WO2014100206A1 - Pesticidal compositions and processes related thereto - Google Patents

Pesticidal compositions and processes related thereto Download PDF

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Publication number
WO2014100206A1
WO2014100206A1 PCT/US2013/076170 US2013076170W WO2014100206A1 WO 2014100206 A1 WO2014100206 A1 WO 2014100206A1 US 2013076170 W US2013076170 W US 2013076170W WO 2014100206 A1 WO2014100206 A1 WO 2014100206A1
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Prior art keywords
alkyl
halo
substituted
alkoxy
heterocyclyl
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PCT/US2013/076170
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French (fr)
Inventor
William C. Lo
James E. HUNTER
Gerald B. Watson
Akshay PATNY
Pravin S. IYER
Joshodeep BORUWA
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Dow Agrosciences Llc
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Publication of WO2014100206A1 publication Critical patent/WO2014100206A1/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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated

Definitions

  • the invention disclosed in this document is related to the field of processes to produce molecules that are useful as pesticides (e.g., acaricides, insecticides, molluscicides, and nematicides), such molecules, and processes of using such molecules to control pests.
  • pesticides e.g., acaricides, insecticides, molluscicides, and nematicides
  • Alkenyl means an acyclic, unsaturated (at least one carbon-carbon double bond), branched or unbranched, substituent consisting of carbon and hydrogen, for example, vinyl, allyl, butenyl, pentenyl, and hexenyl.
  • Alkenyloxy means an alkenyl further consisting of a carbon-oxygen single bond, for example, allyloxy, butenyloxy, pentenyloxy, hexenyloxy.
  • Alkoxy means an alkyl further consisting of a carbon-oxygen single bond, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and ieri-butoxy.
  • Alkynyl means an acyclic, unsaturated (at least one carbon-carbon triple bond), branched or unbranched, substituent consisting of carbon and hydrogen, for example, ethynyl, propargyl, butynyl, and pentynyl.
  • (C x -C y ) where the subscripts "x” and “y” are integers such as 1, 2, or 3, means the range of carbon atoms for a substituent - for example, (Ci-C 4 )alkyl means methyl, ethyl, n- propyl, isopropyl, n-butyl, sec -butyl, isobutyl, and ieri-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,
  • Cycloalkenyloxy means a cycloalkenyl further consisting of a carbon-oxygen single bond, for example, cyclobutenyloxy, cyclopentenyloxy, norbornenyloxy, and bicyclo[2.2.2]octenyloxy.
  • Cycloalkyl means a monocyclic or polycyclic, saturated substituent consisting of carbon and hydrogen, for example, cyclopropyl, cyclobutyl, cyclopentyl, norbornyl, bicyclo[2.2.2]octyl, and decahydronaphthyl.
  • Cycloalkoxy means a cycloalkyl further consisting of a carbon-oxygen single bond, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, norbornyloxy, and
  • Halo means fluoro, chloro, bromo, and iodo.
  • Haloalkoxy means an alkoxy further consisting of, from one to the maximum possible number of identical or different, halos, for example, fluoromethoxy, trifluoromethoxy, 2,2-difluoropropoxy, chloromethoxy, trichloromethoxy, 1,1,2,2- tetrafluoroethoxy, and pentafluoroethoxy.
  • Haloalkyl means an alkyl further consisting of, from one to the maximum possible number of, identical or different, halos, for example, fluoromethyl, trifluoromethyl, 2,2- difluoropropyl, chloromethyl, trichloromethyl, and 1,1,2,2-tetrafluoroethyl.
  • Heterocyclyl means a cyclic substituent that may be fully saturated, partially unsaturated, or fully unsaturated, where the cyclic structure contains at least one carbon and at least one heteroatom, where said heteroatom is nitrogen, sulfur, or oxygen. In the case of sulfur, that atom can be in other oxidation states such as a sulfoxide and sulfone.
