26: Preparation of (E)methyl(5-(4,4,4-trifluoro(3,4,5-trichlorophenyl)- butenyl)-2,3-dihydro-1H-indenyl)thiourea (BC1) wo 2012/177813 Cl NH To a stirred solution of (E)(4,4,4-trifluoro(3,4,5-trichlorophenyl)butenyl)-2,3- dihydro-lH-indenamine (0.1 g, 0.23 mmol) in Et20 (5 mL) was added methylisothiocyanate (0.026 g, 0.35 mmol), and the mixture was stirred for 2 h at 25 oc. The reaction mixture was concentrated under d pressure, and the residue was purified by flash column chromatography (Si02, 20% EtOAc in petroleum ether). The title nd was isolated as a liquid (65 mg, 50%): 1H NMR (400 MHz, CDCb) o7.39 (s, 2H), 7.25- 7.18 (m, 3H), 6.58 (d, J = 16.0 Hz, lH), 6.30 (dd, J = 16.0, 8.4 Hz, lH), 5.91- 5.70 (br, 2H), 4.05 (m, lH), 3.05-2.80 (m, 6H), 2.70 (m, lH), 1.81 (m, lH); ESIMS m/z 492.17 ([M+Ht); IR (thin film) 3211, 1569, 1113, 806 cm-1. nds BC2 - BC3 in Table 1 were made in ance with the procedures disclosed in Example 26.
Example 27: Preparation of (E)-3,3,3-trifluoro-N-(5-(4,4,4-trifluoro(3,4,5- trichlorophenyl)butenyl)-2,3-dihydro-1H-indenyl)propanamide (BC4) Cl .o Cl ;pNH F To a stirred solution of (E)(4,4,4-trifluoro(3,4,5-trichlorophenyl)butenyl)-2,3- dihydro-1H-indenamine (0.1 g, 0.23 mmol) in CH2Ch (10 mL) were added trifluoropropionic acid (0.044 g, 0.34 mmol), EDC•HCl (0.038 g, 0.35 mmol), HOBt•H20 (0.07 g, 0.46 mmol) and DIEA (0.074 g, 0.57 mmol), and the reaction mixture was stirred for 16 hat 25 oc. The reaction mixture was diluted with CH2Ch and washed with H20. The combined organic layer was washed with brine, dried over anhydrous Na2S04, and concentrated under d pressure. The crude material was purified by flash column chromatography (Si02, 15% EtOAc in petroleum ether) to afford the title compound as a liquid (65 mg, 65%): 1H NMR (400 MHz, CDCb) o7.39 (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), wo 2012/177813 2012/043418 3.10 (m, 2H), 2.86-3.07 (m, 2H), 2.86 (m, 1H), 1.81 (m, 1H); ESIMS m/z 529.02 ([M+Ht); IR (thin film) 3283, 1652, 1241, 811 cm-1. nds BC5 - BC9, BCll in Table 1 were made in accordance with the procedures disclosed in Example 27.
Example 28: ation of tert-butyl5-vinylindolinecarboxylate (BilO) Step 1. 5-Bromo-indoline (Bill): 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 oc over the period of 20 min. After that the reaction mixture was stirred at R T for 3 h. The reaction mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with saturated NaHC03, water and brine solution. The combined ether layer was dried over anhydrous Na2S04 and concentrated under reduced pressure to afford title compound as a pale yellow semi-solid (1.8 g, 71%).
Step 2. tert-Butylbromoindolinecarboxylate (BI12): To a stirred solution of 5-bromo-indoline (3.0 g , 15mmol) 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 RT for 16 h. The reaction mixture was trated on reduced pressure to obtain a e which was diluted with diethyl ether and washed with water and brine solution (2X). The combined ether layer was dried over anhydrous Na2S04 and concentrated under d pressure to afford the crude product as a off-white solid, which was used in the next step t further purification (3.0 g).
Step 3. utylvinylindolinecarboxylate (BilO): A stirred solution of tert- butylbromoindolinecarboxylate (2.0 g, 6. 73 mmol), potassium vinyl trifluoroborate (2.6 g, 20.20 mmol) and K2C03 (2.78 g, 20.2 mmol) in DMSO (50.0 mL) was degassed with argon for 20 min at RT. PdCb(dppf) (0.49 g, 0.67mmol) was added at RT, then the reaction mixture was heated to 100 oc for 3 h. The reaction mixture was cooled toRT and filtered through a celite bed under vacuum and washed with diethyl ether. The reaction mixture was extracted with l ether. The combined diethyl ether layer was dried over Na2S04 and concentrated under reduced pressure to afford crude t. The crude compound was purified by column chromatography (Si02, 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 wo 2012/177813 oc; 1H NMR (400 MHz, CDCb) o7.23 (m, 3H), 6.69 (dd, J = 17.4, 10.8 Hz, 1H), 5.64 (d, J = .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 3,5-dichlorofluorophenyl)-4,4,4- trifluorobutenyl)indolinecarboxylate (Bil3) To a stirred solution of tert-butylvinylindolinecarboxylate (1.28 g, 5.23mmol) in1 ,2-dichlorobenzene (10.0 mL), was added 5-(1-bromo-2,2,2-trifluoroethyl)-1,3-dichloro 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 e was degassed with argon for 30 min and heated to 150 oc for 1 h. The reaction mixture was cooled toRT and filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography (Si02, 0 mesh; 2% ethyl acetate/ petroleum ether) to afford the title nd as a pale yellow gummy solid (0.3 g, 61 %): 1H NMR (400 MHz, CDCb) o7.34 (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-HD; IR (thin film) 1168, 858 cm-1.
Example 30: Preparation of (E)(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobut l)indolinamine (BI14) Step 1. (E)- 5-(3-(3,5-Dichlorofluorophenyl)-4,4,4-trifluorobutenyl)indoline (BI15) To a stirred solution of (E)-tert-butyl(3-(3,5-dichlorofluorophenyl)-4,4,4- trifluorobutenyl)indolinecarboxylate (0.2 g, 0.4 mmol) in DCM (10.0 mL) was added TFA (0.6 mL) and the reaction was stirred at RT for 2 h. The on mixture was diluted with DCM, washed with saturated aq NaHC03 , water and brine solution. The separated DCM layer was dried over anhydrous Na2S04 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, CDCb) o7.33 (d, J =6.4 Hz, 2H), wo 2012/177813 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 ); IR (thin film) 3385, 1112,816 cm-1.
Step 2. 5-(3-(3,5-Dichlorofluorophenyl)-4,4,4-trifluorobutenyl) nitrosoindoline (BI16): To (E)- 5-(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobut enyl)indoline (0.2 g, 0.5 mmol) in concentrated HCl (5.0 ml) at 5 oc, was added slowly NaN02 in water and the reaction was allowed to stir at RT for 2 h. The reaction e was diluted with DCM, and the DCM layer washed with water and brine solution. The separated DCM layer was dried over anhydrous Na2S04 and concentrated under d 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, CDCb) o7.33 (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+Ht); IR (thin film) 1488, 1112, 860 cm-1.
Step 3. (E)(3-(3,5-Dichlorofluorophenyl)-4,4,4-trifluorobuten yl)indolinamine (BI14): To (E)- 5-(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobut enyl)nitrosoindoline (0.1 g, 0.2 mmol) in methanol(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 RT for 3 h. The reaction mixture was diluted with DCM and the DCM layer was washed with water and brine solution. The separated DCM layer was dried over anhydrous Na2S04 and concentrated under reduced pressure to afford the crude nd, which was purified by column chromatography (Si02, 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+Ht). e 31: Preparation of (E)-N-(5-(3-(3,5-dichlorofluorophenyl)-4,4,4- trifluorobutenyl)indolinyl)-3,3,3-trifluoropropanamide (BC12) F ~ 0 Cl HN~CF3 To a stirred solution of (E)(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobut enyl)indolineamine (0.1 g, 0.247 mmol) in DCM (10.0 ml) was added 3,3,3- trifluoropropanoic acid (0.038 g, 0.297 mmol), PyBOP (0.192 g, 0.370 mmol) and DIEA (0.047 g, 0.370 mmol) and the on was stirred at RT for 18 h. The reaction mixture was wo 2012/177813 d with DCM, and the separated DCM layer dried over anhydrous Na2S04 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (Si02, 100-200 mesh; 20-25% ethyl acetate/ eum ether) to afford the title compound as a light brown gummy material (0.12 g, 33%): 1H NMR (400 MHz, CDCb) o7.32, (d, J = 6.0 Hz, 2H) 7.28 (m, lH), 7.20 (d, J = 8.0, lH), 7.14 (d, J = 8.8, lH ), 6.70 (d, J = 8.0 Hz, lH), 6.60 (m, 2H), 4.15 (m, lH), 3.85 (m, lH), 3.65 (m, lH), 3.46 (m, 2H), 3.19 (m, 2H); ESIMS mlz 514.86 ([M+Ht); IR (thin film) 3428, 1112, 857 em- Example 32: Preparation of tert-butylvinyl-1H-indolecarboxylate (BI17) 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), Cs2C03 (12.53 g, 38.46 mmol) and triphenylphosphine (201 mg, 0.769 mmol) in THF/water (9:1, 75 ml) was ed with argon for 20 min, then charged with PdCb (45.3 mg,0.256 mmol). The reaction mixture was heated to reflux for 16 h, then cooled toRT, filtered through celite bed and washed with ethyl acetate. The te was again extracted with ethyl acetate, and the combined organic layer washed with water and brine, dried over Na2S04 and concentrated under reduced pressure to afford the crude compound. The crude nd was purified by column chromatography (Si02, 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, CDCb) o8.20 (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 = .5 Hz, 1H), 5.21 (d, J = 10.5 Hz, 1H); ESIMS m/z 142.05 ([M-HD.
Step 2. tert-Butylvinyl-1H-indolecarboxylate (BI17): To a stirred solution of -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 onate (1.38 g, 6.36 mmol), and the reaction was stirred at RT for 3 h. The reaction mixture was concentrated under reduced pressure to obtain a residue which was diluted with DCM and washed with water and brine solution. The combined DCM layer was dried over anhydrous Na2S04 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (Si02, 0 mesh; 2% ethyl e/ petroleum ether) to afford the title compound as an off-white semi-solid (0.7 g, 59%): 1H NMR (400 MHz, CDCb) o8.15 (d, J wo 2012/177813 = 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-HD; IR (thin film) 1630 cm-1.
Example 33: Preparation of (E)-tert-butyl 5-(3-(3,5-dichlorofluorophenyl)-4,4,4- orobutenyl)-1H-indolecarboxylate (BI19) Cl ~ To a stirred solution of tert-butyl 5-vinyl-1H-indolecarboxylate (0.65 g, 2.67 mmol), in 1,2-dichlorobenzene (10.0 mL) was added 5-(1-bromo-2,2,2-trifluoroethyl)-1,3- dichlorofluorobenzene (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 oc for 2 h. The reaction mixture was cooled toRT and filtered, and the filtrate trated under reduced pressure. The crude compound was ed by column chromatography (Si02, 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, CDCb) o 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 = .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-HD; IR (thin film) 1165, 854 cm-1.
Example 34: Preparation of (E)(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobut enyl)-1H-indole (BI20) To a stirred solution of (E)-tert-butyl 5-(3-(3,5-dichlorofluorophenyl)-4,4,4- trifluorobutenyl)-1H-indolecarboxylate (0.2 g, 0.40 mmol) in DCM (10.0 mL) was added TFA (70 mg, 0.61 mmol) and the reaction was d at RT for 2 h. The on mixture was diluted with DCM and washed with saturated NaHC03 solution, water and brine solution. The separated DCM layer was dried over anhydrous Na2S04 and concentrated under reduced pressure to afford the title compound as a light brown solid (0.2 g, 97%): mp 132.9- 138.8 oc; 1H NMR (400 MHz, CDCb) o11.19 (br, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.60 (m, wo 2012/177813 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+Ht).
Example 35: Preparation of 4-nitrophenyl2-((tert-butoxycarbonyl)amino)acetate (BI21) 02N~ O Oyo V0~NH/< To a stirred solution of 4-nitrophenol (1.0 g, 7.19 mmol) in DCM (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 d at RT for 24 h. The reaction mixture was diluted with DCM and washed with water and saturated brine solution. The separated DCM layer was dried over anhydrous Na2S04 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, CDCb) o8.29 (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+Ht). e 36: Preparation of (E)-tert-butyl (2-(5-(3-(3,5-dichlorofluorophenyl)-4,4,4- trifluorobutenyl)-1H-indolyl)oxoethyl)carbamate (BI22) To a stirred on of (E)(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobut 1H-indole (0.1 g, 0.258 mmol) in acetonitrile (5.0 mL) was added 4-nitrophenyl2-(tertbutoxycarbonylamino ) acetate (0.114 g, 0.387 mmol), potassium de (0.03 g, 0.516 mmol), 18-crownether (0.075 g, 0.283 mmol) and DIEA (0.0332 g, 0.258 mmol) and the reaction was stirred at RT for 16 h. The on mixture was concentrated to obtain a residue which was diluted with DCM and washed with water and brine solution. The separated DCM layer was dried over anhydrous Na2S04 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+Ht).
Example 37: Preparation of (E)-N-(2-(5-(3-(3,5-dichlorofluorophenyl)-4,4,4- trifluorobutenyl)-1H-indolyl)oxoethyl)-3,3,3-trifluoropropanamide (BC13) wo 2012/177813 F N ~~CF3 Cl 0~ 0 Step 1. (E)amino(5-(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobut enyl)-1H-indolyl)ethanone (BI23): To a d solution of (E)-tert-butyl2-(5-(3-(3,5- dichlorofluorophenyl)-4,4,4-trifluorobutenyl)-1H-indolyl)oxoethylcarbamate (0.05 g, 0.09 mmol) in DCM (5.0 mL) was added TFA (0.01 mL) and the reaction was d at RT for 16 h. The reaction mixture was diluted with DCM and washed with saturated NaHC03 solution, water and brine solution. The separated DCM layer was dried over anhydrous Na2S04 and concentrated under reduced pressure to afford the crude title compound which was used in the next step without r purification (50 mg).
Step 2. (E)-N-(2-(5-(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobutenyl)- 1H-indolyl)oxoethyl)-3,3,3-trifluoropropanamide (BC13): To a stirred solution of (E)amino(5-(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobutenyl)-1H-indolyl) ethanone (0.04 g, 0.09 mmol) in DCM (5.0 ml) was added 3,3,3-trifluoropropanoic acid (17.5 mg, 0.136 mmol), PyBOP (70 mg, 0.135 mmol) and DIEA (29 mg, 0.225 mmol) and the reaction was stirred at RT for 16 h. The reaction mixture was d with DCM, and the DCM layer was washed with water and saturated brine solution .The separated DCM layer was dried over ous Na2S04 and concentrated under reduced pressure to afford the crude compound, which was purified by column chromatography (Si02, 100-200 mesh; 10% ethyl acetate/ petroleum ether) to afford the title compound as an off-white solid (30 mg, 60%): mp 121-126 oc; 1H NMR (400 MHz, CDCb) o8.33 (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-HD.
Example 38: Preparation of ethyl2-(1-oxovinylphthalazin-2(1H)-yl)acetate (BI24) ~~Jo~ Step 1. 5-Bromohydroxyisoindolineone (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 oc. 5-Bromoisoindoline-1,3-dione (5 g, 22mmol) was added at the same temperature over the period of 30 min. The reaction e was stirred at 0 oc for 30 min and 3 hat RT. The on mixture was filtered and the filtrate was neutralized wo 2012/177813 2012/043418 with concentrated HCI. The reaction e was diluted with ethanol and extracted with ethyl e. The combined ethyl acetate layer was dried over Na2S04 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 oc; 1H NMR (400 MHz, DMSO-d6) o9.03 (br, lH), 7.81 (m, 2H), 7.69 (m, lH), 6.44 (m, lH), 5.88 (d, J = 9.3 Hz, lH); ESIMS m/z 225.83 ([M-HD; IR (thin film) 1684, 3246,606 cm-1.
Step 2. 6-Bromophthalazine-1(2H)-one (BI26): To a stirred solution of 5-bromo yisoindolineone (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 toRT, 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+Ht).
Step 3. 6-vinylphthalazine-1(2H)-one (BI27): A solution of 6-bromophthalazine- 1(2H)-one (0.25 g, 1.11 mmol), potassium vinyl oroborate (0.446 g, 3.33 mmol) and K2C03 (0.46 g, 3.33 mmol) in DMSO (2 mL) was degassed with argon for 20 min at RT.
PdCb(dppf) (0.04 g, 0.055 mmol) was added at RT, and the reaction mixture was heated to 80 oc for 2 h. The reaction mixture was cooled toRT 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 Na2S04 and trated under reduced pressure to afford the crude product. The crude nd was purified by column chromatography (Si02, 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) o13.61 (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(1-oxovinylphthalazine-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 Cs2C03 (0.94 g, 2.90 mmol) and the reaction was stirred for 10 min. Ethyl cetate (0.48 g,2.90 mmol) was added to the reaction mixture at RT and the reaction was stirred for 8 hat RT. The reaction mixture was diluted and extracted with ethyl acetate, and the ethyl acetate layer was washed with water and brine solution (2X). The separated ethyl acetate layer was dried over anhydrous Na2S04 and concentrated under reduced pressure to afford crude product. The crude compound was ed by column tography (Si02, 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) o8.45 (m, 1H), 8.24 (m, 1H), 8.04 (m, 2H), 7.01 wo 2012/177813 2012/043418 (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)-ethyl2-(6-(3-(3,5-dichlorofluorophenyl)-4,4,4- trifluorobutenyl)oxophthalazin-2(1H)-yl)acetate (BI28) To a stirred solution of ethyl(1-oxovinylphthalazine-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 oc for 12 h. The reaction mixture was cooled toRT and filtered and the filtrated was trated under reduced pressure. The crude compound was purified by column chromatography (Si02, 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-d 6) o 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)(6-(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobut- 1-enyl)oxophthalazin-2(1H)-yl)acetic acid (BI29) A solution of hyl(6-(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobut enyl)oxophthalazin-2(1H)-yl) acetate (0.04 g, 0.07mmol) in HCl (0.5 mL) and acetic acid (0.5 mL) was heated to 100 oc for 3 h. The t was d 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 Na2S04 and concentrated under reduced pressure to afford the crude compound. The crude nd 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) o13.0 (br s, 1H), 8.43 (m, 1H), 8.23 (d, J = 8.1 Hz, 1H), 8.14 (m, 2H), 7.91 wo 2012/177813 (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-HD; IR (thin film) 1629, 1168,817 cm-1. e 41: Preparation of (6-(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobut- 1-enyl)oxophthalazin-2(1H)-yl)-N-(2,2,2-trifluoroethyl)acetamide (BC14) To a stirred solution of (6-(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobut enyl)oxophthalazin-2(1H)-yl)acetic acid (0.15 g, 0.31 mmol) in DCM (20.0 ml) was added 2,2,2,-trifluoroethanamine (0.03 g, 0.31mmol), PyBOP (0.17 g, 0.34 mmol) and DIEA (0.15 ml, 0.93 mmol) at RT, and the on was stirred for 18 h. The reaction mixture was diluted with DCM and washed with 3N HCl (2 x 20 mL), NaHC03 (2 x 20 mL) and brine on (2x).The separated DCM layer was dried over anhydrous Na2S04 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column tography (Si02, 100-200 mesh; 20-25% ethyl acetate/ petroleum ether) to afford the title compound as a brown solid (0.11 g): mp 172-175 oc; 1H NMR (400 MHz, CDCb) o8.83 (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-HD.
Example 42: Preparation of 2-(4-vinylbenzyl)isoindoline-1,3-dione (Cil) To a stirred solution of 1-(chloromethyl)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 oc for 16 h. The reaction mixture was diluted with H20 and extracted with CHCb. The combined CHCb layer was washed with brine, dried over Na2S04 and concentrated under reduced pressure. Recrystallization from CH30H afforded the title compound as an off-white solid (8 g, 46%): 1H NMR (400 MHz, CDCb) o 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 wo 2012/177813 (d, J = 10.8 Hz, 1H), 4.82 (s, 2H); GCMS m/z 263.2 ([Mt); IR (thin film) 3420, 1133, 718 em.-1 Example 43: Preparation of (E)(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobuten yl)benzyl)isoindoline-1,3-dione (CI2) 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 oc; 1H NMR (400 MHz, CDCb) o7.86 (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-HD.
The following compound was made in accordance with the procedures disclosed in e 43.
(E)(4-(4,4,4-Trifluoro(3,4,5-trichlorophenyl)butenyl)benzyl)isoindoline-1,3- dione (CI3) The title nd was isolated as an off white solid (0.3 g, 56%): mp 145-146 oc; 1H NMR (400 MHz, CDCb) o7.86 (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-HD; IR (thin film) 1716, 1110,712 cm-1. tically, 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-trifluorobuten yl)phenyl)methanamine (CI6) To a stirred solution of (E)(4-(3-(3,5-dichlorophenyl)butenyl)benzyl)- isoindoline-1,3-dione (1.2 g, 2.45 mmol) in EtOH was added hydrazine hydrate (0.61 g, 12 wo 2012/177813 mmol), and the resultant on mixture was heated at 90 oc for 1 h. The on mixture was ed, and the filtrate was concentrated. The residue was dissolved in CH2Ch, washed with brine, dried over , 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(3,4,5-trichlorophenyl)butenyl)phenyl)methanamine (CI7) The title compound was isolated and used without further purification.
Prophetically, compounds CI8-CI9 (Table 1) could be made in ance with the procedures disclosed in Example 44.
Example 45: Preparation of 4-(bromomethyl)chlorobenzonitrile (CilO) To a stirred solution of 3-chloromethylbenzonitrile (5 g, 25.4 mmol) in carbon tetrachloride (CC14 ; 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 isobutyronitrile (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 H20, and extracted with CH2Cb.
The combined CH2Ch layer was washed with brine, dried over Na2S04, and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (Si02, 100-200 mesh; 5% EtOAc xane) to afford the title compound as a white solid (4.8 g, 68%): mp 87-88 oc; 1H NMR (400 MHz, CDCb) o7.71 (s, 1H), 7.59 ( s, 2H ), 4.60 (s, 2H); ESIMS m/z 229.77 ([M+Ht); IR (thin film) 2235, 752, 621 cm-1.
The following compounds were made in accordance with the procedures disclosed in Example 45. 4-(Bromomethyl)(trifluoromethyl)benzonitrile (CI11) wo 2012/177813 ~CF3 The title compound was isolated as an off-white gummy al (5 g, 66%): 1H NMR (400 MHz, CDCb) o7.96 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 4.62 (s, 2H); ESlMS m!z 262.11 ([M-HD; lR (thin film) 2236, 1132, 617 cm-1. 3-Bromo(bromomethyl)benzonitrile (CI12) The title compound was isolated as an off-white solid(5 g, 67%): mp 82-83 oc; 1H NMR (400 MHz, CDCb) o7.90 (s, 1H), 7.61 (m, 2H ), 4.62 (s, 2H); ElMS m/z 272.90; lR (thin film) 2229, 618 cm-1. 4-(Bromomethyl)fluorobenzonitrile (CI13) The title nd was isolated as an off-white solid (2 g, 60%): mp 79-81 oc; 1H NMR (400 MHz, CDCb) o7.54 (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); ElMS m/z 215.
Example 46: Preparation of 4-(bromomethyl)chlorobenzaldehyde (CI14)octCI To a stirred solution of 4-(bromomethyl)chlorobenzonitrile (4.8 g, 17 mmol) in toluene (50 mL) at 0 oc was added se diisobutylaluminum hydride (DIBAL-H, 1.0 M solution in toluene; 23.9 mL), and the reaction mixture was stirred at 0 oc for 1 h. 10M HCl in H20 (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 CHCb. The combined organic layer was dried over Na2S04 and trated under reduced pressure. The crude compound was purified by flash column wo 2012/177813 chromatography (Si02, 100-200 mesh; 5% EtOAc inn-Hexane) to afford the title nd as a white solid (3.8 g, 80%): mp 64-66 oc; 1H NMR (400 MHz, CDCb) o10.00 (s, lH), 7.92 (s, lH), 7.78 (d, J = 8.0 Hz, lH), 7.64 (d, J = 8.0 Hz, lH), 4.60 (s, 2H); ESlMS m/z 232.78 ([M+Ht).
The following compounds were made in ance with the procedures disclosed in Example 46. 4-(Bromomethyl)(trifluoromethyl)benzaldehyde (CllS) h_CF ~Br1 The title compound was isolated as a pale yellow low-melting solid (5 g, 60%): 1H NMR (400 MHz, CDCb) o10.09 (s, 1H), 8.19 (s, 1H), 8.09 (m, 1H), 7.81 (m, 1H), 4.61 (s, 2H); ESlMS m!z 265.04 ([M-HD; lR (thin film) 1709, 1126, 649 cm-1. 3-Bromo(bromomethyl)benzaldehyde (CI16) h_Br The title compound was isolated as a pale yellow solid (5 g, 62%): mp 94-95 oc; 1H NMR (400 MHz, CDCb) o9.96 (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); ElMS m/z 275.90. 4-(Bromomethyl)fluorobenzaldehyde (CI17) oh_F The title compound was isolated as an off-white solid (5 g, 61%): mp 43-45 oc; 1H NMR (400 MHz, CDCb) o9.1 (s, 1H), 7.54 (t, J =8Hz, 1H), 7.48 (d, J =8Hz, 1H), 7.38 (d, J = 5 Hz, 1H ), 4.5 (s, 2H); ElMS m/z 216.
Example 47: Preparation of 3-chloro((1,3-dioxoisoindolinyl)methyl)benzaldehyde (CI18) wo 2012/177813 2012/043418 0~c1 ~ovo To a stirred solution of 4-(bromomethyl)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 H20 (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 oc; 1H NMR (400 MHz, CDCb) o9.95 (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-HD.
The following compounds were made in accordance with the ures disclosed in Example 47. 4-((1,3-Dioxoisoindolinyl)(trifluoromethyl)benzaldehyde (CI19) O~CF3 ~ovo The title compound was isolated as an off white solid (1 g, 62%): mp 142-143 oc; 1H NMR (400 MHz, CDCb) o10.05 (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-HD. 3-Bromo((1,3-dioxoisoindolinyl)methyl)benzaldehyde (CI20) o~'ovo The title nd was isolated as an off-white solid (0.5 g, 64%): mp 159-161 oc; 1H NMR (400 MHz, CDCb) o9.95 (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-CHOD. 4-((1,3-Dioxoisoindolinyl)fluorobenzaldehyde (CI21) wo 2012/177813 The title compound was isolated as a white solid (2 g, 60%): mp 154-156 oc; 1H NMR (400 MHz, CDCb) o9.95 (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); ElMS m/z 283.1.
Example 48: Preparation of 2-(2-chlorovinylbenzyl)isoindoline-1,3-dione (CI22) ~avo To a stirred solution of 3-chloro((1,3-dioxoisoindolinyl)methyl)benzaldehyde (2.8 g, 8.2 mmol) in 1,4-dioxane (30 mL) were added K2C03 (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 oc for 18 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the ed filtrate was concentrated under reduced pressure. The residue was purified by flash tography (Si02, 100-200 mesh; 20% EtOAc inn-Hexane) to afford the title compound as a white solid (1.94 g, 70%): mp 141-143 oc; 1H NMR (400 MHz, CDCb) o 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), .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-Hr The following nds were made in accordance with the ures disclosed in Example 48. 2-(2-(Trifluoromethyl)vinylbenzyl)isoindoline-1,3-dione (CI23) wo 2012/177813 The title compound was isolated as a light brown solid (0.5 g, 60%): mp 134-135 oc; 1H NMR (400 MHz, CDCb) o7.92 (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); ESlMS m/z 332.10 ([M+Ht). 2-(2-Bromovinylbenzyl)isoindoline-1,3-dione (CI24) ~rovo The title nd was isolated as a off white solid (0.5 g, 62%): mp 126-128 oc; 1H NMR (400 MHz, CDCb) o7.92 (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); ElMS m/z . 2-(2-Fluorovinylbenzyl)isoindoline-1,3-dione (CI25) ~ovo The title compound was isolated as a white solid (0.5 g, 61 %): mp 140-142 oc; 1H NMR (400 MHz, CDCb) o7.85 (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); ElMS m/z 282.08.
Example 49: Preparation of (E)(2-chloro(3-(3,5-dichlorophenyl)-4,4,4- trifluorobutenyl)benzyl)isoindoline-1,3-dione (CI26) Cl # Cl ovo To a stirred solution of 2-(2-chlorovinylbenzyl)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- wo 2012/177813 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 ed with argon for 30 min and then was d at 180 oc for 24 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and ed, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (Si02, 100-200 mesh; 25-30% EtOAc inn-hexane) to afford the title compound as solid (1.3 g, 50%): mp 141-143 oc; 1H NMR (400 MHz, CDCb) o7.92 (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+Ht).
The following compounds were made in accordance with the procedures disclosed in Example 49.
(E)(2-Chloro(4,4,4-trifluoro(3,4,5-trichlorophenyl)buten yl)benzyl)isoindoline-1,3-dione (CI27) Cl ovo The title compound was isolated as a pale white solid (0.2 g, 55%): mp 128-129 oc; 1H NMR (400 MHz, CDCb) o7.92 (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+Ht).
(E)(2-Chloro(3-(3,5-dichlorofluorophenyl)-4,4,4-trifluorobuten yl)benzyl)isoindoline-1,3-dione (CI28) The title compound was ed as a off white solid (0.2 g, 54%): mp 177-180 oc; 1H NMR (400 MHz, CDCb) o7.90 (m, 2H), 7.77 (m, 2H), 7.42 (s, 1H), 7.32 (d, J = 8.0 Hz, 2H), wo 2012/177813 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-HD; IR (thin film) 1716 cm-1.
(E)(2-Chloro(3-(3,4-dichlorophenyl)-4,4,4-trifluorobuten yl)benzyl)isoindoline-1,3-dione (CI29) Cl ovo u The title compound was isolated as an off-white solid (0.2 g, 59%): 1H NMR (400 MHz, CDCb) o7.89 (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- HD; IR (thin film) 3064, 1717, 1111,715 cm-1.
(E)(4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobutenyl)(trifluoromethyl)- benzyl)isoindoline-1,3-dione (CI30) Cl ovo The title compound was ed as an off-white solid (0.2 g, 54%): mp 141-142 oc; 1H NMR (400 MHz, CDCb) 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), .10 (s, 2H), 4.11 (m, 1H); ESIMS m/z 556.00 ([M-HD.
(E)(4-(4,4,4-Trifluoro(3,4,5-trichlorophenyl)butenyl)(trifluoromethyl)- benzyl)isoindoline-1,3-dione (CI31) wo 2012/177813 Cl ovo The title compound was isolated as an off-white solid (0.2 g, 56%): mp 130-132 °C; 1H NMR (400 MHz, CDCb) o7.94 (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-2HD.
(E)(2-Bromo(4,4,4-trifluoro(3,4,5-trichlorophenyl)butenyl)benzyl)- isoindoline-1,3-dione (CI32) Cl ovo The title compound was isolated as a pale yellow solid (0.2 g, 55%): mp 160-162 oc; 1H NMR (400 MHz, CDCb) o7.92 (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-HD. (2-Fluoro(4,4,4-trifluoro(3,4,5-trichlorophenyl)butenyl)benzyl)- isoindoline-1,3-dione (CI33) Cl ovo u The title compound was isolated as an off-white solid (0.2 g, 55%): mp 72-74 oc; 1H NMR (400 MHz, CDCb) o7.88 (m, 2H), 7.74 (m, 2H), 7.38 (s, 2H), 7.34 (m, 1H), 7.18 (m, wo 2012/177813 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 ; IR (thin film)1773 cm-1.
Prophetically, compounds CI34-CI41 (Table 1) could be made in accordance with the procedures disclosed in e 49.
Example 50: Preparation of (E)-(2-chloro(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut- 1-enyl)phenyl)methanamine (CI42) To a stirred solution of (E)(2-chloro(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut- 1-enyl)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 oc for 2 h.
The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2Ch, washed with brine, dried over Na2S04, and trated 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 ures disclosed in Example 50.
(E)-(2-Chloro(4,4,4-trifluoro(3,4,5-trichlorophenyl)butenyl)phenyl)- methanamine (CI43) The t obtained in this on was carried on to the next step without further purification.
(E)-(2-Chloro(3-(3,4-dichlorophenyl)-4,4,4-trifluorobutenyl)phenyl)- methanamine (CI44) The product obtained in this reaction was carried on to the next step without further purification.: 1H NMR (400 MHz, CDCb) o7.48 (d, J = 8.4 Hz, 2H), 7.39 (m, 2H), 7.23 (m, wo 2012/177813 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-HD; IR (thin film) 3370, 3280, 1111, 817 cm-1.
(E)-(4-(4,4,4-Trifluoro(3,4,5-trichlorophenyl)butenyl)(trifluoromethyl)- phenyl)methanamine (CI45) Cl 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(3-(3,5-dichlorophenyl)-4,4,4-trifluorobutenyl)phenyl)- methanamine (CI46) Cl The title compound was isolated as a gummy material: The product obtained in this reaction was d on to the next step without further purification.
(E)-(2-Bromo(4,4,4-trifluoro(3,4,5-trichlorophenyl)butenyl)phenyl)- methanamine (CI47) Cl The title compound was isolated as a gummy al. The product obtained in this reaction was carried on to the next step without further purification.
-Fluoro(4,4,4-trifluoro(3,4,5-trichlorophenyl)butenyl)phenyl)- methanamine (CI48) Cl The title compound was ed as a gummy material: 1H NMR (400 MHz, CDCb) o 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 = wo 77813 16.0, 7.6 Hz, 1H), 4.08 (m, 1H), 3.90 (s, 2H); ESIMS m/z 413.84 ); 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. e 51: Preparation of 3-chloro((pyridinylamino)methyl)benzaldehyde (CI58) 0~-..-::::ci I H .& N~ To a stirred solution of 4-(bromomethyl)chlorobenzaldehyde (2 g, 9 mmol) in N,N- ylacetamide (DMA; 20 mL) was added K2C03 (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 H20 and extracted with EtOAc.
The combined organic layer was washed with brine, dried over Na2S04, and concentrated under reduced pressure. The residue was purified by flash column chromatography (Si02, 100-200 mesh; 20% EtOAc inn-Hexane) to afford the title compound as off-white solid (1.05 g, 50%): mp 122-123 oc; 1H NMR (400 MHz, CDCb) o9.94 (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+Ht).
Example 52: Preparation of hlorovinylbenzyl)pyridinamine (CI59) To a stirred solution of 3-chloro((pyridinylamino)methyl)benzaldehyde (1 g, 4. mmol) in 1,4-dioxane (20 mL) were added K2C03 (0.84 g, 6.09 mmol) and methyl triphenyl phosphonium bromide (2.17 g, 6.09 mmol) at t temperature. Then the resultant reaction mixture was heated at 100 oc for 18 h. After the reaction was deemed complete by TLC, the on mixture was cooled to ambient temperature and filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (Si02, 0 mesh; 10% EtOAc inn-Hexane) to afford the title compound as a white solid (0.5 g, 50%): mp 119-121 oc; 1H NMR (400 MHz, CDCb) o8.12 (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+Ht). wo 2012/177813 Example 53: Preparation of ethyl 2-amino(5-bromochloropyridinyl)acetate (CI60) Br~CI I /. NH N 2 0 0~ Ethyl2-(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 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 t temperature. The e was extracted with EtOAc. The ed EtOAc layer was washed with brine, dried over anhydrous , 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, %): 1H NMR (400 MHz, CDCb) o8.52 (s, 1H), 7.89 (s, 1H ), 5.09 (s1H), 4.23 (m, 2H), 2.27 (br s, 2H), 1.26 (m, 3H); ESIMS m/z 293.05 ([M+Ht); IR (thin film) 3381, 3306, 1742, 759, 523 cm-1.
Example 54: Preparation of (5-bromochloropyridinyl)methanamine hydrochloride (CI61) BryyCl ~N~NH2 •HC1 A stirred solution of ethyl2-amino(5-bromochloropyridinyl)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 H20. The combined ether layer was concentrated under d pressure to afford the title compound as an off-white solid (400 mg, 65%): 1H NMR (400 MHz, CDCb) o8.78 (s, 1H), 8.70 (br s, 2H), 8.45 (s, 1H), 4.56 (m, 2H); ESIMS m/z 221.15 ([M+Ht).
Example 55: Preparation of 2-((5-bromochloropyridinyl)methyl)isoindoline-1,3- dione (CI62) Br~Cl Iovo"' wo 2012/177813 To a stirred solution of (5-bromochloropyridinyl)methanamine hydrochloride (0.3 g, 1.4 mmol) in toluene (40 mL) was added Et3N (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 e was diluted with H20 and extracted with EtOAc . The combined EtOAc layer was washed with brine, dried over anhydrous , and concentrated under reduced pressure. The residue was purified by column tography (20-30% EtOAc in hexane) to afford the title compound as a white solid (0.25 g, 65%): 1H NMR (400 MHz, CDCh) o8.78 (s, lH), 8.45 (s, lH), 7.88 (m, 2H), 7.74 ( m, 2H), 4.56 (m, 2H); ESIMS m/z 349 ([M-HD; IR (thin film) 3307, 1665, 1114, 813 cm-1.
Example 56: Preparation of 2-((3-chlorovinylpyridinyl)methyl)isoindoline-1,3- dione (CI63) ~Iovo To a stirred solution of 2-((5-bromochloropyridinyl)methyl)isoindoline-1,3- diane (0.23 g, 0.65 mmol) in toluene (10 mL) were added Pd(PPh3)4 (3.7 mg, 0.003 mmol), K 2C03 (0.269 g, 1.95 mmol) and vinyl boronic anhydride pyridine x (0.78 g, 3.28 mmol), and the reaction mixture was heated at reflux for 16 h. The on mixture was filtered, and the filtrate was washed with H20 and brine, dried over anhydrous Na2S04, 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, CDCh) o8.30 (s, 1H), 7.91 (m, 2H), 7.77 (m, 3H), 7.72 (m, 1H), 6.63 (m, 1H), .79 (d, J = 16.0 Hz, 1H), 5.39 (d, J = 16.0 Hz, 1H), 5.12 (s, 2H); ESIMS m/z 299.20 Example 57: Preparation of (E)((3-chloro(4,4,4-trifluoro(3,4,5-trichloro- phenyl)butenyl)pyridinyl)methyl)isoindoline-1,3-dione (CI64) wo 2012/177813 Cl ~ Cl I ~ Cl ovoN To a stirred solution of 2-((3-chlorovinylpyridinyl)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 on mixture was heated at 180 oc for 16 h. The on e was concentrated under reduced pressure and purified by column chromatography % EtOAc in hexane) to afford the title compound as a liquid (0.4 g, 50%): mp 79-82 oc; 1H NMR (400 MHz, CDCb) o8.27 (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+Ht).