  • aromatic heterocyclyls include, but are not limited to, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl, benzoxazolyl, benzothienyl, benzothiazolyl, cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolinyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolinyl, thiazolyl, thienyl, triaziny
  • Rl is selected from
  • substituted halo(Ci-Cs)alkoxy wherein said substituted halo(Ci- C 8 )alkoxy has one or more substituents selected from CN and N0 2 ;
  • R2 is selected from
  • C 8 )alkoxy has one or more substituents selected from CN and N0 2 ;
  • R3 is selected from (1) H, F, CI, Br, I, CN, N0 2 , (C C 8 )alkyl, halo(C C 8 )alkyl, (C C 8 )alkoxy, halo(C C 8 )alkoxy, S(C C 8 )alkyl, S(halo(C C 8 )alkyl), S(0)(C C 8 )alkyl, S(0)(halo(Ci-C 8 )alkyl), S(0) 2 (C C 8 )alkyl, S(0) 2 (halo(C C 8 )alkyl), N(R14)(R15),
  • substituted halo(Ci-C 8 )alkoxy wherein said substituted halo(Ci- C 8 )alkoxy has one or more substituents selected from CN and N0 2 ;
  • R4 is selected from
  • substituted halo(Ci-C 8 )alkoxy wherein said substituted halo(Cr C 8 )alkoxy has one or more substituents selected from CN and N0 2 ;
  • R7 is selected from H, F, CI, Br, I, OH, (C C 8 )alkoxy, and halo(C
  • R8 is selected from H, (C C 8 )alkyl, halo(C C 8 )alkyl, OR14, and
  • R9 is selected from H, F, CI, Br, I, (C C 8 )alkyl, halo(C C 8 )alkyl, (C
  • substituted (Ci-C 8 )alkyl wherein said substituted (Ci-C 8 )alkyl has one or more substituents selected from OH, (Ci-C 8 )alkoxy, S(Ci-C 8 )alkyl, S(0)(Ci-C 8 )alkyl, S(0) 2 (Ci-C 8 )alkyl, NR14R15, and
  • substituted halo(Ci-C 8 )alkyl wherein said substituted halo(d- C 8 )alkyl, has one or more substituents selected from (Ci-C 8 )alkoxy, S(Ci-C 8 )alkyl, S(0)(Cr C 8 )alkyl, S(0) 2 (C C 8 )alkyl, and N(R14)(R15);
  • each X5 is independently selected from O or S, and
  • each Rlla is independently selected from H, (Ci-C 8 )alkyl, substituted (C C 8 )alkyl, halo(C C 8 )alkyl, substituted halo(C r C 8 )alkyl, cyclo(C 3 -C 8 )alkyl, substituted cyclo(C 3 -C 8 )alkyl, halocyclo(C 3 -C 8 )alkyl,
  • substituted halo(Ci-C 8 )alkyl has one or more substituents selected from CN and N0 2 ,
  • substituted halo(C 2 -C 8 )alkenyl has one or more substituents selected from CN and N0 2 ,
  • substituted (C 2 -C 8 )alkynyl has one or more substituents selected from CN and N0 2 ,
  • substituted halo(C 2 -C 8 )alkynyl has one or more substituents selected from CN and N0 2 ,
  • substituted cyclo(C3-C 8 )alkenyl has one or more substituents selected from CN and N0 2 ,
  • substituted halocyclo(C 3 -C 8 )alkenyl has one or more substituents selected from CN and N0 2 ;
  • R12 is selected from (v), H, F, CI, Br, I, CN, (C C 8 )alkyl, halo(C C 8 )alkyl, (Ci-C 8 )alkoxy, halo(Ci-C 8 )alkoxy, and cyclo(C 3 -C6)alkyl;
  • R13 is selected from (v), H, F, CI, Br, I, CN, (C C 8 )alkyl, halo(C C 8 )alkyl, (Ci-C 8 )alkoxy, and halo(Ci-C 8 )alkoxy;
  • each R14 is independently selected from H, (Ci-C 8 )alkyl, (C 2 -C 8 )alkenyl, substituted (Ci-C 8 )alkyl, halo(Ci-C 8 )alkyl, substituted halo(Ci-C 8 )alkyl), (Ci-C 8 )alkoxy, cyclo(C 3 -C6)alkyl, aryl, substituted-aryl, (Ci-C 8 )alkyl-aryl, (Ci-C 8 )alkyl-(substituted-aryl), O- (Ci-C 8 )alkyl-aryl, 0-(Ci-C 8 )alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C C 8 )alkyl-heterocyclyl, (C C 8 )alkyl-(substituted-heterocyclyl),