Example 58: Preparation of (E)-(3-chloro(4,4,4-trifluoro(3,4,5- trichlorophenyl)butenyl)pyridinyl)methanamine (CI65) Cl ~ Cl To a stirred solution of (E)((3-chloro(4,4,4-trifluoro(3,4,5- trichlorophenyl)butenyl)pyridinyl)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 CH2Cb. The organic layer was washed with H20 and brine, dried over anhydrous Na2S04, 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 cation.
Example 59: Preparation of 4-(bromomethyl)naphthonitrile (CI66) wo 77813 To a stirred solution of 4-methylnaphthonitrile (5 g, 30 mmol) in CC14 (50 mL) under argon atmosphere was added NBS (6.06 g, 34.09 mmol), and the on 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 t temperature, diluted with H20 and extracted with CH2Ch (3 x 100 mL). The combined CH2Ch layer was washed with brine, dried over Na2S04, and concentrated under reduced pressure. The residue was purified by flash column chromatography (Si02, 0 mesh; 5% EtOAc xane) to afford the title compound as a white solid (3.8 g, 52%): mp 131-133 oc; 1H NMR (400 MHz, CDCb) o8.33 (m, lH), 8.24 (m, lH), 7.88 (d, J = 8.0 Hz, lH), 7.78 (m, 2H), 7.62 (d, J = 8.0 Hz, lH), 4.95 (s, 2H); ESIMS m/z 245.92 ([M+Ht); IR (thin film) 2217 cm-1.
Example 60: Preparation of 4-(bromomethyl)naphthaldehyde (CI67) To a stirred solution of 4-(bromomethyl)naphthonitrile (8 g, 33mmol) in toluene (100 mL) at 0 oc was added dropwise DIBAL-H (1.0 M solution in toluene; 43 mL), and the reaction mixture was stirred at 0 oc for 1 h. 3 N HCl in H20 (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 x100 mL).
The combined organic layer was dried over Na2S04 and concentrated under reduced pressure.
Purification by flash column chromatography (Si02, 100-200 mesh; 5% EtOAc in petroleum ether) afforded the title compound as a white solid (7 g, 88%): mp 115-116 oc; 1H NMR (400 MHz, CDCb) o10.41 (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+Ht).
Example 61: Preparation of 4-((1,3-dioxoisoindolinyl)methyl)naphthaldehyde (CI68) ~0 wo 2012/177813 To a stirred solution of momethyl)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 oc for 2 h. The reaction mixture was cooled to ambient temperature and diluted with H20 (100 mL). The obtained solid was ted by filtration and dried under vacuum to afford the title compound as a white solid (8.8 g, 98%): mp 190-192 oc; 1H NMR (400 MHz, CDCb) o10.39 (s, lH), 9.25 (m, lH), 8.41 (m, lH), 8.10 (d, J = 8.0 Hz, lH), 7.95 (m, 4H), 7.80 (m, 4H), 7.61 (m, 4H), 5.39 (s, 2H); ESIMS mlz 316.09 ([M+Ht); IR (thin film) 1708 em.-1 Example 62: Preparation of 2-((4-vinylnaphthalenyl)methyl) isoindoline-1,3-dione (CI69) To a stirred solution of 4-((1,3-dioxoisoindolinyl)methyl)naphthaldehyde (9 g, 28.5 mmol) in 1,4-dioxane (100 mL) were added K2C03 (6 g, 42.8 mmol) and methyl triphenyl phosphonium bromide (15.3 g, 35.7 mmol) at ambient temperature. The on mixture was heated at 100 oc for 14 hand then was cooled to ambient temperature. The reaction mixture was filtered, and the obtained filtrate was concentrated under reduced pressure. Purification by flash chromatography (Si02, 100-200 mesh; 20% EtOAc in petroleum ether) afforded the title nd as a white solid (6 g, 67%): mp 146-147 oc; 1H NMR (400 MHz, CDCb) o8.35 (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+Ht).
Example 63: ation of (E)((4-(4,4,4-trifluoro(3,4,5-trichlorophenyl)buten- 1-yl)naphthalenyl)methyl)isoindoline-1,3-dione (CI70) To a stirred solution of 2-((4-vinylnaphthalenyl)methyl)isoindoline-1,3-dione (1.5 g, 4.79 mmol) in chlorobenzene (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 wo 2012/177813 g, 0.95 mmol), and the resultant reaction mixture was degassed with argon for 30 min and then stirred at 180 oc for 14 h. After the reaction was deemed te by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (Si02, 100-200 mesh; 25-30% EtOAc in petroleum ether) afforded the title compound as an ite solid (1.5 g, 56%): mp 158-160 oc; 1H NMR (400 MHz, CDCb) o8.40 (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-HD.
Example 64: Preparation of (E)-(4-(4,4,4-trifluoro(3,4,5-trichlorophenyl)buten yl)naphthalenyl)methanamine (CI71) To a stirred solution of (E)((4-(4,4,4-trifluoro(3,4,5-trichlorophenyl)buten yl)naphthalenyl)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 e was heated at 80 oc for 2 h. The reaction mixture was ed, and the filtrate was concentrated. The residue was dissolved in CH2Ch, and the solution was washed with brine, dried over Na2S04, and concentrated under reduced pressure. The title compound was isolated as a gummy liquid (150 mg, 50%). The t 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) 0~0u 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 d at 130 oc for 1 h under a nitrogen here. The reaction mixture was quenched with satd aq. NaHC03 solution and filtered to give a solid. cation by column chromatography (Si02, 0-10% EtOAc in petroleum ether) afforded the title compound as a solid (60 mg, 84%): mp 205-206 oc; 1H NMR (400 MHz, CDCb) o8.71 (s, wo 2012/177813 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-HD.
Example 66: Preparation of 2-((4-vinylphenyl)amino)isoindoline-1,3-dione (CI73) To a solution of 2-(4-bromophenylamino)isoindoline-1,3-dione (2 g, 6. mmol) in 1,2- dimethoxyethane (20 mL) and H20 (4 mL) were added vinyl c anhydride pyridine complex (4.57 g, 18.98 mmol) and K2C03 (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 oc in a microwave for 30 min and then was concentrated under reduced pressure. Purification by column chromatography (Si02, 15% EtOAc in petroleum ether) afforded the title compound as a solid (200 mg, 13%): mp 174-176 oc; 1H NMR (400 MHz, CDCb) o8.65 (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 .
Example 67: Preparation of (E)((4-(4,4,4-trifluoro(3,4,5-trichlorophenyl)buten- 1-yl)phenyl)amino)isoindoline-1,3-dione (CI74) 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 ed with argon for 30 min and was heated at 180 oc for 2 h. The reaction mixture was then concentrated under reduced re, and the residue was purified by column chromatography (Si02, 0-30% EtOAc in petroleum ether) to afford the title compound as a solid (450 mg, 75%): mp 187-189 oc; 1H NMR (400 MHz, CDCb) o 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-HD. e 68: Preparation of (E)-(4-(4,4,4-trifluoro(3,4,5-trichlorophenyl)buten yl)phenyl)hydrazine (CI75) wo 2012/177813 ... NH 2 Cl N Cl H To a stirred solution of (E)(4-(4,4,4-trifluoro(3,4,5-trichlorophenyl)but 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 oc for 1 h.
The reaction mixture was cooled to ambient ature and ed, and the filtrate was trated 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) 0~0u 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 on mixture was stirred at t temperature for 48 h. The reaction mixture was diluted with H20 and extracted with CHCb. The combined CHCb layer was washed with brine, dried over Na2S04 and concentrated under reduced pressure. Purification by flash column chromatography (Si02; 20% EtOAc in petroleum ether) afforded the title compound as a white solid (2 g, 63%): mp 129-131 oc; 1H NMR (400 MHz, CDCb) o7.93 (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+Ht).
Example 70: Preparation of (E)(4-(4,4,4-trifluoro(3,4,5-trichlorophenyl)buten- 1-yl)phenoxy)isoindoline-1,3-dione (CI77) Cl ......::; To a stirred solution of2-(4-vinylphenoxy)isoindoline-1,3-dione (0.3g, 1.1 mmol) in 1,2-dichlorobenzene (10 mL) was added 1-(1-bromoethyl)-3,4,5-trichlorobenzene (769 mg, wo 2012/177813 2.26 mmol), CuCl (22 mg, ol) 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 oc for 24 h.
The reaction mixture was cooled to ambient temperature and ed, and the filtrate was concentrated under reduced pressure. The crude material was ed by column chromatography (Si02, 100-200 mesh; 20% EtOAc in petroleum ether) to afford the title compound as a solid (0.29 g, 50%): 1H NMR (400 MHz, CDCb) o7.90 (m, lH), 7.62 (m, 2H), 7.50 (m, lH), 7.40 (s, 2H), 7.12 (s, lH), 6.90 (m, 2H), 6.60 (m, 2H), 6.20 (m,lH), 4.08 (m, lH); ESIMS m/z 524.09 . e 71: ation of (4-(4,4,4-trifluoro(3,4,5-trichlorophenyl)buten- 1-yl)phenyl)hydroxylamine (CI78) Cl o'· To a stirred solution of (E)(4-(4,4,4-trifluoro(3,4,5-trichlorophenyl)but 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 oc for 1 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2Cb. washed with brine, dried over Na2S04 and concentrated under reduced pressure to afford the crude title compound as a gummy liquid (0.08 g, 53%): 1H NMR (400 MHz, CDCb) o7.40 (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-HD.
Example 72: Preparation of (E)-N-(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut enyl)benzyl)acetamide (CC1) To a stirred solution of (E)-(2-chloro(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut enyl)phenyl)methanamine (0.3 g, 0.8 mmol) in DCM (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 H20 and extracted with DCM. The combined DCM layer was washed with brine, dried over Na2S04, and concentrated under reduced pressure. Purification by flash column chromatography wo 2012/177813 (Si02, 100-200 mesh; 30-50% ethyl acetate in hexane) afforded the title compound as a offwhite solid (0.2 g, 60%) mp 107-109 oc; 1H NMR (400 MHz, CDCb) o7.37 (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 =6Hz, 2H), 4.01 (m, 1H), 2.11 (s, 3H); ESIMS m/z 402.00 ([M+Ht).
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 ures disclosed in Example 72.
Example 73: Preparation of (E)-N-(2-chloro(3-(3,5-dichlorophenyl)-4,4,4- trifluorobutenyl)benzyl)acetamide (CC7) Cl ~ Cl Cl 0 To a stirred solution of (E)-(2-chloro(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut enyl)phenyl)methanamine (0.3 g, 0.8 mmol) in DMF (5 mL) was added trifluoropropanoic acid (97 mg, 0.76 mmol), HOBt•H20 (174 mg, 1.14 mmol) and EDC•HCl (217 mg, 1.14 mmol) and DIEA (196 mg, 1.52 mmol), and the resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction e was diluted with H20 and extracted with EtOAc. The combined EtOAc layer was washed with brine, dried over Na2S04, and trated under reduced pressure. Purification by flash column chromatography (Si02, 100-200 mesh; ethyl acetate in hexane (30-50% afforded the title nd as a off-white solid (0.2 g, 60%): mp 127-128 oc; 1H NMR (400 MHz, CDCb) o 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+Ht).
Compounds CC8 - CC28 in Table 1 were made in accordance with the procedures disclosed in e 73.
Example 74: Preparation of (E)-N-(pyridinylmethyl)-N-(4-(4,4,4-trifluoro(3,4,5- trichlorophenyl)butenyl)(trifluoromethyl)benzyl)cyclopropanecarboxamide (CC29) wo 2012/177813 Step 1: (E)(Pyridinyl)-N-(4-(4,4,4-trifluoro(3,4,5-trichlorophenyl)but enyl)(trifluoromethyl)benzyl)methanamine. (E)-(4-(4,4,4-Trifluoro(3,4,5- trichlorophenyl)butenyl)(trifluoromethyl)phenyl)methanamine (0.46 g, 1 mmol) was dissolved in CH30H (3 mL). To this was added pyridinecarbaldehyde (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 (Si02, 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, CDCb) 8 8.58 (d, 1= 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+Ht); IR (thin film) 3338, 1114, 808 cm-1.
Step 2: (E)-N-(Pyridinylmethyl)-N-(4-(4,4,4-trifluoro(3,4,5- orophenyl)butenyl)(trifluoromethyl)benzyl)cyclopropanecarboxamide. (E)- 1-(Pyridinyl)-N-(4-(4,4,4-trifluoro(3,4,5-trichlorophenyl)butenyl) (trifluoromethyl)benzyl)methanamine (0.27 g, 0.05 mmol) was taken up in CH2Ch (3 mL).
To this was added Et3N (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 ropylcarbonyl chloride (0.08 mL, 0.075 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hand then was washed with H20 and satd aq NaHC03 solution. The organic layer was dried over anhydrous Na2S04 and evaporated to obtain pale yellow gummy al (0.15 g, 50%): 1H NMR (400 MHz, CDCb) 8 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 =10Hz, 2H), 4.10 (m, 1H), 1.8 (m, 1H), 1.2 (m, 2H), 0.6 (m, 2H); ESIMS m/z 620.86 ([M-HD; IR (thin film) 1645, 1115, 808 cm-1. e 75: Preparation of (2-chloro(4,4,4-trifluoro(3,4,5- trichlorophenyl)butenyl)benzyl)(methylsulfonyl)propanamide (CC30) wo 2012/177813 2012/043418 Cl Cl O H II Cl N~s, II II Cl 0 0 (E)-N-(2-Chloro(4,4,4-trifluoro(3,4,5-trichlorophenyl)butenyl)benzyl) (methylthio)propanamide (0.15 g, 0.28 mmol) was treated with axone (0.175 g, 0.569 mmol) in 1:1 acetone:water (20mL) for 4 h at ambient temperature. The acetone was evaporated to obtain a white solid (0.095 g, 60%): mp 101-104 oc; 1H NMR (400 MHz, CDCb) o7.41 (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-HD.
Example 76: Preparation of (2-chloro(3-(3,5-dichlorophenyl)-4,4,4- trifluorobutenyl)benzyl)ethylurea (CC31) To a stirred solution of (E)-(2-chloro(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut enyl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cb (5 mL) at 0 oc were added Et3N (0.141 mL, 1 mmol) and ethylisocyanate (0.053 g, 0.75 mmol), and the on mixture was stirred for 1 h at 0 °C. The reaction mixture was diluted with CH2Cb. The organic layer was washed with H20 and brine, dried over Na2S04, and concentrated under reduced pressure.
Purification by column chromatography (Si02, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.141 g, 60%): mp 177-178 oc; 1H NMR (400 MHz, CDCb) o7.58 (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-HD.
Compounds CC32 - CC35 in Table 1 were made in accordance with the procedures disclosed in Example 76.
Example 77: Preparation of (2-chloro(4,4,4-trifluoro(3,4,5- trichlorophenyl)butenyl)benzyl)-1,1-dimethylurea (CC36) wo 2012/177813 To a d solution of (E)-(2-chloro(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut- 1-enyl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Ch (5 mL) at 0 oc were added Et3N (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 oc. The reaction mixture was diluted with CH2Cb.
The organic layer was washed with H20 and brine, dried over Na2S04, and concentrated under reduced pressure. cation by column chromatography (Si02, 100-200 mesh; 30- 50% EtOAc in hexane) afforded the title compound as a solid (0.15 g, 60%): 1H NMR (400 MHz, CDCb) o7.39 (m, 4H), 7.28 (m, lH), 6.54 (d, J = 16.0 Hz, lH), 6.34 (dd, J = 16.0, 8.0 Hz, lH), 4.97 (br s, lH), 4.38 (d, J = 6.0 Hz, 2H), 4.10 (m, lH), 2.9 (s, 3H), 2.7 (s, 3H); ESIMS m/z 497 ([M-HD; IR (thin film) 3350, 1705, 1114, 808 cm-1.
Example 78: Preparation of (E)(2-chloro(4,4,4-trifluoro(3,4,5- trichlorophenyl)butenyl)benzyl)ethylthiourea (CC37) To a stirred solution of (E)-(2-chloro(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobutyl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cb (5 mL) at 0 oc were added Et3N (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 CH2Cb. The organic layer was washed with H20 and brine, dried over Na2S04, and concentrated under reduced pressure. cation by column chromatography (Si02, 0 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.14 g, 60%): mp 88-91 oc; 1H NMR (400 MHz, CDCb) o7.49 (d, J =8Hz, 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+Ht).
Compound CC38 in Table 1 was made in ance with the procedures disclosed in Example 78.
Example 79: Preparation of (E)-tert-butyl (2-chloro(3-(3,5-dichlorophenyl)-4,4,4- trifluorobutenyl)benzyl)ethylurea (CC39) wo 2012/177813 To a stirred solution of (E)-(2-chloro(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut- 1-enyl)phenyl)methanamine (0.2 g, 0.5 mmol in CH2Ch (5 mL) at 0 oc were added Et3N (0.141 mL, 1 mmol) and di-tert-butyl dicarbonate (0.163 mL, 0.75 mmol), and the on mixture was d for 4 h at ambient temperature. The reaction mixture was diluted with CH2Cb. The organic layer was washed with H20 and brine, dried over Na2S04, and concentrated under reduced pressure. Purification by column chromatography (Si02, 100-200 mesh; 10-20% EtOAc in hexane) afforded the title compound as a white solid (0.147 g, 60%): 1H NMR (400 MHz, CDCb) o7.39 (m, 4H), 7.28 (m, lH), 6.54 (d, J = 16.0 Hz, lH), 6.34 (dd, J = 16.0, 8.0 Hz, lH), 4.97 (br s, lH), 4.38 (d, J = 6.0 Hz, 2H), 4.10 (m, lH), 1.53 (s, 9H); ESIMS m/z 526.09 ([M-HD; 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)-methyl2-((2-chloro(4,4,4-trifluoro(3,4,5- trichlorophenyl)butenyl)benzyl)amino)oxoacetate (CC41) Cl To a d solution of (E)-(2-chloro(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut- 1-enyl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Ch (5 mL) at 0 oc were added Et3N (0.141 mL, 1 mmol) and methyl2-chlorooxoacetate (0.09 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0 oc. The reaction mixture was d with CH2Cb. The organic layer was washed with H20 and brine, dried over , and concentrated under reduced pressure. Purification by column chromatography (Si02, 100-200 mesh; 20% EtOAc in hexane) ed the title compound as a solid (0.12 g, 50%): 1H NMR (400 MHz, CDCb) o7.48 (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-HD; IR (thin film) 1740, 1701, 1114,808 cm-1.
Example 81: Preparation of (E)-N1-(2-chloro(4,4,4-trifluoro(3,4,5- trichlorophenyl)butenyl)benzyl)-N2-(2,2,2-trifluoroethyl)oxalamide (CC42) wo 2012/177813 To a stirred solution of 2,2,2-trifluoroethylamine hydrochloride (0.1 g, 0.77 mmol) in CH2Ch (10 mL) was added dropwise trimethylaluminum (2M solution in e; 0.39 mL, 0.77 mmol), and the reaction mixture was stirred at 25 oc for 30 min. A solution of (E)- methyl 2-((2-chloro(4,4,4-trifluoro(3,4,5-trichlorophenyl)butenyl)benzyl) oxoacetate (0.2 g, 0.38 mmol) in CH2Ch (5 mL) was added dropwise to the reaction mixture at 25 oc. 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 x 50 mL). The combined organic extracts were washed with brine, dried over Na2S04, and concentrated under reduced pressure. The crude compound was ed by flash chromatography (Si02, 100-200 mesh; 20%-40% EtOAc inn-hexane) to afford the title compound (0.13 g, 60%): mp 161-163 oc; 1H NMR (400 MHz, DMSO-d6) o9.45 (br s, 2H), 7.90 (s, 2H), 7.75 (s, lH), 7.46 (s, lH), 7.28 (s, lH), 6.93 (m, lH), 6.75 (m, lH), 4.80 (m, lH), 4.40 (s, 2H), 3.90 (s, 2H); ESIMS m/z 578.96 ([M-HD.
Example 82: Preparation of (E)-N-(2-chloro(4,4,4-trifluoro(3,4,5- trichlorophenyl)butenyl)benzyl)pyridinamine (CC43) Cl Cl Cl N~ Cl N~ To a stirred solution of hlorovinylbenzyl)pyridinamine (0.3 g, 1.22 mmol) in 1,2-dichlorobenzene (5 mL) were added 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3- orobenzene (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 d at 180 oc 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 (Si02, 0 mesh; 15% EtOAc inn-hexane) afforded the title compound as an off-white solid (0.2 g, 35%): mp 140- 142 oc; 1H NMR (400 MHz, CDCb) o8.11 (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+Ht).
Example 83: ation of ((3-chloro(4,4,4-trifluoro(3,4,5- trichlorophenyl)-butenyl)pyridinyl)methyl)-3,3,3-trifluoropropanamide (CC44) wo 2012/177813 Cl Cl Cl 3 Cl 0 To a stirred solution of (E)-(3-chloro(4,4,4-trifluoro(3,4,5-trichlorophenyl)but- -yl)pyridinyl)methanamine (0.1 g, 0.2 mmol) in CH2Ch (5 mL) were added 3,3,3- trifluoropropanoic acid (45 mg, 0.350 mmol), EDC•HCl (67 mg, 0.350 mmol), HOBt•H20 (71 mg, 0.467 mmol) and DIEA (60.2 mg, 0.467 mmol), and the reaction mixture was stirred at ambient temperature for 18 h. The on e was diluted with CH2Ch and washed with H20. The combined CH2Ch layer was washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure. Purification by flash column chromatography (Si02, 100-200 mesh; 15% EtOAc in petroleum ether) afforded the title compound as a pale yellow liquid (30 mg, 35%): 1H NMR (400 MHz, CDCb) o8.41 (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-HD; 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(3,4,5- trichlorophenyl)butenyl)naphthalenyl)methyl)propanamide (CC46) Cl N!T'CF3 To a stirred solution of (E)-(4-(4,4,4-trifluoro(3,4,5-trichlorophenyl)buten yl)naphthalenyl)methanamine (0.1 g, 0.22 mmol) in CH2Ch (8 mL) were added 3,3,3- trifluoropropanoic acid (0.032 g, 0.24 mmol), 20 (52 mg, 0.33 mmol), l (0.065 g, 0.33 mmol) and DIEA (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 H20 and extracted with EtOAc (3 x30 mL). The combined EtOAc layer was washed with brine, dried over Na2S04, and trated under reduced pressure. Purification by flash column chromatography (Si02, 100-200 mesh; 15% EtOAc inn-hexane) afforded the title compound as a gummy material (60 mg, 50%): mp 151-153 oc; 1H NMR (400 MHz, CDCb) o8.06 (m, wo 2012/177813 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-HD.
Compounds CC47- CC48 in Table 1 were made in accordance with the procedures disclosed in Example 84.
Example 85: Preparation of (E)ethyl((4-(4,4,4-trifluoro(3,4,5- trichlorophenyl)butenyl)naphthalenyl)methyl)urea (CC49) To a d on of (E)-(4-(4,4,4-trifluoro(3,4,5-trichlorophenyl)buten yl)naphthalenyl)methanamine (0.1 g, 0.22 mmol) in CH2Ch at 0 oc were added Et3N (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 on mixture was diluted with CH2Cb. The organic layer was washed with H20 and brine, dried over Na2S04, and trated under reduced pressure. Purification by column chromatography (Si02, 100-200 mesh; 30% EtOAc in hexane) afforded the title compound as a solid (0.07 g, 60%): mp 84-87 oc; 1H NMR (400 MHz, CDCb) o8.06 (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+Ht).
Example 86: Preparation of (E)-N'-(4-(4,4,4-trifluoro(3,4,5-trichlorophenyl)buten- 1-yl)phenyl)cyclopropanecarbohydrazide (CC50) To a stirred solution of (E)-(4-(4,4,4-trifluoro(3,4,5-trichlorophenyl)buten yl)phenyl)hydrazine (0.1 g, 0. 3 mmol) in CH2Ch (10 mL) was added DIEA (65 mg, 0.51 mmol), HOBt•H20 (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 d at ambient temperature for 1 h. The reaction e was diluted with satd aq NaHC03 solution and extracted with CH2Cb. The combined CH2Ch layer was washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure. Purification by flash column chromatography (Si02; 5-25% EtOAc in petroleum ether) afforded the title compound as a wo 2012/177813 solid (65 mg, 55%): mp 138-140 oc; 1H NMR (400 MHz, CDCb) o9.81 (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-HD.
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(3,4,5-trichlorophenyl)buten- 1-yl)phenoxy)cyclopropanecarboxamide (CC52) Cl .0 To a stirred solution of (E)(4-(4,4,4-trifluoro(3,4,5-trichlorophenyl)but- 1-enyl)phenyl)hydroxylamine (0.15 g, 0.38 mmol) in CH2Ch (5 mL) was added EDC•HCl (0.109 g, 0.569 mmol), HOBt•H20 (0.087 g, 0.569 mmol), DIEA (0.097 g, 0.758 mmol) and cyclopropanecarboxylic acid (0.049 g, 0.569 mmol). The resultant on mixture was stirred at ambient temperature for 18 h. The reaction mixture was d with H20 and extracted with CHCb (35 mL) The combined CHCb layer was washed with brine, dried over Na2S04 and concentrated under reduced pressure. Purification by flash column chromatography (Si02; 20% EtOAc in hexane) ed the title compound as a brown liquid (0.06 g, 34%): 1H NMR (400 MHz, CDCb) o7.40 (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-HD.
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(3,4,5- trichlorophenyl)butenyl)benzyl)propanamide (CC54) Cl A n borate vial was charged with (E)-3,3,3-trifluoro-N-(4-(4,4,4-trifluoro -trichlorophenyl)butenyl)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 wo 2012/177813 bank of eight 115 watt Sylvania FR48T12/350BL/VH0/180 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, CDCb) o7.28 (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, CDCb) o162.44, 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 , 43.59, 42.12 (q, J =30Hz); ESIMS m/z 504 ([M+Ht).
Compounds OC46, 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)chlorobenzene (012)cfoH CF3 __ The title compound was synthesized in two steps via 1-(3-chlorophenyl)-2,2,2- oroethanol (011, prepared as in Step 1, Method Bin Example 1); isolated as a colorless viscous oil (1.5 g, 75%): 1H NMR (400 MHz, CDCb) o7.50 (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, CDCb) o7.50 (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 (014) ~OH ------- 013 014 Trifluorophenylethanol (013) was isolated (10 g, 80%): 1H NMR (300 MHz, CDCb) o7.48 (m, 2H), 7.40 (m, 3H), 5.02 (m, 1H), 2.65 (d, J = 7.1 Hz, 1H). The title compound (014) was isolated as a liquid (8.0 g, 60%): 1H NMR (400 MHz, CDCb) o7.50 (m, 2H), 7.40 (m, 3H), 5.00 (q, J = 7.5 Hz, 1H). 1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-dimethylbenzene (0120) wo 2012/177813 1-(3,5-Dimethylphenyl)-2,2,2-trifluoroethanol (0119) was ed an off white solid: 1H NMR (400 MHz, CDCb) 8 7.05 (s, 2H), 7.02 (s, lH), 4.95 (m, lH), 2.32 (s, 6H); ESIMS m/z 204 ([MD. The title compound (0120) was isolated (3.0 g, 51%). 1-(1-Bromo-2,2,2-trifluoroethyl)-2,4-dichlorobenzene (0122) ~~H ____ ~~r CIAACI CIAACI 0121 0122 1-(2,4-Dichloropheny1)-2,2,2-trifluoroethanol (0121) was isolated as an off white powder (5.3 g, 61 %): mp 49-51 oc; 1H NMR (400 MHz, CDCb) 8 7.62-7.66 (d, lH), 7.42- 7.44 (d, lH), 7.32-7.36 (d, lH), 5.6 (m, lH), 2.7 (s, lH); ESIMS m/z 244 ([Mt). The title compound (0122) was isolated (3.2 g, 50%): 1H NMR (400 MHz, CDCb) 8 7.62-7.72 (m, lH), 7.4-7.42 (m, lH), 38 (m, lH), 5.7-5.8 (m, lH). 1-(1-Bromo-2,2,2-trifluoroethyl)-2,3-dichlorobenzene (0124) ~~H ____ ~~r 0123 Cl 0124 1-(2,3-Dichlorophenyl)-2,2,2-trifluoroethanol (0123) was isolated as a pale yellow oil (5.2 g, 60%): 1H NMR (400 MHz, CDCb) 8 7.62-7.64 (d, lH), 7.52-7.54 (m, lH), 7.29-7.33 (t, lH), 5.6-5.76 (m, lH), 2.7 (s, lH); ESIMS m/z 243.9 ([Mt). The title nd (0124) was isolated as an oil (8.7 g, 60%): 1H NMR (400 MHz, CDCb) 8 7.62-7.71 (m, lH), 7.44- 7.52 (m, lH), 7.27-7.3 (s, lH), 5.81-5.91 (m, lH). 2-(1-Bromo-2,2,2-trifluoroethyl)-1,4-dichlorobenzene (0126) rr:YOHCl CF3 __ cYBrCl CF3 0125 Cl 0126 wo 2012/177813 1-(2,5-Dichlorophenyl)-2,2,2-trifluoroethanol (0125) was isolated as a yellow oil (4.1 g, 60%): 1H NMR (400 MHz, CDCb) 8 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 ([Mt)). The title compound (0126) was ed (3.0 g, 60%): 1H NMR (400 MHz, CDCb) 8 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 (0128) 1-(3,5-Bis(trifluoromethy1)pheny1)-2,2,2-trifluoroethanol (0127) was isolated (3. 8 g, 60%): 1H NMR (400 MHz, CDCb) 8 7.98 (m, 3H), 5.25 (m, 1H), 3.2 (br, 1H); ESIMS m/z 312.2 ([Mt). The title compound (0128) was prepared and carried on crude. 1-(1-Bromo-2,2,2-trifluoroethyl)-2,3,5-trichlorobenzene (0130) CF3 CF3 Cl~OH ___ Cl~Br ~Cl ~Cl 0129 Cl 0130 2,2,2-Trifluoro(2,3,5-trichlorophenyl)ethanol (0129) was isolated as a white solid (4.0 g, 60%): mp 113-115 oc; 1H NMR (400 MHz, CDCb) 8 7.62 (d, 1H), 7.50 (d, 1H), 5.60- 5.70 (m, 1H), 2.75 (s, 1H); ESIMS m/z 278.0 . The title compound (0130) was isolated (2.9 g, 60%): 1H NMR (400 MHz, CDCb) 8 7.70 (d, 1H), 7.50 (d, 1H), 5.72-5.82 (m, 1H). 1-(1-Bromo-2,2,2-trifluoroethyl)chloro(trifluoromethyl)benzene (0132) ClyYOHy ---- CF3 0131 1-(3-Chloro(trifluoromethyl)phenyl)-2,2,2-trifluoroethanol (0131) was isolated as a pale yellow oil (2.0 g, 50%): 1H NMR (400 MHz, CDCb) 8 7.51 (m, 3H), 5.08 (m, 1H), 2.81 (s, 1H); ESIMS m/z 278.1 ([Mt). The title nd (0132) was isolated oil (2.0 g, 40%): ESIMS m/z 342 ([Mt). wo 2012/177813 -(1-Bromo-2,2,2-trifluoroethyl)-1,3-dichloromethoxybenzene (0134) CF3 CF3 Cl~OH ___ Cl~Br 'oAf 'oAf 0133 Cl 0134 -Dichloromethoxyphenyl)-2,2,2-trifluoroethanol (0133) was isolated as an off white solid (0.8 g, 60%); mp 92-95 oc: 1H NMR (400 MHz, CDCb) 8 7.41 (s, 2H), 5.00 (m, 1H), 3.89 (s, 3H), 2.64 (m, 1H); ESIMS m/z 274 ([Mt). The title compound (0134) was isolated as a colorless liquid (0.6 g, 57%).
Example 90: Preparation of 1-(1-bromo-2,2,2-trifluoroethyl)-3,5-difluorobenzene (0136) The title compound was sized in two steps via 1-(3,5-difluorophenyl)-2,2,2- trifluoroethanol (0135, prepared as in Step 1, Method A in Example 1; isolated as a colorless oil (0.2 g, 75%): 1H NMR (400 MHz, CDCb) 8 7.05 (m, 2H), 6.88 (m, 1H), 5.06 (m, 1H), 2.66 (s, 1H); ESIMS m/z 212 ([Mt) and Step 2 in Example 1 and ed (3.2 g, 50%); 1H NMR (400 MHz, CDCb) 8 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)chlorobenzene (0138) 0137 0138 1-(4-Chlorophenyl)-2,2,2-trifluoroethanol (0137) was isolated as a colorless oil (5.0 g, 99%): 1H NMR (400 MHz, CDCb) 8 7.44-7.38 (m, 4H), 5.05 (m, 1H), 2.55 (s, 1H); ESIMS m/z 210 ([Mt). The title compound (0138) was isolated (3.0 g, 46 %): 1H NMR (400 MHz, CDCb) 8 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)methoxybenzene (0140) wo 2012/177813 DI39 DI40 2,2,2-Trifluoro(4-methoxyphenyl)ethanol (DI39) was ed as a pale yellow liquid: 1H NMR (400 MHz, CDCb) 8 7.41 (d, J =8.8 Hz, 2H), 6.95 (m, J =8.8 Hz, 2H), .00 (m, 1H), 3.82 (s, 3H), 2.44 (s, 1H); ESIMS m/z 206.1 ([Mt). The title compound (DI40) was isolated (3.8 g, 62%). 1-(1-Bromo-2,2,2-trifluoroethyl)fluorobenzene (DI42) DI41 DI42 2,2,2-Trifluoro(4-fluorophenyl)ethanol (DI41) was isolated as a colorless oil (5 g, 99%): 1H NMR (400 MHz, CDCb) 8 7.48-7.45 (m, 2H), 7.13-7.07 (m, 2H), 5.06 (m, 1H), 2.53 (s, 1H); ESIMS m/z 194 ([Mt). The title compound (DI42) was prepared and d on as crude intermediate. 1-(1-Bromo-2,2,2-trifluoroethyl)methylbenzene (DI44) DI43 DI44 2,2,2-Trifluoro(p-tolyl)ethanol (DI43) was isolated as colorless oil (5.0 g, 99%): 1H NMR (400 MHz, CDCb) 8 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 ([Mt). The title compound (DI44) was isolated (3.0 g, 45%). 1-(1-bromo-2,2,2-trifluoroethyl)fluorobenzene (D146) DI45 DI46 wo 2012/177813 2,2,2-Trifluoro(3-fluorophenyl)ethanol (0145) was isolated as a colorless viscous oil (2.8 g, 93%): 1H NMR (400 MHz, CDCb) 8 7.41 (m, 1H), 7.25 (m, 2H), 7.14 (m, 1H), .06 (m, 1H), 2.60 (s, 1H); ESIMS m/z 194 ([Mt). The title nd (0146) was isolated (2.0 g, 61 %). romo-2,2,2-trifluoroethyl)fluorobenzene (0148) ()AoHF CF3 ___ 0147 0148 2,2,2-Trifluoro(2-fluorophenyl)ethanol (0147) was isolated as a colorless oil (2.5 g, 99%): 1H NMR (400 MHz, CDCb) 8 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 ([Mt). The title compound (0148) was isolated (2.0 g, 61 %): 1H NMR (400 MHz, CDCb) 8 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-HD.
Example 91: Preparation of 4-(1H-1,2,4-triazolyl)benzaldehyde (DIS) -'l'Nv~H N I \::::.N To a stirring solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K 2C03 (13.3 g, 96.7 mmol) and 1,2,4- le (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120 oc for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with H20 and extracted with EtOAc (3 x100 mL).
The ed EtOAc layer was washed with H20 and brine, dried over Na2S04, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65%): mp 145-149 oc: 1H NMR (400 MHz, CDCb) 8 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+Ht).
The following compound was made in accordance with the procedures disclosed in e 91.
-Formyl(1H-1,2,4-triazolyl)benzonitrile (0149) -'l'NvNC~H N I \::::.N wo 77813 The title compound was isolated (2.8 g, 60%); 1H NMR (400 MHz, CDCb) 8 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(1H-1,2,4-triazolyl)benzaldehyde (0150) N~NAJlCII ~N The title compound was ed as an off white solid (3.0 g, 40%): mp 1 oc; 1H NMR (400 MHz, CDCb) 8 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+Ht).
-Methyl(1H-1,2,4-triazolyl)benzaldehyde (0151) N I \.:::::N The title compound was isolated as a white solid (0.5 g, 74 %): mp 109-111 oc; 1H NMR (400 MHz, D6-DMSO) 8 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+Ht).
Example 92: Preparation of 5-formyl(3-nitro-1H-1,2,4-triazolyl)benzonitrile (0152) NC~H NFNI 0 2N To a stirring solution of 2-fluoroformylbenzonitrile (0.5 g, 3.3 mmol) in DMF (25 mL) were added K2C03 (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 RT 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 Na2S04 and concentrated under reduced pressure to afforded the title compound as a pale yellow solid (0.36 g, 45%): mp 170-172 oc; 1H NMR (300 MHz, DMSO-d6) 8 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-HD; IR (thin film) 2238, 1705, 1551, 1314 cm-1. wo 2012/177813 Example 93: ation of 4-(3-methyl-1H-1,2,4-triazolyl)benzaldehyde (0153) NINI To a stirring solution of 4-fluorobenzaldehyde (5.0 g, 40.32 mmol) in DMF (50 mL), were added K2C03 (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 R T for 4 h. After tion of the reaction (TLC), the reaction mixture was diluted with water and extracted with EtOAc (3x). The combined EtOAc layer was washed with water and brine then dried over Na2S04 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, CDCb) 8 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+Ht).
The following compound was made in accordance with the procedures disclosed in Example 93. 4-(1H-1,2,4-triazolyl)(trifluoromethyl)benzaldehyde (0154) F3C~H N I \::::oN The title compound was isolated as white solid (1.05 g, 60%): mp 81-83 oc; 1H NMR (400 MHz, CDCb) 8 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 ([Mt). 4-(3-nitro-1H-1,2,4-triazolyl)benzaldehyde (0155) N I 0 2N The title compound was isolated as pale yellow solid (0.10 g, 23%): mp 159-161 oc; 1H NMR (400 MHz, CDCb) 8 10.10 (s, 1H), 8.89 (s, 1H), 8.15 (m, 2H), 8.00 (m, 2H); ESIMS m/z 217.11 ([M-HD. 3-bromo(1H-1,2,4-triazolyl)benzaldehyde (0156) wo 2012/177813 -'l'NvBr~H N I \:::::N The title compound was ed as white solid (3.2 g, 51%): mp 126-128 oc; 1H NMR (400 MHz, CDCb) 8 10.04 (s, lH), 8.69 (s, lH), 8.27 (M, lH, 8.18 (s, lH) 7.99 (d, J = 9.2 Hz, lH), 7.76 (d, J = 9.2 Hz, lH); ESIMS m/z 250.9 ([Mt). 5-formyl(3-methyl-1H-1,2,4-triazolyl)benzonitrile (0157) -'l'NvNC~H NrNI The title compound was isolated as white solid (0.13 g, 30%): mp 147-149 oc; 1H NMR (400 MHz, CDCb) 8 10.07 (s, lH), 8.89 (s, lH), 8.32 (d, J = 1.8 Hz, lH), 8.24 (dd, J = 8.6, 1.3 Hz, lH), 8.06 (d, J = 8.6 Hz, lH), 2.54 (s, 3H); ESIMS m/z 213.09 ([M+Ht); IR (thin film) 2239, 1697 cm-1. 3-nitro(1H-1,2,4-triazolyl)benzaldehyde (0158) -'l'Nv02N~H N I \:::::N The title compound was ed as pale yellow solid (3.0 g, 60 %): mp 116-118 oc; 1H NMR (400 MHz, CDCb) 8 10.15 (s, lH), 8.48 (s, lH), 8.46 (s, lH), 8.26 (d, J = 6.9 Hz, lH), 8.16 (s, lH), 7.83 (d, J =6.9 Hz, lH); ESIMS m/z 219.00 ([M+Ht).
Example 94: Preparation of 1-(4-vinylphenyl)-1H-1,2,4-triazole (0159) ij-N~ \:::::N To a stirred solution of 4-[1,2,4]triazolyl-benzaldehyde (9.0 g, 52 mmol) in 1,4- dioxane (100 mL), were added K2C03 (10.76 g, 78 mmol) and methyl triphenyl phosphonium bromide (22.2 g, 62.4 mmol) at room temperature. The resultant reaction mixture was heated to 70 oc for 18 h. After completion of the on (TLC), the on mixture was cooled to room temperature and filtered and the obtained filtrate was concentrated under reduced wo 2012/177813 re. Purification by flash chromatography (Si02, 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+Ht).
The following compound was made in accordance with the procedures disclosed in Example 94. 1-(2-Methylvinylphenyl)-1H-1,2,4-triazole (0160)0;cr N I \::::::N The title compound was isolated as an off white solid (1.5 g, 76%): 1H NMR (400 MHz, CDCb) 8 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+Ht). 2-(1H-1,2,4-Triazolyl)vinylbenzonitrile (0161) /J'N~ N I \::::::N The title compound was isolated as an off-white solid (1.40 g, 71%): mp 126-129 oc; 1H NMR (400 MHz, CDCb) 8 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 = .8 Hz, 1H); ESIMS m/z 197.03 ([M+Ht). e 95: Preparation of 2-(3-nitro-1H-1,2,4-triazolyl)vinylbenzonitrile (0162) /J'N~ )::=:NI 0 2N To a stirred solution of 5-formyl(3-nitro-1H-1,2,4-triazolyl)benzonitrile (0.36 g, 1.49 mmol) in 1,4-dioxane (25 mL), were added K2C03 (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 oc for 18 h. After completion of the reaction (TLC), the reaction mixture was cooled to room temperature and filtered and the ed filtrate was trated under reduced re. Purification by flash tography (Si02, 100-200 mesh; 25-30% EtOAc in petroleum ether) to afford the title compound as a solid (0.25 g, 70%): mp 103-105 oc; 1H NMR (400 MHz, DMSO-d6) 8 9.50 (s, 1H), 8.34 (m, 1H), 7.98 (d, J =7.8 Hz, 1H), 7.68 (d, wo 2012/177813 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-HD; IR (thin film) 2240, 1514, 1312 cm-1.
The following compound was made in accordance with the procedures disclosed in Example 95. 1-(3-chlorovinylphenyl)-1H-1,2,4-triazole (0163) N~~~Cl \::::::N The title nd was isolated as an off-white solid (2.3 g, 80%): mp 134-137 oc; 1H NMR (400 MHz, CDCb) 8 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+Ht. 3-methyl(4-vinylphenyl)-1H-1,2,4-triazole (0164) 4-N~ NIN' The title compound was isolated as a white solid (0.6 g, 60%): mp 109-111 oc; 1H NMR (400 MHz, CDCb) 8 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 1-(2-(trifluoromethyl)vinylphenyl)-1H-1,2,4-triazole (0165) F3C~ N\::::::N' The title compound was isolated as a colorless oil (0.6 g, 60%): 1H NMR (400 MHz, CDCb) 8 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), .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+Ht). 3-nitro(4-vinylphenyl)-1H-1,2,4-triazole (0166) 4-N~ NyN' 0 2N wo 2012/177813 The title compound was isolated as a pale yellow solid (61 mg, 20%): mp 9 oc; 1H NMR (400 MHz, CDCb) 8 8.60 (s, 1H), 7.68 (d, J = 7.7 Hz, 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 ). 1-(2-bromovinylphenyl)-1H-1,2,4-triazole (0167) \;:::::NI The title compound was isolated as a white solid (1.2 g, 40%): mp 75-77 oc; 1H NMR (400 MHz, CDCb) 8 8.48 (s, 1H), 8.12 (s, 1H), 7.75 (s, 1H) 7.42 (s, 2H), 6.70 (m, 1H), 5.83 (d, J =18Hz, 1H), 5.42 (d, J =12Hz, 1H); ESIMS m/z 249.1 ([Mt). 2-(3-methyl-1H-1,2,4-triazolyl)vinylbenzonitrile (0168) NrNI The title compound was isolated as an off-white solid (0.6 g, 60%): mp 96-97 oc; 1H NMR (400 MHz, CDCb) 8 8.66 (s, 1H), 7.80 (s, 1H), 7.74 (m, 2H), 6.73 (dd, J = 17.6 Hz, .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+Ht); IR (thin film) 2229 cm-1. 1-(2-nitrovinylphenyl)-1H-1,2,4-triazole (0169) 02N~ \;:::::NI The title compound was isolated as a yellow solid (1.78 g, 60%): mp 102-104 oc; 1H NMR (400 MHz, CDCb) 8 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+Ht).
Example 96: Preparation of 3-methyl(1H-1,2,4-triazolyl)vinylbenzonitrile (0170) NCVI'-':::: 0N::::,...
\;:::::NI wo 2012/177813 Step 1. 5-Bromofluoromethylbenzaldehyde: To a stirred solution of diisopropyl amine (4.01 g, 39.88 mmol) in THF (20 mL) was added n-butyllithium (1.6 Min hexane) (19.9 mL, 31.91 mmol) at -78 oc slowly dropwise over the period of 10 min, the reaction mixture was stirred at -78°C for 30 min. A solution of 4-bromofluoro benzene (5.0 g, 26.6 mmol) in THF (30.0 mL) was added at -78°C, and the on mixture was d for lh 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 e was quenched with IN HCI solution (aq) at 0°C. The aqueous layer was extracted with diethyl ether, washed with water and saturated brine solution. The ed organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude compound purified by flash column chromatography (Si02, 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- 500C: 1H NMR (400 MHz, CDCb) 8 8.33 (s, IH), 8.22 (s, IH), 7.67 (s, IH), 7.60 (s, IH), 6.75 (dd, J = 17.6, 10.8 Hz, IH), 5.92 (dd, J = 17.6, 10.8 Hz, IH), 5.52 (d, J = 17.6 Hz, IH), 2.21 (s, 3H); ESIMS m/z 211.35 ([M-HD.
Step 2. -Bromofluoromethylbenzaldehyde oxime: To a stirred solution of 5-bromofluoromethylbenzaldehyde (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 RT. The reaction mixture was stirred at RT 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 oc; 1H NMR (400 MHz, CDCb) 8 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+Ht).
Step 3. 5-Bromofluoromethylbenzonitrile: A stirred solution of (E)bromo- 2-fluoromethylbenzaldehyde 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 Na2S04 and concentrated under reduced re to afford the crude compound as a light brown gummy al (0.4 g, crude): ESIMS m/z 213.82 ([M+Ht).
Step 4. 5-Bromomethyl(1H-1,2,4-triazolyl)benzonitrile (0171): To a stirred solution of ofluoromethylbenzonitrile (1.0 g, 47.716 mmol), in DMF (10.0 mL) was added potassium carbonate (1.95 g, 14.14 mmol) ed by 1H-1 ,2,4- triazole (0.811 g, 9.433 mmol) at RT. The reaction mixture was heated to 140 oc for 18 h.
The reaction mixture was cooled toRT, diluted with water and extracted with ethyl acetate (2 wo 2012/177813 x 100 mL). The combined ethyl acetate layer was washed with brine and dried over Na2S04 and concentrated under reduced pressure to afford the crude compound purified by flash column chromatography (Si02, 100-200 mesh; eluting with 30% ethyl acetate/ pet ether) to afford the title nd as a pink solid (0.6 g, 49 %): 1H NMR (400 MHz, CDCb) 8 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+Ht); IR (thin film) 2231, 554 cm-1.
Step 5. 3-Methyl(1H-1,2,4-triazolyl)vinylbenzonitrile (0170): A mixture of omethyl(1H-1,2,4-triazolyl)benzonitrile (0.6 g, 2.3 mmol), ium carbonate (0.95 g, 6.87 mmol), vinyl boronic ide (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 toRT, diluted with water and extracted with ethyl acetate (2 x 100 mL). The combined ethyl acetate layer was washed with brine, dried over Na2S04 and concentrated under reduced pressure to afford the crude compound that was purified by flash column chromatography (Si02, 100-200 mesh; eluting with 30% ethyl e/ pet ether) to afford the title nd as a pink solid (0.25 g, 52%): 1H NMR (400 MHz, CDCb) 8 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+Ht); 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-fluorovinylphenyl)-1H-1,2,4-triazole (0172) 0N0F~ N ' \::::N 1-(4-Bromofluorophenyl)-1H-1,2,4-triazole (0173) was isolated as a pale yellow solid (3.0 g, 75%): mp 113-116 oc; 1H NMR (400 MHz, CDCb) 8 8.69 (s, 1H), 8.13 (m, 2H), 7.50 (m, 1H), 7.21 (m, 1H); ESIMS m/z 241.93 ([Mt). The title compound (0172) was isolated as a yellow solid (1.0 g, 71 %): mp 67-70 oc; 1H NMR (400 MHz, CDCb) 8 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 ), .81 (d, J = 17.6 Hz, 1H), 5.37 (d, J = 10.8 Hz, 1H); ESIMS m/z 190.00 ([M+Ht).
Example 119: Preparation of 1-(1-(4-vinylphenyl)-1H-1,2,4-triazolyl)ethanone (0178) wo 77813 --fo ~ }-_N~ N I \::::::N 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 oc 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 R T for 16 h. The reaction e was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (3 x50 mL). The combined EtOAc layer was washed with brine and dried over sodium sulphate and concentrated under reduced re. The crude compound was purified by flash chromatography (Si02, 100-200 mesh, 40% EtOAc in Pet ether) to afford the title compound as an off white solid (280 mg, 23%): mp 97-98 oc; 1H NMR (400 MHz, CDCb) 8 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+Ht).
Example 120: Preparation of cyclopropyl(1-(4-vinylphenyl)-1H-1,2,4-triazol yl)methanone (0179) N I 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 oc 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 RT for 16 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and ted with EtOAc (3 x25 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 (Si02, 100-200 mesh, 40% EtOAc in Pet ether) to afford the title compound as an off white solid (420 mg, %): mp 90-91 oc; 1H NMR (400 MHz, CDCb) 8 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 ); IR (thin film) 2922, 1630 cm-1.
Example 121: Preparation of 5-(methylthio)(4-vinylphenyl)-1H-1,2,4-triazole (0180) wo 2012/177813 -s ~ \;::;NI 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 oc 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 RT for 16 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (3 x 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 (Si02, 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 oc; 1H NMR (400 MHz, CDCb) 8 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+Ht). e 122: Preparation of yl(4-vinylphenyl)-1H-1,2,4-triazole (0181) J--.N~ \;::;NI To a d on 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 oc 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 RT for 16 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (3 x 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 (Si02, 100-200 mesh, 40% EtOAc in Pet ether) afford the title compound as a pale brown liquid (250 mg, 46%): 1H NMR (400 MHz, CDCb) 8 7.93 (s, 1H), 7.55 (d, J =9Hz, 2H), 7.42 (d, J = 9Hz, 2H), 6.76 (dd, J = 18, 11 Hz, 1H), 5.83 (d, J =18Hz, 1H), 5.38 (d, J = 11 Hz, 1H), 2.55 (s, 3H); ESIMS m/z 186.13 ([M+Ht); IR (thin film) 1517, 1386, 1182, 847 cm-1. e 97: ation of (E)(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobuten yl)phenyl)-1H-1,2,4-triazole (DC1) wo 2012/177813 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 oc for 24 h. After completion of on (TLC), the reaction mixture was cooled to RT and filtered and the te concentrated under reduced pressure. Purification by flash chromatography (Si02, 100-200 mesh; 25-30% EtOAc in petroleum ether) afforded the title nd as an ite solid (0.8 g, 32%): mp 93-97 oc; 1H NMR (300 MHz, CDCb) 8 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+Ht).
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)(3-nitro-1H-1,2,4-triazolyl)(4,4,4-trifluoro (3,4,5-trichlorophenyl)butenyl)benzonitrile (DC40) Cl CN Cl N.N ~N02 To a stirred solution of2-(3-nitro-1H-1,2,4-triazolyl)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 pyridyl (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 toRT and filtered and the filtrate was concentrated under reduced pressure.
Purification by flash chromatography (Si02, 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 oc; 1H NMR (300 MHz, CDCb) 8 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-2HD. wo 2012/177813 Example 99: Preparation of (E)(3-amino-1H-1,2,4-triazolyl)(4,4,4-trifluoro (3,4,5-trichlorophenyl)butenyl)benzonitrile (DC41) To a stirred solution of (E)(3-nitro-1H-1,2,4-triazolyl)(4,4,4-trifluoro (3,4,5-trichlorophenyl)butenyl)benzonitrile (0.6 g, 1.2 mmol) in MeOH (10 mL), were added Zn dust (0.39g, 5.98 mmol) and sat. aq NH4Cl solution (5 mL) and the resultant reaction mixture was stirred at RT for 2 h. After completion of the reaction (TLC), the reaction mass was concentrated under reduced pressure. The reaction mass was diluted with DCM, filtered through a celite bed, and the obtained filtrate concentrated under reduced pressure to afford the title nd as a solid (0.5 g, 89%): mp 72-75 oc; 1H NMR (300 MHz, DMSO-d6) 8 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-HD.
Compound DC38 in Table 1 was made in accordance with the procedures disclosed in e 99. Also, compound DC55 in Table 1 was made from compound DC54 in accordance with the procedures disclosed in Example 99, with the ion of using ammonium formate in place of ammonium chloride.
Example 100: Preparation of (E)-N-(1-(2-cyano(4,4,4-trifluoro(3,4,5- orophenyl)butenyl)phenyl)-1H-1,2,4-triazolyl)-N- (cyclopropanecarbonyl)cyclopropanecarboxamide (DC42) To a stirred solution of (E)(3-amino-1H-1,2,4-triazolyl)(4,4,4-trifluoro (3,4,5-trichlorophenyl)butenyl)benzonitrile (0.1 g, 0.21 mmol) in DCM at RT, was added cyclopropylcarbonyl chloride (0.045 g, 0.42 mmol) and the reaction mixture was stirred for 2 hat RT. The reaction mixture was d with DCM and washed with water and brine and dried over . Concentration under reduced pressure and purification by preparative HPLC afforded the title compound as a solid (0.09g, 79%): mp 104-107 oc; 1H NMR (300 wo 2012/177813 MHz, CDCb) 8 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+Ht); IR (thin film) 2234, 1714, 1114,807 cm-1. e 101: Preparation of (E)-N-(1-(2-cyano(4,4,4-trifluoro(3,4,5- trichlorophenyl)butenyl)phenyl)-1H-1,2,4-triazolyl)cyclopropanecarboxamide (DC43) Cl CN O Cl N -N H To a stirred solution of (E)(3-amino-1H-1,2,4-triazolyl)(4,4,4-trifluoro (3,4,5-trichlorophenyl)butenyl)benzonitrile (0.15 g,0.31 mmol) in DCM at 0 °C, were added triethylamine (0.1 g, 1 mmol) and cyclopropylcarbonyl de (0.04 g, 0.38mmol) and the reaction mixture was stirred for 1 h at 0 °C. The reaction mixture was diluted with DCM and washed with water and brine and dried over Na2S04. Concentration under reduced pressure and purification by column chromatography (Si02, 100-200 mesh) afforded the title nd as a solid (66 mg, 34%): mp 109-112 oc; 1H NMR (300 MHz, 6) 8 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+Ht); IR (thin film) 3233,2233, 1699, 1114, 807cm-1.
Compound DC39 in Table 1 was made in accordance with the ures disclosed in Example 101.
Example 102: Preparation of 1-(4-(1H-1,2,4-triazolyl)phenyl)ethanone (0174) 0Nif N I \.::::N To a stirred solution of 4-bromoacetophenone (10 g, 50 mmol) in DMF (100 mL), were added 1,2,4-triazole (5 g, 75mmol), Cs2C03 (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 toRT and diluted with water (200 mL) and extracted with EtOAc. The combined organic layer was washed with brine and dried over Na2S04 and concentrated under reduced re. Purification by washing with diethyl ether ed the title compound as a solid (5 g, 96%): 1H NMR (400 MHz, CDCb) 8 8.71 (s, 1H), wo 2012/177813 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-HD.
Example 103: Preparation of 1-(4-(1H-1,2,4-triazolyl)phenyl)(3,5-dichlorophenyl)- 4,4,4-trifluorobutanone : CF3 0 Cl Step 1. 1-(4-(1-(trimethylsilyloxy)vinyl)phenyl)-1H-1,2,4-triazole (0176) To a stirred on of 1-(4-(1H-1,2,4-triazolyl)phenyl)ethanone (4.5 g, 24.0 mmol) in DCM at 0 °C, were added TEA (3. 7 g, 36.1 mmol) and trimethylsilyl triflluoromethanesulfonate (8 g, 36 mmol) and the resultant on mixture was stirred for 1 h. The reaction mixture was quenched with a e of sat aq sodium bicarbonate solution and ether. The ether layer and was separated, washed with brine, dried over Na2S04 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-triazolyl)phenyl)(3,5-dichlorophenyl)-4,4,4- trifluorobutanone (0175): To a stirred solution of 1-(4-(1- (trimethylsilyloxy)vinyl)phenyl)-1H-1,2,4-triazole (6g, 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 (0.23g, 2.31 mmol) and 2,2-bipyridyl (0.73g, 4.63 mmol) was added to the above reaction mixture and the resultant reaction e was heated to 180 oc for 18 h. After tion of the reaction (by TLC), the reaction mixture was absorbed onto silica gel and purified by column chromatography (Si02; 10% EtOAc in petroleum ether) to afford title compound as a solid (3 g, 31 %): 1H NMR (400 MHz, CDCb) 8 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-HD.
Example 104: Preparation of 2-(4-(1H-1,2,4-triazolyl)phenyl)(3,5-dichlorophenyl)- 5,5,5-trifluoropentanol (0177) To a solution of 1-(4-(1H-1 ,2,4-triazolyl)phenyl)(3,5-dichlorophenyl)-4,4,4- trifluorobutanone (300 mg, 0.726 mmol) in THF cooled to 0 oc was added wo 2012/177813 methylmagnesium e (450 mg, 5 mmol) drop wise. The reaction was stirred for 3 hat 0 °C, then the reaction mixture was ed with sat aq N~Cl solution and extracted with ethyl acetate. The combined EtOAc layer was washed with water and brine, dried over Na2S04 and concentrated under reduced pressure. Purification by column chromatography (Si02, 100-200 mesh; 20%-25% EtOAc in eum ether) afforded the title compound as a solid (100 mg, 32%): 1H NMR (400 MHz, CDCb) 8 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, 1 = 9.0 Hz, 2H, minor), 7.53 (d, 1 = 9.0 Hz, 2H, minor), 7.40 (d, 1 = 9.0 Hz, 2H, major), 7.31 (m, 1H, minor), 7.27 (d, 1 = 9.0 Hz, 2H, major), 7.20 (m, 2H, , 7.01 (m, 1H, , 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+Ht).
Example 105: Preparation of (E)(4-(4-(3,5-dichlorophenyl)-5,5,5-trifluoropenten- 2-yl)phenyl)-1H-1,2,4-triazole (DC68) To a solution of 2-(4-(1H-1 ,2,4-triazolyl)phenyl)(3,5-dichlorophenyl)-5,5,5- trifluoropentanol (100 mg, 0.233 mmol) in e was added a catalytic amount uenesulfonic acid (PTSA) and the water was removed by azeotropic distillation over the course of 12 h. The reaction mixture was cooled to room temperature and dissolved in ethyl acetate. The solution was washed with sat aq NaHC03 solution and brine, dried over Na2S04 and concentrated under reduced pressure. Purification by column chromatography (Si02, 0 mesh; 20%-25% EtOAc in petroleum ether) afforded the title compound as a solid (30 mg, 31 %).
Example 123: Preparation of (E)(3-(3,5-dichlorophenyl)-4,4,4-trifluorobutenyl)- 2-(1H-1,2,4-triazolyl)benzaldehyde (DC52) To a stirred solution of (E)(3-(3,5-dichlorophenyl)-4,4,4-trifluorobutenyl) (1H-1,2,4-triazolyl)benzonitrile (0.3 g, 0.71 mmol) in toluene (10 mL) at -78 oc was added dropwise diisobutylaluminum hydride (DIBAL-H, 1.0 M solution in toluene; 0.85 wo 2012/177813 mL), and the reaction e was stirred at -78 oc for 20 min. The reaction mixture was quenched with the addition of 1 N HCl solution, then the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2S04 and concentrated under reduced pressure. The crude compound was ed by flash column chromatography (Si02; 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)(3-(3,5-dichlorophenyl)-4,4,4-trifluorobutenyl)- N-methyl(1H-1,2,4-triazolyl)aniline (DC57) Cl N, Cl To a stirred solution of (E)(3-(3,5-dichlorophenyl)-4,4,4-trifluorobutenyl) (1H-1,2,4-triazolyl)aniline (0.3 g, 0.7 mmol) in DCM (10 mL) was added triethylamine (0.155 mL, 1.09 mmol) and methyl iodide (0.124 g, 0.873 mmol). The reaction was stirred at RT for 18 h. The DCM layer was washed with water and brine, dried over Na2S04 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (Si02; 50% EtOAc/ Pet ether) to afford the title compound as a yellow semisolid (0.07 g, 70%). e 125: Preparation of (E)(3-(3,5-dichlorophenyl)-4,4,4-trifluorobutenyl)- 2-(1H-1,2,4-triazolyl)benzoic acid (DC61) A solution of hyl 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobutenyl)(1H- 1,2,4-triazolyl)benzoate (0.2 g, 0.4 mmol) in 6 N HCl (10 mL) was stirred at 100 oc for 18 h. The reaction was cooled toRT, 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 ((E)(3,5-dichlorophenyl)-4,4,4-trifluorobuten- 1-yl)-N'-hydroxy(lH-1,2,4-triazolyl)benzimidamide (DC59) wo 2012/177813 2012/043418 A solution of (E)(3-(3,5-dichlorophenyl)-4,4,4-trifluorobutenyl)(lH-1,2,4- triazolyl)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 oc for 8 h. The reaction was cooled toRT, and the ethanol was evaporated.
The residue was dissolved in water and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2S04 and concentrated under reduced re to afford the title compound as an off white solid.
Example 127: Preparation of (E)(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro methoxybutenyl)phenyl)-1H-1,2,4-triazole (DC70) F3C 0 Step 1. (E)(4-(1H-1,2,4-triazolyl)phenyl)(3,5-dichlorophenyl)propen 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-triazolyl)benzaldehyde (0.46 g, 2.65 mmol) and the reaction was cooled to 0 oc. 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 Na2S04 and concentrated under reduced pressure to afford the title compound (0.149 g, 17%): ); ESIMS m/z 430.05 ([M+Ht) 344.08 Step 2. (E)(4-(1H-1,2,4-triazolyl)phenyl)(3,5-dichlorophenyl)-1,1,1- trifluorobutenol (DC69): To a solution of (E)(4-(1H-1,2,4-triazolyl)phenyl) (3,5-dichlorophenyl)propenone (1 g, 3 mmol) in THF (150 mL) was added oromethyltrimethylsilane (0.517 g, 3.644 mmol) and tetra-n-butylammonium fluoride (TBAF) (1.0 M, 1 mL) at 0 oc. The on was slowly warmed toRT and allowed to stir for 2 h. The reaction was then cooled to 0 oc and 5 M HCl solution was added and the reaction was d for an additional4 hat RT. The reaction was extracted with DCM and the ed c layers were dried over Na2S04 and concentrated under reduced pressure.
The crude compound was purified by flash column chromatography (Si02; 25% EtOAc/ hexanes) to afford the title compound as an off-white solid (0.3 g, 25%). wo 2012/177813 Step 3. (E)(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoromethoxybuten yl)phenyl)-1H-1,2,4-triazole (DC70): To a solution of (E)(4-(1H-1 ,2,4-triazol nyl)(3,5-dichlorophenyl)-1,1, 1-trifluorobutenol (0.15 g, 0.36 mmol) in THF (5 mL) was added NaH (60%, 10 mg, 0.44 mmol) at 0 oc. The reaction was d to stir at 0 oc for 30 min, then methyl iodide (61 mg, 0.44 mmol) was added slowly and the reaction was warmed toRT and allowed to stir for 4 h. The reaction was quenched with aq N~Cl solution and extracted with DCM. The combined organic layers were dried over Na2S04 and concentrated under reduced pressure to afford the title compound as an off-white solid (55 mg, 35%).
Example A: BIOASSAYS ON BEET RM ("BAW") AND CORN EARWORM ("CEW") 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, , peas, sunflowers, and citrus, among other plants. CEW is known to attack corn and tomatoes, but it also attacks artichoke, asparagus, cabbage, cantaloupe, collards, s, cucumbers, eggplant, lettuce, lima beans, melon, okra, peas, peppers, potatoes, pumpkin, snap beans, spinach, squash, sweet es, and watermelon, among other plants. CEW is also known to be resistant to certain insecticides. Consequently, e of the above factors control of these pests is important. rmore, molecules that control these pests are useful in controlling other pests.
Certain molecules disclosed in this document were tested against BAW and CEW using procedures described in the following examples. In the reporting of the s, the "BAW & CEW 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 11glcm2 of the test compound (dissolved in 50 11L 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 dhesive cover, and held at 25 oc, 14:10 light-dark for five to seven days. Percent mortality was recorded for the larvae in each well; ty in the eight wells was then averaged. The results are indicated in the table entitled "Table 3: Assay Results" (See Table Section).
AYS ON CEW (Helicoverpa zea) wo 2012/177813 2012/043418 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 11g /cm2 of the test compound (dissolved in 50 11L of 90:10 e-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 oc, 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 n).
Example B: BIOASSAYS ON GREEN PEACH APHID ("GPA") (Myzus persicae).
GPA is the most significant aphid pest of peach trees, causing sed 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 s of the nightshade/potato family Solanaceae, and various mosaic viruses to many other food crops. GPA s such plants as broccoli, k, 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 t GPA using procedures described in the following example. In the ing 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 em) 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 nds (2 mg) were dissolved in 2 mL of acetone/methanol (1:1) solvent, forming stock solutions of 1000 ppm test compound. The stock solutions were diluted 5X with 0.025% Tween 20 in H20 to obtain the solution at 200 ppm test compound. A eld 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 e/methanol (1:1) solvent. Treated plants were held in a g room for three days at approximately 25 oc 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 wo 2012/177813 correction formula (W.S. Abbott, "A Method of Computing the Effectiveness of an Insecticide" J. Econ. Entomol. 18 (1925), pp.265-267) as follows. ted % l = 100 * (X - Y) I X where X= No. of live aphids on t check plants and Y =No. of live aphids on d 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 on 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 miting example, an acid function can form salts including those d from alkali or alkaline earth metals and those derived from a and amines. Examples of preferred cations e sodium, potassium, and magnesium.
Molecules of Formula One may be formulated into salt derivatives. By way of a nonlimiting example, a salt derivative can be prepared by contacting a free base with a sufficient amount of the desired acid to e a salt. A free base may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute s 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 ylamine salt..