  • each said substituted (Ci-C 8 )alkyl has one or more substituents selected from CN, and N0 2 ,
  • each said substituted halo(C]-C 8 )alkyl has one or more substituents selected from CN, and N0 2 ,
  • each said substituted- aryl has one or more substituents selected from F, CI, Br, I, CN, N0 2 , (C C 8 )alkyl, halo(C C 8 )alkyl, (C C 8 )alkoxy, halo(C C 8 )alkoxy, S(Ci-C 8 )alkyl, S(halo(C C 8 )alkyl), N((C C 8 )alkyl) 2 (wherein each (C C 8 )alkyl is independently selected), and oxo, and
  • each R15 is independently selected from H, (Ci-C 8 )alkyl, (C 2 -C 8 )alkenyl, substituted (C C 8 )alkyl, halo(C C 8 )alkyl, substituted halo(C C 8 )alkyl), (C C 8 )alkoxy, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (Ci-C 8 )alkyl-aryl, (Ci-C 8 )alkyl-(substituted-aryl), O- (C]-C 8 )alkyl-aryl, 0-(Ci-C 8 )alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (Ci-C 8 )alkyl-heterocyclyl, (C C 8 )alkyl-(substituted-heterocyclyl), 0-(C C 8 )
  • each said substituted-aryl has one or more substituents selected from F, CI, Br, I, CN, N0 2 , (C C 8 )alkyl, halo(C C 8 )alkyl, (C C 8 )alkoxy, halo(C C 8 )alkoxy, S(Ci-C 8 )alkyl, S(halo(C C 8 )alkyl), N((C C 8 )alkyl) 2 (wherein each (C C 8 )alkyl is independently selected), and oxo, and wherein each said substituted-heterocyclyl has one or more substituents selected from F, CI, Br, I, CN, N0 2 , (C C 8 )alkyl, halo(C C 8 )alkyl, (C C 8 )alkoxy, halo(C C 8 )alkoxy, (C 3 -C 6 )cycloalkyl S(C C 8 )alkyl,
  • each said substituted (Ci-C 8 )alkyl has one or more substituents selected from CN, and N0 2 ,
  • each said substituted halo(Ci-C 8 )alkyl has one or more substituents selected from CN, and N0 2 ,
  • each said substituted-aryl has one or more substituents selected from F, CI, Br, I, CN, N0 2 , (C C 8 )alkyl, halo(C C 8 )alkyl, (C C 8 )alkoxy, halo(C C 8 )alkoxy, S(Ci-C 8 )alkyl, S(halo(C C 8 )alkyl), N((C C 8 )alkyl) 2 (wherein each (C C 8 )alkyl is independently selected), and oxo, and
  • each said substituted-heterocyclyl has one or more substituents selected from F, CI, Br, I, CN, N0 2 , (C C 8 )alkyl, halo(C C 8 )alkyl, (C C 8 )alkoxy, halo(C C 8 )alkoxy, S(C C 8 )alkyl, S(halo(C C 8 )alkyl), N((C C 8 )alkyl) 2 (wherein each (C C 8 )alkyl is independently selected), and oxo;
  • C 8 )alkyl halo(Ci-C 8 )alkyl, substituted-halo(Ci-C 8 )alkyl, cyclo(C3-C6)alkyl, aryl, substituted- aryl, (Ci-C 8 )alkyl-aryl, (C C 8 )alkyl-(substituted-aryl), 0-(C C 8 )alkyl-aryl, 0-(C C 8 )alkyl- (substituted-aryl), heterocyclyl, substituted-heterocyclyl, (Ci-C 8 )alkyl-heterocyclyl, (Cr C 8 )alkyl-(substituted-heterocyclyl), 0-(C C 8 )alkyl-heterocyclyl, 0-(C C 8 )alkyl- (substituted-heterocyclyl), 0-(C C 8 )alkyl- (substi
  • each said substituted (Ci-C 8 )alkyl has one or more substituents selected from CN, and N0 2 ,