Molecules of Formula One may be formulated into stable complexes with a solvent, such that the complex s 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. wo 2012/177813 les 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 a One may be made with different uclides. 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 iated 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 tic procedures, by conventional synthetic procedures using resolved starting als, or by conventional resolution procedures. Certain molecules sed in this nt 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 lly 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 ric 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 aneous or sequential application) with one or more compounds having idal, algicidal, avicidal, bactericidal, idal, herbicidal, insecticidal, molluscicidal, nematicidal, rodenticidal, or virucidal properties. Additionally, the les of Formula One may also be used in ation (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 ters, 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-triiodobenzoic acid, 2,3,6-TBA, 2,3,6-TBA-dimethylammonium, 2,3,6-TBA-lithium, 2,3,6- wo 2012/177813 TEA-potassium, 2,3,6-TEA-sodium, 2,4,5-T, 2,4,5-Tbutoxypropyl, 2,4,5-Tethylhexyl, 2,4,5-Tbutoxypropyl, 2,4,5-TE, 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, T-triethylammonium, 2,4,5-T-trolamine, 2,4-D, 2,4-Dbutoxypropyl, 2,4-D- 2-ethylhexyl, 2,4-Dbutoxypropyl, 2,4-D-ammonium, 2,4-DE, -butyl, 2,4-DE- dimethylammonium, -isoctyl, 2,4-DE-potassium, 2,4-DE-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, E, P, 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-DE, 3,4-DP, opyridine, 4-CPA, 4-CPA-potassium, 4-CPA- sodium, 4-CPE, 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, orfen-methyl, acifluorfen-sodium, aclonifen, acrep, acrinathrin, acrolein, acrylonitrile, acypetacs, acypetacs-copper, acypetacs-zinc, alachlor, alanycarb, albendazole, aldicarb, aldimorph, aldoxycarb, aldrin, rin, n, allidochlor, allosamidin, alloxydim, alloxydim-sodium, allyl alcohol, allyxycarb, alorac, alpha-cypermethrin, alpha-endosulfan, ametoctradin, ametridione, ametryn, amibuzin, bazone, 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 a-naphthaleneacetate, amobam, ampropylfos, anabasine, ancymidol, anilazine, anilofos, anisuron, anthraquinone, antu, apholate, aramite, arsenous oxide, asomate, n, asulam, asulam-potassium, asulamsodium , thion, atraton, atrazine, aureofungin, aviglycine, aviglycine hydrochloride, azaconazole, azadirachtin, azafenidin, azamethiphos, lfuron, azinphos-ethyl, azinphos- methyl, aziprotryne, ram, azobenzene, azocyclotin, azothoate, azoxystrobin, bachmedesh, barban, barium hexafluorosilicate, barium polysulfide, barthrin, ECPC, beflubutamid, benalaxyl, benalaxyl-M, benazolin, benazolin-dimethylammonium, benazolinethyl , benazolin-potassium, bencarbazone, thiaz, bendiocarb, benfluralin, benfuracarb, benfuresate, benodanil, benomyl, cor, benoxafos, benquinox, bensulfuron, wo 77813 bensulfuron-methyl, bensulide, bensultap, bentaluron, bentazone, bentazone-sodium, benthiavalicarb, benthiavalicarb-isopropyl, benthiazole, bentranil, benzadox, benzadoxammonium , benzalkonium chloride, acril, 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, hrin, bifujunzhi, fos, bilanafos-sodium, binapacryl, bingqingxiao, bioallethrin, bioethanomethrin, biopermethrin, bioresmethrin, biphenyl, bisazir, bismerthiazol, bispyribac, bispyribac-sodium, bistrifluron, bitertanol, bithionol, bixafen, cidin-S, borax, ux mixture, boric acid, boscalid, brassinolide, brassinolide-ethyl, omin, 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, ol, bucarpolate, bufencarb, buminafos, bupirimate, ezin, Burgundy mixture, busulfan, rb, butachlor, butafenacil, butamifos, butathiofos, butenachlor, butethrin, buthidazole, buthiobate, buthiuron, butocarboxim, butonate, butopyronoxyl, butoxycarboxim, butralin, butroxydim, buturon, butylamine, butylate, cacodylic acid, cadusafos, trole, calcium arsenate, calcium chlorate, calcium cyanamide, calcium lfide, calvinphos, cambendichlor, camphechlor, camphor, captafol, captan, carbamorph, olate, carbaryl, ulam, carbendazim, dazim benzenesulfonate, carbendazim sulfite, carbetamide, carbofuran, carbon ide, carbon tetrachloride, carbophenothion, carbosulfan, carboxazole, carboxide, carboxin, carfentrazone, carfentrazone-ethyl, carpropamid, cartap, cartap hydrochloride, carvacrol, carvone, CDEA, cellocidin, CEPC, ceralure, Cheshunt mixture, chinomethionat, an, chlobenthiazone, chlomethoxyfen, chloralose, chloramben, chloramben-ammonium, chloramben-diolamine, chloramben-methyl, chloramben-methylammonium, mben-sodium, chloramine orus, chloramphenicol, chloraniformethan, nil, chloranocry1, chlorantraniliprole, chlorazifop, chlorazifop-propargyl, chlorazine, chlorbenside, chlorbenzuron, chlorbicyclen, chlorbromuron, chlorbufam, chlordane, chlordecone, chlordimeform, chlordimeform hydrochloride, chlorempenthrin, chlorethoxyfos, chloreturon, chlorfenac, chlorfenacammonium , chlorfenac-sodium, chlorfenapyr, chlorfenazole, chlorfenethol, chlorfenprop, enson, chlorfensulphide, chlorfenvinphos, chlorfluazuron, chlorflurazole, chlorfluren, wo 2012/177813 chlorfluren-methyl, chlorflurenol, chlorflurenol-methyl, chloridazon, chlorimuron, chlorimuron-ethyl, ephos, chlormequat, chlormequat de, chlornidine, chlornitrofen, chlorobenzilate, chlorodinitronaphthalenes, chloroform, mebuform, chloromethiuron, neb, chlorophacinone, chlorophacinone-sodium, chloropicrin, chloropon, chloropropylate, chlorothalonil, chlorotoluron, chloroxuron, chloroxynil, chlorphonium, chlorphonium chloride, chlorphoxim, chlorprazophos, chlorprocarb, chlorpropham, chlorpyrifos, yrifos-methyl, chlorquinox, chlorsulfuron, chlorthal, chlorthal-dimethyl, chlorthal-monomethyl, chlorthiamid, chlorthiophos, chlozolinate, choline chloride, chromafenozide, cinerin I, cinerin II, cinerins, cinidon-ethyl, cinmethylin, lfuron, ciobutide, cisanilide, cismethrin, clethodim, climbazole, cliodinate, clodinafop, clodinafop-propargyl, cloethocarb, clofencet, clofencet-potassium, clofentezine, clofibric acid, clofop, clofop-isobutyl, clomazone, clomeprop, cloprop, cloproxydim, alid, clopyralid-methy1, 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, etralyl, coumithoate, coumoxystrobin, CPMC, CPMF, CPPC, credazine, cresol, crimidine, crotamiton, yphos, crufomate, cryolite, cue-lure, cufraneb, cumyluron, cuprobam, cuprous oxide, curcumenol, cyanamide, cyanatryn, cyanazine, cyanofenphos, cyanophos, cyanthoate, cyantraniliprole, cyazofamid, cybutryne, cyclafuramid, cyclanilide, cyclethrin, te, cycloheximide, rate, cycloprothrin, cyclosulfamuron, cycloxaprid, ydim, cycluron, cyenopyrafen, cyflufenamid, cyflumetofen, cyfluthrin, cyhalofop, cyhalofop-butyl, cyhalothrin, cyhexatin, cymiazole, cymiazole hydrochloride, cymoxanil, cyometrinil, cypendazole, cypermethrin, cyperquat, uat chloride, cyphenothrin, cyprazine, ole, cyproconazole, cyprodinil, cyprofuram, cypromid, cyprosulfamide, cyromazine, cythioate, daimuron, dalapon, dalapon-calcium, dalapon-magnesium, dalaponsodium , daminozide, dayoutong, dazomet, dazomet-sodium, DBCP, hor, DCIP, DCPTA, DDT, debacarb, decafentin, decarbofuran, dehydroacetic acid, delachlor, deltamethrin, demephion, demephion-0, demephion-S, demeton, n-methyl, demeton- 0, demetonmethyl, demeton-S, demeton-S-methyl, demeton-S-methylsulphon, ipham, desmetryn, d-fanshiluquebingjuzhi, diafenthiuron, dialifos, di-allate, diamidafos, aceous earth, on, dibutyl phthalate, l succinate, dicamba, wo 2012/177813 dicamba-diglycolamine, a-dimethyIammonium, dicamba-diolamine, dicambaisopropylammonium , dicamba-methyl, dicamba-olamine, dicamba-potassium, dicambasodium , dicamba-trolamine, dicapthon, dichlobenil, dichlofenthion, dichlofluanid, dichlone, dichloralurea, dichlorbenzuron, dichlorflurenol, dichlorflurenol-methyl, dichlormate, dichlormid, dichlorophen, dichlorprop, dichlorpropethylhexyl, dichlorprop-butotyl, dichlorprop-dimethy!ammonium, dichlorprop-ethy!ammonium, dichlorprop-isocty1, dichlorprop-methy1, dichlorprop-P, dichlorprop-Pethylhexy1, dichlorprop-P- dimethylammonium, dichlorprop-potassium, rprop-sodium, dichlorvos, dichlozoline, diclobutrazol, diclocymet, diclofop, diclofop-methyl, diclomezine, diclomezine-sodium, dicloran, ulam, 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, enican, diflufenzopyr, diflufenzopyr-sodium, diflumetorim, dikegulac, dikegulac-sodium, dilor, f, dimefluthrin, dimefox, dimefuron, dimepiperate, dimetachlone, dimetan, dimethacarb, dimethachlor, ametryn, dimethenamid, dimethenamid-P, ipin, dimethirimol, dimethoate, dimethomorph, dimethrin, dimethyl carbate, yl phthalate, dimethylvinphos, dimetilan, dimexano, dimidazon, dimoxystrobin, dinex, dinex-diclexine, dingjunezuo, diniconazole, nazole-M, dinitramine, dinobuton, dinocap, dinocap-4, dinocap-6, dinocton, dinofenate, nton, dinoprop, dinosam, dinoseb, dinoseb e, dinoseb-ammonium, dinoseb-diolamine, dinoseb-sodium, b-trolamine, dinosulfon, dinotefuran, dinoterb, rb 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, ether, dithiopyr, diuron, dlimonene , DMPA, DNOC, DNOC-ammonium, otassium, DNOC-sodium, dodemorph, rph acetate, dodemorph benzoate, dodicin, dodicin hydrochloride, dodicin-sodium, dodine, pyn, dominicalure, ctin, drazoxolon, DSMA, dufulin, EBEP, EBP, ecdysterone, edifenphos, eglinazine, eglinazine-ethyl, emamectin, emamectin benzoate, EMPC, hrin, endosulfan, endothal, endothal-diammonium, endothaldipotassium , endothal-disodium, endothion, , enestroburin, EPN, epocholeone, epofenonane, epoxiconazole, eprinomectin, epronaz, EPTC, erbon, ergocalciferol, erlujixiancaoan, esdepallethrine, esfenvalerate, esprocarb, etacelasil, etaconazole, etaphos, wo 2012/177813 etem, ethaboxam, ethachlor, ethalfluralin, ethametsulfuron, ethametsulfuron-methyl, ethaprochlor, ethephon, ethidimuron, ethiofencarb, ethiolate, ethion, ethiozin, ethiprole, ethirimol, e-methyl, ethofumesate, ethohexadiol, ophos, ethoxyfen, fenethyl , ethoxyquin, ethoxysulfuron, ethychlozate, ethyl formate, ethyl a-naphthaleneacetate, ethyl-DDD, ethylene, ethylene dibromide, ethylene ride, ethylene oxide, ethylicin, ethylmercury 2,3-dihydroxypropyl tide, ethylmercury e, ethylmercury bromide, ethylmercury chloride, ethylmercury phosphate, etinofen, omid, etobenzanid, etofenprox, etoxazole, azole, etrimfos, eugenol, EXD, famoxadone, famphur, fenamidone, fenaminosulf, fenamiphos, fenapanil, fenarimol, fenasulam, flor, fenazaquin, fenbuconazole, fenbutatin oxide, fenchlorazole, fenchlorazole-ethyl, fenchlorphos, fenclorim, fenethacarb, fenfluthrin, fenfuram, fenhexamid, fenitropan, fenitrothion, fenjuntong, fenobucarb, fenoprop, fenopropbutoxypropyl, opbutomety1 , fenoprop-butoty1, fenoprop-buty1, fenoprop-isocty1, fenoprop-methy1, fenoproppotassium , fenothiocarb, fenoxacrim, fenoxanil, fenoxaprop, fenoxaprop-ethyl, fenoxaprop-P, prop-P-ethyl, fenoxasulfone, fenoxycarb, fenpiclonil, fenpirithrin, fenpropathrin, fenpropidin, fenpropimorph, fenpyrazamine, fenpyroximate, fenridazon, azonpotassium , fenridazon-propyl, fenson, fensulfothion, fenteracol, fenthiaprop, fenthiapropethyl , fenthion, fenthion-ethyl, , fentin acetate, fentin chloride, fentin hydroxide, fentrazamide, fentrifanil, fenuron, fenuron TCA, fenvalerate, ferbam, one, ferrous e, fipronil, flamprop, flamprop-isopropyl, flamprop-M, flamprop-methyl, flamprop-M- isopropyl, op-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, oralin, flucofuron, flucycloxuron, flucythrinate, fludioxonil, fluenetil, fluensulfone, flufenacet, flufenerim, flufenican, flufenoxuron, flufenprox, flufenpyr, flufenpyr-ethyl, flufiprole, flumethrin, flumetover, flumetralin, flumetsulam, in, flumiclorac, flumiclorac-pentyl, flumioxazin, ropyn, flumorph, fluometuron, fluopicolide, fluopyram, fluorbenside, fluoridamid, fluoroacetamide, fluorodifen, fluoroglycofen, fluoroglycofen-ethyl, fluoroimide, fluoromidine, fluoronitrofen, fluothiuron, fluotrimazole, fluoxastrobin, flupoxam, flupropacil, padine, flupropanate, flupropanate-sodium, flupyradifurone, flupyrsulfuron, flupyrsulfuron-methyl, flupyrsulfuronmethyl-sodium , fluquinconazole, flurazole, flurenol, flurenol-butyl, flurenol-methyl, fluridone, flurochloridone, fluroxypyr, fluroxypyr-butometyl, fluroxypyr-meptyl, flurprimidol, flursulamid, mone, flusilazole, flusulfamide, fluthiacet, fluthiacet-methyl, wo 2012/177813 flutianil, flutolanil, flutriafol, fluvalinate, fluxapyroxad, fluxofenim, folpet, fen, fomesafen-sodium, fonofos, foramsulfuron, forchlorfenuron, formaldehyde, formetanate, formetanate hydrochloride, formothion, ranate, formparanate hydrochloride, fosamine, fosamine-ammonium, fosetyl, fosetyl-aluminium, fosmethilan, fospirate, fosthiazate, fosthietan, frontalin, fuberidazole, fucaojing, fucaomi, funaihecaoling, fuphenthiourea, furalane, xyl, furamethrin, furametpyr, furathiocarb, furcarbanil, furconazole, furconazole-cis, furethrin, al, furilazole, yclox, furophanate, furyloxyfen, gamma-cyhalothrin, gamma-HCH, genit, gibberellic acid, gibberellins, r, inate, glufosinate-ammonium, glufosinate-P, glufosinate-P-ammonium, inate-P-sodium, n, glyoxime, sate, glyphosate-diammonium, sate-dimethylammonium, glyphosate-isopropylammonium, sate-monoammonium, sate-potassium, glyphosate-sesquisodium, glyphosate-trimesium, glyphosine, gossyplure, grandlure, griseofulvin, guazatine, guazatine acetates, halacrinate, halfenprox, halofenozide, halosafen, lfuron, 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, aoling, huanjunzuo, hydramethylnon, gaphen, hydrated lime, hydrogen cyanide, hydroprene, hymexazol, hyquincarb, IAA, IBA, icaridin, imazalil, imazalil nitrate, imazalil sulfate, imazamethabenz, imazamethabenz-methyl, imazamox, imazamoxammonium , imazapic, imazapic-ammonium, yr, 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, ofos, isazofos, isobenzan, isocarbamid, isocarbophos, isocil, isodrin, isofenphos, phos-methyl, isolan, hiozin, 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 wo 2012/177813 II, jasmonic acid, jiahuangchongzong, jiajizengxiaolin, jiaxiangjunzhi, wan, jiecaoxi, phos, juvenile hormone I, juvenile hormone II, juvenile hormone III, kadethrin, karbutilate, karetazan, karetazan-potassium, kasugamycin, kasugamycin hydrochloride, kejunlin, kelevan, ketospiradox, ketospiradox-potassium, kinetin, kinoprene, im- methyl, kuicaoxi, lactofen, lambda-cyhalothrin, latilure, lead arsenate, lenacil, lepimectin, leptophos, lindane, lineatin, n, os, 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, mecopropethylhexyl, mecoprop-dimethylammonium, mecoprop-diolamine, mecoprop-ethadyl, mecoprop-isoctyl, mecoprop-methyl, mecoprop-P, mecoprop-P exy1, mecoprop-P-dimethy!ammonium, mecoprop-P-isobuty1, mecoprop-potassium, mecoprop-P-potassium, op-sodium, mecoprop-trolamine, form, medinoterb, terb acetate, medlure, mefenacet, mefenpyr, mefenpyr-diethyl, dide, mefluidide-diolamine, mefluidide-potassium, megatomoic acid, menazon, pyrim, meperfluthrin, mephenate, mephosfolan, mepiquat, mepiquat chloride, mepiquat pentaborate, mepronil, dinocap, mercuric chloride, mercuric oxide, mercurous chloride, merphos, azine, mesosulfuron, mesosulfuron-methyl, mesotrione, mesulfen, mesulfenfos, metaflumizone, metalaxyl, metalaxyl-M, ehyde, metam, metam-ammonium, metamifop, metamitron, metam-potassium, metam-sodium, metazachlor, sulfuron, metazoxolon, metconazole, metepa, metflurazon, enzthiazuron, 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, acetophos, methylchloroform, methyldymron, methylene chloride, methylmercury benzoate, methylmercury dicyandiamide, methylmercury pentachlorophenoxide, methylneodecanamide, metiram, metobenzuron, metobromuron, uthrin, metolachlor, metolcarb, metominostrobin, metosulam, metoxadiazone, metoxuron, enone, metribuzin, metsulfovax, metsulfuron, metsulfuron-methyl, mevinphos, mexacarbate, wo 2012/177813 mieshuan, milbemectin, milbemycin oxime, milneb, x, mirex, MNAF, moguchun, molinate, molosultap, monalide, monisouron, monochloroacetic acid, monocrotophos, monolinuron, monosulfuron, monosulfuron-ester, n, monuron TCA, morfamquat, morfamquat dichloride, moroxydine, moroxydine hydrochloride, morphothion, morzid, moxidectin, MSMA, muscalure, myclobutanil, myclozolin, N-(ethylmercury)-ptoluenesulphonanilide , nabam, naftalofos, naled, naphthalene, naphthaleneacetamide, naphthalic anhydride, oxyacetic 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, mide, norflurazon, nornicotine, noruron, novaluron, noviflumuron, nuarimol, OCH, octachlorodipropyl ether, octhilinone, ofurace, ate, 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, ngding, para-dichlorobenzene, parafluron, paraquat, paraquat dichloride, paraquat dimetilsulfate, parathion, parathion-methyl, parinol, pebulate, pefurazoate, pelargonic acid, penconazole, pencycuron, pendimethalin, penflufen, penfluron, penoxsulam, hlorophenol, pentanochlor, opyrad, 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 techol, phenylmercury nitrate, phenylmercury salicylate, phorate, phosacetim, one, phosdiphen, phosfolan, lan-methyl, phosglycin, phosmet, phosnichlor, amidon, phosphine, ocarb, phosphorus, phostin, phoxim, phoxim-methyl, phthalide, picloram, picloramethylhexyl, picloram-isoctyl, piclorammethy1 , picloram-olamine, picloram-potassium, picloram-triethy!ammonium, picloram-tris(2- ypropyl)ammonium, picolinafen, picoxystrobin, pindone, pindone-sodium, pinoxaden, piperalin, piperonyl butoxide, piperonyl cyclonene, piperophos, tanyl, piproctanyl bromide, piprotal, pirimetaphos, pirimicarb, pirimioxyphos, pirimiphos-ethyl, pirimiphosmethyl , plifenate, rbamate, polyoxins, polyoxorim, polyoxorim-zinc, polythialan, potassium te, potassium azide, ium cyanate, potassium gibberellate, potassium wo 2012/177813 2012/043418 naphthenate, potassium polysulfide, potassium thiocyanate, potassium a-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, nazine-ethyl, prohexadione, prohexadionecalcium , prohydrojasmon, yl, promecarb, prometon, prometryn, promurit, hlor, propamidine, propamidine dihydrochloride, propamocarb, propamocarb hydrochloride, propanil, hos, propaquizafop, propargite, proparthrin, propazine, amphos, propham, propiconazole, eb, propisochlor, propoxur, propoxycarbazone, propoxycarbazone-sodium, propyl isome, propyrisulfuron, propyzamide, proquinazid, prosuler, prosulfalin, prosulfocarb, prosulfuron, prothidathion, prothiocarb, prothiocarb hydrochloride, prothioconazole, prothiofos, prothoate, protrifenbute, , proxan-sodium, prynachlor, pydanon, ozine, pyracarbolid, pyraclofos, pyraclonil, pyraclostrobin, pyraflufen, ufen-ethyl, pyrafluprole, pyramat, pyrametostrobin, pyraoxystrobin, pyrasulfotole, pyrazolynate, pyrazophos, pyrazosulfuron, sulfuron-ethyl, pyrazothion, pyrazoxyfen, ethrin, pyrethrin I, pyrethrin II, pyrethrins, mbenz-isopropyl, pyribambenz-propyl, pyribencarb, pyribenzoxim, pyributicarb, pyriclor, pyridaben, pyridafol, pyridalyl, pyridaphenthion, pyridate, pyridinitril, pyrifenox, pyrifluquinazon, alid, pyrimethanil, pyrimidifen, pyriminobac, pyriminobac-methyl, pyrimisulfan, pyrimitate, pyrinuron, pyriofenone, pyriprole, pyripropanol, pyriproxyfen, pyrithiobac, pyrithiobacsodium , pyrolan, pyroquilon, pyroxasulfone, pyroxsulam, pyroxychlor, pyroxyfur, quassia, quinacetol, quinacetol sulfate, quinalphos, quinalphos-methyl, quinazamid, quinclorac, quinconazole, quinmerac, lamine, quinonamid, quinothion, quinoxyfen, ofos, quintozene, quizalofop, ofop-ethyl, quizalofop-P, quizalofop-P-ethyl, quizalofop-P- tefuryl, hi, quyingding, rabenzazole, rafoxanide, rebemide, resmethrin, rhodethanil, rhodojaponin-III, ribavirin, rimsulfuron, rotenone, ryania, saflufenacil, saijunmao, saisentong, salicylanilide, sanguinarine, santonin, schradan, scilliroside, sebuthylazine, secbumeton, sedaxane, ctin, semiamitraz, semiamitraz chloride, sesamex, sesamolin, sethoxydim, jiaancaolin, siduron, siglure, silafluofen, ane, 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 a-naphthaleneacetate, ide, spinetoram, spinosad, spirodiclofen, spiromesifen, spirotetramat, spiroxamine, streptomycin, streptomycin wo 2012/177813 sesquisulfate, strychnine, sulcatol, sulcofuron, uron-sodium, sulcotrione, sulfallate, sulfentrazone, sulfiram, sulfluramid, sulfometuron, sulfometuron-methyl, sulfosulfuron, sulfotep, sulfoxaflor, sulfoxide, sulfoxime, sulfur, sulfuric acid, sulfuryl fluoride, sulglycapin, sulprofos, pen, swep, tau-fluvalinate, tavron, tazimcarb, TCA, TCA-ammonium, TCA- calcium, TCA-ethadyl, TCA-magnesium, TCA-sodium, TDE, tebuconazole, nozide, tebufenpyrad, oquin, tebupirimfos, tebutam, tebuthiuron, tecloftalam, ene, m, teflubenzuron, tefluthrin, tefuryltrione, tembotrione, temephos, tepa, TEPP, oxydim, terallethrin, terbacil, terbucarb, terbuchlor, terbufos, terbumeton, terbuthylazine, terbutryn, tetcyclacis, tetrachloroethane, tetrachlorvinphos, tetraconazole, ifon, tetrafluron, tetramethrin, tetramethylfluthrin, tetramine, tetranactin, tetrasul, thallium e, thenylchlor, theta-cypermethrin, ndazole, oprid, thiadifluor, thiamethoxam, thiapronil, thiazafluron, thiazopyr, thicrofos, thicyofen, thidiazimin, thidiazuron, thiencarbazone, thiencarbazone-methy1, thifensulfuron, thifensulfuron-methy1, thifluzamide, thiobencarb, thiocarboxime, thiochlorfenphim, thiocyclam, thiocyclam hydrochloride, thiocyclam oxalate, thiodiazole-copper, thiodicarb, thiofanox, thiofluoximate, thiohempa, thiomersal, thiometon, thionazin, thiophanate, thiophanate-methyl, inox, thiosemicarbazide, thiosultap, thiosultap-diammonium, thiosultap-disodium, thiosultapmonosodium , thiotepa, thiram, thuringiensin, tiadinil, tiaojiean, tiocarbazil, tioclorim, tioxymid, e, tolclofos-methyl, tolfenpyrad, tolylfluanid, tolylmercury acetate, topramezone, tralkoxydim, tralocythrin, tralomethrin, tralopyril, transfluthrin, transpermethrin, tretamine, ntanol, triadimefon, triadimenol, triafamone, tri-allate, phos, nthenol, triarathene, triarimol, triasulfuron, triazamate, triazbutil, triaziflam, triazophos, triazoxide, tribenuron, tribenuron-methyl, tribufos, tributyltin oxide, tricamba, trichlamide, trichlorfon, ormetaphos-3, oronat, triclopyr, triclopyr-butotyl, triclopyr-ethyl, triclopyr-triethylammonium, tricyclazole, tridemorph, tridiphane, trietazine, trifenmorph, trifenofos, trifloxystrobin, trifloxysulfuron, trifloxysulfuron-sodium, triflumizole, triflumuron, trifluralin, triflusulfuron, triflusulfuron-methyl, trifop, trifopmethyl , trifopsime, triforine, trihydroxytriazine, lure, trimethacarb, trimeturon, trinexapac, apac-ethyl, triprene, tripropindan, triptolide, tritac, triticonazole, tritosulfuron, call, uniconazole, uniconazole-P, urbacide, uredepa, valerate, validamycin, valifenalate, valone, thion, 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, wo 2012/177813 zuomihuanglong, a-chlorohydrin, a-ecdysone, istriatin, and a-naphthaleneacetic acid.
For more information consult the "COMPENDIUM OF PESTICIDE COMMON NAMES" located at http://wvv·w.a1anwood.netipesticides/index.htm1. 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 ial 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 , including derma spp. and Ampelomyces quisqualis (a control agent for grape y 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, tera, and Diptera. Because it has little effect on other organisms, it is considered more nmentally friendly than synthetic pesticides. Biological insecticides include products based on: 1. entomopathogenic fungi (e.g. Metarhizium anisopliae); 2. entomopathogenic des (e.g. Steinernemafeltiae); and 3. pathogenic viruses (e.g. Cydia pomonella granulovirus).
Other examples of entomopathogenic organisms e, but are not limited to, baculoviruses, bacteria and other prokaryotic organisms, fungi, protozoa and Microsproridia.
Biologically derived insecticides e, but not d 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 ed 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 ofBiocontrol Agents gives a review of the available biological insecticide (and other biology-based control) products. g L.G. (ed.) (2004). The Manual ofBiocontrol Agents (formerly the Biopesticide Manual) 3rd Edition. British Crop Production Council (BCPC), Farnham, Surrey UK.
OTHER ACTIVE COMPOUNDS wo 2012/177813 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)hydroxyoxaazaspiro[4,5]decenone; 2. 3-(4'-chloro-2,4-dimethyl[1,1'-biphenyl]yl)hydroxyoxaazaspiro[4,5]dec- -one; 3. 4-[[(6-chloropyridinyl)methyl]methylamino]-2(5H)-furanone; 4. -chloropyridinyl)methyl]cyclopropylamino]-2(5H)-furanone; . 3-chloro-N2-[(1S)methyl(methylsulfonyl)ethyl]-N1-[2-methyl[ 1,2,2,2- tetrafluoro(trifluoromethy1)ethy1]pheny1] -1 ,2-benzenedicarboxamide; 6. 2-cyano-N-ethylfluoromethoxy-benenesulfonamide; 7. 2-cyano-N-ethylmethoxy-benzenesulfonamide; 8. 2-cyanodifluoromethoxy-N-ethylfluoro-benzenesulfonamide; 9. 2-cyanofluoromethoxy-N-ethyl-benzenesulfonamide; 10. ofluoromethoxy-N,N-dimethyl-benzenesulfonamide; 11. 2-cyano-N-ethylfluoromethoxy-N-methyl-benzenesulfonamide; 12. 2-cyanodifluoromethoxy-N,N-dimethylbenzenesulfon-amide; 13. 3-(difluoromethyl)-N-[2-(3,3-dimethylbutyl)phenyl]methyl-1H-pyrazole carboxamide; 14. N-ethyl-2,2-dimethylpropionamide(2,6-dichloro-a,a,a-trifluoro-p-tolyl) hydrazone; . N-ethy1-2,2-dichloromethylcyclopropane-carboxamide(2,6-dichloro-a,a,atrifluoro-p-tolyl ) hydrazone ne; 16. 0-{(E-)-[2-(4-chloro-phenyl)cyano(2-trifluoromethylphenyl)-vinyl]} S-methyl thiocarbonate; 17. (E)-N1-[(2-chloro-1 ,3-thiazolylmethyl)]-N2-cyano-N1-methylacetamidine; 18. 1-(6-chloropyridinylmethyl)methylnitro-1 ,2,3,5,6,7-hexahydro-imidazo[1 ,2- a]pyridinol; 19. 4-[4-chloropheny1-(2-butylidine-hydrazono)methy1)]pheny1mesylate; and . N-Ethyl-2,2-dichloromethylcyclopropanecarboxamide(2,6-dichloro- alpha,alpha,alpha-trifluoro-p-tolyl)hydrazone.
SYNERGISTIC MIXTURES Molecules of a One may be used with certain active compounds to form synergistic es 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 wo 2012/177813 modes of action include, but are not limited to: acetylcholinesterase tor; sodium channel modulator; chitin biosynthesis inhibitor; GABA and glutamate-gated chloride channel antagonist; GABA and glutamate-gated de channel agonist; acetylcholine receptor agonist; choline 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 a 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, ncapsulations, seed treatments, suspension concentrates, mulsions, tablets, water soluble s, water dispersible granules or dry flowables, wettable powders, and ultra low volume solutions. For further information on formulation types see "Catalogue of ide Formulation Types and International Coding System" Technical Monograph n°2, 5th n by CropLife International (2002).
Pesticides are applied most often as s suspensions or emulsions prepared from concentrated ations of such pesticides. Such water-soluble, water-suspendable, or emulsifiable formulations are either solids, usually known as wettable powders, or water dispersible granules, or s 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 r, 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, sing from about 0.5% to about 10% of the wettable powder, are found among sulfonated lignins, condensed alenesulfonates, naphthalenesulfonates, alkylbenzenesulfonates, alkyl sulfates, and non-ionic tants 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 wo 2012/177813 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 se 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 usly 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 ive to grind and mix the pesticide at the same time by preparing the aqueous mixture and nizing it in an implement such as a sand mill, ball mill, or -type homogenizer. ides may also be applied as granular compositions that are particularly useful for applications to the soil. Granular itions usually contain from about 0.5% to about % by weight of the ide, 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 r 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 d granular le size.
Dusts ning a pesticide are prepared by intimately mixing the ide in ed 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 t, 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 pressuregenerating propellant mixture. The aerosol composition is packaged in a container from which the mixture is sed through an atomizing valve. wo 2012/177813 ide 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 trations to kill pests in soil or enclosed spaces. The toxicity of the fumigant is proportional to its concentration and the exposure time. They are terized by a good capacity for diffusion and act by penetrating the pest'srespiratory system or being ed through the pest'scuticle. 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 ide particles or droplets in plastic polymers of various types. By altering the chemistry of the polymer or by changing factors in the sing, microcapsules can be formed of various sizes, solubility, wall thicknesses, and s of penetrability. These factors govern the speed with which the active ingredient within is released, which in turn, s 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 es 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 nonionic hydrophilic surface-active agent and (3) at least one ionic surface-active agent, wherein the globules having a mean particle diameter of less than 800 nanometers. r information on the ment is disclosed in U.S. patent publication 20070027034 published February 1, 2007, having Patent Application serial number 111495,228. For ease of use, this ment will be referred to as "OIWE".
For further information consult "Insect Pest Management" 2nd Edition by D. Dent, ght CAB International (2000). Additionally, for more detailed information consult wo 2012/177813 "Handbook of Pest Control- The Behavior, Life History, and Control of Household Pests" by Arnold , 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 e, but are not limited to, (this is a non-exhaustive and non-mutually exclusive list) wetters, spreaders, stickers, penetrants, buffers, sequestering , drift reduction agents, compatibility agents, anti-foam agents, cleaning agents, and emulsifiers. A few ents 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. g 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 g time of wettable powders and to improve the penetration of water into water-dispersible granules. Examples of g 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 sing 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 les redisperse into water in a spray tank. They are widely used in wettable powders, suspension concentrates and dispersible granules. Surfactants that are used as dispersing agents have the y 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 late 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 tants have been developed as dispersing agents. wo 2012/177813 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 e the hydrophobic backbones have many anchoring points onto the particle surfaces. Examples of sing 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 ts of one liquid phase in r liquid phase. t the emulsifying agent the two s 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 oilsoluble 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 tant 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 tants usually used for solubilization are non-ionics, sorbitan monooleates, sorbitan eate 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 ical 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 ide. r, 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 ts are used in the formulation of dusts, le s, granules and water- dispersible granules.
Organic solvents are used mainly in the formulation of fiable concentrates, oilin-water emulsions, suspoemulsions, and ultra low volume formulations, and to a lesser extent, granular formulations. Sometimes es of solvents are used. The first main groups of solvents are aliphatic paraffinic oils such as kerosene or refined paraffins. The wo 77813 2012/043418 second main group (and the most ) comprises the aromatic solvents such as xylene and higher molecular weight fractions of C9 and CIO ic 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 tion and settling of the dispersed particles or droplets.
Thickening, gelling, and ettling agents generally fall into two categories, namely waterinsoluble 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, ite, magnesium um 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; c acid and its sodium salt; p-hydroxybenzoic acid sodium salt; methyl p- hydroxybenzoate; and 1,2-benzisothiazolinone (BIT).
The ce of surfactants often causes water-based ations 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 oam agents, namely silicones and non-silicones. Silicones are usually aqueous ons of dimethyl polysiloxane, while the licone 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. wo 2012/177813 2012/043418 "Green" agents (e.g., adjuvants, surfactants, solvents) can reduce the overall environmental footprint of crop protection formulations. Green agents are biodegradable and lly derived from natural and/or sustainable sources, e.g. plant and animal sources.
Specific es 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 hers.
Also see ticides 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, es, moths, flies, lice, grasshoppers, locusts, crickets, fleas, thrips, bristletails, mites, ticks, des, and symphylans.
In another ment, 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 ment, the molecules of a 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 Polyp/ax spp. A non-exhaustive list of ular species includes, but is not limited to, Haematopinus asini, opinus 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., orus spp., Phyllophaga spp., Phyllotreta spp., Rhizotrogus spp., Rhynchites spp., ophorus spp., Scolytus spp., Sphenophorus spp., Sitophilus spp., and wo 2012/177813 Tribolium spp. A non-exhaustive list of particular s includes, but is not limited to, oscelides obtectus, Agrilus planipennis, phora glabripennis, Anthonomus s, Ataenius spretulus, Atomaria is, Bothynoderes punctiventris, Bruchus pisorum, Callosobruchus maculatus, Carpophilus hemipterus, Cassida vittata, Cerotoma cata, hynchus 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 a, Hypothenemus hampei, Lasioderma serricorne, Leptinotarsa decemlineata, ysfuscus, Liogenys suturalis, Lissorhoptrus oryzophilus, Maecolaspis joliveti, Melanotus communis, Meligethes aeneus, Melolontha melolontha, Oberea , Oberea linearis, Oryctes rhinoceros, Oryzaephilus mercator, Oryzaephilus surinamensis, Oulema melanopus, Oulema oryzae, Phyllophaga cuyabana, Popillia japonica, Prostephanus truncatus, Rhyzopertha dominica, Sitona lineatus, ilus 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 ular species includes, but is not limited to, Blattella germanica, Blatta orienta/is, Parcoblatta pennsylvanica, Periplaneta ana, Periplaneta australasiae, Periplaneta brunnea, Periplanetafuliginosa, Pycnoscelus mensis, and Supella longipalpa.
In r embodiment, the molecules of Formula One may be used to control pests of the Order Diptera. A non-exhaustive list of ular 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., hila spp., Fannia spp., Hylemyia spp., Liriomyza spp., Musca spp., Phorbia spp., Tabanus spp., and Tipula spp. A haustive list of particular species includes, but is not limited to, Agromyzafrontella, Anastrepha sa, Anastrepha ludens, epha 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 , Musca autumnalis, Musca domestica, Oestrus ovis, wo 2012/177813 Oscinellafrit, Pegomya betae, Psila rosae, Rhagoletis cerasi, Rhagoletis pomonella, Rhagoletis mendax, Sitodiplosis mosellana, and Stomoxys calcitrans.
In another embodiment, the les of a 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 haustive list of particular species includes, but is not limited to, Acrosternum , Acyrthosiphon pisum, Aleyrodes proletella, Aleurodicus dispersus, Aleurothrixusfloccosus, Amrasca biguttula biguttula, Aonidiella aurantii, Aphis gossypii, Aphis es, Aphis pomi, Aulacorthum solani, Bemisia argentifolii, Bemisia , Blissus leucopterus, corynella asparagi, nia rehi, Brevicoryne brassicae, Calocoris norvegicus, Ceroplastes rubens, Cimex hemipterus, Cimex lectularius, Dagbertusfasciatus, Dichelopsfurcatus, Diuraphis noxia, Diaphorina citri, Dysaphis plantaginea, Dysdercus suturellus, Edessa meditabunda, Eriosoma lanigerum, Eurygaster maura, Euschistus heros, Euschistus , Helopeltis antonii, ltis theivora, Icerya purchasi, Idioscopus nitidulus, Laodelphax striatellus, Leptocorisa oratorius, Leptocorisa varicornis, Lygus hesperus, Maconellicoccus hirsutus, Macrosiphum euphorbiae, iphum granarium, Macrosiphum rosae, Macrosteles quadrilineatus, Mahanarvafrimbiolata, Metopolophium um, Mictis ornis, Myzus persicae, Nephotettix cinctipes, Neurocolpus longirostris, Nezara viridula, Nilaparvata , oria dii, Parlatoria ziziphi, Peregrinus maidis, Phylloxera vitifoliae, Physokermes piceae, Phytocoris californicus, Phytocoris relativus, Piezodorus guildinii, Poecilocapsus us, Psallus vaccinicola, Pseudacysta perseae, Pseudococcus brevipes, Quadraspidiotus perniciosus, Rhopalosiphum maidis, Rhopalosiphum padi, Saissetia oleae, Scaptocoris ea, Schizaphis um, Sitobion avenae, Sogatellafurcifera, Trialeurodes vaporariorum, Trialeurodes abutiloneus, Unaspis yanonensis, and Zulia entrerriana.
In another embodiment, the les 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., wo 2012/177813 Vespula spp., and Xylocopa spp. A non-exhaustive list of particular species includes, but is not limited to, a rosae, Atta texana, Iridomyrmex humilis, Monomorium minimum, Monomorium nis, Solenopsis invicta, Solenopsis ta, Solenopsis molesta, Solenopsis richtery, Solenopsis xyloni, and Tapinoma sessile.
In another embodiment, the molecules of a 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., nitermes 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 litermes 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., nia 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, rsia gemmatalis, Archips argyrospila, Archips rosana, Argyrotaenia citrana, Autographa gamma, Bonagota cranaodes, Barbo cinnara, atrix thurberiella, Capua reticulana, ina niponensis, tia transversa, toneura rosaceana, Cnaphalocrocis medina/is, Conopomorpha cramerella, Cossus cossus, Cydia a, Cydia funebrana, Cydia molesta, Cydia nigricana, Cydia pomonella, Darna diducta, Diatraea saccharalis, Diatraea grandiosella, Earias insulana, Earias vittella, Ecdytolopha ianum, Elasmopalpus lignosellus, Ephestia cautella, Ephestia elutella, Ephestia kuehniella, ia aporema, Epiphyas postvittana, Erionota thrax, Eupoecilia ambiguella, Euxoa auxiliaris, Grapholita molesta, Hedylepta indicata, Helicoverpa armigera, Helicoverpa zea, Heliothis ens, Hellula s, Keiferia lycopersicella, Leucinodes wo 2012/177813 orbonalis, tera coffeella, Leucoptera malifoliella, Lobesia botrana, otis albicosta, Lymantria dispar, Lyonetia clerkella, Mahasena corbetti, Mamestra brassicae, Maruca alis, Metisa plana, Mythimna unipuncta, cinodes 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, la xylostella, Polychrosis viteana, Prays endocarpa, Prays oleae, Pseudaletia unipuncta, Pseudoplusia includens, Rachiplusia nu, Scirpophaga incertulas, Sesamia inferens, Sesamia nonagrioides, Setora nitens, Sitotroga ella, Sparganothis pilleriana, Spodoptera exigua, Spodoptera erda, Spodoptera eridania, Thecla basi/ides, Tineola liella, Trichoplusia ni, Tuta ta, Zeuzera coffeae, and Zeuzera pyrina.
In r 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 haustive list of particular species includes, but is not limited to, Bovicola bovis, Bovicola caprae, Bovicola ovis, Chelopistes meleagridis, Goniodes dissimilis, Goniodes gigas, Menacanthus stramineus, n 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 d to, Melanoplus spp., and Pterophylla spp. A non-exhaustive list of particular species includes, but is not d to, Anabrus simplex, Gryllotalpa africana, Gryllotalpa australis, Gryllotalpa brachyptera, Gryllotalpa hexadactyla, Locusta migratoria, Microcentrum retinerve, Schistocerca gregaria, and riafurcata.
In another embodiment, the molecules of Formula One may be used to control pests of the Order Siphonaptera. A non-exhaustive list of ular species includes, but is not d to, Ceratophyllus gallinae, phyllus 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 nonexhaustive list of particular sp. includes, but is not limited to, Frankliniella fusca, Frankliniella occidentalis, Frankliniella schultzei, Frankliniella williamsi, Heliothrips wo 2012/177813 2012/043418 haemorrhoidalis, Rhipiphorothrips cruentatus, Scirtothrips citri, Scirtothrips dorsalis, and Taeniothrips rhopalantennalis, Thrips hawaiiensis, Thrips nigropilosus, Thrips orienta/is, 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 r 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., entor 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, is woodi, Acarus siro, Aceria mangiferae, Aculops lycopersici, Aculus pelekassi, Aculus schlechtendali, Amblyomma americanum, Brevipalpus obovatus, Brevipalpus phoenicis, Dermacentor variabilis, Dermatophagoides pteronyssinus, Eotetranychus carpini, res cati, Oligonychus coffeae, Oligonychus ilicis, Panonychus citri, Panonychus ulmi, Phyllocoptruta oleivora, Polyphagotarsonemus latus, Rhipicephalus sanguineus, Sarcoptes scabiei, Tegolophus perseaflorae, ychus urticae, and Varroa ctor.
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. es, but is not limited to, erella immaculata.
In r 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, nchoides spp., Belonolaimus spp., Criconemella spp., Ditylenchus spp., Heterodera spp., Hirschmanniella spp., aimus 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 ita, 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 lly 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 wo 2012/177813 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 ted, or traversed by) a pest, for e: 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, , wheat, rice, sorghum, barley, oats, potatoes, oranges, alfalfa, lettuce, strawberries, es, peppers, crucifers, pears, tobacco, s, 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 s can occur. Generally, pest tions, 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 les 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 les may be used during times when pest activity is low, such as before the plants that are g 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 t with the pest, or the pest will consume the pesticide when eating leaf, fruit mass, or extracting sap, that ns the ide. The les 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 wo 2012/177813 molecule taking it up into the foliar portions of the plant to control above ground g 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 , or placed on the surface of a capsule. The size of the capsules can range from ter size (about 100-900 nanometers in diameter) to eter 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 l pests on one portion of the plant by applying (for example by spraying an area) the les of Formula One to a ent portion of the plant. For example, control of foliar-feeding insects can be achieved by drip irrigation or furrow application, by ng 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 d 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 sing insecticidal toxins, herbicide resistance, nutrition-enhancement, drought resistance, or any other cial 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 ed 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 lized traits, such as Bacillus thuringiensis or other insecticidal , or those expressing herbicide resistance, or those wo 2012/177813 with "stacked" foreign genes expressing insecticidal toxins, ide resistance, nutritionenhancement , or any other cial traits.
The molecules of a One may be used for controlling endoparasites and ectoparasites in the veterinary medicine sector or in the field of man animal keeping.
The molecules of Formula One are d, such as by oral stration 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 some to such animals. Suitable formulations are administered orally to the s with the ng 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 ed in therapeutic methods for human health care. Such methods e, but are limited to, oral administration in the form of, for example, tablets, capsules, drinks, granules, and by dermal ation.
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. sed biomass and/or sed 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 ities (local, regional, state, wo 2012/177813 national, and international). Voluminous data requirements are specified by regulatory authorities and must be sed through data generation and submission by the product registrant or by a third party on the product rant's behalf, often using a computer with a tion 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 d and supported, such user or seller may use or sell such pesticide.
A molecule according to Formula One can be tested to ine 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 ides. 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. wo 2012/177813 TABLE SECTION BAW & CEW Rating Table % Control (or Mortality) Rating 50-100 A More than 0 - Less than 50 B Not Tested c No activity noticed in this bioassay D GPA Rating Table % Control (or Mortality) Rating 80-100 A More than 0 - Less than 80 B Not Tested c No activity noticed in this bioassay D Table 1: Structures for nds Compound Structure Number AI34 OH Cl 0 AI36 OH AI37 OH Cl 0 wo 77813 wo 77813 AClO H Cl oN'C's wo 77813 wo 2012/177813 AC24 H 0 Cl H Cl ~ AC25 H Cl N \J~~O Cl 0 &;0 Cl N AC26 HNJ!--s1/ ;>-c1 wo 77813 AC27 Cl HxON ~ Cl 0 Cl Cl~Cl AC28 H I Cl ~N Cl 0 Cl Cl AC29 H Cl N Cl o 'Cs Cl Cl AC30 H Cl N 'Q~O Cl o s.;o Cl Ilr ~Cl AC31 H I Cl ~N Cl 0 Cl Br AC32 H Cl N Cl o 'Cs Cl Br AC33 H Cl N 'Q-,0 Cl o s.;o Cl CF3 AC34 H Cl o 'Cs wo 77813 wo 77813 wo 77813 wo 77813 AC61 F oN'C.'s wo 77813 wo 77813 wo 77813 AC78 Cl H 0 N__)lN"""CF H 3 AC79 Br F H 0 N__)lN"""CF H 3 AC80 F H 0 N __AN"""CF, H _, AC81 ~JNJ:_f~o 0 H AC82 0 ~s~o AC83 0 'Cs:::o,, wo 77813 AC84 F H 0 ~~;=0 wo 77813 Cl Br AC92 H S Cl N~N""'CF Cl 3 NH HN-<] Cl '-----{ AC93 0 AC94 NH 0 Cl '----{ CF3 AC95 Br HN_; AC96 AC97 AC98 wo 2012/177813 2012/043418 Cl Br 0 CF AC99 !t,_)lN) F 3 0 H Cl Br H 0 AClOO Cl N~CF1 Cl o I .o Cl Br rN,.....__CF AC101 N~ 3 Cl 0 F Br AC102 H 0 Cl NJN,.....__CF F 3 Cl Br AC103 Cl 0 N~l.r( Cl Br AC104 H o NDI('cF, wo 77813 AClOS AC106 AC107 AC108 AC109 Cl wo 2012/177813 2012/043418 ACllO Cl Br H 0 NJN.O'- 0 H AClll Cl Br H 0 NJN~ 0 H AC112 Cl Br H 0 I NJN.N' 0 H Cl Br AC113 H Cl N~ Cl 0 IN"' Cl wo 77813 AC117 AC118 BCl Cl Cl NH Cl NH BC3 Cl NH wo 77813 BC4 Cl NH BCS Cl Cl HNY'tF F 0 F BC6 Cl Cl 0\NH BC7 Cl b Cl HN~ BC8 Cl 0VNH wo 2012/177813 BC9 Cl aNH BClO F Cl NH BCll Cl ;yNH BC12 F ~ 0 Cl HN--c_ '\:: BC13 F N ~~CF3 Cl J 0 "'N 0 BC14 F N___)lN-""'cF H 3 Cl 0 wo 77813 CI4 otP CIS otP0 Cl NH2 CI34 Cl obo ~ 0 CI35 obo ~ 0 CI36 Cl obo ~ 0 wo 77813 CI37 Cl oso ~ /; CI38 oso ~ /; CI39 Cl oso ~ /; CI40 Cl oso ~ /; CI41 oso ~ /; wo 77813 CI49 CISO CISl CI52 CI53 CI54 Cl NH2 CISS CI56 CI57 Cl NH2 wo 2012/177813 cCl NyH Cl 0 Cl ~ CC2 ~~ CC3 H Cl 0 CC4 H N'r("- Cl 0 Cl ~~ CC6 H Cl Nrf'CF3 Cl Cl CC7 NyH Cl 0 Cl Cl CC8 ~~ Cl 0 wo 77813 CClO Cl Cl CCll Cl }j~ Cl 0 Cl Cl CC12 Cl ~0 Cl 0 CC13 Cl Cl CC14 H Cl N~ Cl O ~N~Cl Cl Cl CClS ~~ Cl 0 CC16 wo 77813 Cl Cl CC17 Cl ~~ Cl Cl CC18 H Cl NI('CF3 Cl Cl CC19 H Cl N~S, Cl 0 Cl ~ Cl CC20 Cl ~~ Cl s Cl ~ CF3 CC21 ~~ Cl 0 Cl CF3 CC22 Cl ~~ Cl 0 CF3y0H CC23 I Cl N ~ Cl 0 Cl CF3 CC24 H NI('CF3 Cl 0 wo 2012/177813 Cl Br c C25 H Cl 3 Cl 0 Cl Br CC26 Cl }J~ Cl 0 Cl F CC27 H C l NI('CF3 Cl 0 C l F C C28 C l }J~ Cl 0 C l .0 c;r0 C C29 Cl C l Cl 0 C C30 H II C l N~~---- Cl 0 0 C l Cl C C31 H H NI(N-.../ Cl 0 C l CF3 C C32 H H Cl NI(N-.../ Cl 0 wo 77813 CC33 CC34 CC35 CC36 CC37 CC38 CC39 CC40 wo 77813 Cl Cl CC41 H 0 N0o/ Cl 0 Cl Cl CC42 H 0 Cl N0N............._CF3 Cl 0 H Cl Cl CC43 Cl NnH Cl N.& Cl ~ Cl CC44 H Cl N!T'CF3 Cl 0 Cl ~ Cl CC45 ~~ Cl 0 wo 77813 CC49 ccso Cl N~~~ Cl H 0 CCSl H Cl N"N'r("CF3 Cl H 0 CC52 Cl 0/~~ Cl 0 CC53 H Cl O'N'r("CF3 Cl 0 N'r("CF3 CC54 Cl 0 Cl ~ wo 77813 F N'N F ~ DClO ~ .N wo 77813 DCll DC12 DC13 DC14 Cl ~ DClS Cl ~ DC16 CF3 ~ DC17 Cl ~ DC18 Cl N'N Cl ~ wo 77813 DC19 CF3 ~ DC20 Cl ~ DC21 Cl ~ DC22 Cl ~N02 DC23 DC24 DC25 wo 2012/177813 2012/043418 1'-'::: DC26 o N-N Cl ~-J DC27 N.N Cl -s~ 6'() DC28 Cl N.N Cl ~ Cl CN DC29 Cl ~ F3C CN DC30 CF3 \.::::') Cl CN DC31 Cl N'N Cl ~ Cl CN DC32 wo 77813 Cl CN DC33 CF3 kJ Cl CN DC34 Cl kJ Cl CN DC35 F N'N Cl kJ Cl CN DC36 Cl ~ Cl CN DC37 Cl ~N02 Cl CN DC38 Cl ~NH2 Cl CN O DC39 N.N ~ Cl ~NH Cl CN DC40 Cl N-N Cl ~N02 wo 77813 Cl CN DC41 Cl N.N Cl ~NH2 Cl CN DC42 Cl N.N H Cl ~N~ Cl CN DC43 N'N OH Cl ~NH Cl CN DC44 Cl ~ Cl CN DC45 Cl N.N Cl ~ DC46 DC47 wo 77813 Cl F DC48 Cl ~ Cl Cl DC49 Cl N.N Cl ~ Cl Cl DCSO Cl ~ Cl CF3 DCSl Cl ~ DC52 DC53 Cl ~ Cl N02 DC54 Cl ~ Cl NH 2 DCSS Cl ~ wo 2012/177813 Cl NH DC56 Cl ~ Cl NH DC57 Cl lJ DC58 Cl lJ Cl ~N.OH DC59 DC60 Cl '-====~ DC61 DC62 DC63 wo 77813 DC64 DC65 Cl ~ DC66 Cl N.N Cl ~ DC67 Cl ~ DC68 Cl ~ DC69 Cl ~ DC70 Cl ~ wo 2012/177813 Table 2: Analytical Data for Compounds in Table 1.
Compound mp ESIMS 1H NMR (8) 1 IR (cm-1) Number (oC) 7.83 (m, 2H), 7.68-7.63 (m, 5H), 6.93 ( dd, J = 156- 386.09 15.6, 8.0 Hz, 1H), 6.81 161 ([M-HD (d J = 15.6 Hz, 1H,), 4.15 (m, 1H), 2.80 (s, 7.80 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.38 (m, 1H), 7.30 (s, 110- 374 AC2 2H), 6.65 (d, J = 16.0 112 ([M+Ht) Hz, 1H), 6.46 (dd, J = 16.0, 8.0 Hz, 1H), 4.15 (m, 1H) 7.42 (m, 4H), 7.37 (t, J = 1.8 Hz, 1H), 7.28 (s, 2H), 6.63 (d, J = 16.0 162- 402.24 AC3 Hz, 1H), 6.41 (dd, J = 166 ) 16.0, 8.4 Hz, 1H), 4.15 (m, 1H), 3.20 (s, 3H), 3.00 (s, 3H) 7.79 (d, J = 1.2 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.38 (t, J = 1.8 Hz, 1H), 122- 454 7.30 (s, 2H), 6.64 (d, J = 126 ([M-HD 15.6 Hz, 1H), 6.40 (dd, J = 15.6, 8.0 Hz, 1H), 6.30 (m, 1H), 4.15 (m, 7.67 (s, 3H), 7.64 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 6.91 (dd, J 444.12 ACS = 15.6, 8.0 Hz, 1H), ([M+Ht) 6.80 (d, J = 15.6 Hz, 1H), 4.80 (m, 1H), 3.60 (br s, 8H) wo 2012/177813 7.40 (m, 2H), 7.26 (m, 3H), 6.56 (d, J = 16.0 468.40 Hz, 1H), 6.48 (dd, J = 1657, 1113, ([M-HD 16.0, 8.0 Hz, 1H), 5.82 804 (br s, 1H), 4.08 (m, 3H), 2.52 (s, 3H) 8.39 (s, 1H), 7.74 (m, 1H), 7.39 (m, 3H), 7.24 (m, 4H), 6.58 (d, J = 511.02 16.0 Hz, 1H), 6.38 (dd, 3276, 1645, ([M-HD J = 16.0, 8.0 Hz, 1H), 01 6.16 (br s, 1H), 4.63 (m, 2H), 4.12 (m, 1H), 2.41 (s, 3H) 7.39 (s, 1H), 7.22 (m, 2H), 7.19 (m, 3H), 6.53 (d, J = 16.0 Hz, 1H), 6.39-6.34 (dd, J = 16.0, 454.11 1748, 1112, AC8 8.0 Hz, 1H), 4.22 (m, ([M-HD 801 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) 7.45 (t, J =7.6 Hz, 1H), 7.36 (m, 2H), 7.21 (m, 3H), 7.15 (m, 4H), 6.56 (d, J = 16.0 Hz, 1H), 494.02 3276, 1645, AC9 6.38 (dd, J = 16.0, 8.4 ([M-HD 1112,801 Hz, 1H), 6.08 (br s, 1H), 4.68 (d, J = 5.6 Hz, 2H), 4.11 (m, 1H), 2.44 (s, 7.38 (t, J = 1.6 Hz, 1H), 7.34 (d, J =7.6 Hz, 1H), 7.27 (m, 2H), 7.24 (m, 2H), 6.57 (d, J = 16.0 140- 458.00 Hz, 1H), 6.40 (dd, J = 143 ([M-HD 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) wo 2012/177813 7.39-7.29 (m, 9H), 7.24 (m, 2H), 6.56 (d, J = 16.0 Hz, 1H), 6.38 (dd, 476.17 3287, 1644, ACll J = 16.0, 8.0 Hz, 1H), ([M-HD 1112,801 .99 (br s, 1H), 4.63 (d, J = 6.0 Hz, 1H), 4.11 (m, 1H), 2.47 (s, 3H) 8.63 (d, J =4.4 Hz, 1H), 7.71 (m, 1H), 7.47 (d, J =8.4 Hz, 1H), 7.37 (m, 2H), 7.32 (m, 2H), 7.23 479.30 (m, 2H), 7.13 (m, 1H), 3293, 1653, AC12 ([M+Ht) 6.58 (d, J = 16.0 Hz, 00 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) 7.38 (m, 2H), 7.27 (m, 3H), 7.23 (br s, 1H), 6.58 (d, J = 16.0 Hz, 1H), 6.45 (m 1H), 6.42 490.04 AC13 75-78 (dd, J = 16.0, 8.4 Hz, ([M-HD 1H), 4.91 (m 1H), 4.64 (m, 2H), 4.14 (m, 1H), 4.04 (m, 2H), 2.46 (s, 8.63 (s, 2H), 7.76 (d, J = 8.0 Hz, 1H), 7.36 (m, 3H), 7.22 (m, 1H), 7.13 480.99 (m, 2H), 6.57 (d, J = 3293, 1645, AC14 ([M+2Ht 16.0 Hz, 1H), 6.39 (dd, 1113, 800 ) 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) 7.45 (s, 1H), 7.37 (m, 1H), 7.34 (m, 1H), 7.26 (m, 3H), 7.22 (m, 1H), 6.57 (d, J = 16.0 Hz, 516.86 3246, 1635, AClS 59-61 1H), 6.40 (dd, J = 16.0, ([M-HD 1112,801 8.0 Hz, 1H), 6.18 (m, 1H), 4.71 (d, J = 6.4 Hz, 2H), 4.11 (m, 1H), 2.46 (s, 3H) wo 2012/177813 8.47 (m, 1H), 8.19 (s, 1H), 7.76 (m, 1H), 7.47 (m, 2H), 7.37 (m, 1H), 7.28 (m, 2H), 7.24 (m, 506.93 1H), 7.21 (m, 1H), 6.59 1657, 1113, AC16 ([M+Ht) (d, J = 16.0 Hz, 1H), 801 6.39 (dd, J = 16.0, 8.4 Hz, 1H), 4.12 (m, 1H), 2.48 (s, 3H), 1.88 (s, 7.49 (m, 2H), 7.38 (m, 1H), 7.29 (m, 4H), 7.08 (m, 3H), 6.91 (m, 1H), 494.98 6.61 (d, J = 16.0 Hz, AC17 70-73 ([M-HD 1H), 6.48 (m, 1H), 6.43 (dd, J = 16.0, 8.0 Hz, 1H), 4.13 (m, 1H), 2.49 (s, 3H) 8.73 (d, J = 4.8 Hz, 2H), 7.53 (d, J = 8.4 Hz, 1H), 7.37 (m, 1H), 7.27 (m, 4H), 7.23 (m, 1H), 7.11 155- 480.44 (m, 1H), 6.60 (d, J = AC18 158 ) 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, 7.37 (m, 1H), 7.33 (d, J =7.6 Hz, 1H), 7.27 (m, 2H), 7.22 (m, 2H), 6.57 (d, J = 16.0 Hz, 1H), 6.39 (dd, J = 16.0, 8.0 471.66 AC19 55-57 Hz, 1H), 6.10 (brs, 1H), ([M+Ht) 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). wo 2012/177813 2012/043418 7.37 (m, 2H), 7.27 (m, 2H), 7.23 (m, 2H), 6.57 (d, J = 16.0 Hz, 1H), 3437, 1664, 467.68 AC20 6.38 (m, 3H), 6.01 (m, 1265, 1114, ([M+Ht) 1H), 4.63 (d, J = 5.6 Hz, 746 2H), 4.13 (m, 1H), 2.45 (s, 3H) 8.44 (s, 1H), 8.18 (s, 1H), 7.83 (br s, 1H), 7.38 (m, 2H), 7.27 (m, 2H), 7.25 (m, 2H), 7.21 528.78 AC21 61-64 (m, 1H), 6.57 (d, J = ([M+Ht) 16.0 Hz, 1H), 6.40 (dd, J = 16.0, 8.0 Hz, 1H), .01 (s, 2H), 4.11 (m, 1H), 2.43 (s, 3H) 8.39 (s, 1H), 7.73 (m, 1H), 7.40 (s, 1H), 7.35 (m, 2H), 7.22 (m, 3H), 6.57 (d, J = 16.0 Hz, 545.08 3270, 1642, AC22 1H), 6.38 (dd, J = 16.0, ([M-HD 1111,809 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) 7.42 (s, 2H), 7.36 (m, 1H), 7.24 (m, 2H), 6.59 (d, J = 16.0 Hz, 1H), 3273, 1641, 492.35 6.40 (dd, J = 16.0, 8.0 AC23 1250, 1113, ([M-HD Hz, 1H), 6.20 (br s, 1H), .46 (m, 1H), 4.15 (m, 1H), 3.52 (m, 2H), 3.41 (m, 2H), 2.45 (s, 3H) 7.40 (m, 2H), 7.27 (m, 2H), 7.25 (m, 2H), 6.92 (br s, 2H), 6.60 (m, 1H), 129- 526.98 6.48(dd, J = 16.0, 8.0 3298, 1664, AC24 132 ([M+Ht) Hz, 1H), 4.19 (d, J = 1113, 803 .2, 2H), 4.08 (m, 1H), 3.99 (m, 2H), 2.46 (s, wo 77813 7.41 (m, 3H), 7.27 (m, 2H), 6.58 (d, J = 15.6 3257, 1652, 542.24 Hz, 1H), 6.42 (m, 2H), AC25 1316, 1109, ([M-HD 4.92 (m, 1H), 4.65 (m, 2H), 4.14 (m, 1H), 4.09 (m, 2H), 2.46 (s, 3H) 7.45 (s, 1H), 7.40 (s, 2H), 7.34 (d, J = 8.0 Hz, 1H), 7.22 (m, 2H), 6.54 550.69 (d, J = 16.0 Hz, 1H), 3255, 1638, AC26 ([M-HD 6.38 (dd, J = 16.0, 8.0 1113, 809 Hz, 1H), 4.71 (d, J =6.0 Hz, 2H), 4.11 (m, 1H), 2.46 (s, 3H) 8.46 (d, J =4.0 Hz, 1H), 8.20 (s, 1H), 7.76 (m, 1H), 7.47 (m, 2H), 7.41 (s, 2H), 7.23 (m, 2H), 541.00 1653, 1113, AC27 7.21 (m, 1H), 6.59 (d, J ([M-HD = 16.0 Hz, 809 1H), 6.37 (dd, J = 16.0, 8.4 Hz, 1H), 4.11 (m, 1H), 2.48 (s, 3H), 1.88 (s, 6H) 8.40 (s, 1H), 7.74 (m, 2H), 7.42 (m, 3H), 7.36 (m, 2H), 6.72 (br s, 1H), 564.84 6.52 (d, J = 16.0 Hz, 3267,1650, AC28 65-67 ([M-HD 1H), 6.43 (dd, J = 16.0, 1112,809 8.0 Hz, 1H), 4.66 (d, J = 6.4 Hz, 2H), 4.12 (m, 7.71 (d, J = 8.4 Hz, 1H), 7.42 (m, 3H), 7.35 (m, 1H), 6.75 (br s, 1H), 511.78 6.56 (d, J = 16.0 Hz, AC29 75-78 ([M-HD 1H), 6.43 (dd, J = 16.0, 8.0 Hz, 1H), 5.49 (m, 1H), 4.14 (m, 1H), 3.50 (m, 4H) wo 2012/177813 2012/043418 7.42 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H), 7.40 (s, 1H), 7.38 (m, 1H), 7.06 110- 543.72 (br s, 1H), 6.58 (d, J = AC30 113 ([M-HD 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) 8.42 (s, 1H), 7.76 (m, 1H), 7.61 (m, 2H), 7.39 610.73 AC31 68-70 (m, 4H), 6.54 -6.39 (m, ([M+Ht) 3H), 4.66 (d, J = 6.0 Hz, 2H), 4.12 (m, 1H) 7.61 (m, 2H), 7.40 (m, 3H), 6.54 (m, 2H), 6.40 555.89 AC32 78-80 (dd, J = 16.0, 8.0 Hz, ([M-HD 1H), 5.46 (m, 1H), 4.14 (m, 1H), 3.50 (m, 4H) 7.62 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.40 (m, 3H), 6.84 (br s, 1H), 182- 587.68 6.55 (d, J = 15.6 Hz, AC33 184 ([M-HD 1H), 6.45 (dd, J = 15.6, 7.6 Hz, 1H), 4.93 (m 1H), 4.65 (m, 2H), 4.13 (m, 4H) 7.67 (s, 1H), 7.61 (d, J = 6.0 Hz, 1H), 7.53 (m, 1H), 7.41 (s, 2H), 6.64 (d, J = 16.0 Hz, 1H), 151- 545.83 AC34 6.40 (dd, J = 16.0, 8.0 153 ([M-HD Hz, 1H), 6.18 (br s, 1H), .44 (m, 1H), 4.14 (m, 1H), 3.50 (m, 2H), 3.40 (m, 2H) 7.70 (s, 1H), 7.63 (m, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.41 (s, 2H), 6.53 100- 577.71 3257, 1655, AC35 (d, J = 16.0 Hz, 1H), 102 ([M-HD 1113, 808 6.49 (m, 2H), 4.93 (m, 1H), 4.64 (m, 2H), 4.13 (m, 1H), 4.03 (m, 2H) wo 2012/177813 2012/043418 8.40 (s, 1H), 7.73 (m, 2H), 7.61 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.40 (s, 2H), 7.35 600.83 (d, J = 8.0 Hz, 1H), 6.63 AC36 81-83 ([M+Ht) (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) 8.39 (s, 1H), 7.73 (m, 1H), 7.48 (m, 2H), 7.34 (d, J =7.6 Hz, 1H), 7.24 (m, 3H), 6.55 (d, J = 512.68 3268, 1644, AC37 16.0 Hz, 1H), 6.41 (dd, ([M+Ht) 1109,820 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) 8.46 (m, 1H), 7.73 (m, 1H), 7.35 (m, 4H), 7.22 (m, 2H), 6.56 (d, J = 528.85 16.0 Hz, 1H), 6.38 (dd, AC38 79-80 ([M-HD J = 16.0, 8.0 Hz, 1H), 4.62 (d, J = 6.0 Hz, 2H), 4.10 (m, 1H), 2.45 (s, 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, 141- 477.83 AC39 1H), 6.40 (dd, J = 16.0, 144 ([M-HD 7.6 Hz 1H), 6.21 (m, 1H), 4.65 (s, 2H), 4.11 (m, 1H), 2.46 (s, 3H) wo 2012/177813 8.33 (t, J = 5.6 Hz, 1H), 8.61 (m, 1H), 7.68 (m, 3H), 7.48 (m, 2H), 6.86 (dd, J = 15.6, 8.2 Hz 484.67 1H), 6.74 (d, J = 15.6 AC40 69-72 ) 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) 8.66 (d, J = 7.6 Hz, 1H), 8.39 (t, J = 5.6 Hz, 1H), 7.65 (s, 3H), 7.45 (m, 3H), 6.86 (dd, J = .6, 8.8 Hz, 1H), 6.74 196- 515.00 AC41 (d, J = 15.6 Hz, 1H), 199 ([M-HD 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, 7.99 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.51 (m, 2H), 7.44 (m, 2H), 7.27 (m, 534.72 4H), 6.71 (t, J = 5.2 Hz, AC42 79-82 1H), 6.59 (d, J = 16.0 ([M+Ht) 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, 8.69 (s, 1H), 8.52 (s, 2H), 7.45 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.26 (m, 2H), 7.21 481.75 1663, (m, 1H), 6.83 (s, 1H), AC43 1608,1168, ([M+Ht) 6.58 (d, J = 16.0 Hz, 1114, 801 1H), 6.40 (dd, J = 16.0, 8.4 Hz, 1H), 4.81 (d, J = .6 Hz, 2H), 4.12 (t, J = 8.4 Hz 1H), 2.45 (s, 3H) wo 2012/177813 8.44 (d, J = 2.4 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.37 (m, 1H), 7.33 (s, 1H), 7.31 (s, 1H), 7.26 (m, 1H), 7.24 (m, 528.01 3H), 6.57 (d, J = 16.0 1640, 1166, AC44 Hz, 1H), 6.39 (dd, J = ) 1112,800 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) 7.66 (s, 1H), 7.37 (d, J = 6.8 Hz, 2H), 7.26 (m, 3H), 7.18 (m, 1H), 7.11 512.88 (m, 2H), 6.99 (m, 1H), 1657, 1167, AC45 6.57 (d, J = 15.6 Hz, ([M+Ht) 1106,800 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) 8.42 (d, J =2.0 Hz, 1H), 7.76 (d, J =2.4 Hz, 1H), 7.61 (m, 2H), 7.39 (m, 575.93 3H), 7.26 (s, 2H), 6.54 AC46 61-64 ([M+Ht) (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) .02 (s, 1H), 9.87 (s, 1H), 8.47 (t, J = 6.0 Hz, 1H), 7.66 (s, 3H), 7.44 (s, 1H), 7.40 (d, J = 3.6 525.89 Hz, 2H), 6.86 (dd, J = AC47 15.6, 9.2 Hz, 1H), 6.74 3280, 1640 ([M-HD (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) wo 77813 7.37 (m, 7H), 7.34 (m, 3H),, 6.57 (d, J = 16.0 509.96 Hz, 1H), 6.39 (dd, J = AC48 16.0, 8.0 Hz, 1H), 6.01 3275, 1642 ([M-HD (m, 1H), 4.60 (d, J = 6.0 Hz, 2H), 4.13 (m, 1H), 2.46 (s, 3H) 8.39 (d, J =2.0 Hz, 1H), 8.11 (m, 1H), 7.71 (d, J =2.4 Hz, 1H), 7.41 (m, 518.85 3H), 7.17 (m, 3H), 6.59 1658, 1112, AC49 (d, J = 16.0 Hz, 1H), ([M+Ht) 1025,2219 6.47 (dd, J = 16.0, 8.0 Hz, 1H), 4.66 (d, J = .6 Hz, 2H), 4.14 (m, 8.72 (m, 1H), 7.67 (s, 3H), 7.46 (s, 1H), 7.40 481.88 (m, 2H), 7.08 (s, 1H), 1654, 1112, ACSO 6.82 (m, 2H), 6.55 (d, J ([M+Ht) =7.6 Hz, 800,3069 1H), 4.82 (m, 1H), 4.48 (s, 2H), 3.65 (s, 3H), 2.38 (s, 3H) 7.45 (d, J =7.6 Hz, 1H), 7.38 (m, 1H), 7.27 (m, 2H), 7.22 (m, 2H), 6.85 540.83 (m, 1H), 6.58 (d, J = 1652, 1571, ACSl 16.0 Hz, 1H), 6.40 (dd, 802, 1114, ([M+Ht) J = 16.0, 8.0 Hz, 1H), 2926 4.33 (m, 2H), 4.14 (m, 3H), 3.18 (s, 3H), 2.48 (s, 3H) 7.33 (m, 2H), 7.25 (m, 3H), 6.56 (d, J = 15.6 Hz, 1H), 6.37 (dd, J = .6, 8.0 Hz, 1H), 5.61 488.29 (d, J =8.0 Hz, 1H), 4.21 1635, 11134, AC52 ([M-HD (m, 1H), 4.01 (m, 1H), 813,2927 4.08 (m, 2H), 3.56 (t, J = 10.0 Hz, 2H), 2.48 (m, 2H), 2.08 (m, 2H), 1.5 (m, 3H) wo 2012/177813 8.49 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.34 (m, 3H), 7.26 (m, 532.92 2H), 6.95 (m, 1H), 6.58 1651, 3027, AC53 ([M+Ht) (d, J = 16.0 Hz, 1H), 815,1113 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) 8.37 (d, J = 5.2 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.36 (m, 3H), 7.31 (m, 1H), 7.26 (m, 2H), 6.58 529.06 (d, J = 16.0 Hz, 1H), 1654, 3434, AC54 ([M-HD 6.40 (dd, J = 16.0, 7.6 814, 1112 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) 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 = 464.96 8.4 Hz, 1H), 7.0 (m, 3417, 1658, AC57 ([M+Ht) 1H), 6.76 (d, J = 15.6 17 Hz, 1H), 6.76 (dd, J = .6, 8.0 Hz, 1H), 4.01 (m, J = 8.0 Hz, 1H), 3.71 (m, 2H), 3.49 (m, 7.62 (m, 2H), 7.40 (s, 2H), 7.37 (d, J = 1.6 Hz, 1H), 6.61 (t, J = 4.8 Hz, 124.4- 599.76 1H), 6.55 (d, J = 16.0 AC58 126.9 ([M+Ht) 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) wo 2012/177813 2012/043418 8.42 (d, J = 2.1 Hz, 1H), 8.29 (d, J =7.5 Hz, 1H), 7.51 (m, 2H), 7.39 (m, 497.40 1H), 7.36 (m, 4H), 7.28 AC59 80-83 (m, 1H), 6.61 (d, J = ([M-HD 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) 8.52 (s, 1H), 8.39 (d, J = 1.8 Hz, 2H), 7.70 (d, J = 2.1 Hz, 1H), 7.62 (s, 1H), 7.43 (s, 1H), 7.35 515.09 1668, 1589, (m, 3H), 6.62 (d, J = AC60 1167, 1113, ([M+HD 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) 8.07 (t, J =8.0 Hz, 1H), 7.39 (t, J =2.0 Hz, 1H), 7.28 (d, J = 1.2 Hz, 3H), 7.17 (d, J = 1.6 Hz, 1H), 461.90 7.11 (m, 1H), 6.59 (d, J 1658, 1114, AC61 ([M-HD = 15.6 Hz, 1H), 6.47 801 (dd, J = 15.6, 7.6 Hz, 1H), 5.49 (m, 1H), 4.14 (t, J = 8.4 Hz, 1H), 3.48 (m, 4H) 8.62 (t, J =6.4 Hz, 1H), 8.46 (m, 1H), 7.73 (m, 528.88 5H), 7.48 (d, J = 7.6 Hz, 105- AC62 1H), 7.03 (dd, J = 15.6, 108 ([M-HD 9.2 Hz, 1H), 6.81 (d, J = .6 Hz, 1H), 4.86 (m, 1H), 3.97 (m, 4H) 8.43 (s, 1H), 7.76 (d, J =2.4 Hz, 1H), 7.60 (m, 2H), 7.38 (d, J = 7.6 Hz, 594.67 1H), 7.33 (d, J = 6.4 Hz, AC63 77-80 3H), 6.54 (d, J = 16.0 3257, 1653 ([M+Ht) 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) wo 2012/177813 2012/043418 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, 580.72 1H), 6.70 (t, J = 5.2 Hz, AC64 83-85 ([M-HD 1H), 6.57 (d, J = 15.6 Hz, 1H), 6.44 (dd, J = .6, 8.0 Hz, 1H), 4.23 (d, J = 5.6 Hz, 2H), 4.15 (m, 1H), 4.01 (m, 2H) 8.39 (d, J = 2.0 Hz, 1H), 8.12 (t, J = 8.4 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.34 (m, 3H), 7.26 534.72 (m, 1H), 7.11 (m, 2H), 1658, 1113, AC65 ([M-HD 6.59 (d, J = 16.0 Hz, 817,2925 1H), 6.46 (dd, J = 16.0, 8.0 Hz, 1H), 4.66 (d, J = .2 Hz, 2H), 4.13 (m, 7.88 (s, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.40 (m, 2H), 6.80 (t, J = 5.6 Hz, 624.61 1H), 6.70 (t, J = 5.6 Hz, AC66 73-75 ([M-HD 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) 8.07 (t, J = 8.0 Hz, 1H), 7.34 (d, J = 6.0 Hz, 2H), 7.28 (s, 1H), 7.17(s, 479.82 2H), 6.59 (d, J = 15.6 AC67 3272, 1644 ([M-HD Hz, 1H), 6.46 (dd, J = .6, 8.0 Hz, 1H), 5.49 (m, 1H), , 4.12 (m, 1H), 3.49 (m, 4H). wo 77813 8.6 (t, J = 6.4 Hz, 1H), 8.45 (m, 1H), 7.86 (d, J =6.4 Hz, 2H), 7.75 (t, J =8.0 Hz, 1H), 7.63 (d, J 546.80 = 12.0 Hz, 1H), 7.48 (d, AC68 90-93 3315, 1684 ([M-HD 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) 7.41 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 5.6 Hz, 2H), 7.26 (m, 1H), 7.23 (m, 1H), 6.81 (s, 1H), 6.57 542.82 (d, J = 15.6 Hz, 1H), AC69 3294, 1685 ([M-HD 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) 8.38 (d, J =2.4 Hz, 1H), 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), 176- 545.23 7.15 (d, J = 1.6 Hz, 1H), AC70 178 ([M-HD 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) 8.24 (d, J =7.6 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 6.0 Hz, 2H), 7.13 (d, J = 1.2 Hz, 1H), 492.20 6.92 (s, 1H), 6.61 (d, J = 1639, 3079, AC71 ([M-HD 16.0 Hz, 1H), 6.43 (dd, 858 J = 16.0, 7.6 Hz, 1H), .48 (m, 1H), 4.13 (m, 1H), 4.03 (s, 3H), 3.48 (m, 4H) wo 2012/177813 8.42 (d, J =2.4 Hz, 1H), 7.75 (d, J =2.4 Hz, 1H), 7.34 (m, 4H), 7.20 (m, 2H), 6.60 (d, J = 16.0 543.05 Hz, 1H), 6.36 (dd, J = 1642,3246, AC72 ([M-HD 16.0, 8.0 Hz, 1H), 6.12 814, 1113 (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) 8.72 (s, 1H), 7.97 (d, J = 7.2 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.61 (m, 644.78 2H), 7.40 (m, 2H), 6.55 3431, 1652, AC75 ([M+Ht) (m, 2H), 6.42 (dd, J = 1171, 809 16.0, 8.0 Hz, 1H), 4.76 (d, J =6.0 Hz, 2H), 4.12 (m, 1H) 8.87 (t, J = 6.0 Hz, 1H), 8.34 (d, J = 2.1 Hz, 1H), 7.85 (d, J = 6.3 Hz, 3H), 7.48 (m, 4H), 6.57 (d, J 531.34 = 15.6 Hz, 1H), 6.45 3120, 1708, AC76 ([M+Ht) (dd, J = 15.6, 9.0 Hz, 1171 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) 8.87 (t, J = 6.0 Hz, 1H), 8.34 (d, J = 2.1 Hz, 1H), 7.85 (d, J = 6.3 Hz, 3H), 531.1 7.48 (m, 4H), 6.57 (d, J 3444, 1648, AC77 = 15.6 Hz, 1H), 6.45 ) 1114, 814 (dd, J = 15.6, 8.0 Hz, 1H), 4.84 (m, 1H), 4.49 (d, J =5.7 Hz, 2H), 2.36 (s, 3H) 8.59 (t, J = 6.4 Hz, 1H), 8.47 (t, J =5.6 Hz, 1H), 7.89 (s, 2H), 7.45 (m, 3432, 1631, 561.06 3H), 6.87 (m, 1H), 6.75 AC78 1161, 840 ([M+Ht) (d, J = 15.6 Hz, 1H), 4.85 (t, J =8.0 Hz 1H), 3.98 (m, 4H), 2.58 (s, wo 2012/177813 8.69 (t, J = 6.0 Hz, 1H), 8.58 (t, J = 6.0 Hz, 1H), 7.92 (s, 1H), 7.87 (d, J = 610.97 6.4 Hz, 2H), 7.62 (d, J = 3303, 1658, AC79 8.4 Hz, 1H), 7.45 (d, J = ([M+Ht) 1166,817 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) 7.37 (m, 3H), 7.26 (m, 1H), 7.24 (m, 1H), 6.59 561.06 (d, J = 15.6 Hz, 1H), 3412, 1624, AC80 6.39 (dd, J = 15.6, 8.0 ) 1157, 825 Hz, 1H), 4.24 (m, 4H), 3.90 (m, 1H), 2.83 (m, 2H), 1.26 (m, 3H) 8.73 (d, J = 5.6 Hz, 1H), 8.45 (t, J = 6.0 Hz, 1H), 7.76 (s, 3H), 7.45 546.93 (m, 3H), 6.86 (dd, J = AC81 16.0, 9.2 Hz, 1H), 4.83 9-92 ([M-HD (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) 7.38 (d, J = 1.8 Hz, 2H), 7.33 (s, 1H), 7.27 (s, 3H), 6.58 (d, J = 16.0 477.69 Hz, 1H), 6.42 (d, J = 8.1 1646, 1353, AC82 Hz, 1H), 6.36 (dd, J = 1196, 1112, ([M+Ht) 16.0, 7.8 Hz, 1H), 4.71 800 (m, 1H), 4.23 (m, 3H), 3.26 (m, 2H), 2.45 (s, 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, 493.83 1H), 7.19 (d, J = 1.6 Hz, 1527, 1113, AC83 1H), 6.60 (d, J = 16.8 801, 1167, ([M-HD Hz, 1H), 6.49 (dd, J = 1321 16.8, 7.6 Hz, 1H), 4.90 (m, 1H), 4.64 (m, 2H), 4.14 (m, 2H), 4.10 (m, wo 77813 8.07 (t, J =8.0 Hz, 1H), 7.34 (m, 3H), 7.19 (d, J 511.75 = 13.2 Hz, 1H), 6.60 (d, 1645, 1113, AC84 J = 16.4 Hz, 1H), 6.48 804, 3030, ([M-HD (dd, J = 16.4, 8.0 Hz, 1245 1H), 4.88 (m, 1H), 4.62 (m, 2H), 4.12 (m, 3H) 8.60 (d, J = 6.8 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 6.0 Hz, 1H), 523.83 7.15 (d, J =7.2 Hz, 1H), 1652,3039, AC85 6.94 (s, 1H), 6.60 (d, J = ([M-HD 802, 1114 .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) 7.35 (d, J = 6.3 Hz, 3H), 7.26 (m, 2H), 7.20 (m, 1H), 6.60 (d, J = 15.9 524.36 Hz, 1H), 6.47 (dd, J = 3333, 1651, AC86 15.9, 6.6 Hz, 1H), 4.86 ([M+Ht) 815 (m, 1H), 4.65 (m, 2H), 4.13 (m, 3H), 2.84 (q, 2.8 Hz, 2H), 1.26 (m, 8.07 (t, J =8.0 Hz, 1H), 7.52 (m, 3H), 7.19 (d, J 495.82 = 13.2 Hz, 1H), 6.59 (d, 1623, 1114, AC87 J = 16.4 Hz, 1H), 6.47 ([M-HD 816 (dd, J = 16.4, 8.0 Hz, 1H), 4.69 (m, 1H), 4.23 (m, 3H), 3.29 (m, 2H) 7.43 (m, 2H), 7.27 (m, 2H), 7.23 (m, 2H), 6.58 (d, J = 16.0 Hz, 1H), 509.89 6.41 (dd, J = 16.0, 7.6 1666, 1166, AC89 Hz, 1H), 4.79 (d, J = ([M+Ht) 1112,800 .6 Hz, 2H), 4.14 (m, 1H), 2.48 (s, 3H), 2.18 (m, 1H), 1.16 (m, wo 77813 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), 7.36 656.9 (dd, J = 8.2, 1.7 Hz, AC90 1H), 6.53 (d, J = 16.0 ([M-HD Hz, 1H), 6.38 (dd, J = .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) 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 640.9 = 8.1, 1.6 Hz, 1H), 6.52 AC91 ([M-HD (m, 2H), 6.37 (dd, J = .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) 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 640.9 = 5.6 Hz, 1H), 6.55 (d, J AC92 = 15.9 Hz, 1H), 6.41 ([M-HD (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) wo 2012/177813 13 C NMR (8)3 169.91, 169.84, 7.52-7.41 (d, J = 8.2 Hz, 138.23, 1H), 7.39-7.34 (m, 1H), 137.41, 7.24-7.17 (d, J = 1.8 Hz, 136.84, 2H), 7.02-6.92 (m, 2H), 134.79, 6.90-6.83 (d, J = 11.4 134.69, Hz, 1H), 6.71 (br s, 1H), 131.07' 485.5 6.17 (br s, 1H), 6.12- 128.69, AC93 6.01 (dd, J = 11.4, 10.3 127.49, ([M+Ht) Hz, 1H), 4.44-4.38 (d, J , = 4.2 Hz, 1H), 4.35-4.27 126.72, (m, 1H), 4.10-3.99 (d, J 126.61 (q, J = = 5.1 Hz, 2H), .67 212.10 Hz), (m, 1H), 2.44 (s, 3H), 125.61, 0.88-0.78 (m, 2H), 0.60- 123.76, 47.89 0.45 (m, 2H) (q, J = 28.28 Hz), 43.46, 22.65, 19.97, 8.21 8.36- 8.24 (d, J = 2.4 Hz, 1H), 7.75- 7.64 (m, 1H), 7.38- 7.24 (m, 3H), 7.24- 7.09 (d, J = 1.8 Hz, 2H), 6.99 - 6.90 511.6 3262, 1607, (m, 2H), 6.89- 6.74 (d, AC94 1247, 1164, ([MD J = 11.4 Hz, 1H), 6.63 - 1111 6.43 (m, 1H), 6.14- .