  • each said substituted halo(Ci-C 8 )alkyl has one or more substituents selected from CN, and N0 2 , wherein each said substituted- aryl has one or more substituents selected from F, CI, Br, I, CN, N0 2 , (C C 8 )alkyl, halo(C C 8 )alkyl, (C C 8 )alkoxy, halo(C C 8 )alkoxy, S(Ci-C 8 )alkyl, S(halo(C C 8 )alkyl), N((C C 8 )alkyl) 2 (wherein each (C C 8 )alkyl is independently selected), and oxo, and
  • each said substituted-heterocyclyl has one or more substituents selected from F, CI, Br, I, CN, N0 2 , (C C 8 )alkyl, halo(C C 8 )alkyl, (C C 8 )alkoxy, halo(C C 8 )alkoxy, S(C C 8 )alkyl, S(halo(C C 8 )alkyl), N((C C 8 )alkyl) 2 (wherein each (C C 8 )alkyl is independently selected), and oxo;
  • (t) X3 is selected from N and CR9;
  • R3 may be selected from any combination of one or more of the following - H, F, CI, Br, I, CN, N0 2 , methyl, ethyl, (C 3 )alkyl, (C 4 )alkyl, (Cs)alkyl, (C 6 )alkyl, (C 7 )alkyl, (C 8 )alkyl, halomethyl, haloethyl, halo(C 3 )alkyl, halo(C 4 )alkyl, halo(Cs)alkyl, halo(C 6 )alkyl, halo(C7)alkyl, halo(Cs)alkyl, methoxy, ethoxy, (C 3 )alkoxy, (C 4 )alkoxy, (Cs)alkoxy, (C 6 )alkoxy, (C 7 )alkoxy, (Cs)alkoxy, halomethoxy, halo
  • R4 may be selected from any combination of one or more of the following - H, F, CI, Br, I, CN, N0 2 , methyl, ethyl, (C 3 )alkyl, (C 4 )alkyl, (Cs)alkyl, (C 6 )alkyl, (C 7 )alkyl, (C 8 )alkyl, halomethyl, haloethyl, halo(C 3 )alkyl, halo(C 4 )alkyl, halo(Cs)alkyl, halo(C 6 )alkyl, halo(C 7 )alkyl, halo(Cs)alkyl, methoxy, ethoxy, (C 3 )alkoxy, (C 4 )alkoxy, (Cs)alkoxy, (C 6 )alkoxy, (C 7 )alkoxy, (Cs)alkoxy, halomethoxy,
  • R5 may be selected from any combination of one or more of the following - H, F, CI, Br, I, CN, N0 2 , methyl, ethyl, (C 3 )alkyl, (C 4 )alkyl, (Cs)alkyl, (C 6 )alkyl, (C 7 )alkyl, (C 8 )alkyl, halomethyl, haloethyl, halo(C 3 )alkyl, halo(C 4 )alkyl, halo(Cs)alkyl, halo(C 6 )alkyl, halo(C 7 )alkyl, halo(Cs)alkyl, methoxy, ethoxy, (C 3 )alkoxy, (C 4 )alkoxy, (Cs)alkoxy, (C 6 )alkoxy, (C 7 )alkoxy, (Cs)alkoxy, halomethoxy,
  • R2 and R4 are selected from F, CI, Br, I, CN, and N0 2 and Rl, R3, and R5 are H.
  • R2, R3, and R4 are independently selected from F and CI and Rland R5 are H.
  • R2 is selected from CF 3 , CH 3 , CI, F, and H.
  • R3 is selected from OCH 3 , CH 3 , F, CI, or H.
  • R4 is selected from CF 3 , CH 3 , CI, F, and H.
  • R5 is selected from F, CI, and H.
  • R6 is trifluoromethyl.
  • R7 may be selected from any combination of one or more of the following - H, F, CI, Br, and I.
  • R8 may be selected from any combination of one or more of the following - H, methyl, ethyl, (C 3 )alkyl, (C 4 )alkyl, (Cs)alkyl, (C 6 )alkyl, (C 7 )alkyl, (C 8 )alkyl, halomethyl, haloethyl, halo(C 3 )alkyl, halo(C 4 )alkyl, halo(C 5 )alkyl, halo(C 6 )alkyl, halo(C 7 )alkyl, and halo(C 8 )alkyl.
  • R8 is selected from CH 3 and H.
  • R12 may be selected from any combination of one or more of the following - H, F, CI, Br, I, methyl, ethyl, (C 3 )alkyl, (C 4 )alkyl, (Cs)alkyl, (C 6 )alkyl, (C 7 )alkyl, (C 8 )alkyl, halomethyl, haloethyl, halo(C 3 )alkyl, halo(C 4 )alkyl, halo(Cs)alkyl, halo(C 6 )alkyl, halo(C 7 )alkyl, halo(Cs)alkyl, halomethoxy, haloethoxy, halo(C 3 )alkoxy, halo(C 4 )alkoxy, halo(Cs)alkoxy, halo(C 6 )alkoxy, halo(C 7 )alkoxy, and halo
  • R12 is selected from CH3, and H.