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) 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 = 626.9 11.4 Hz, 1H), 6.76 (t, J AC95 48-61 ([M+Ht) = 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) wo 77813 8.83 (s, 1H), 8.06 (br, 1H), 7.90 (s, 2H), 7.63 (d, J = 8.1 Hz, 2H), 7.53 61 (m, 1H), 6.94 (m, 1H), AC96 9.6 6.77 (d, J = 15.3 Hz, 1616, 1114 ([M+Ht) 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) 8.20 (d, J = 2.1 Hz, 1H), 7.73 (d, J = 2.7 Hz, 1H), 7.60 (m, 2H), 7.39 (s, 2H), 7.29 (m, 1H), 606.6 AC97 6.79 (d, J = 8.4 Hz, 1H), 1644, 1113 ([M+Ht) 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) 9.04 (t, J =6.0 Hz, 1H), 8.60 (t, J =6.6 Hz, 1H), 8.25 (s, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.87 (d, J = 577.87 6.3 Hz, 2H), 7.69 (d, J AC98 ([M+Ht) =7.5 1663, 1168 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). 8.69 (t, J = 6.0 Hz, 1H), 8.58 (t, J = 6.6 Hz, 1H), 7.91 (s, 1H), 7.85 (m, 1H), 7.61 (m, 2H), 7.52 574.81 AC99 (m, 2H), 6.98 (dd, J = 1650, 1164 ([M+Ht) .3, 9.0 Hz, 1H), 6.76 (d, J = 15.3 Hz, 1H), 4.81 (m, 1H), 4.01 (m, wo 2012/177813 8.29 (s, 1H), 8.22 (d, J =8.1 Hz, 1H), 7.93 (d, J =7.8 Hz, 1H), 7.72 (m, 1H), 7.65 (m, 2H), 7.40 673.80 (s, 2H), 7.18 (br, 1H), AClOO 3403, 1659 ) 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, 7.56 (d, J = 9.0 Hz, 1H), 7.39 (d, J = 6.0 Hz, 2H), 7.26 (m, 2H), 6.54 (d, J = 15.9 Hz, 636.83 1H), 6.37 (dd, J =8.0, AC101 1637, 1113 ([M+Ht) 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, 7.60 (m, 2H), 7.32 (m, 1H), 7.03 (d, J = 7.2 Hz, 2H), 6.74 (br, 1H), 6.62 592.84 (br, 1H), 6.56 (d, J = AC102 16.2 Hz, 1H), 6.41 (dd, 1668, 1167 ([M+Ht) J = 16.2, 7.8 Hz, 1H), 4.22 (d, J = 5.4 Hz, 2H), 4.14 (m, 1H), 4.01 (m, 2H) 8.40 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 5.2 Hz, 1H), 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 = 612.7 16.0 Hz, 1H), 4.84 (m, 99.2- AC103 ([M+Ht) 1634, 1113, 1H), 4.23 (d, J = 13.2 105.0 809 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) wo 2012/177813 7.60 (m, 2H), 7.40 (m 3H), 6.55 (d, J = 15.6 3437, Hz, 1H), 6.41 (dd, J = 1644, 680.97 15.6, 7.8 Hz, 1H), 4.24 AC104 1113, ([M+Ht) (m, 1H), 3.34 (m, 2H), 2.90 (m, 1H), 2.24 (m, 807, 2H), 1.52(m, 2H), 1.34 511 (m, 4H) 7.59 (s, 1H), 7.55 (m, 1H), 7.50 (m, 1H),7.40 (m, 2H), 6.54(d, J = 3303, 1649, 609.9 16.0 Hz, 1H), 6.50 (1 = AClOS 1115,2242, ([M+Ht) 16.0, 8.0 Hz, 1H), 4.14 809,506 (m, 2H), 3.08 (m, 4H), 2.67 (m, 2H), 2.12 (m, 2H), 1.70 (m, 2H). 7.59 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.40 (s, 2H), 7.36 (d, J = 6.8 Hz, 1H), 6.54 (d, J = 16.0 3417, 584.95 Hz, 1H), 6 .40 (dd, J = 1648, AC106 16.0, 8.0 Hz, 1H), 6.03 ([M+Ht) (d, J = 8.0 Hz, 1H), 4.11 1112, (m, 2H), 3.10 (m, 2H), 805,555 2.50 (m, 2H ), 2.50 (s, 3H) (m, 2H ), 1.94 (m, 8.41 (d, J = 7.8 Hz, 1H), 7.90 (s, 2H), 7.62 (m, 2H), , 1H), 6.92 3303, (dd, J = 15.9, 9.0 Hz, 1645, 1H), 6.77 (d, J = 15.9 609.9 Hz, 1H), 4.81 (m, 1H), 1115, AC107 ([M+Ht) 3.73 (s, 2H), 3.31 (m, 2243, 1H), 3.28 (m, 1H), 2.82 (t, J = 11.4 Hz, 2H), 810, 2.82 (m, 2H), 2.30 (m, 507 2H), 1.88 (m, 2H), 1.57 (m, 2H) wo 2012/177813 2012/043418 7.60 (m, 2H) 7.39 (s, 2H), 7.28 (m, 1H), 6.56 3420, (d, J = 15.6 Hz, 1H), 1649, 6.40 (dd, J = 15.6, 7.8 626.9 Hz, 1H), 5.91 (m, 1H), 1113, AC108 ([M+Ht) 4.65 (m, 2H), 4.10 (m, 809, 1H), 4.07 (m, 2H), 3.59 (m, 1H), 2.74 (m, 2H), 554 2.13 (m, 4H), 2.07 (m, 7.56 (m, 2H), 7.39 (s, 2H), 7.29 (s, 1H), 6.50 (d, J = 15.9 Hz, 1H), 6.41 (dd, J = 15.9, 8.0 614.6 AC109 Hz 1H), 4.09 (m, 1H), 1647, 1113 ([M+Ht) 3.88 (m, 2H), 3.49 (m, 2H), 2.92 (m, 2H), 2.81 (m, 1H), 2.74 (m, 2H), 2.25 (m, 4H) 11.20 (s, 1H), 8.66 (br, 1H), 7.92 (m, 3H), 7.62 (d, J = 8.0 Hz, 1H), 7.45 572.6 (d, J = 8.0 Hz, 1H), 6.77 3412, 1690, ACllO (dd, J = 15.6, 9.2 Hz, 1114, 846, ([M+Ht) 1H), 6.77 (d, J = 15.6 559 Hz, 1H), 4.85 (m, 1H), 3.74 (d, J = 5.2 Hz, 2H), 3.61 (s, 3H) 8.63 (t, J = 6.0 Hz, 1H), 8.04 (t, J = 6.0 Hz, 1H), 7.92 (m, 3H), 7.62 (d, J = 1.2 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.00 (dd, 582.79 J = 15.6, 8.8 Hz, 1H), 3419, 1659, AClll ([M+Ht) 6.77 (d, J = 15.6 Hz, 843,557 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) wo 2012/177813 8.84 (br, 1H), 8.58 (m, 1H), 8.30 (m, 1H), 7.91 (s, 2H), 7.61 (d, J = 8.1 Hz, 1H), 7.42 (d, J =7.8 582.79 Hz, 1H), 7.00 (dd, J = 3399, 1662, AC112 15.6, 9.3 Hz, 1H), 6.77 1114, 807, ([M+Ht) (d, J = 15.6 Hz, 1H), 582 4.85 (m, 1H), 4.11 (d, J =5.6 Hz, 1H), 3.73 (d, J =5.6 Hz, 1H), 3.04 (s, 8.48 (t, J =5.2 Hz, 1H), 8.3 (s, 1H), 7.90 (s, 2H), 7.79 (dd, J = 2.0, 2.0 Hz 2H), 7.58 (d, J = 8.4 Hz, 626.88 1H) 7.46 (d, J =7.6 Hz, 3431, 1651, AC113 ([M+Ht) 1H) 7.26 (d, J =7.6 Hz, 1113, 808, 1H), 6.98 (m, 1H), 6.75 554 (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) 8.77 (s, 1H), 8.58 (d, J = 7.2 Hz, 2H), 7.93 (d, J = 7.2 Hz, 2H), 7.60 (dd, J = 1.2, 0.8 Hz, 1H), 7.37 113.7- 570.7 AC114 (d, J =7.6 Hz, 1H), 6.99 117.5 ) (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) 8.43 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.51 (m, 1H), 7.36 (d, J = 8.4 Hz, 529.00 3H), 7.21 (m, 3H), 6.55 ACllS 1589, 3459, (d, J = 15.6 Hz, 1H), ([M+Ht) 801, 1110 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) wo 2012/177813 2012/043418 7.99 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.34 (d, J = 6.4 Hz, 2H), AC116 614.87 7.28 (m, 2H), 6.62 (m, 3424, 1657, ([M+Ht) 2H), 6.47 (dd, J = 16.0, 1165 7.2 Hz, 1H), 4.23 (m, 2H), 4.12 (m, 1H), 4.00 (m, 2H) 8.39 (br, 1H), 7.85 (br, 1H), 7.62 (m, 3H), 7.53 (d, J =8.0 Hz, 1H), 7.46 (s, 1H), 7.40 (d, J = 8.0 525.42 Hz, 1H), 7.17 (m, AC117 1H), 3401, 1636, ([M-HD 6.78 (dd, J = 16.0, 8.8 1113, 750 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) 7.36 (d, J = 8.0 Hz, 2H), 7.27 (m, 2H), 7.22 (m, 2H), 6.57 (d, J = 16.0 Hz, 1H), 6.38 (dd, J = 471.79 16.0, 8.0 Hz, 1H), 6.10 3437, 1655, AC118 (br, 1H), 4.15 (m, 2H), 1262, 1105, ([M+Ht) 3.89 (m, 1H), 3.80 (m, 802 2H), 3.35 (m, 1H), 2.46 (s, 3H), 2.06 (s,lH), 1.96 (m, 2H), 1.65 (m, 7.39 (s, 2H), 7.25-7.18 (m, 3H), 6.58 (d, J = 16.0 Hz, 1H), 6.30 (dd, BCl 492.17 J = 16.0, 8.4 Hz, 1H), 3211, 1569, ([M+Ht) 5.91-5.70 (br, 2H), 1113, 806 4.05 (m, 1H), 3.05- 2.80 (m, 6H), 2.70 (m, 1H), 1.81 (m, 1H) wo 77813 8.80 (s, 1H), 8.20 (s, 1H), 7.82 (m, 3H), 7.4 (s, 2H), 6.62 (d, J = 16.0 Hz, 1H), 6.52 (dd, J = 506.4 2923, 1542, BC2 16.0, 8.0 Hz, 1H), ([M+Ht) 1033,805 4.18(m, 1H), 3.38 (m, 2H), 2.98 (m, 2H), 2.71 (m, 1H), 2.04 (m, 2H), 1.54 (s, 3H). 7.40 (s, 2H), 7.33-7.22 (m, 3H), 6.61 (d, J = 16.0 Hz, 1H), 6.34- 6.28 (dd, J = 16.0, 8.0 518.04 3120, 1592, BC3 Hz, 1H), 5.96- 5.80 (m, ([M-HD 1146,895 3H), 5.22 (m, 4H), 4.01 (m, 2H), 2.84-2.99 (m, 2H), 2.71 (m, 1H), 1.86 (m, 1H) 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), 529.02 5.81 (br, 1H), 5.48 (m, 3283, 1652, ([M+Ht) 1H), 4.10 (m, 1H), 3.10 1241, 811 (m, 2H), 2.86-3.07 (m, 2H), 2.86 (m, 1H), 1.81 (m, 1H); 7.40 (s, 2H), 7.21 (s, 1H), 7.12 (m, 1H), 6.56 (d, J = 16.0 Hz, 1H), 6.32 (dd, J = 16.0, 8.4 Hz, 1H), 5.85 (br s, 1H), 3489, 3291, 544.25 BCS 5.23 (br s, 1H), 4.12 (m, 1655, 1112, ([M-HD 1H), 3.18 (m, 3H), 2.80 808 (m, 3H), 2.08 (m, 2H), 1.83 (m, 5H), 1.25 (m, 2H), 1.01 (m, 3H), 0.78 (m, 2H) wo 2012/177813 7.40 (s, 2H), .18 (m, 3H), 6.58 (d, J = 16.0 Hz, 1H), 6.24- 6.28 (dd, J = 16.0, 8.0 485.96 Hz, 1H), 5.40 (br, 1H), 3429, 1114, ([M-HD 4.01 (m, 2H), 2.78- 804 3.01 (m, 2H), 2.51 (s, 1H), 1.86 (m, 1H), 1.20 (m, 2H), 1.01 (m, 2H), 0.78 (m, 2H) 7.40 (s, 2H), 7.31 (s, 1H), 7.18 (m, 1H), 7.18 (s, 1H), 6.58 (d, J = 16.0 Hz, 1H), 6.32 (dd, J = 16.0, 8.0 Hz, 1H), 5.78 500.01 3296, 1115, BC7 (br s, 1H), 5.21 (br s, ([M-HD 806 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) 7.38-7.20 (m, 5H), 6.62 (d, J = 16.0 Hz, 1H), 6.34 (dd, J = 16.0, 8.0 511.88 Hz, 1H), 5.83 (br, 1H), 1657, 1113, ([M-HD 5.52 (m, 1H), 4.12 (m, 855 1H), 3.12 (m, 2H), 3.06- 2.82 (m, 2H), 2.75 (m, 1H), 1.85 (m, 1H) 8.30 (s, 1H), 7.68 (d, J = 6.4 Hz, 1H), 7.38-7.20 (m, 5H), 6.60 (d, J = 16.0 Hz, 1H), 6.34 (dd, 179- 556.83 J = 16.0, 8.0 Hz, 1H), 181 ([M-HD 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) wo 2012/177813 .20 (m, 5H), 6.62 (d, J = 16.0 Hz, 1H), 6.34 (dd, J = 16.0, 8.0 497.98 Hz, 1H), 5.83 (br, 1H), 3027, 1654, BClO 5.52 (m, 1H), 4.12 (m, ([M-HD 815 1H), 3.02 (m, 3H), 2.82 (m, 1H), 2.50 (m, 3H), 1.82 (m, 1H), 1.42 (m, 7.80 (m, 1H), 7.48 (m, 2H), 7.32 6.65 (d, J = 530.09 16.0 Hz, 1H), 6.54 (dd, BCll ([M-HD J = 16.0, 8.0 Hz, 1H), 1715, 1113, .38 (m, 1H), 4.18 (m, 816 1H), 3.62 (m, 1H), 3.32 (m, 1H), 2.86 (m, 1H), 1.81 (m, 1H) 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 = 514.86 8.0 Hz, 1H), 6.60 (m, 3428, 1112, BC12 ([M+Ht) 2H), 4.15 (m, 1H), 3.85 857 (m, 1H), 3.65 (m, 1H), 3.46 (m, 2H), 3.19 (m, 2H); 8.33 (br, 1H), 7.59 (s, 553.06 1H), 7.45 (m, 3H), 6.72 121- BC13 ([M-HD (d, J =3.6, 1H) , 6.39 (m, 1H), 4.71 (t, J =7.2 Hz, 2H), 4.15 (m, 2H) 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 = 6.3 172- 554.0 BC14 Hz, 1H), 7.98-7.86 (m, 175 ([M-HD 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) wo 77813 7.37 (m, 3H), 7.28 (m, 4H), 6.60 (d, J = 16.0 Hz, 1H), 6.36 (dd, J = 107- 402.00 CCl 16.0, 8.0 Hz, 1H), 5.75 109 ([M+Ht) (br s, 1H), 4.46 (d, J = 6 Hz, 2H), 4.01 (m, 1H), 2.11 (s, 3H) 7.37 (m, 3H), 7.28 (m, 4H), 6.60 (d, J = 16.0 Hz, 1H), 6.35 (dd, J = 118- 428.11 16.0, 8.0 Hz, 1H), 5.83 120 ([M+Ht) (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) 7.38 (m, 3H), 7.27 (m, 3H), 6.60 (d, J = 16.0 Hz, 1H), 6.36 (dd, J = 119- 468.20 16.0, 8.4 Hz, 1H), 5.00 122 ([M-HD (br s, 1H), 4.48 (d, J = .6 Hz, 2H), 4.11 (m, 1H), 3.15 (q, J = 10.4 Hz, 2H) 7.37 (m, 3H), 7.28 (m, 3H), 6.60 (d, J = 16.0 Hz, 1H), 6.35 (dd, J = 16.0, 8.0 Hz, 1H), 5.69 414.16 CC4 (br s, 1H), 4.46 (d, J = ([M-HD 6.0 Hz, 2H), 4.21 (m, 1H), 2.29 (q, J = 5.8 Hz, 2H), 1.30 (t, J = 7.2 Hz, 7.40 (m, 3H), 7.28 (m, 2H), 6.60 (d, J = 15.6 Hz, 1H), 6.33 (dd, J = ccs 460.28 15.6, 8.0 Hz, 1H), 5.84 ([M-HD (br s, 1H), 4.46 (d, J = .6 Hz, 2H), 4.10 (m, 1H), 1.36 (m, 1H), 1.02 (m, 2H), 0.77 (m, 2H) wo 77813 7.40 (m, 3H), 7.26 (m, 1H), 6.60 (d, J = 16.0 Hz, 1H), 6.34 (dd, J = 106- 504.08 16.0, 8.0 Hz, 1H), 5.96 108 ([M-HD (br s, 1H), 4.49 (d, J = .6 Hz, 2H), 4.10 (m, 1H), 3.15 (q, J = 10.8 Hz, 2H) 7.42 (m, 4H), 7.24 (m, 2H), 6.53 (d, J = 16.0 Hz, 1H), 6.36 (dd, J = 127- 436.03 CC7 16.0, 8.0 Hz, 1H) , 5.86 128 ([M+Ht) (br s, 1H), 4.51 (d, J = 6.0 Hz, 2H), 4.05 (m, 1H), 2.02 (s, 3H) 8.58 (t, J =5.6 Hz, 1H), 7.72 (m, 1H), 7.66 (m, 3H), 7.49 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 129- 462.15 1H), 6.90 (dd, J = 16.0, 131 ([M+Ht) 8.0 Hz, 1H), 6.73 (d, J = 16Hz, 1H), 4.81 (m, 1H), 4.33 (d, J = 6.0 Hz, 1H), 1.64 (m, 1H), 0.68 (m, 4H) 7.41 (m, 3H), 7.26 (m, 3H), 6.54 (d, J = 16.0 Hz, 1H), 6.37 (dd, J = 132- 504.25 CC9 16.0, 8.0 Hz, 1H), 6.13 134 ([M+Ht) (br s, 1H), 4.56 (d, J = 6.0 Hz, 2H), 4.11 (m, 1H), 3.13 (m, 2H) 7.38 (m, 4H), 6.56 (d, J = 16.0 Hz, 1H), 6.38 538.03 (dd, J = 16.0, 8.0 Hz, 1651, 1112, CClO ([M+2Ht 1H), 6.18 (m, 1H), 4.58 807 (m, 2H), 4.08 (m, 1H), 3.08 (m, 2H) wo 2012/177813 7.42 (m, 3H), 7.24 (m, 1H), 6.54 (d, J = 15.6 Hz, 1H), 6.34 (dd, J = 111- 494.12 16.0, 8.0 Hz, 1H), 6.03 CCll 112 ([M-HD (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) 7.39 (s, 4H), 7.34 (d, J = 8.0 Hz, 1H), 7.26 (m, 1H), 6.57 (d, J = 16.0 510.07 Hz, 1H), 6.35 (dd, J = CC12 76-78 ([M-HD 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) 8.51 (d, J = 5.2 Hz, 1H), 7.63 (s, 1H), 7.51 (m, 1H), 7.45 (m, 2H), 7.39 563.37 (s, 2H), 7.28 (m, 1H), CC13 73-76 ([M-HD 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) 8.51 (m, 1H), 8.30 (d, J = 2.4 Hz, 1H), 7. 73 (m, 1H), 7.61 (s, 2H), 7.51 581.45 (s, 1H), 7.32 (m, 3H), 3430, 1656, CC14 ([M+1Ht 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) 7.40 (m, 3H), 7.33 (m, 1H), 7.22 (m, 2H), 6.54 (d, J = 15.6 Hz, 1H), 6.34 (dd, J = 16.0, 8.0 3293, 1651, 480.24 CClS Hz, 1H), 6.03 (br s, 1H), 1543, 1114, ([M+Ht) 4.53 (d, J = 6.0 Hz, 2H), 812 4.13 (m, 1H), 1.41 (m, 1H), 1.00 (m, 2H), 0.77 (m, 2H) wo 2012/177813 7.42 (s, 1H), 7.37 (m, 3H), 7.22 (m, 1H), 6.54 (d, J = 16.0 Hz, 1H), 520.33 6.36 (dd, J = 16.0, 8.0 3307, 1665, CC16 ([M-HD Hz, 1H), 6.19 (br s, 1H), 1114, 813 4.51 (d, J = 6.0 Hz, 2H), 4.21 (m, 1H), 3.33 (m, 7.51 (m, 2H), 7.39 (m, 2H), 7.24 (m, 2H), 6.52 (d, J = 15.6 Hz, 1H), 6.38 (dd, J = 15.6, 7.6 117- 459.83 3293, 1633, CC17 Hz, 1H), 6.02 (br s, 1H), 119 ([M-HD 1110,820 4.53 (d, J = 6.0 Hz, 2H), 4.14 (m, 1H), 1.38 (m, 1H) ), 1.00 (m, 2H), 0.77 (m, 2H) 7.48 (m, 2H), 7.41 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.23 (m, 2H), 6.52 (d, J = 16.0 Hz, 1H), 119- 501.88 3435, 1644, CC18 6.39 (dd, J = 16.0, 8.0 123 ([M-HD 17 Hz, 1H), 6.13 (br s, 1H), 4.56 (d, J = 6.0 Hz, 2H), 4.15 (m, 1H), 3.13 (m, 7.41 (m, 2H), 7.24 (m, 1H), 6.53 (d, J = 16.0 Hz, 1H), 6.35 (dd, J = 530 3435, 1644, CC19 16.0, 8.0 Hz, 1H), 4.53 ([M+Ht) 1111,817 (m, 2H), 4.10 (m, 1H), 3.42 (m, 2H), 2.97 (s, 3H), 2.78 (m, 2H) 7.42 (m, 3H), 7.24 (m, 1H), 6.54 (d, J = 15.6 Hz, 1H), 6.34 (dd, J = 512 15.6, 8.0 Hz, 1H), 6.03 3293, 1633, CC20 ([M+Ht) (m 1H), 4.53 (d, J = 6.0 1110,820 Hz, 1H), 4.10 (m, 1H), 1.19 (m, 1H), 1.00 (m, 2H), 0.77 (m, 2H) wo 2012/177813 (DMSO-d6) 8.62 (m, 1H), 7.95 (s, 1H), 7.85 (m, 1H), 7.66 (m, 3H), 7.47 (d, J = 8.0 Hz, 1H), 493.99 CC21 55-58 6.98 (dd, J =16.0, 8.0 ([M-HD 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) 8.62 (m, 1H), 7.90 (s, 3H), 7.82 (m, 1H), 7.45 (m, 1H), 6.98 (m, 1H), 530.01 CC22 67-69 6.84 (d, J = 16.0 Hz, 1H), 4.82 (m, 1H), 4.4 (s, 2H), 1.66 (m, 1H), 0.72 (m, 4H) 9.02 (br s, 1H), 8.54 (br s, 1H), 8.26 (br s, 1H), 7.48-7.54 (m, 3H), 564.99 7.22-7.42 (m, 3H), CC23 69-71 ([M-HD 6.59 - 6.62 (m, 2H), 6.38 - 6.42 (m, 1H), 4.82 (m, 2H), 4.19 (s, 7.64 (s, 1H), 7.54 (s, 2H), 7.46 (s, 2H), 6.62 (d, J = 16.0 Hz, 1H), 125- 570.26 6.41 (dd, J = 16.0, 8.4 CC24 127 ([M-HD 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) 7.60 (s, 1H), 7.40 (s, 2H), 7.37 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.53 (d, 1H, J = 579.86 16.0 Hz), 6.35 (dd, J = 3297, 1663, CC25 ([M-HD 16.0, 8.0 Hz, 1H), 6.17 1114, 809 (br s, 1H), 4.56 (d, J = 6.4 Hz, 2H), 4.12 (m, 1H), 3.15 (q, J = 10.6 Hz, 2H) wo 77813 7.59 (s, 1H), 7.39 (m, 2H), 7.30 (s, 1H), 6.53 (d, J = 16.0 Hz, 1H), 6.35 (dd, J = 16.0, 8.0 129- 539.89 CC26 Hz, 1H), 6.06 (br s, 1H), 131 ([M+Ht) 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) 7.39 (s, 2H), 7.33 (t, J = 7.6 Hz, 1H), 7.14 (m, 2H), 6.56 (d, J = 16.0 519.95 Hz, 1H), 6.35 (dd, J = CC27 16.0, 7.6 Hz, 1H), 6.06 3306, 1786 ([M-HD (br s, 1H), 4.52 (d, J = 16.0 Hz, 2H), 4.08 (m, 1H), 3.90 (s, 2H), 3.13 (m, 2H) 7.39 (s, 2H), 7.35 (m, 1H), 7.14 (m, 2H), 6.55 (d, J = 15.6 Hz, 1H), 477.93 6.33 (dd, J = 15.6, 8.0 3625, 1747 CC28 Hz, 1H), 5.93 (br s, 1H), ([M-HD 4.49 (d, J = 16.0 Hz, 2H), 4.10 (m, 1H), 1.36 (m, 1H), 1.00 (m, 2H), 0.77 (m, 2H) 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 = 620.86 16.0 Hz, 1H), 6.38 (dd, 1645, 1115, CC29 ([M-HD J = 16.0, 8.0 Hz, 1H), 808 .02 (s, 1H), 4.8 (s, 1H), 4.8 (d, J =10Hz, 2H), 4.10 (m, 1H), 1.8 (m, 1H), 1.2 (m, 2H), 0.6 (m, 2H) wo 2012/177813 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), 6.12 101- 559.75 CC30 (br s, 1H), 4.53 (m, 2H), 104 ([M-HD 4.10 (m, 1H), 3.42 (m, 2H), 2.91 (s, 3H), 2.78 (m, 2H) 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, 8.0 177- 463 CC31 Hz, 1H), 4.70 (br s, 1H), 178 ([M-H]") 4.43 (s, 2H), 4.08 (m, 1H), 3.21 (m, 2H), 1.25 (m, 3H); 7.66 (m, 2H), 7.54 (m, 1H), 7.41 (s, 2H), 6.62 (d, J = 16.0 Hz, 1H), 141- 532.99 CC32 6.40 (dd, J = 16.0, 8.0 142 ) Hz, 1H), 4.59 (s, 3H), 4.19 (m, 1H), 3.25 (m, 2H), 1.15 (m, 2H) 7.57 (s, 1H), 7.40 (m, 2H), 7.30 (s, 1H), 7.20 (br s, 1H), 6.53 (d, J = 16.0 Hz, 1H), 6.33 (dd, 3338, 1631, 540.88 J = 16.0, 8.0 Hz, 1H), CC33 1578, 1114, ([M-HD 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, 7.42 (m, 3H), 7.28 (m, 2H), 6.54 (d, J = 16.0 Hz, 1H), 6.36 (dd, J = 118- 541.40 16.0, 8.0 Hz, 1H), 4.96 CC34 120 ([M+Ht) (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) wo 2012/177813 2012/043418 9.95 (br s, 1H), 8.17 (d, J = 4.8 Hz, 1H), 7.61 (d, J = 6.4 Hz), 7.43 (m, 3H), 7.24 (m, 2H), 6.90 547.82 (t, J = 5.6 Hz, 1H), 6.66 CC35 78-79 ([M+Ht) (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) 7.39 (m, 4H), 7.28 (m, 1H), 6.54 (d, J = 16.0 Hz, 1H), 6.34 (dd, J = 497 16.0, 8.0 Hz, 1H), 4.97 3350, 1705, CC36 ([M-HD (br s, 1H), 4.38 (d, J = 1114, 808 6.0 Hz, 2H), 4.10 (m, 1H), 2.9 (s, 3H), 2.7 (s, 7.49 (d, J =8Hz, 1H), 7.41 (d, J = 7.2 Hz, 2H), 7.26 (m, 2H), 6.50 (d, J = 16Hz, 1H), 6.35 (dd, 515.01 CC37 88-91 J = 16.0, 8.0 Hz, 1H), ([M+Ht) 6.0 (brs, 1H), 5.73 (br s, 1H), 4.80 (br s, 2H), 4.09 (m, 1H), 1.23 (m, 7.48 (d, J =8Hz, 1H), 7.39 (m, 3H), 7.27 (m, 1H), 6.54 (d, J =16Hz, 1H), 6.33 (dd, J = 6.0, 526.97 8.0 Hz, 1H), 6.17 (br s, CC38 63-66 ([M+Ht) 1H), 5.92 (br s, 1H), .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) 7.39 (m, 4H), 7.28 (m, 1H), 6.54 (d, J = 16.0 Hz, 1H), 6.34 (dd, J = 526.09 3350, 1705, CC39 16.0, 8.0 Hz, 1H), 4.97 ([M-HD 1114, 808 (br s, 1H), 4.38 (d, J = 6.0 Hz, 2H), 4.10 (m, 1H), 1.53 (s, 9H) wo 2012/177813 7.46 (m, 5H), 7.29 (m, 1H), 7.20 (m, 3H), 6.55 (d, J = 16.0 Hz, 1H), 159- 580.25 CC40 6.37 (dd, J = 16.0, 8.0 160 ([M-HD Hz, 1H), 5.62 (br s, 1H), 4.55 (d, J = 6.4 Hz, 2H), 4.11 (m, 1H) 7.48 (m, 1H), 7.43 (m, 3H), 7.38 (m, 1H), 7.23 (s, 1H), 6.55 (d, J = 16.0 512.22 1740, 1701, CC41 Hz, 1H), 6.36 (d, J = ([M-HD 1114, 808 16.0 Hz, 1H), 4.60 (d, 2H), 4.18 (m, 1H), 3.85 (s, 3H) d6) 9.45 (br s, 2H), 7.90 (s, 2H), 7.75 (s, 1H), 7.46 (br s, 1H), 161- 578.96 CC42 7.28 (br s, 1H), 6.93 (m, 163 ([M-HD 1H), 6.75 (br s, 1H), 4.80 (m, 1H), 4.40 (br s, 2H), 3.90 (br s, 2H) 8.11 (d, J =4.0 Hz, 1H), 7.40 (m, 5H), 7.22 (m, 140- 505.39 1H), 6.61 (m, 2H), 6.35 CC43 142 ([M+Ht) (m, 2H), 4.94 (br s, 1H) 4.61 (d, J = 6.4 Hz, 2H), 4.11 (m, 1H) 8.41 (s, 1H), 7.77 (s, 1H), 7.47 (br s, 1H), 7.40 (s, 2H), 6.58 (d, J = 536.88 16.0 Hz, 1H), 6.45 (dd, 3320, 1674, CC44 ([M-HD J = 16.0, 8.0 Hz, 1H), 1114, 808 4.68 (d, J =4.0 Hz, 2H), 4.14 (m, 1H), 3.24 (q, J = 10.8 Hz, 2H) 8.41 (s, 1H), 7.76 (s, 1H), 7.40 (s, 2H), 7.15 (br s, 1H), 6.58 (d, J = 494.88 16.0 Hz, 1H), 6.44 (dd, 3309, 1659, CC45 J = 16.0, 8.0 Hz, 1H), ([M-HD 1115, 808 4.67 (d, J =4.4 Hz, 2H), 4.16 (m, 1H), 1.57 (m, 1H), 1.04 (m, 2H), 0.87 (m, 2H) wo 2012/177813 8.06 (m, 1H), 7.61 (m, 4H), 7.48 (s, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.38 151- 554.04 (m, 1H), 6.42 (m, 1H), CC46 153 5.92 (br s, 1H), 4.92 (m, ([M-HD 2H), 4.24 (m, 1H), 3.12 (m, 2H) 8.06 (m, 2H), 7.61 (m, 4H), 7.48 (s, 2H), 7.44 (d, J =8.0 Hz, 1H), 7.38 478.09 3309, 1659, CC47 (m, 2H), 6.42 (m, 1H), ([M+Ht) 1115, 808 4.92 (s, 2H), 1.36 (m, 1H), 1.00 (m, 2H), 0.77 (m, 2H) 8.06 (m, 2H), 7.61 (m, 3H), 7.48 (s, 2H), 7.44 (d, J =8.0 Hz, 1H), 7.38 511.05 3309, 1659, CC48 (m, 2H), 6.42 (m, 1H), ([M+Ht) 1115, 808 4.92 (s, 2H), 1.36 (m, 1H), 1.00 (m, 2H), 0.77 (m, 2H) 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), 515.33 CC49 84-87 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) 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), ccso 138- 461.32 6.61 (m, 1H), 6.57 (s, 140 1H), 6.48 (dd, J = 15.6, ([M-1HD 8.8 Hz, 1H), 4.74 (m, 1H), 1.64 (m, 1H), 0.75 (m, 4H); wo 2012/177813 7.56 (br s, 1H), 7.4 (s, 3H), 7.3 (m, 3H), 7.05 505.31 (br s, 1H), 6.8 (d, J = 6 149- CCSl Hz, 2H), 6.57 (m, 2H), 150 ([M-HD 6.20 (m, 2H), 4.05 (m, 1H), 3.2 (q, J = 10.4 Hz, 7.40 (s, 2H), 7.18 (s, 1H), 7.08 (s, 1H), 6.85 (m, 1H), 6.45 (m, 1H), 464.87 3309, 1659, CC52 6.20 (m, 1H), 5.55 ([M-HD 1115, 808 (s,1H), 4.08 (m, 1H), 1.30-1.10 (m, 4H), 1.90 (m,1H) 7.40 (s, 2H), 7.18 (s, 1H), 7.08 (s, 1H), 6.85 506 (m, 1H), 6.45 (m, 1H), 3309, 1659, CC53 ([M+Ht) 6.20 (m, 1H), 5.55 1115, 808 (s,1H), 4.08 (m, 1H), 3.21 (m, 2H) 7.28 (s, 2H), 7.25 (m, 2H), 7.10 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 11.4 504 Hz, 1H), 6.07 (br s, 1H), CC54 ([M+Ht) 6.01 (m, 1H), 4.51 (d, J = 5.8 Hz, 2H), 4.34 (m, 1H), 3.12 (q, J = 7.5 Hz, 8.56 (s, 1H), 8.11 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 398.05 2H), 7.38 (t, J = 1.8 Hz, DCl 93-97 ([M+Ht) 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) 8.59 (s, 1H), 8.13 (s, 1H), 7.69 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.5 Hz, 3121, 1524, 363.0746 2H), .29 (m, DC2 1251, 1165, (363.075) 4H), 6.64 (d, J = 15.7 1119 Hz, 1H), 6.47 (dd, J = .9, 8.0 Hz, 1H), 4.17 (m, 1H) wo 2012/177813 8.56 (s, 1H), 8.11 (s, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.3 Hz, 1521, 1246, 329.1144 DC3 2H), 7.40 (m, 5H), 6.61 1219, 1162, (329.114) (d, J = 15.8 Hz, 1H), 1152, 1107 6.51 (dd, J = 15.9, 7.7 Hz, 1H), 4.18 (m, 1H) 8.56 (s, 1H), 8.10 (s, 1H), 7.66 (d, J = 2.0 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 2.4 Hz, 3147, 1528, 364.11 DC4 2H), 7.34 (d, J = 8.4 Hz, 1494, 1246, 2H), 6.61 (d, J = 16.0 1165, 1108 Hz, 1H), 6.40 (dd, J = 16.0, 7.6 Hz, 1H), 4.15 (m, 1H) 8.54 (s, 1H), 8.10 (s, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.3 Hz, 3122, 3047, 344.25 DCS 2H), 7.20 (d, J = 8.0 Hz, 1523, 1252, ([M+Ht) 2H), 6.60 (d, J = 16.0 1160, 1107 Hz, 1H), 6.51 (dd, J = 16.0, 8.0 Hz, 1H), 4.15 (m, 1H), 2.37 (s, 3H) 8.55 (s, 1H), 8.10 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.8 Hz, 3124,2936, 360.28 DC6 2H), 6.95 (d, J = 8.8 Hz, 1522, 1249, ([M+Ht) 2H), 6.60 (d, J = 16.0 1160 Hz, 1H), 6.56 (dd, J = 16.0, 7.4 Hz, 1H), 4.15 (m, 1H), 3.82 (s, 3H) 8.55 (s, 1H), 8.10 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.5 (d, J = 8.4 Hz, 348 2H), 7.38 (m, 2H), 7.12 3141, 1512, ([M+Ht) (m, 2H), 6.61 (d, J = 1246, 1118 16.0 Hz, 1H), 6.40 (dd, J = 16.0, 7.6 Hz, 1H), 4.15 (m, 1H) wo 2012/177813 8.57 (s, 1H), 8.11 (s, 1H), 7.65 (d, J = 7.2 Hz, 2H), 7.52 (d, J = 8.0 Hz, 3116, 1628, 366.13 2H), 6.95 (m, 2H), 6.82 DC8 1524, 1252, ) (m, 1H), 6.65 (d, J = 1168, 1118 16.0 Hz, 1H), 6.50 (dd, J = 16.0, 8.0 Hz, 1H), 4.15 (m, 1H) 8.71 (s, 1H), 8.20 (s, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 348.11 2H), 7.40(m, 1H), 7.19 3115, 1525, ([M+Ht) (m, 3H), 6.60 (d, J = 1248, 1174 16.0 Hz, 1H), 6.40 (dd, J = 16.0, 8.4 Hz, 1H), 4.15 (m, 1H) 8.75 (s, 1H), 8.20 (s, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.6 (d, J = 8.4 Hz, 3114, 1526, 348.11 2H), 7.20-7.40 (m, DClO 1259, 1238, ([M+Ht) 4H), 6.60 (d, J = 16.0 1193, 1114 Hz, 1H), 6.40 (dd, J = 16.0, 8.0 Hz, 1H,), 4.60 (m, 1H) 8.55 (s, 1H), 8.10 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.4 Hz, 75.5- 358.14 2H), 7.01 (s, 3H), 6.60 DCll 78.5 ([M+Ht) (d, J = 16.0 Hz, 1H), 6.51 (dd, J = 16.0, 7.8 Hz, 1H), 4.15 (m, 1H), 2.34 (s, 6H) 8.58 (s, 1H), 8.10 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.53 (m, 4H), 7.2 3055,2930, 398.05 DC12 (s, 1H) 6.62 (d, J = 15.6 1523, 1250, ([M+Ht) Hz, 1H), 6.44 (dd, J = 1165 .6, 8.0 Hz, 1H), 4.15 (m, 1H) wo 2012/177813 8.58 (s, 1H), 8.10 (s, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.55 (m, 4H), 7.25 3108, 1523, 396.16 DC13 (m, 1H), 6.64 (d, J = 1249, 1166, 16.0 Hz, 1H), 6.40 (dd, 1127 J = 16.0, 8.0 Hz, 1H), 4.90 (m, 1H) 8.58 (s, 1H), 8.10 (s, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.55 (m, 4H), 7.25 3117,2925, 398.05 DC14 (m, 1H), 6.67 (d, J = 1526, 1246, ([M+Ht) 16.0 Hz, 1H), 6.40 (dd, 1172, 1117 J = 16.0, 8.0 Hz, 1H), .00 (m, 1H) 8.58 (s, 1H), 8.10 (s, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.52 (m, 3H), 7.40 (d, J = 8.0 Hz, 1H), 7.30 3120, 1524, 397.95 DClS (dd, J = 8.4, 2.9 Hz, 1267, 1176, ([M+Ht) 1H), 6.64 (d, J = 16.0 1112 Hz, 1H), 6.40 (dd, J = 16.0, 8.0 Hz, 1H), 4.90 (m, 1H) 8.61 (s, 1H), 8.13 (s, 1H), 7.92 (s, 1H), 7.86 (s, 2H), 7.70 (d, J = 7.0 466 Hz, 2H), 7.54 (d, J = 7.0 DC16 ([M+Ht) Hz, 2H), 6.67 (d, J = 16.0 Hz, 1H), 6.46 (dd, J = 16.0, 8.0 Hz, 1H), 4.35 (m, 1H) 8.58 (s, 1H), 8.1 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 3122, 3076, 430.06 7.51 (s, 1H), 7.42 (s, 2929, 1523, DC17 ([M+Ht) 1H), 6.68 (d, J = 16.0 1250, 1168, Hz, 1H), 6.35 (dd, J = 1114 16.0, 8.0, Hz, 1H), 4.98 (m, 1H) wo 2012/177813 2012/043418 8.57 (s, 1H), 8.11 (s, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.4 Hz, 429.91 DC18 92-95 2H), 7.42 (s, 2H), 6.65 ([M+Ht) (d, J = 16.0 Hz, 1H), 6.40 (dd, J = 16.0, 8.0 Hz, 1H), 4.10 (m, 1H) 8.58 (s, 1H), 8.12 (s, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.64 (s, 1H), 7.59 430.321 (s, 1H), 7.55 (m, 3H), DC19 97-99 ([M+Ht) 6.60 (d, J = 16.0 Hz, 1H), 6.40 (dd, J = 16.0, 8.0 Hz, 1H), 4.22 (m, 8.58 (s, 1H), 8.15 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2937, 1524, 427.0463 2H), 7.36 (s, 2H), 6.62 1482, 1278, DC20 (427.0466 (d, J = 16.0 Hz, 1H), 1249, 1166, 6.43 (dd, J = 16.0, 8.0 1112 Hz, 1H), 4.12 (m, 1H), 3.88 (s, 3H) 8.42 (s, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.40 (s, 3108, 1572, 412.04 1H), 7.22 (s, 2H), 6.60 DC21 1531, 1242, ([M+Ht) (d, J = 16.0 Hz, 1H), 1172, 1104 6.42 (dd, J = 16.0, 8.0 Hz, 1H), 4.15 (m, 1H), 2.5 (s, 3H) 8.62 (s, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 7.40 (s, 147- 441.01 DC22 1H), 7.30 (s, 2H), 6.67 149 ([M-HD (d, J = 16.0 Hz, 1H), 6.48 (dd, J = 16.0, 8.0 Hz, 1H), 4.15 (m, 1H) wo 2012/177813 7.95 (s, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.39 (s, 412.05 1H), 7.29 (s, 2H), 6.67 DC23 99 ([M+Ht) (d, J = 16.0 Hz, 1H), 6.45 (dd, J = 16.0, 8.0 Hz, 1H), 4.12 (m, 1H), 2.51 (s, 3H) 8.10(s, 1H), 7.52(d,l= 8.0 Hz, 2H), 7.42-7.38 (m, 3H), 7.28 (s, 2H), 133- 440.03 DC24 6.67 (d, J = 16.0 Hz, 134 ([M+Ht) 1H), 6.45 (dd, J = 16.0, 8.0 Hz, 1H), 4.16 (m, 1H), 2.79 (s, 3H) 7.97 (s, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.38 (m, 442.02 1H), 7.29 (s, 2H), 6.65 1167, 1114, DC25 ([M-HD (d, J = 16.0 Hz, 1H), 800 6.42 (dd, J = 16.0, 8.0 Hz, 1H), 4.17 (m, 1H), 2.74 (s, 3H) 8.12 (s, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.40-7.37 (m 3H), 7.28 (s, 2H), 1689, 1253, 464.03 6.66 (d, J = 16.0 Hz, DC26 1166, 1114, ([M-HD 1H), 6.44 (dd, J = 16.0, 979,964 8.0 Hz, 1H), 4.14 (m, 1H), 3.22 (m, 1H), 1.09 -1.16 (m, 4H) 8.19 (s, 1H), 7.64 (d, J = 7.2 Hz, 2H), 7.55 (d, 7.2 Hz, 2H), 7.39 (s, 1H), 1571, 1331, 473.94 7.30 (s, 2H), 6.62 (d, J = DC27 1170, 1113, ([M-HD 16.0 Hz, 1H), 6.42 (dd, J = 8.0, 16.0 Hz, 1H), 4.18 (m, 1H), 3.58 (s, wo 2012/177813 8.79 (s, 1H), 8.18 (s, 1H), 7.80 (m, 3H), 7.52 (m, 2H), 7.24 (m, 1H), 3126,2233, 421.22 DC28 6.63 (d, J = 16.0 Hz, 1516, 1250, ([M+Ht) 1H), 6.54 (d, J = 16.0, 1165, 1109 7.6 Hz, 1H), 4.19 ( m, 8.80 (s, 1H), 8.2 (s, 1H), 7.75 -7.82 (m, 3H), 7.41 (t, J =2Hz, 1H), 421.22 3005, 1716, DC29 7.26 (m, 2H), 6.65 (d, J ([M+Ht) 1363, 1223 = 16.0 Hz, 1H), 6.52 (dd, J = 16.0, 7.6 Hz, 1H), 4.16 (m, 1H) 8.81 (s, 1H), 8.20 (s, 1H), 7.94 (s, 1H), 7.85 (m, 3H), 7.79 (m, 2H), 2964,2234, 489.17 DC30 6.70 (d, J = 16.0 Hz, 1289, 1166, ([M+Ht) 1H), 6.58 (dd, J = 16.0, 1136 8.0 Hz, 1H), 4.35 (m, 8.80 (s, 1H), 8.20 (s, 1H), 7.82 (m, 3H), 7.4 117- 455.27 (s, 2H), 6.62 (d, J = 16.0 DC31 118 ([M+Ht) Hz, 1H), 6.52 (dd, J = 16.0, 8.0 Hz, 1H), 4.18 (m, 1H) 8.82 (s, 1H), 8.22 (s, 1H), .78 (m, 3H), 388.0705 3126,2234, 7.38-7.30 (m, 3H), 6.62 DC32 (388.0703 1520, 1280, (d, J = 16.1 Hz, 1H), ) 1164, 1112 6.56 (dd, J = 16.1, 6.8 Hz, 1H), 4.18 (m, 1H) 8.80 (s, 1H), 8.20 (s, 1H), 7.82-7.80 (m, 3H), 3122,3086, 455.22 7.70-7.50 (m, 3H), 6.65 2234, 1517, DC33 ([M-HD (d, J = 16.9 Hz, 1H), 1327, 1168, 6.54 (dd, J = 16.9, 6.8 1113 Hz, 1H), 4.25 (m, 1H) wo 2012/177813 8.85 (s, 1H), 8.23 (br s, 1H), 7.83-7.78 (m, 3H), 3122,2934, 452.0412 7.33 (s, 2H), 6.69 (d, J = 2231, 1516, DC34 (452.0419 14.9 Hz, 1H), 6.50 (dd, 1480, 1248, ) J = 14.9, 7.2 Hz, 1H), 1211, 1165, 4.15 (m, 1H), 3.90 (s, 1111 8.60 (s, 1H), 8.20 (s, 1H), 7.82 (m, 3H), 7.28 2233, 1518, 439.01 (m, 2H), 6.65 (d, J = DC35 1250, 1169, ([M-HD 16.0 Hz, 1H), 6.48 (dd, J = 16.0, 8.0 Hz, 1H), 4.20 (m, 1H) 8.70 (s, 1H), 7.80 (m, 3H), 7.40 (s, 1H), 7.28 2927,2233, 437.25 (s, 2H), 6.63 (d, J = 16.0 1572, 1531, DC36 ([M+Ht) Hz, 1H), 6.50 (dd, J = 1248, 1166, 16.0, 8.0 Hz, 1H), 4.18 1112 (m, 1H), 2.50 (s, 1H) 8.86 (s, 1H), 7.89 (m, 3H), 7.40 (s, 1H), 7.30 109- 466.10 (s, 2H), 6.68 (d, J = 16.0 DC37 111 ([M-HD Hz, 1H), 6.57 (dd, J = 16.0, 8.0 Hz, 1H), 4.18 (m, 1H) 8.58 (s, 1H), 7.75 (m, 3H), 7.40 (s, 1H), 7.28 436.11 (s, 2H), 6.61 (d, J = 16.0 DC38 96-98 ([M-HD Hz, 1H), 6.42 (dd, J = 16.0, 8.2 Hz, 1H), 4.40 (br s, 2H), 4.15 (m, 1H) 8.65 (s, 1H), 8.18 (br s, 1H), 7.80-7.70 (m, 3H), 7.40 (s, 1H), 7.27 (s, 3352,2237, 224- 480.30 2H), 7.36 (m, 1H), 7.28 DC39 1707, 1163, 226 ([M+Ht) (m, 2H), 6.60 (d, J = 16.8 Hz, 1H), 6.47 (m, 1H), 4.16 (m, 1H), 2.40 (br s, 3H) 8.86 (s, 1H), 7.88 (m, 3H), 7.44 (s, 2H), 6.67 436.11 DC40 70-73 (d, J = 16.0 Hz, 1H), ([M-2HD 6.56 (dd, J = 16.0 7.6 Hz, 1H), 4.19 (m, 1H) wo 2012/177813 (DMSO-d6) 8.72 (s, 1H), 8.26 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.91 (s, 2H), 7.77 (d, J = 8.4 469.95 DC41 72-75 Hz, 1H), 6.42 (dd, J = ([M-HD .6, 9.2 Hz, 1H), 6.83 (d, J = 15.6 Hz, 1H), .87 (s, 2H), 4.89 (m, 8.78 (s, 2H), 7.83 (s, 1H), 7.80 (m, 2H), 7.42 (s, 2H), 6.65 (d, J = 16.4 104- 609.98 Hz, 1H), 6.51 (dd, J = 2234, 1714, DC42 107 ([M+Ht) 16.4, 7.8 Hz, 1H), 4.17 1114, 807 (m, 1H), 4 2.16 (m, 2H), 1.25 (m, 4H), 1.00 (m, 4H), (DMSO-d6) 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 = 233, 109- 540.04 DC43 8.4 Hz, 1H), 7.13 (dd, J 1699, 1114, 112 ([M+Ht) = 15.6, 9.2 Hz, 1H), 807 6.87 (d, J = 15.6 Hz, 1H), 4.92 (m, 1H), 1.99 (br s, 1H), 0.82 (s, 4H) 8.33 (s, 1H), 8.23 (s, 1H), 7.66 (s, 1H), 7.60 (s, 1H), 7.41 (m, 1H), 435.26 7.28 (m, 2H), 6.62 (d, J 2236,1510, DC44 [M-Hr = 16.0 Hz, 1H), 6.51 1114, 801 (dd, J = 16.0, 7.8 Hz, 1H), 4.16 (m, 1H), 2.20 (s, 3H) 8.36 (s, 1H), 8.23 (s, 1H), 7.66 (s, 1H), 7.60 468.87 (s, 1H), 7.41 (s, 2H), DC45 75-78 6.62 (d, J = 16.4 Hz, [M-Hr 1H), 6.51 (dd, J = 16.4, 7.6 Hz, 1H), 4.16 (m, 1H), 2.20 (s, 3H) wo 2012/177813 13C NMR (8) 3 155.63, 153.27, 8.83 (s, 1H), 8.21 (s, 153.12, 1H), 7.83 (d, J = 8.5 Hz, 143.01, 1H), 7.61 (d, J = 1.9 Hz, 137.89, 411.4 1H), 7.52 (dd, J = 8.4, 136.25, DC46 1.9 Hz, 1H), 7.28 (d, J = 134.03, ([Mt) 3.8 Hz, 2H), 6.93 (d, J = , 11.5 Hz, 1H), 6.26- 132.23, 6.20 (m, 1H), 4.22 (m, 131.23, 1H) 131.18, 129.20, 126.17, 125.04, 124.99 8.51 (s, 1H), 8.14 (s, 1H), 7.75 (s, 1H), 7.5 (m, 2H), 7.4 (s, 1H), 139- 474.16 DC47 7.30 (m, 2H), 6.60 (d, J 141 ([M-HD = 16.0 Hz, 1H), 6.50 (dd, J = 16.0, 8.0 Hz, 1H), 4.15 (m, 1H) 8.69 (s, 1H), 8.14 (s, 1H), 7.96 (d, J = 4.8 Hz, 414.05 1H), 7.39-7.27 (m, 5H), 124- DC48 6.95 (d, J = 16.0 Hz, 126 [M-Hr 1H), 6.51 (dd, J = 16.0, 7.6 Hz, 1H), 4.13 (m, 8.57 (s, 1H), 8.14 (s, 1H), 7.60 (m, 2H), 7.44 463.96 (m, 3H), 6.95 (d, J = DC49 81-83 [M-Hr 16.0 Hz, 1H), 6.51 (dd, J = 16.0, 7.6 Hz, 1H), 4.13 (m, 1H) 8.56 (s, 1H), 8.13 (s, 1H), 7.59 (d, J = 1.2 Hz, 430.07 2H), 7.44 (m, 2H), 7.28 140- DCSO (m, 2H), 6.61 (d, J = 1110,803 143 [M-HD 16.0 Hz, 1H), 6.47 (dd, J = 16.0, 8.0 Hz, 1H), 4.15 (m, 1H) wo 2012/177813 8.32 (s, 1H), 8.15 (s, 1H), 7.82 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.41 118- 464.22 DC51 (s, 1H), 7.29 (s, 2H), 121 ([M-HD 6.70 (d, J = 15.6 Hz, 1H), 6.50 (dd, J = 15.6, 8.0 Hz, 1H), 4.20 (m, 9.99 (s, 1H), 8.42 (s, 1H), 8.12 (s, 1H), 8.01 3123, 3079, (s, 1H), 7.68 (m, 1H), 2925, 1692, 7.44 (m, 1H), 7.33 (m, DC52 1571, 1512, 1H), 7.22 (s, 2H), 6.62 1253, 1164, (d, J = 16.7 Hz, 1H), 1111 6.45 (dd, J = 16.7, 9.3 Hz, 1H), 4.10 (m, 1H) 8.30 (m, 1H), 8.00 (br s, 1H), 7.75 (m, 1H),7.68 (m, 1H), 7.55 (m, 1H), 7.36 (m, 1H), 7.28 (m, 043, DC53 2H), 6.70 (m, 1H), 6.58 1683, 1116 (br s, 1H), 6.33 (m, 1H), .88 (m, 2H), 4.10 (m, 8.40 (s, 1H), 8.13 (s, 1H), 8.02 (s, 1H), 7.76 (d, J =8.4 Hz, 1H), 7.59 (d, J =8.0 Hz, 1H), 7.4 441.07 DC54 56-58 (s, 1H), 7.29 (m, 2H), ([M-HD 6.69 (d, J = 15.6 Hz, 1H), 6.57 (dd, J = 15.6, 7.8 Hz, 1H), 4.15 (m, 8.37 (s, 1H), 8.18 (s, 1H), 7.39 (s, 1H), 7.30 (m, 2H), 7.19 (d, J = 8.0 412.97 Hz, 1H), 6.90 (m, 2H), DCSS ([M+Ht) 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) wo 77813 9.59 (br s, 1H), 8.55 (s, 1H), 8.47 (s, 2H), 8.23 (s, 1H), 7.30 (m, 4H), 175- 453 DC56 6.62 (d, J = 16.0 Hz, 177 ([M-HD 1H), 6.40 (dd, J = 16.0, 8.0 Hz, 1H), 4.15 (m, 1H), 2.20 (s, 3H) 8.33 (s, 1H), 8.16 (s, 1H), 7.38 (s, 1H), 7.29 (s, 2H), 7.15 (d, J =7.6 Hz, 1H), 6.80 (d, J =7.6 3342,3112, 426.0627 Hz, 1H), 6.74 (m, 1H), 2931, 1606, DC57 (426.0626 6.60 (d, J = 15.6 Hz, 1583, 1574, 1H), 6.35 (dd, J = 15.6, 1528, 1153 8.4 Hz, 1H), 5.40 (br s, 1H), 4.15 (m, 1H), 2.90 (s, 3H) (DMSO-d6) 8.76 (s, 1H), 8.16 (s, 1H), 7.90 (br s, 1H), 7.83 (s, 1H), 7.70 (d, J =7.9 Hz, 1H), 3403,3304, 440.0424 7.71-7.67 (m, 3H), 7.58 3178, 1674, DC58 94-97 (440.0419 (d, J =7.9 Hz, 1H), 7.52 1571, 1169, (br s, 1H), 7.00 (dd, J = 1108 .8, 8.7 Hz, 1H), 6.85 (d, J = 15.8 Hz, 1H), 4.85 (m, 1H) (DMSO-d6) 9.00 (s, 1H), 8.63 (s, 1H), 8.17 (s, 1H), 7.70-7.59 (m, DC59 87-90 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) 8.32 (s, 1H), 8.10 (s, 1H), 7.97 (s, 1H), 7.65 (d, J =8.1 Hz, 1H), 7.47 (d, J =8.1 Hz, 1H), 7.40 469.0577 2987, 1725, (m, 1H), 7.28 (s, 2H), DC60 (469.0572 1518, 1275, 6.62 (d, J = 16.5 Hz, ) 1166, 1113 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) wo 2012/177813 (DMSO-d6) 9.90 (s, 1H), 8.17 (s, 1H), 8.15 (m, 1H), 7.90 (m, 1H), 7.71 (m, 2H), 7.67 (m, 442.15 130- 1H), 7.62 (d, J = 7.3 Hz, DC61 ([M+Ht) 132 1H), 7.03 (dd, J = 16.5, 8.3 Hz, 1H), 6.62 (d, J = 16.5 Hz, 1H), 4.87 (m, 8.27 (s, 1H), 8.23 (s, 1H), 7.40 (m, 3H), 7.30 (m, 3H), 6.64 (d, J = 1513, 1252, 412.10 DC62 16.0 Hz, 1H), 6.45 (dd, 1166, 1112, ([M+Ht) J = 16.0, 8.0 Hz, 1H), 801 4.19 (m, 1H), 2.21 (s, 8.26 (s, 1H), 8.12 (s, 1H), 7.42 (s, 2H), 7.18- 2928, 446.01 7.28 (m, 3H), 6.62 (d, J 2525,1249, DC63 = 15.6 Hz, 1H), 6.39 ([M+Ht) 1169, 1114, (dd, J = 15.6, 9.4 Hz, 1H), 4.10 (m, 1H), 2.25 (s, 3H) 8.84 (d, J = 5.8 Hz, 2H), 8.33 (s, 1H), 8.20 (s, 1H), 7.75 (m, 1H), 7.60 (d, J =28.6 Hz, 1H), 475.03 7.58-7.48 (m, 3H), 7.42 1683, 1167, DC64 ) (m, 1H), 7.28 (s, 2H), 650,479 6.71 (d, J = 16.9 Hz, 1H), 6.39 (dd, J = 16.9, 8.2 Hz, 1H), 4.15 (m, 8.55 (s, 1H), 8.12 (s, 1H), 7.55 (m, 3H), 7.39 (m, 1H), 7.30 (d, J = 1.6 412.05 Hz, 1H), 6.85 (d, J = DC65 722, 111 ([M+Ht) 16.0 Hz, 1H), 6.41 (dd, J = 16.0, 8.0 Hz, 1H), 4.17 (m, 1H), 2.40 (s, wo 2012/177813 8.59 (s, 1H), 8.14 (s, 1H), 7.94 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.61 468.26 (d, J = 8.0 Hz, 1H), 7.43 DC66 60-61 ([M+Ht) (s, 2H), 7.23 (d, J = 16.0 Hz, 1H), 6.41 (dd, J = 16.0, 8.0 Hz, 1H), 4.20 (m, 1H) 8.59 (s, 1H), 8.12 (s, 1H), 7.78 (br s, 1H), 7.71 (m, 1H), 7.62 (m, 133- 432.30 1H), 7.39 (s, 1H), 7.32 DC67 800, 114 134 ([M+Ht) (s, 2H), 7.03 (d, J = 16.0 Hz, 1H), 6.43 (dd, J = 16.0, 8.0 Hz, 1H), 0.21 (m, 1H) 8.71 (s, 1H), 8.18 (s, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 412.03 DC68 2H), 7.37 (s, 1H), 7.28 ([M+Ht) (m, 2H), 6.08 (d, J = 16.0 Hz, 1H), 4.26 (m, 1H), 2.05 (s, 3H) 8.56 (s, 1H), 8.11 (s, 1H), 7.70 (d, J = 8.5 Hz, 2H), 7.56 (d, J = 8.5 Hz, 162- 414.03 DC69 2H), 7.54 (m, 2H), 7.40 168 ([M+Ht) (m, 1H), 6.91 (d, J = 16.5 Hz, 1H), 6.66 (d, J = 16.5 Hz, 1H) 8.58 (s, 1H), 8.13 (s, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.60 (d, J = 8.7 Hz, 99- 428.05 2H), 7.46 (m, 2H), 7.42 DC70 103 ) (m, 1H), 6.85 (d, J = 16.2 Hz, 1H), 6.40 (d, J = 16.2 Hz, 1H), 3.42 (s, 11H NMR spectral data were acqurred usmg a 400 MHz mstrument m CDCh except where noted.
HRMS data are noted observed value (theoretical value). wo 2012/177813 Table 3: Assays s Compound BAW CEW GPA Number Rating Rating Rating ACl D D B AC2 c c c AC3 D D B AC4 D A B ACS D D B AC6 D A B AC7 A A B AC8 D B B AC9 A A B AClO A A B ACll A A D AC12 A A D AC13 A A B AC14 A B D AClS 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 wo 77813 Compound BAW CEW GPA Number Rating Rating Rating 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 wo 2012/177813 2012/043418 Compound BAW CEW GPA Number Rating Rating Rating AC48 A A B AC49 A A B ACSO A D B ACSl 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 wo 2012/177813 2012/043418 Compound BAW CEW GPA Number Rating Rating Rating 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 AClOO c c c wo 77813 Compound BAW CEW GPA Number Rating Rating Rating AC101 D D c AC102 D A c AC103 A A D AC104 A A B AClOS A A D AC106 A A B AC107 B A D AC108 B D D AC109 D D c ACllO A A c AClll A A c AC112 A A c AC113 B A D AC114 A B D ACllS A A D AC116 c c c AC117 A D B AC118 A D D BCl A A D BC2 A A D BC3 A A D BC4 A A B BCS A A B BC6 A A D wo 2012/177813 2012/043418 Compound BAW CEW GPA Number Rating Rating Rating BC7 A A D BC8 A A B BC9 A A D BClO A A B BCll c c c BC12 c c c BC13 A A D BC14 A D D CCl D D D CC2 A A B CC3 A A D CC4 A B B ccs A A B CC6 A A B CC7 A A B CC8 A A D CC9 A A B CClO A A B CCll A A B CC12 D D B CC13 A A B CC14 A D D CClS A A B CC16 A A B wo 77813 Compound BAW CEW GPA Number Rating Rating Rating 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 wo 2012/177813 2012/043418 Compound BAW CEW GPA Number Rating Rating Rating 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 ccso A A D CCSl A A D CC52 A D D CC53 D D B CC54 A A c DCl A A D DC2 D D c DC3 B D c DC4 A D c DCS D D c DC6 D D c DC7 A D c DC8 A D c DC9 D D c DClO D D c wo 77813 Compound BAW CEW GPA Number Rating Rating Rating DCll A D c DC12 A A B DC13 A A c DC14 D D c DClS 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 wo 77813 Compound BAW CEW GPA Number Rating Rating Rating 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 DCSO A A c DCSl A A c DC52 D D c DC53 D A c DC54 D D c DCSS D D c DC56 D D c DC57 A A c DC58 D D c 1000900130 Compound Number Rating DC61 OO DC62 O DC63 —i >U>>>UU>>U> U>>U> O DC64 O DC65 ('3 DC66 O DC67 O DC68 O DC69 O DC70 O As used herein, except where the context requires otherwise, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude other additives, components, integers or steps.
Reference to any prior art in the specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in New d or any other jurisdiction. 1000900130 WE

Claims (73)

CLAIM 1.
1.l. A molecule according to Formula One: R5 R6 R7 R8 R4 / X3 R10 X2\ / R3 R1 X1 R1 1 Formula One wherein: (a) R] is selected from (1) H, F, Cl, Br, 1, CN, N02, (Cl-Cg)alkyl, halo(C]—C8)alkyl, (C1— Cg)alkoxy, halo(C1—Cg)alkoxy, S(C]-Cg)all
2. A le according to claim 1 wherein R1 is selected from H, F, Cl, Br, 1, CN, N02, , ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (Cdalkyl, (C7)a1kyl, (Cg)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, 10 halo(C7)a1kyl, g)alky1, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (Cg)alkoxy, thoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, 6)alkoxy, halo(C7)alkoxy, and halo(Cg)alkoxy.
3. A molecule according to claim 1 or claim 2 wherein R2 is selected from H, F, Cl, Br, 15 1, CN, N02, , ethyl, (C3)alkyl, ky1, (C5)alkyl, (C6)all
4. A molecule according to any one of the preceding claims wherein R3 is selected from H, F, Cl, Br, 1, CN, N02, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (Cg)all
5. A molecule according to any one of the preceding claims n R4 is selected from H, F, Cl, Br, 1, CN, N02, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alky1, (C7)alkyl, 30 (Cg)alky1, halomethyl, haloethyl, 3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alky1, halo(C7)alkyl, halo(Cg)alkyl, methoxy, , (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (Cg)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C3)alkoxy. 1000900130
6. A le according to any one of the preceding claims wherein R5 is ed from H, F, Cl, Br, 1, CN, N02, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, ky1, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(Cg)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, koxy, (C6)alkoxy, (C7)alkoxy, (Cg)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(Cg)alkoxy.
7. A molecule according to any one of the preceding claims wherein R2 and R4 are selected from F, Cl, Br, 1, CN, and N02 and R1, R3, and R5 are H.
8. A molecule according to any one ofclaims l to 6 wherein R2, R3, and R4 are selected from F, Cl, Br, 1, CN, and N02 and R1, and R5 are H.
9. A molecule according to any one of claims 1 to 6 wherein R2, R3, and R4 are 15 independently selected from F and Cl and Rland R5 are H.
10. A molecule according to any one of claims 1 to 6 wherein R1 is selected from C1 and 20 11. A molecule according to any one of claims 1 to 6 wherein R2 is selected from CF3,
11.CH3, Cl, F, and H.
12. A molecule according to any one ms 1 to 6 wherein R3 is selected from OCH3, CH3, F, C1, or H.
13. A molecule according to any one of claims 1 to 6 n R4 is ed from CF3, CH3, C1, F, and H.
14. A molecule according to any one of claims 1 to 6 wherein R5 is selected from F, Cl, 30 and H.
15. A molecule according to any one of the preceding claims wherein R6 is selected from halomethyl, haloethyl, 3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, and halo(C8)alkyl. 1000900130
16. A molecule according to claim 15 wherein R6 is trifluoromethyl.
17. A molecule ing to any one of the ing claims wherein R7 is selected from H, F, Cl, Br, and l.
18. A molecule ing to any one of claims 1 to 16 n R7 is selected from H,
19.OCH3, and OH. 10 19. A molecule according to any one of the preceding claims wherein R8 is selected from
20.H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)all
21. A molecule ing to any one of the preceding claims wherein R9 is selected from H, F, Cl, Br, 1, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)a1kyl, (C7)alkyl, (Cg)alkyl, halomcthyl, haloethyl, 3)alkyl, 4)alkyl, halo(C5)alkyl, halo(C6)alky1, 20 halo(C7)alkyl, halo(Cg)alkyl, methoxy, ethoxy, koxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, koxy, (Cg)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(Cg)alkoxy.
22. A molecule according to any one of the preceding claims wherein R10 is selected 25 from F, Cl, Br, 1, CN, methyl, ethyl, (C3)alky1, (C4)a1ky1, (C5)all
23. A molecule according to claim 22 wherein R10 is selected from Cl, Br, CH3, and CF3. 1000900130
24. A molecule according to any one of claims 1 to 21 wherein R10 is selected from Br, C(=NOH)NH2, C(=O)H, C(=O)NH2, C(=O)OCH2CH3, C(=O)OH, CF3, CH2CH3, CH20H, CH3, Cl, CN, F, NHZ, NHC(=O)H, NHCH}, N02, OCH3, OCHFZ, and pyridyl.
25. A molecule according to any one of the preceding claims wherein R11 is selected from C(=O)(substituted- (C1—C8)alkyl), (R14)(R15), C(=O)heterocyclyl, and C(=0)(substituted—heterocyclyl).
26. A molecule according to claim 25 wherein R11 is C(=O)morpholinyl.
27. A molecule according to any one of claims 1 to 24 n R1 1 is ed from CHZN(H)C(=O)CH3, CH2N(H)C(:O)cyclopropyl, CHZN(H)C(:O)CH2CF3, CH2N(H)C(:O)C1~12CH3, CH2N(H)C(:O)C(CH3)3, Cle12N(H)C(=O)(chloropyridyl), C1—12N(H)C(=O)CH3(chloropyridyl), CH2N(H)C(=O)CH2CHZSCH3, N(H)C(=O)(pyridyl), 15 CH2N(Cngyridyl)C(=O)cyclopropyl, CHgN(H)C(:O)N(H)(CHZCH3), CH2N(H)C(=O)morpholinyl, CH2N(H)C(=O)N(H)(pyridyl), CH2N(H)C(=O)NH2, CH2N(H)C(=O)NH(CH2CH3), )C(=O)NH(CI~IzCHCHz), CHZN(H)C(=O)OC(CH3)3, CH2N(H)C(=O)O(chlorophenyl), CH2N(l-l)C(=O)(C=O)OCHg, CH2N(H)C(=O)(C:O)N(H)CH2CF3, CI-12N(H)(pyridyl), H)C(=O)cyclopropyl, 20 N(H)N(H)C(:O)Cl-12CF3, ON(H)C(:O)cyclopropyl, and ON(H)C(=O)CHzCF3.
28. A molecule according to any one of claims 1 to 24 wherein R11 is selected from triazolyl, l,2,4-triazolyl—C(=O)cyclopropyl, 1,2,4—triazolyl—C(:O)CH3, 1,2,— methyltriazolyl, 1,2,4—triazolyl-N(C(=O)cyclopropyl)2, 1,2,4— 25 triazolle(H)(C(=O)cyclopropyl), 1,2,4—triazolleH2, 1,2,4-triazolyl—N02, 1,2,4— triazolylS(O)2CH3, 1,2,4—triazolylSCH3, C(ZOXmorpholinyl), C(=O)N(CH3)(CH3), C(=O)N(H)(CH(CH3)chloropyridinyl), C(=O)N(H)(CH2C(=O)N(CH3)(CHZCF3)), C(=O)N(H)(CH2—benzothiazolyl), C(=O)N(H)(CH2C(=O)N(H)(CH2CF3)), C(=0)N(H)(CH2C(=O)N(H)(CH2CH=CH2))a C(=O)N(H)(CH2C(=O)N(H)(CYCIOPI‘OPYID, 30 (H)(CH2C(=O)N(H)(N(CH3)2)), C(=O)N(H)(CH2C(=0)N(H)(OCH3)), (H)(CH2C(=O)N(H)(thietanyl)), C(=O)N(H)(CH2C(=O)N(H)(thietanyl-dioxide)) C(=O)N(H)(CH2C(=O)0C(CH3)3), C(=0)N(H)(CH2C(=S)N(H)(CH2CF3)), C(=O)N(H)(CH2CF3), C(=O)N(H)(CHzCHz-chloropyridinyl) C(=O)N(H)(CH2-furanyl), C(=0)N(H)(CHz-methylimidazolyl) 1000900130 C(=0)N(H)(CH2—cyclopropyloxadiazolyl), C(=O)N(H)(CH2-phenyl), C(=O)N(H)(CH2- trifluoromethylphenyl), C(=O)N(H)(CH2-fluorophenyl), C(=O)N(H)(CH2~pyrazinyl), (H)(CH2-trifluoromethylpyridinyl), C(=O)N(H)(CHg-chloropyridinyl), C(=O)N(H)(CHz-pyridinyl—Noz), (H)(CH2—pyridinyl~OCH3), C(=O)N(H)(CH2- dinyl), C(=O)N(H)(CHz-tetrahydrofuranyl), C(=O)N(H)(CHg-chlorothiazolyl), C(=O)N(H)(CH3), C(=O)NH2, C(=O)N(H)(N(CH3)(fluorophenyl)), C(=O)N(H)(N(H)(fluoropheny1)), C(=O)N(H)(OCHg—chloropyridinyl), C(ZO)N(H)(piperidinyl), C(=O)N(H)(piperidinle(=O)CH2CF3), C(:0)N(H)(piperidinyl-- CHZCN), C(:O)N(H)(piperidinle(=O)CH3), C(=O)N(H)(piperidinleHzCHzOH), 10 C(=O)N(H)(piperidiny1—oxetanyl), C(=O)N(H)(chloropyridinyl), C(=O)N(H)(CH2— tetrahydropyranyl), C(ZO)N(H)(thietanyl), C(ZO)N(H)(thietanyl~dioxide), C(=O)N(H)(thietanyl—oxide), C(=O)N(H)(CH2—pyrazinyl) C(=O)pyrrolidinyI—oxo, C(2S)N(H)(CI‘12C(=O)N(HXCHZCFQ), C(=S)N(H)(CHQC(=S)N(H)(CH2CF3)), C(ZS)N(H)(CHz—chloropyridinyl), CH2N(CHZ~ 15 pyridinyl)(C(=O)—cyclopropyl), CHZN(H)(CFO)C(=O)N(H)(CH2CF3), CH2N(H)(C(=O)C(:O)OCH3), CH2N(H)(C(=O)C(CH3)3), CH2N(H)(C(=O)-CHZ— pyridinyl), CH2N(H)(C(:O)CH2CF3), )(C(=O)CI-IzCH28(O)2CH3), CH2N(H)(C(:O)CH2CH;;SC113), CHZN(H)(C(=O)CH2CHg), CH2N(H)(C(:O)—cyclopropyl), C1712N(H)(C(=O)morpholinyl), CH2N(H)(C(=O)N(CH3)2, C1~{2N(H)(C(=O)N(H)(CH2CHg)), 20 CHZN(H)(C(=O)N(H)(pyridiny1)), CH2N(H)(C(=O)OC(CH3)3), CH2N(H)(C(:O)O— chlorophenyl), CHZN(H)(C(=O)—pyridinyl), Cl-12N(H)(C(=0)—chloropyridinyl), CH2N(H)(C(=S)cyc10propy1), ClelgN(H)(C(:S)N(H)(Cl-12CH:CI~12)), CHZN(H)(C(=S)N(H)(CH2CH3)), CH2N(H)(pyridinyl), N(H)(N(H)(C(=O)CH2CF3), N(H)(N(H)(C(=O)cyclopropyl), C(:O)CH2CF3), and ON(H)(C(=O)cyclopropyl).
29. A molecule ing to any one of the preceding claims wherein R12 is selected from H, F, Cl, Br, 1, methyl, ethyl, (C3)a1kyl, (C4)a1kyl, (C5)a1kyl, (C6)alkyl, (C7)alkyl, (Cg)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, 5)alkyl, halo(C6)alkyl, halo(C7)a1ky1, halo(C8)alkyl, halomethoxy, haloethoxy, halo(C3)alkoxy, 4)a1koxy, 30 halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(Cg)alkoxy.
30. A molecule according to claim 29 wherein R12 is selected from CH3 and H. 1000900130
31. A molecule according to any one of the preceding claims wherein R13 is ed from H, F, Cl, Br, I, , ethyl, (C3)alkyl, kyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (Cg)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(Cg)alkyl, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(Cg)alkoxy.
32. A le according to any one of the preceding claims wherein R13 is selected from CH3, Cl, and H. 10
33. A le according to any one of claims 1 to 28 wherein R12—Rl3 is the hydrocarbyl linkage H=CH.
34. A molecule according to any one of the preceding claims wherein R14 and R15 are independently selected from H, methyl, ethyl, (C3)alkyl, (C4)all
35. A molecule according to any one of the ing claims wherein R14 and R15 are independently selected from H, CH3, CH2CF3, lopyridyl, oxo-pyrrolidinyl, halophenyl, thietanyl, CH2~phenyl, CHz-pyridyl, thietanyl—dioxide, CHz—halothiazolyl, C((CH3)2)—pyridyl, N(H)(halophenyl), CHQ—pyriinidinyl, CHg—tetrahydrofuranyl, CHz—furanyl, 10 O—CH2~halopyi‘idyl, and CH2C(=O)N(H)(CH2CF3).
36. A molecule according to any one ofthe ing claims n R16 and R17 are independently selected from H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (Cg)alkyl, halomethyl, hyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alky1, 15 halo(C6)alkyl, 7)alkyl, halo(Cg)alkyl, methyl—aryl, ethyl—aryl, (C3)alkyl—aryl, (C4)alkyl— aryl, (C5)alkyl—aryl, (C6)alkyl—ary1, (C7)alkyl—aryl, (C8)alkyl—aryl, —(substituted~aryl), ethyl~(substituted~aryl), (C3)alkyl—(substituted—aryl), (C4)alkyl—(substitutcd—aryl), (C5)alkyl— (substituted—aryl), (C6)alkyl—(substituted—aryl), (C7)alkyl—(substituted—aryl), (Cg)alkyl— (substituted—ai‘yl), yl—aryl, O-ethyl—aryl, O—(C3)alkyl—aryl, O—(C4)alkyl~aryl, O— 20 (C5)alkyl—aryl, O—(CQalkyl—aryl, O—(C7)a1kyl—aryl, O—(Cg)alkyl—aryl, O—methyl—(substituted— aryl), O—ethyl—(substituted-aryl), O—(C3)alky1—(substituted—aryl), O—(C4)alkyl—(substituted— aryl), Ov(C5)alkyl~(substituted—aryl), O—(C6)alkyl~(substituted—aryl), O—(C7)alkyl—(substituted— aryl), O-(Cg)alkyl—(substituted—aryl), methyl—heterocyclyl, ethyl—heterocyclyl, (C3)alkyl- heterocyclyl, (C4)alkyl—heterocyclyl, (C5)all
37. A molecule according to claim 36 wherein R16 and R17 are independently selected from H, CH2CF3, cyclopropyl, thietanyl, nyl dioxide, and halophenyl.