  • R13 may be selected from any combination of one or more of the following - H, F, CI, Br, I, methyl, ethyl, (C 3 )alkyl, (C 4 )alkyl, (Cs)alkyl, (C 6 )alkyl, (C 7 )alkyl, (C 8 )alkyl, halomethyl, haloethyl, halo(C 3 )alkyl, halo(C 4 )alkyl, halo(Cs)alkyl, halo(C 6 )alkyl, halo(C 7 )alkyl, halo(Cs)alkyl, halomethoxy, haloethoxy, halo(C 3 )alkoxy, halo(C 4 )alkoxy, halo(Cs)alkoxy, halo(C 6 )alkoxy, halo(C 7 )alkoxy, and halo
  • R13 is selected from CH 3 , CI and H.
  • R14 may be selected from any combination of one or more of the following - H, methyl, ethyl, (C 3 )alkyl, (C 4 )alkyl, (Cs)alkyl, (C 6 )alkyl, (C 7 )alkyl, (C 8 )alkyl, halomethyl, haloethyl, halo(C 3 )alkyl, halo(C 4 )alkyl, halo(C 5 )alkyl, halo(C 6 )alkyl, halo(C 7 )alkyl, halo(C 8 )alkyl, methyl-aryl, ethyl-aryl, (C 3 )alkyl-aryl, (C 4 )alkyl- aryl, (Cs)alkyl-aryl, (C 6 )alkyl-aryl, (C 7 )alkyl-aryl, (Cs)alkyl-aryl-aryl
  • R15 may be selected from any combination of one or more of the following - H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (Cs)alkyl, (C 6 )alkyl, (C 7 )alkyl, (C 8 )alkyl, halomethyl, haloethyl, halo(C 3 )alkyl, halo(C 4 )alkyl, halo(C 5 )alkyl, halo(C 6 )alkyl, halo(C 7 )alkyl, halo(C 8 )alkyl, methyl-aryl, ethyl-aryl, (C 3 )alkyl-aryl, (C 4 )alkyl- aryl, (Cs)alkyl-aryl, (C6)alkyl-aryl, (C7)alkyl-aryl, (C 8 )alkyl-aryl, methyl-(
  • R15 may be selected from any combination of one or more of the following - H, C3 ⁇ 4, CH 2 CF 3 , CH 2 -halopyridyl, oxo-pyrrolidinyl, halophenyl, thietanyl, CH 2 -phenyl, CH 2 -pyridyl, thietanyl-dioxide, CH 2 -halothiazolyl,
  • R17 may be selected from any combination of one or more of the following - H, methyl, ethyl, (C3)alkyl, (C 4 )alkyl, (Cs)alkyl, (C 6 )alkyl, (C 7 )alkyl, (C 8 )alkyl, halomethyl, haloethyl, halo(C 3 )alkyl, halo(C 4 )alkyl, halo(C 5 )alkyl, halo(C 6 )alkyl, halo(C 7 )alkyl, halo(C 8 )alkyl, methyl-aryl, ethyl-aryl, (C 3 )alkyl-aryl, (C 4 )alkyl- aryl, (Cs)alkyl-aryl, (C6)alkyl-aryl, (C7)alkyl-aryl, (Cs)alkyl-aryl, methyl-
  • R17 may be selected from any combination of one or more of the following - H, CH 2 CF 3 , cyclopropyl, thietanyl, thietanyl dioxide, and halophenyl.
  • XI is CR12
  • X2 is CR13
  • X3 is CR9.
  • a heterocyclyl has preferably about 6 to 10 atoms in the ring structure, more preferably, 6 to 8 atoms.
  • the molecules of Formula One will generally have a molecular mass of about 100 Daltons to about 1200 Daltons. However, it is generally preferred if the molecular mass is from about 120 Daltons to about 900 Daltons, and it is even more generally preferred if the molecular mass is from about 140 Daltons to about 600 Daltons.
  • styrene coupling partners can be accomplished as in Schemes II, III IV and V.
  • DMF N,N-dimethylformamide
  • step / 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 °C.
  • a base such as n-butyllithium (n-BuLi)
  • DMF a polar, aprotic solvent
  • THF a polar, aprotic solvent
  • an acid such as sulfuric acid (H 2 SO 4 )
  • an alcohol such as ethyl alcohol (EtOH)
  • EtOH ethyl alcohol
  • the vinyl benzoic acid ester of Formula Vllbl is accessed via reaction of the compounds of Formula IX, with a base, such as potassium carbonate (K 2 CO 3 ), and methyl triphenyl phosphonium bromide in a polar aprotic solvent, such as 1 ,4-dioxane, at ambient temperature, as in step h of Scheme III.
  • a base such as potassium carbonate (K 2 CO 3 )
  • methyl triphenyl phosphonium bromide in a polar aprotic solvent, such as 1 ,4-dioxane
  • a base such as triethylamine (Et 3 N)
  • DMAP 4-(dimethylamino)pyridine
  • a palladium catalyst such a tetrakis(triphenylphospine)palladium(0) (Pd(PPh 3 ) 4 )
  • a base such as K 2 C0 3
  • a non- reactive solvent such as toluene at reflux temperature
  • CuCN copper(I) cyanide
  • step m of Scheme VII the ester of Formula Xa is saponified to the corresponding acid under acidic conditions, such as about 11 Normal (N) hydrochloric acid (HCl), in a polar aprotic solvent, such as 1,4-dioxane, at about 100 °C.
  • acidic conditions such as about 11 Normal (N) hydrochloric acid (HCl)
  • a polar aprotic solvent such as 1,4-dioxane
  • the compounds of Formula Xb are then converted to the molecules of Formula One, wherein R
  • the acid of Formula Xb can be coupled to an amine (HN(R14)(R15)), wherein R14 and R15 are as previously disclosed, using peptide coupling reagents, such as 1- hydroxybenzotriazole (HOBt), N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (EDOHC1) , benzotriazol- 1 -yl-oxytripyrrolidinophosphonium
  • step j of Scheme IX the halobenzoketone of Formula VHIb, wherein R18 is Br, R10 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, XI, X2, and X3 are as previously disclosed, is allowed to react with vinyl boronic anhydride pyridine complex in the presence of a palladium catalyst, such as Pd(PPh 3 ) 4 , and a base, such as K 2 CO 3 , in a non-reactive solvent such as toluene at reflux temperature, to provide the vinyl benzoketone of Formula VIIb4, wherein R10 and Rl 1 together form a linkage, having 3-4 carbon atoms and an oxo substituent and with the ring carbon atoms form a 5- or 6-membered ring, and R8, R9, R12, R
  • step I of Scheme X the compound of Formula V, wherein Y, Rl, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the vinylbenzoketone of Formula VIIb4 as previously disclosed, wherein R8, R9, R12, R13, 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 180 °C to provide the compounds of Formula Xc, wherein R10 and Rl 1 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 Rl, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, XI, X2, and X3 are as previously disclosed.
  • step p of Scheme X the ketone of Formula Xc is allowed to react with hydroxylamine hydrochloride in the presence of sodium acetate and in a polar protic solvent, such as EtOH, at a temperature of about 78 °C, to give the molecules of Formula Xd as previously disclosed.
  • a polar protic solvent such as EtOH
  • the compounds of Formula Xc are also converted to the molecules of Formula Xe, wherein R10 and Rl l 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 Rl, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, XI, X2, and X3 are as previously disclosed, as demonstrated in step q of Scheme XI.
  • the ketone of Formula Xc is allowed to react with ammonium acetate in the presence of sodium cyanoborohydride and in a polar protic solvent, such as CH 3 OH, at a temperature of about 65 °C, to give the molecules of Formula Xe. heme XI
  • the compounds of Formula Xe are converted to the molecules of Formula One, wherein RIO and Rl l together form a linkage as previously disclosed in (u), and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, XI, X2, and X3 are as previously, in one step as disclosed in steps r or s.
  • step r of Scheme XII the amine of Formula Xe is allowed to react with an isocyanate in a polar, aprotic solvent such as diethyl ether at ambient temperature to provide the molecules of Formula One as previously disclosed.
  • step s of Scheme XII the amine of Formula Xe is coupled to an acid with ⁇ 2 0 and EDOHC1 in the presence of a base, such as DIEA, in a non-reactive solvent, such as CH 2 CI 2 , to give the molecules of Formula One, as previously disclosed.
  • a base such as DIEA
  • a non-reactive solvent such as CH 2 CI 2
  • step t of Scheme XIII the vinyl benzyl chloride of Formula XIa, wherein Rl 1 is - CH 2 C1 and R8, R9, R10, R12, R13, XI, X2, and X3 are as previously defined, can be transformed into the corresponding phthalimide-protected benzyl amine of Formula Xlla, wherein Rl l is CH 2 N(Phthalimide), and R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed, by reaction with potassium phthalimide in a polar aprotic solvent, such as DMF, at 70 °C.