38. A molecule according to any one of the preceding claims n X1 is CR12, X2 is CR13, and X3 is CR9.
39. A molecule according to any one of claims 1 to 21 wherein R10 and R11 form a linkage and said linkage is selected from (a) — (1). >l< *3 (a) O\N * / (b) \< (C) N * * \N\ * \N/ a: /0 X4 X4 N““‘X4 \N (g) T Y/N >I< X4 \H/N 0)- * * /\>' (10 where "*" indicates attachment back to the ring, (Note while the structures are drawn this way, they can be flipped from bottom to top thereby rotating the structure 180 degrees, and hydrogens for carbons atoms are implied and not shown)
40. A molecule ing to any one of the preceding claims having one of the following structures 1000900130 AC66 0 AC78 0 AC79 O | F o C] OBrH N NACF3
41. A composition comprising a molecule of Formula One according to any one of the preceding claims and: (a) one or more compounds having acaricidal, algicidal, avicidal, bactericidal, fungicidal, herbicidal, insecticidal, molluscicidal, nematicidal, rodenticidal, or Virucidal properties; or (b) one or more compounds that are antifeedants, bird ents, chemosterilants, herbicide safeners, insect attractants, insect repellents, mammal repellents, mating disrupters, 10 plant tors, plant growth regulators, or synergists; or (c) both (a) and (b).
42. A composition according to claim 41 wherein the one or more compounds are selected from: (3—ethoxypropy1)mercury bromide, 1,2-dichloropropane, 1,3-dichloropropene, 15 1-methy1cyclopropene, l-naphthol, ylthio)ethanol, tri-iodobenzoic acid, 2,3,6— TBA, TBA-dimethy1ammonium, 2,3,6-TBA-lithium, 2,3,6—TBA-potassium, 2,3,6- TBA—sodium, 2,4,5-T, 2,4,5-T-2—butoxypropy1, T-2—ethy1hexy1, 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- 1000900 I 30 triethylammonium, 2,4,5—T-trolamine, 2,4—D, 2,4—D-2—butoxypropyl, 2,4-Dethylhexyl, 2,4- Dbutoxypropyl, 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, dimethylammonium, 2,4-D—diolamine, 2,4-D—dodecylammonium, 2,4-DEB, P, 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, tris(2—hydroxypropyl)ammonium, 2,4— D—trolamine, 2iP, 2—methoxyethylmercury chloride, 2—phenylphenol, 3,4—DA, 3,4—DB, 3,4— 10 DP, 4-aminopyridine, 4—CPA, 4—CPA—potassium, 4—CPA~sodium, 4—CPB, 4—CPP, 4~ hydroxyphenethyl alcohol, 8—hydroxyquinoline sulfate, 8—phenylmercurioxyquinoline, abamectin, ic acid, ACC, acephate, acequinocyl, acetamiprid, acethion, acetochlor, acetophos, acetoprole, acibenzolar, acibenzolar—S—methyl, acifluorfen, acifluorfen—methyl, rfen—sodium, aclonifen, acrep, acrinathrin, acrolein, acrylonitrile, acypetacs, acypetacs— 15 copper, acs—Zinc, alachlor, alanycarh, albendazole, aldicarb, aldimorph, aldoxycarb, aldrin, allethrin, allicin, allidochlor, allosamidin, alloxydim, alloxydim—sodium, allyl alcohol, allyxycarb, alorac, alpha~cypermethrin, endosulfan, ametoctradin, ametridione, ametryn, in, amicarbazone, thiazol, amidithion, amidoflumet, amidosulfuron, arb, aminocyclopyrachlor, aminocyclopyrachlor—methyl, aminocyclopyrachlor— 20 potassium, aminopyralid, yralid—potassium, aminopyralid—tris(2— hydroxypropyl)ammonium, amiprofos-methyl, amiprophos, amisulbrom, amiton, amiton oxalate, amitraz, amitrole, ammonium sulfamate, ammonium a—naphthaleneacetate, amobam, ampropylfos, anabasine, ancymidol, anilazine, anilofos, anisuron, anthraquinone, antu, apholate, aramite, arsenous oxide, asomate, aspirin, asulam, asulam-potassium, asulam- 25 sodium, athidathion, atraton, atrazine, aureofungin, aviglycine, aviglycine hydrochloride, azaconazole, azadirachtin, azafenidin, azamethiphos, azimsulfuron, azinphos—ethyl, azinphos~ methyl, aziprotryne, azithiram, azobenzene, azocyclotin, ate, azoxystrobin, desh, barban, barium hexafluorosilicate, barium polysulfide, barthrin, BCPC, tamid, benalaxyl, benalaxyl-M, benazolin, benazolin-dimethylammonium, benazolin- 30 ethyl, benazolin-potassium, bencarbazone, benclothiaz, bendiocarb, alin, acarb, benfuresate, benodanil, benomyl, benoxacor, benoxafos, benquinox, bensulfuron, bensulfuron-methyl, bensulide, bensultap, bentaluron, bentazone, bentazone-sodium, avalicarb, benthiavalicarb—isopropyl, benthiazole, bentranil, benzadox, benzadox— ammonium, konium chloride, benzamacril, benzamacril-isobutyl, benzamorf, 1000900130 benzfendizone, benzipram, icyclcn, benzofenap, benzofluor, benzohydroxamic acid, benzoximate, benzoylprop, lprop—ethyl, benzthiazuron, benzyl benzoate, benzyladenine, berberine, berberine chloride, beta—cyfluthrin, beta-cypermethrin, bethoxazin, bicyclopyrone, bifenazate, x, bifenthrin, nzhi, 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, nolide, brassinolide—ethyl, brevicomin, brodifacoum, brofenvalerate, brofluthrinate, il, brcmacil—lithium, bromacil-sodium, bromadiolone, bromethalin, bromethrin, bromfenvinfos, 10 bromoacetamide, bromobonil, bromobutide, yclen, bromo—DDT, bromofenoxim, bromophos, bromophos~ethyl, bromopropylate, bromothalonil, bromoxynil, bromoxynil butyrate, bromoxynil heptanoate, bromoxynil octanoate, bromoxynil~potassium, razon, bromuconazole, bronopol, bucarpolate, bufencarb, buminafos, bupirimate, buprofezin, Burgundy mixture, busulfan, butacarb, butachlor, butafenacil, butamifos, 15 butathiofos, butenachlor, butethrin, buthidazole, bate, buthiuron, rboxim, 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 20 benzenesulfonate, carbendazim sulfite, carbetamide, carbofuran, carbon disulfide, carbon tetrachloride, carbophenothion, carbosulfan, carboxazole, carboxide, carboxin, carfentrazone, carfentrazone—ethyl, carpropamid, cartap, carlap hydrochloride, carvacrol, carvone, CDEA, ccllocidin, CEPC, ceralure, Cheshunt mixture, ethionat, chitosan, chlobenthiazone, chlomethoxyfen, chloralose, chloramben, chloramben—ammonium, chloramben~diolamine, 25 chloramben—methyl, chloramben—methylammonium, chloramben—sodium, mine phosphorus, chloramphenicol, chloraniformethan, chloranil, chloranocryl, ntraniliprole, chlorazifop, chlorazifop—propargyl, chlorazine, enside, chlorbenzuron, chlorbicyclen, romuron, chlorbufam, chlordane, chlordecone, chlordimeform, chlordimeform hydrochloride, chlorempenthrin, chlorethoxyfos, chloreturon, chlorfenac, chlorfenac- 30 ammonium, chlorfenac—sodium, chlorfenapyr, enazole, chlorfenethol, chlorfenprop, enson, ensulphide, chlorfenvinphos, chlcrfluazuron, chlorflurazole, chlorfluren, chlorfluren-methyl, chlorflurenol, urenol~methyl, chloridazon, chlorimuron, chlorimuron—ethyl, chlormephos, chlormequat, equat chloride, idine, chlornitrcfen, chlorobenzilate, chlorodinitronaphthalenes, chloroform, chloromebuform, 1000900130 chloromethiuron, chloroneb, chlorophacinone, chlorophacinone—sodium, chloropicrin, chloropon, chloropropylate, thalonil, toluron, chloroxuron, chloroxynil, chlorphonium, chlorphonium chloride, chlorphoxim, chlorprazophos, chlorprocarb, chlorpropham, chlorpyrifos, chlorpyrifos-methyl, chlorquinox, chlorsulfuron, chlorthal, chlorthal-dimethyl, chlorthal-monomethyl, chlorthiamid, chlorthiophos, chlozolinate, e chloride, chromafenozide, cinerin l, cinerin ll, cinerins, cinidon-ethyl, cinmethylin, cinosulfuron, ciobutide, cisanilide, hrin, clethodim, climbazole, cliodinate, clodinafop, clodinafop-propargyl, cloethocarb, Clofencet, clofencet-potassium, clofentezine, clofibric acid, clofop, clofop—isobutyl, one, clomeprop, cloprop, xydim, clopyralid, 10 alid—methyl, clopyralid—olamine, clopyralid—potassium, clopyralid-tris(2— hydroxypropyl)ammonium, cloquintocet, cloquintocet—mexyl, cloransulam, cloransulam— methyl, closantel, anidin, clotrimazcle, cloxyfonac, cloxyfonac—sodium, CMA, codlelure, colophonate, copper acetate, copper acetoarsenite, copper arsenate, copper carbonate, basic, copper hydroxide, copper enate, copper oleate, copper oxychloride, 15 copper silicate, copper e, copper zinc chromatc, coumachlor, coumafuryl, coumaphos, coumatctralyl, coumithoate, coumoxystrobin, CPMC, CPMF, CPPC, credazine, cresol, crimidine, crotamiton, yphos, crufomate, cryolile, cue—lure, cufraneb, ron, cuprobam, cuprous oxide, curcumenol, cyanamide, cyanatryn, cyanazine, cyanofenphos, cyanophos, cyanthoate, cyantraniliprole, cyazofamid, cybutryne, cyclafuramid, ilide, 20 cyclethrin, cycloate, eximide, cycloprate, cycloprothrin, cyclosulfamuron, aprid, cycloxydim, cycluron, yrafen, cyflufenamid, cyflumetofen, cyfluthrin, cyhalofop, cyhalofop—butyl, cyhalothrin, tin, cymiazole, cymiazole hydrochloride, cymoxanil, cyometrinil, cypendazole, cypermethrin, cyperquat, cyperquat chloride, cyphenothrin, cyprazine, cyprazole, cyproconazole, cyprodinil, cyprofuram, cypromid, cyprosulfamide, 25 cyromazine, cythioate, daimuron, dalapon, dalapon—calcium, dalapon—magnesium, n— 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, 30 desmedipham, desmetryn, d—fanshiluquebingjuzhi, diafenthiuron, os, di—allate, diamidafos, diatomaceous earth, on, dibutyl phthalate, dibutyl ate, dicamba, dicamba—diglycolamine, dicamba—dimethylammonium, dicamba-diolamine, dicamba— isopropylammonium, dicamba-methyl, dicamba—olamine, dicamba-potassium, dicamba— sodium, dicamba-trolamine, dicapthon, dichlobenil, dichlofenthion, dichlofluanid, dichlone, 1000900130 dichloralurea, dichlorbenzuron, dichlorflurenol, dichlorflurenol—methyl, dichlormate, dichlormid, dichlorophen, dichlorprop, rprop-Z—ethylhexyl, dichlorprop—butotyl, dichlorprop-dimethylammonium, rprop-ethylammonium, dichlorprop—isoctyl, dichlorprop-methyl, dichlorprop~P, dichlorprop—P—2-ethy1hexy1, dichlorprop-P- ylammonium, dichlorprop-potassium, dichlorprop—sodium, dichlorvos, zoline, diclobutrazol, diclocymet, diclofop, diclofop-methyl, diclomezine, diclomezine—sodium, dicloran, diclosulam, dicofol, dicoumarol, dicresyl, ophos, dicyclanil, dicyclonon, dieldrin, dienochlor, diethamquat, diethamquat dichloride, diethatyl, tyl—ethyl, diethofencarb, dietholate, diethyl pyrocarbonate, diethyltoluamide, difenacoum, 10 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, 15 dimethoate, dimethomorph, rin, dimethyl carbate, dimethyl phthalate, ylvinphos, dimetilan, dimcxano, dimidazon, strobin, dinex, dinex—diclexine, dingjunezuo, diniconazole, nazole—M, dinitramine, dinobuton, dinocap, dinocap-4, dinocap—o, dinocton, dinofenate, dinopenton, dinoprop, dinosam, dinoseb, dinoseb acetate, dinoseb—ammonium, dinoseb—diolamine, dinoseb~sodium, dinoseb-trolamine, lfon, 20 dinotefuran, dinoterb, dinoterb acetate, dinoterbon, diofenolan, dioxabenzofos, dioxacarb, dioxathion, diphacinone, diphacinone—sodium, diphenamid, diphenyl sulfone, diphenylamine, dipropaiin, dipropetryn, thione, diquat, diquat dibromide, lui‘e, disul, disulfiram, disulfoton, disul—sodium, ditalimfos, non, dithicrofos, dithioether, dithiopyr, diuron, d— limonene, DMPA, DNOC, DNOC—ammonium, DNOC—potassium, DNOC—sodium, 25 dodemorph, dodemorph acetate, dodemorph benzoate, dodicin, dodicin hydrochloride, dodicin—sodium, dodine, dofenapyn, dominicalure, doramectin, drazoxolon, DSMA, dufuiin, EBEP, EBP, ecdysterone, edifenphos, eglinazine, eglinazine-ethyl, emamectin, emamectin benzoate, EMPC, hrin, endosulfan, endothal, al-diammonium, endothal- dipotassium, al—disodium, endothion, endrin, enestroburin, EPN, epocholeone, 30 epofenonane, epoxiconazole, eprinomectin, epronaz, EPTC, erbon, lciferol, erlujixiancaoan, esde’palle’thrine, alerate, esprocarb, etacelasil, etaconazole, etaphos, etem, ethaboxam, ethachlor, ethalfluralin, ethametsulfuron, ethametsulfuron-methyl, ochlor, ethephon, ethidimuron, ethiofencarb, ethiolate, ethion, ethiozin, ole, ethirimol, ethoate—methyl, ethofumesate, ethohexadiol, ethoprophos, ethoxyfen, ethoxyfen- 1000900130 ethyl, ethoxyquin, ethoxysulfuron, ethychlozate, ethyl formate, ethyl a-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, prox, etoxazole, etridiazole, etrimfos, eugenol, EXD, famoxadone, famphur, fenamidone, fenaminosulf, fenamiphos, nil, fenarimol, fenasulam, fenazaflor, fenazaquin, onazole, atin oxide, fenchlorazole, fenchlorazole-ethyl, fenchlorphos, fenclorim, fenethacarb, fenfluthrin, fenfuram, fenhexamid, fenitropan, othion, fenjuntong, carb, fencprop, fenoprop-3—butoxypropyl, fenoprop- 10 butometyl, fenoprop-butotyl, fenoprop—butyl, fenoprop—isoctyl, fenoprop—methyl, fenoprop— potassium, fenothiocarb, fenoxacrim, fenoxanil, fenoxaprop, fenoxaprop—ethyl, fenoxaprop—P, apropP—ethyl, fenoxasulfone, fenoxycarb, fenpiclonil, lenpirithrin, fenpropathrin, fenpropidin, fcnpi‘opimorpli, fenpyrazamine, fenpyroximate, fenridazon, l’enridazon— potassium, azon—propyl, fenson, fensulfothion, l’enteracol, fenthiaprop, fenthiaprop— ethyl, fenthion, fenthion—ethyl, leiitiii, fentin acetate, fentin chloride, l’entin hydroxide, fentrazamide, fentril’anil, fenuron, 'l’enuron TCA, fenvalerate, ferbam, ferimzone, ferrous sulfate, lipronil, fiamprop, llamprop—isopropyl, flamprop—M, flamprop—methyl, flamprop~M~ isopropyl, llamprop—M—methyl, llazasulfuron, flocoumafen, flometoquin, flonicamid, florasulam, l'luacrypyrim, l7op, fluazifop—butyl, lluazifop—methyl, fluazifop-P, fluazifop— 20 P—butyl, fluazinam, lluazolate, on, flubendiamide, flubenzimine, flucarbazone, bazone—sodium, flucetosulfiiron, fluchloralin, flucofuron, flucycloxuron, flucythrinate, fludioxonil, fluenetil, lfone, flufenacet, flufenerim, flufenican, flufcnoxuron, flufenprox, flufenpyr, flufenpyr—ethyl, flufiprole, flumethrin, flumetover, flumetralin, flumetsulam, flumezin, flumiclorac, orac—pentyl, flumioxazin, opyn, flumorph, 25 uron, fluopicolide, fluopyram, fluorbenside, amid, fluoroacetamide, fluorodifen, fluoroglycofen, fluoroglycofen—ethyl, fluoroimide, fluoromidine, fluoronitrofen, fluothiuron, fluotrimazole, fluoxastrobin, flupoxam, flupropacil, flupropadine, flupropanate, flupropanate-sodium, difurone, ulfuron, flupyrsulfuron-methyl, flupyrsulfuronmethyl —sodium, fluquinconazole, flurazole, l, flurenol-butyl, flurenol-methyl, 30 fluridone, flurochloridone, fluroxypyr, fluroxypyr-butometyl, fluroxypyr-meptyl, flurprimidol, flursulamid, flurtamone, zole, flusulfamide, fluthiacet, fluthiacet-methyl, flutianil, nil, flutriafol, nate, fluxapyroxad, fluxofenim, folpet, fomesafen, fomesafen-sodium, fonofos, foramsulfuron, forchlorfenuron, formaldehyde, formetanate, formetanate hydrochloride, formothion, formparanate, formparanate hydrochloride, fosamine, 1000900130 fosamine-ammonium, fosetyl, fosetyl—aluminium, fosmethilan, fospirate, fosthiazate, fosthietan, frontalin, fuberidazole, fucaojing, fucaorni, 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, me, glyphosate, glyphosate-diammonium, glyphosate-dimethylammonium, glyphosate—isopropylammonium, glyphosate-monoammonium, glyphosate—potassium, glyphosate~sesquisodium, glyphosate—trimesium, sine, gossyplure, grandlure, 10 griseofulvin, guazatine, guazatine acetates, halacrinate, halfenprox, halofenozide, halosafen, halosulfuron, halosulfuron—methyl, haloxydine, haloxyfop, haloxyfop—etotyl, haloxyfop— methyl, haloxyfop—P, fop—P—etotyl, haloxyfop—P—methyl, fop—sodium, HCH, hemel, hempa, HEOD, heptachlor, heptenophos, heptopargil, phos, hexachloroacctone, hexachlorobenzene, hexachlorobutadiene, hexachlorophene, hexaconazole, hexaflumuron, 15 hexaflurate, hexalure, hexamide, hexazinone, hexylthiofos, hexythiazox, HHDN, holosull’, iwo, huangcaoling, huanjunzuo, hydramethylnon, hydrargaphen, hydrated lime, en cyanide, hydroprene, hymexazol, hyquincarb, 1AA, IBA, in, imazalil, imazalil nitrate, imazalil sulfate, imazamethabenz, ethabenz—methyl, imazamox, imazamox— ammonium, imazapic, imazapic—ammonium, imazapyr, imazapyr—isopropylammonium, 20 imazaquin, uin-ammonium, imazaquin—methyl, imazaquin—sodium, imazethapyr, imazethapyr-ammonium, imazosulfuron, imibenconazole, imicyafos, imidacloprid, imidaclothiz, tadine, iminoctadine triacctate, iminoctadine trialbesilate, imiprothrin, inabenfide, indano fan, indaziflam, indoxaearb, inezin, iodobonil, iodocarb, iodomethane, iodosulfuron, lfuron—methyl, lfuron—methyl—sodium, iofensulfuron, 25 iofensulfuron—sodium, ioxynil, ioxynil octanoate, ioxynil—lithium, ioxynil—sodium, ipazine, ipconazole, ipfencarbazone, nfos, one, iprovalicarb, iprymidam, ipsdienol, ipsenol, IPSP, ofos, isazofos, isobenzan, isocarbamid, isocarbophos, , isodrin, isofenphos, phos—methyl, isolan, isomethiozin, isonoruron, inate, isoprocarb, isopropalin, isoprothiolane, turon, isopyrazam, isopyrimol, isothioate, isotianil, 30 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, j odfenphos, juvenile hormone I, juvenile hormone II, juvenile hormone HI, kadethrin, karbutilate, karetazan, karetazan-potassium, kasugamycin, kasugamycin hydrochloride, 1000900130 kejunlin, n, ketospiradox, ketospiradox—potassium, kinetin, kinoprene, kresoxim— methyl, kuicaoxi, lactofen, —cyhalothrin, latilure, lead arsenate, lenacil, 1epimectin, 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-ethy1hexyl, 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—ethy1, MCPB—methyl, MCPB—sodium, mebeni1, mecarbam, mecarbinzid, mecarphon, 10 mecoprop, mecoprop—Z—ethylhexyl, mecoprop—dimethylammonium, mecoprop—diolamine, mecoprop—ethadyl, op~isoctyl, mecoprop—methyl, op—P, mecoprop-P—Z— ethylhexyl, mecoprop—P—dimethylammonium, mecoprop—P—isobutyl, mecoprop—potassium, mecoprop-P—potassium, op—sodium, mecoprOp—trolamine, medimeform, medinoterb, medinoterb acetate, medlure, mefenacet, mefenpyr, mefenpyr—diethyl, ide, 15 melluidide—diolamine, melluidide-potassium, megatomoic acid, menazon, mepanipyrim, meperfluthrin, mephenate, mephosfolan, mepiquat, mepiquat de, mepiquat pentaborate, mepronil, meptyldinocap, mercuric de, mercuric oxide, mercurous chloride, merphos, mesoprazine, mesosulfuron, mesosulfilron—methyl, mesotrione, mesulfen, mesulfenfos, metaflumizone, metalaxyl, metalaxyl—M, metaldchyde, metam, ammonium, 20 metamil‘bp, metamitron, metam—potassium, metam—sodium, metazachlor, metazosulfuron, metazoxolon, metconazole, metepa, metflurazon, enzthiazuron, methacrifos, methalpropalin, methamidophos, methasulfocarb, ole, methfuroxam, methidathion, methiobencarb, methiocarb, methiopyrisulfiiron, methiotepa, methiozolin, methiuron, methocrotophos, methometon, methomyl, methoprene, methoprotryne, methoquin—butyl, 25 methothrin, methoxychlor, methoxyfenozide, methoxyphenone, methyl te, methyl bromide, methyl eugenol, methyl , methyl isothiocyanate, methylacetophos, methylchloroform, dymron, methylene chloride, methylmercury benzoate, mercury dicyandiamide, methylmercury pentachlorophenoxide, methylneodecanamide, m, metobenzuron, metobromuron, metofluthrin, metolachlor, 30 metolcarb, metominostrobin, metosulam, metoxadiazone, metoxuron, metrafenone, metribuzin, ovaX, metsulfuron, metsulfuron-methyl, mevinphos, mexacarbate, an, milbemectin, ycin oxime, milneb, mipafox, mirex, MNAF, un, molinate, molosultap, monalide, monisouron, monochloroacetic acid, monocrotophos, monolinuron, monosulfuron, monosulfiiron-ester, monuron, monuron TCA, morfamquat, 1000900130 morfamquat ride, moroxydine, moroxydine hydrochloride, morphothion, , moxidectin, MSMA, muscalure, myclobutanil, myclozolin, N—(ethylmercury)—p~ toluenesulphonanilide, nabam, naftalofos, naled, naphthalene, aleneacetamide, naphthalic ide, naphthoxyacetic acids, naproanilide, napropamide, naptalam, naptalam-sodium, natamycin, neburon, niclosamide, niclosamide—olamine, nicosulfuron, ne, 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, 10 ulfamuron, 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, 15 paclobutrazol, ngding, para—dichlorobenzcne, parafluron, paraquat, paraquat ride, paraquat dimetilsul‘l’ate, ion, parathion~methyl, parinol, pebulate, pcfurazoate, pelargonic acid, penconazole, pencycuron, pendimethalin, penflufen, penl‘luron, ulam, pentachlorophenol, pentanochlor, penthiopyrad, pentmethrin, pentoxazone, perfluidone, permethrin, pethoxamid, phenamacril, ine oxide, phenisopham, 20 phenkapton, phenmedipham, phenmedipham—ethyl, phenobenzuron, phenothrin, oxide, phenthoate, phenylmercuriurea, phenylmercury acetate, phenylmercury chloride, phenylmercury derivative of pyrocatechol, phenylmercury nitrate, phenylmercury salicylate, phorate, phosacetim, phosalone, phosdiphen, phosfolan, phosfolan—methyl, phosglycin, t, phosnichlor, amidon, phosphine, phosphocarb, phosphorus, n, phoxim, 25 phoxim~methyl, phthalide, picloram, picloram—Z—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, pirirnioxyphos, pirimiphos-ethyl, pirimiphos- 30 methyl, plifenate, polycarbamate, polyoxins, orim, polyoxorim-zinc, polythialan, ium arsenite, potassium azide, potassium cyanate, potassium gibberellate, potassium enate, potassium polysulfide, potassium thiocyanate, potassium a-naphthaleneacetate, pp’-DDT, prallethrin, ene l, precocene II, precocene Ill, achlor, primidophos, primisulfuron, ulfuron—methyl, probenazole, prochloraz, prochloraz-manganese, 1000900130 proclonol, procyazine, procymidone, mine, profenofos, profluazol, profluralin, profluthrin, profoxydim, proglinazine, nazine-ethyl, prohexadione, prohexadione— calcium, prohydrojasmon, promacyl, promecarb, prometon, prometryn, promurit, hlor, 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, focarb, prosulfuron, prothidathion, prothiocarb, prothiocarb hydrochloride, prothioconazole, prothiofos, prothoate, protrifenbute, proxan, proxan—sodium, 10 prynachlor, pydanon, pymetrozine, pyracarbolid, pyraclofos, pyraclonil, pyraclostrobin, pyraflufen, pyraflufen—cthyl, pyrafluprole, pyramat, pyrametostrobin, pyraoxystrobin, pyrasulfotole, pyrazolynate, pyrazophos, pyrazosulfuron, pyrazosulfuron—ethyl, pyrazothion, pyrazoxyfen, pyresmethrin, pyrethrin I, pyrethrin II, pyrethrins, pyribambenz—isopropyl, pyribambenz—propyl, pyribencarb, pyribenzoxim, ticarb, pyriclor, pyridaben, fol, 15 pyridalyl, pyridaphenthion, pyridate, pyridinitril, pyrifenox, pyrifluquinazon, alid, pyrimethanil, pyrimidifen, pyriminobac, pyriminobac—methyl, pyrimisulfan, pyrimitate, pyrinuron, enone, pyriprole, opanol, pyriproxyfen, pyrithiobac, pyrithiobac— sodium, pyrolan, pyroquilon, pyroxasulfone, pyroxsulam, pyroxychlor, pyroxyfur, quassia, quinacetol, quinacetol sulfate, quinalphos, phos—methyl, quinazamid, quinclorac, 20 quinconazole, quinmerac, quinoclamine, quinonamid, quinothion, quinoxyfen, quintiofos, quintozcnc, quizalofop, quizalofop-ethyl, quizalofop—P, quizalofop—P—ethyl, quizalofop-P- tefuryl, quwenzhi, quyingding, rabenzazole, rafoxanide, rebemide, hrin, rhodethanil, rhodojaponin—HI, ribavirin, rimsulfuron, rotenone, ryania, saflufenacil, saijunmao, tong, lanilide, sanguinarine, santonin, schradan, scilliroside, ylazine, secbumeton, 25 sedaxane, selamectin, semiamitraz, semiamitraz de, sesamex, sesamolin, sethoxydim, shuangjiaancaolin, siduron, siglure, silafluofen, silatrane, silica gel, silthiofam, ne, 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 30 polysulfide, sodium anate, sodium a-naphthaleneacetate, sophamide, spinetoram, spinosad, spirodiclofen, spiromesifen, spirotetramat, spiroxamine, streptomycin, streptomycin sulfate, strychnine, sulcatol, sulcofuron, sulcofuron—sodium, sulcotrione, sulfallate, sulfentrazone, m, sulfluramid, sulfometuron, sulfometuron-methyl, sulfosulfuron, sulfotep, aflor, sulfoxide, sulfoxime, sulfur, sulfuric acid, sulfuryl e, sulglycapin, 1000900130 sulprofos, pen, swep, tau-fluvalinate, tavron, tazimcarb, TCA, TCA-ammonium, TCA- calcium, TCA-ethadyl, TCA—magnesium, TCA—sodium, TDE, tebuconazole, tebufenozidc, tebufenpyrad, tebufloquin, tebupirimfos, tebutam, tebuthiuron, tecloftalam, tecnazene, m, teflubenzuron, tefluthrin, tefuryltrione, tembotrione, temephos, tepa, TEPP, tepraloxydim, terallethrin, terbacil, terbucarb, terbuchlor, terbufos, terbumeton, terbuthylazine, terbutryn, tetcyclacis, tetrachloroethane, tetrachlorvinphos, tetraconazole, tetradifon, uron, tetramethrin, tetramethylfluthrin, tetramine, tetranactin, tetrasul, thallium sulfate, chlor, cype1methrin, thiabendazole, thiacloprid, thiadifluor, thiamethoxam, thiapronil, thiazafluron, thiazopyr, thicrofos, thicyofen, thidiazimin, 10 thidiazuron, thiencarbazone, thiencarbazone~methyL thifensulfuron, thifensulfuron—methyl, thifluzamide, thiobencarb, rboxime, thiochlorfenphim, thiocyclam, thiocyclam hydrochloride, thiocyclam oxalate, thiodiazole—copper, carb, thiofanox, oximate, thiohempa, thiomersal, thiometon, thionazin, thiophanate, thiophanate—methyl, thioquinox, thiosemicarbazide, thiosultap, thiosultap—diammonium, thiosultap—disodium, thiosultap— 15 monosodium, thiotepa, thiram, thuringiensin, tiadinil, tiaojiean, tiocarbazil, tioclorim, tioxymid, tirpate, tolclofos—methyl, pyrad, tolylfluanid, tolylmercury acetate, topramezone, tralkoxydim, tralocythrin, tralomethrin, tralopyril, transfluthrin, transpermethrin, tretamine, triacontanol, triadimefon, triadimenol, mone, tri—allate, phos, triapenthenol, triarathene, triarimol, triasulfuron, triazamate, triazbutil, triaziflam, 20 triazophos, triazoxide, tribenuron, tribenuron—methyl, tribufos, tributyltin oxide, tricamba, trichlamide, trichlorfon, trichlormetaphos—3, trichloronat, triclopyr, triclopyr—butotyl, triclopyr—ethyl, triclopyr—triethylammonium, lazole, tridemorph, tridiphanc, trietazine, trifenmorph, trifenofos, trilloxystrobin, xysulfuron, ysuHuron-sodium, triflumizole, uron, triflurahn, triflusulfuron, ulfuron—methyl, trifop, trifop— 25 , 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, , vamidothion, vangard, vaniliprole, vernolate, Vinclozolin, warfarin, warfarin-potassium, warfarin—sodium, xiaochongliulin, Xinjunan, xiwojunan, XMC, 30 xylachlor, xylenols, xylylcarb, yishijing, zarilamid, zeatin, zengxiaoan, zeta-cypermethrin, zinc naphthenate, zinc phosphide, zinc le, zineb, ziram, zolaprofos, zoxamide, zuomihuanglong, a—chlorohydrin, a—ecdysone, a-multistriatin, and d—naphthaleneacetic acid. 1000900130
43. A composition according to claim 41 or 42 further comprising an agriculturally acceptable carrier.
44. A composition according to any one of claims 41 to 43 wherein said molecule is in the form of a pesticidally acceptable acid addition salt.
45. A composition according to any one of claims 41 to 43 wherein said molecule is in the form of a salt derivative. 10
46. A ition ing to any one of claims 41 to 43 wherein said molecule is in the form a hydrate.
47. A composition according to any one of claims 41 to 43 wherein said molecule is in the form an ester derivative. 15
48. A composition according to any one ofclaims 41 to 43 wherein said molecule is in the form a crystal rph.
49. A composition ing to any one of claims 41 to 48 wherein said molecule has a 2H in place of 1H.
50. A composition according to any one of claims 41 to 49 n said molecule has a Cm place ofa12C.' W
51. A composition according to any one of claims 41 to 50 further comprising a 25 biopesticide.
52. A composition according to any one of claims 41 to 51 r comprising one or more of the following compounds: (a) 3~(4—chloro-2,6—dimethylphenyl)—4—hydroxy—8-oxaazaspiro[4,5]decen 30 one; (b) 3 —(4’ ~chloro-2,4-dimethyl[1,1 ’ -biphenyl]—3-yl)—4-hydroxy—8-oxa— 1 - azaspiro[4,5]decenone; (c) 4-[[(6—chloro—3—pyridinyl)methyl]methylamino]-2(5H)—furanone; (d) 4-[[(6—ch10ropyridinyl)methyl]cyclopropylamino]—2(5H)-furanone; 1000900130 (6) 3 -chloro-N2- [( l S)- l -methy1—2-(methylsulfonyl)ethyl]—N1 - [2-methyl [l ,2,2,2—tetrafluoro— 1 —(trifluoromethyl)ethyl]phenyl] - l zenedicarboxamide; (f) 2—cyano-N-ethyl—4~fluoro-3—methoxy-benenesulfonamide; (g) o-N—ethyl-3~methoxy-benzenesulfonamide; (h) 2—cyano—3 —difluoromethoxy—N—ethyl~4-fluoro—benzenesulfonamide; (i) 2-cyano—3 -fluoromethoxy-N—ethyl-benzenesulfonamide; (j) 2-cyano—6-fluor0—3 -methoxy-N, N—dimethyl-benzenesulfonamide; (k) 2—cyano—N-ethyl—6-fluoro—3 —methoxy~N—methyl~benzenesulfonamide; (l) 2-cyano~3 ~difluoromethoxy—N, N-dimethylbenzenesulfon—amide; 10 (m) 3-(difluoromethyl)~N— [2-(3 ,3-dimethylbutyl)phenyl]—1 —methyl-1H—pyrazole—4— carboxamidc; (n) N—ethyl—2,2—dimethylpropionamide~2~(2,6—dichloro—0L,a,a—trifluoro—p-tolyl) hydrazone; (o) N—ethyl—2,2—dichloro— 1 ylcyclopropane—carboxamide—2—(2,6—dichloro— 15 0t,u,(x-trifluoro—p—tolyl) hydrazone nicotine; (p) O—{(E—)—[2-(4—Cliloro—phenyl)-2—cyano—1—(2—trifluoromethylphenyl)—Vinyl]} S— methyl thiocarbonate; (q) (E)—N1—[(2—chloro—l,3 ol—5-ylmethyl)] —N2~cyano—Nl —methylacetamidine; (r) l—(6—chloropyridin—3—ylmethyl)—7—methyl—8—nitro—l ,2,3 ,5 ,6,7—hexahydro— 20 imidazo [l ,2—a]pyridin—5—ol; (s) 4—[4—Cliloroplienyl—(2—butylidine-hydrazono)methyl)]phenyl mesylate; and (t) N—Ethyl—2,2—dichloro—l ~methylcyclopropanecarboxamide-2—(2,6—dichloro— alpha, alpha, alpha~trifluoro—p—tolyl)hydrazone. 25
53. A composition according to any one of claims 41 to 52 r comprising a compound having one or more of the following modes of action: acetylcholinesterase inhibitor; sodium channel tor; 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- 30 stimulated ATPase inhibitor; nicotinic acetylcholine receptor; Midgut membrane disrupter; oxidative phosphorylation ter, and ryanodine or (RyRs).
54. A composition according to any one of claims 41 to 53 further comprising a seed. 1000900130
55. A composition ing to any one of claims 41 to 54 r comprising a seed that has been genetically d to express one or more specialized traits.
56. A composition according to any one of claims 41 to 55 wherein said composition is encapsulated inside, or placed on the surface of, a capsule.
57. A composition ing to any one of claims 41 to 56 wherein said composition is encapsulated inside, or placed on the surface of, a capsule, wherein said capsule has a diameter of about 0 nanometers or about 10—900 microns.
58. A process comprising applying a composition according to any one of claims 41 to 57, to an area to control a pest, in an amount sufficient to control such pest, wherein the composition is not applied to a human. 15
59. A process according to claim 58 wherein said pest is selected from beetles, earwi gs, cockroaches, flies, aphids, scales, whitetlies, ppers, ants, wasps, es, moths, butterflies, lice, grasshoppers, s, crickets, fleas, thrips, bristletails, mites, ticks, nematodes, and symphylans. 2O
60. A process according to claim 58 wherein said pest is from the Phyla Nematoda or Arthropoda.
61. A process according to claim 58 n said pest is from the Subphyla Chelicerata, Myriapoda, or Hexapoda.
62. A process according to claim 58 wherein said pest is from the Class of Arachnida, Symphyla, or Insecta.
63. A process according to claim 58 wherein said pest is from the Order Anoplura, Order 30 Coleoptera, Order Dermaptera, Order Blattaria, Order Diptera, Order Hemiptera, Order Hymenoptera, Order lsoptera, Order Lepidoptera, Order Mallophaga, Order Orthoptera, Order Siphonaptera, Order Thysanoptera, Order Thysanura, Order Acarina, or Order Symphyla. 1000900130
64. A process according to claim 58 wherein said pest is Beet Armyworm, Green Peach Aphid, or Corn Earworm.
65. A process according to any one of claims 58 to 64 wherein said amount is from about 0.01 grams per e to about 5000 grams per hectare.
66. A process ing to claim 65 wherein said amount is from about 0.1 grams per hectare to about 500 grams per hectare. 10
67. A process according to claim 66 wherein said amount is from about 1 gram per hectare to about 50 grams per hectare.
68. A process according to any one of claims 58 to 67 wherein said area is an area where apples, corn, cotton, soybeans, canola, wheat, rice, sorghum, barley, oats, es, oranges, 15 alfalfa, lettuce, strawberries, tomatoes, peppers, crucifers, pears, tobacco, almonds, sugar beets, or beans, are growing, or the seeds thereof are going to be planted.
69. A process according to any one of claims 58 to 68 further comprising applying said composition to a genetically modified plant that has been cally modified to express one 20 or more specialized traits.
70. A process according to any one of claims 58 to 69 where said composition further comprise ammonium sulfate. 25
71. A s sing: orally administering; or topically applying; a molecule ing to any one of claims 1 to 40, to a man animal, to control endoparasites, ectoparasites, or both.
72. A process comprising applying a molecule according to any one of claims 1 to 40 to a 30 plant to enhance the plant’s health, yield, Vigor, quality, or tolerance, at a time when pest activity is low.
73. A molecule according to claim 1, ntially as herein described.
NZ618926A 2011-06-24 2012-06-21 Pesticidal compositions and processes related thereto NZ618926B2 (en)

Applications Claiming Priority (9)

Application Number Priority Date Filing Date Title
US201161500685P 2011-06-24 2011-06-24
US61/500,685 2011-06-24
US201161540056P 2011-09-28 2011-09-28
US61/540,056 2011-09-28
US201261601077P 2012-02-21 2012-02-21
US61/601,077 2012-02-21
US201261645267P 2012-05-10 2012-05-10
US61/645,267 2012-05-10
PCT/US2012/043418 WO2012177813A1 (en) 2011-06-24 2012-06-21 Pesticidal compositions and processes related thereto

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NZ618926B2 true NZ618926B2 (en) 2016-07-01

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