  • a polar aprotic solvent such as DMF
  • step u of Scheme XIV the 4-methylbenzonitrile of Formula XHIa, wherein Rll is CH 3 and R9, RIO, R12, R13, XI, X2, and X3 are as previously defined, can be transformed into the corresponding benzyl bromide of Formula XlVa, wherein Rl 1 is CH 2 Br and R8, R9, RIO, R12, R13, XI, X2, and X3 are as previously disclosed, by reaction with N- bromosuccinimide (NBS) and azobisisobutyronitrile (AIBN) in a non-reactive solvent, such as carbon tetrachloride at 77 °C.
  • NBS N- bromosuccinimide
  • AIBN azobisisobutyronitrile
  • nitrile group (CN) of Formula XlVa can be reduced to the corresponding aldehyde of Formula XVa, wherein Rl 1 is CH 2 Br and R9, RIO, R12, R13, XI, X2, and X3 are as previously defined via reaction with diisobutylaluminum hydride (DIBAL-H) in an aprotic solvent, such as toluene, at 0 °C, followed by quenching with 1.0 M hydrochloric acid (HC1) as in step v of Scheme XIV.
  • DIBAL-H diisobutylaluminum hydride
  • HC1 hydrochloric acid
  • the compound of Formula XVa can be further transformed to the corresponding phthalimide-protected benzyl amine of Formula XVIa, wherein Rl l is CH 2 N(Phthalimide) and R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed, by reaction with potassium phthalimide in a polar aprotic solvent, such as DMF, at 60 °C as in step t of Scheme XIV.
  • a polar aprotic solvent such as DMF
  • XVIa XI lb The aldehyde of Formula XVa, wherein Rl l is CH 2 Br and R9, RIO, R12, R13, XI, X2, and X3 are as previously defined, can be reacted with a nucleophile, such as 2- aminopyridine, in a polar aprotic solvent, such as N,N-dimethylacetamide (DMA), in the presence of a base, such as K 2 CO 3 , at ambient temperature to provide the compound of Formula XVII, wherein Rl l is CH 2 NH(2-pyridine) and R9, RIO, R12, R13, XI, X2, and X3 are as previously disclosed, as in step x of Scheme XV.
  • a nucleophile such as 2- aminopyridine
  • DMA N,N-dimethylacetamide
  • step w of Scheme XV the compound of Formula XVII can be converted to the olefin of Formula XVIII, wherein Rl l is CH 2 NH(2-pyridine) and R8, R9, RIO, R12, R13, XI, X2, and X3 are as previously disclosed.
  • the compound of Formula XIX can be reacted with the compounds of Formula XX, wherein R10 and Rl l are CI, XI is N, and R9, R13, X2, and X3 are as previously disclosed, in the presence of a base, such as sodium hydride (NaH), and a polar aprotic solvent, such as DMF, at ambient temperature to provide the compounds of Formula XXI, wherein R10 is CI, Rl l is (CH)NH 2 C0 2 CH 2 CH 3 , XI is N, and R9, R13, X2, and X3 are as previously defined.
  • a base such as sodium hydride (NaH)
  • a polar aprotic solvent such as DMF
  • Hydrolysis and decarboxylation of the compounds of Formula XXI can be accomplished by reaction under acidic conditions, such as with 3 N HC1, at reflux temperature, to afford the compounds of Formula XXII, wherein R10 is CI, Rl 1 is CH 2 NH 2 » HC1, XI is N, and R9, R13, X2, and X3 are as previously disclosed, as in step aa in Scheme XVI.
  • the compounds of Formula XXII can be further transformed to the corresponding phthalimide-protected benzyl amines of Formula XXIIIa, wherein R10 is CI, Rl 1 is CH 2 N(Phthalimide), XI is N, and R9, R13, XI, X2, and X3 are as previously disclosed, by reaction with phthalic anhydride in the presence of a base, such as Et 3 N, and an aprotic solvent, such as toluene, at reflux temperature as in step ab of Scheme XVI.
  • a base such as Et 3 N
  • an aprotic solvent such as toluene
  • the bromide of Formula XXIIIa can be converted to the olefin of Formula XIIc, wherein R10 is CI, Rl 1 is CH 2 N(Phthalimide), XI is N, and R8, R9, R13, X2 and X3 are as previously disclosed, by reaction with vinyl boronic anhydride pyridine complex in the presence of a palladium catalyst, such as Pd(PPh 3 ) 4 , and a base, such as K CO 3 , in a non-reactive solvent such as toluene at reflux temperature, as in step ac of Scheme XVI.
  • Scheme XVI
  • step u of Scheme XVII the 4-methylnaphthonitrile of Formula XHIb, wherein X3 is CR9, RIO and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, Rl l is CH 3 , and R12, R13, XI and X2 are as previously defined, can be transformed into the corresponding naphthyl bromide of Formula XlVb, wherein X3 is CR9, RIO and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, Rl l is CH 2 Br, and R12, R13, XI 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 a
  • the nitrile group (CN) of Formula XlVb can be reduced to the corresponding aldehyde of Formula XVb, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring (or if desired a non- aromatic ring), Rl l is CH 2 Br, and R12, R13, XI and X2 are as previously defined via reaction with diisobutylaluminum hydride (DIBAL-H) in an aprotic solvent, such as toluene, at 0 °C, followed by quenching with 1.0 M HCl as in step v of Scheme XVII.
  • DIBAL-H diisobutylaluminum hydride
  • the compound of Formula XVb can be further transformed to the corresponding phthalimide-protected benzyl amine of Formula XVIb, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, Rl l is CH 2 N(Phthalimide), and R12, R13, XI and X2 are as previously disclosed, by reaction with potassium phthalimide in a polar aprotic solvent, such as DMF, at 60 °C as in step t of Scheme XVII.
  • a polar aprotic solvent such as DMF
  • the bromide of Formula XXV can be converted to the olefin of Formula Xlle, wherein Rl 1 is NHN(Phthalimide) and R8, R9, R10, R13, XI, X2 and X3 are as previously disclosed, by reaction with vinyl boronic anhydride pyridine complex in the presence of a palladium catalyst, such as Pd(PPh 3 ) 4 , and a base, such as K2CO 3 , in a polar aprotic solvent such as 1,2- dimethoxyethane at 150 °C under microwave conditions, as in step ae of Scheme XVIII.
  • a palladium catalyst such as Pd(PPh 3 ) 4
  • a base such as K2CO 3
  • step af of Scheme ⁇ the compound of Formula XXVI, wherein Rl 1 is B(OH) 2 , and R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed, are allowed to react with 2-hydroxyisoindoline-l,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 Xllf , wherein Rl l is ON(Phthalimide) and R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed.
  • Scheme XIX is ON(Phthalimide) and R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed.
  • step I of Scheme XX the compound of Formula V, wherein Y, Rl, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula Xlla, wherein Rl 1 is CH 2 N(Phthalimide) and R8, R9, RIO, R12, R13, 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 180 °C to provide the corresponding compounds of Formula XXVIIa, wherein Rl l is CH 2 N(Phthalimide) and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed.
  • a solvent such as 1,2- dichlorobenzene
  • the phthalimide protecting group in the compounds of Formula XXVIIa is removed as in step ag of Scheme XX by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90 °C to provide the compounds of Formula XXVIIIa, wherein Rl l is CH 2 NH 2 and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed.
  • anhydride such as acetic anhydride
  • Et 3 N a non-reactive solvent
  • XXVIIIa Formula One In step I of Scheme XXI, the compound of Formula V, wherein Y, Rl, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula Xllb, wherein Rl l is CH 2 N(Phthalimide) and R8, R9, RIO, R12, R13, 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 180 °C to provide the corresponding compounds of Formula XXVIIb, wherein Rll is CH 2 N(Phthalimide) and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed.
  • a solvent such as 1,2-dichlorobenzene
  • the phthalimide protecting group in the compounds of Formula XXVIIb is removed as in step ag of Scheme XXI by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90 °C to provide the compounds of Formula XXVIIIb, wherein Rl 1 is CH 2 NH 2 and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed.
  • the first step (step ah 3a of Scheme XXI) involves reaction with an aldehyde in a polar protic solvent such as methyl alcohol, followed by reaction with sodium borohydride.
  • the second step involves acylation with an acid chloride, such as cyclopropylcarbonyl chloride, and a base, such as Et 3 N, in a non-reactive solvent such as CH 2 C1 2 at ambient temperature of Scheme XXI.
  • an acid chloride such as cyclopropylcarbonyl chloride
  • a base such as Et 3 N
  • a base such as Et 3 N
  • a non-reactive solvent such as CH 2 C1 2 at 0 °C
  • a dicarbonate such as di-ieri-butyl dicarbonate
  • a base such as Et 3 N
  • a non-reactive solvent such as CH 2 C1 2 at ambient temperature
  • a chlorooxalic acid ester such as 2-chloro-2-oxoacetate
  • a base such as Et 3 N
  • a non-reactive solvent such as CH 2 C1 2 at 0 °C
  • XI is N
  • Rl , R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X2, and X3 are as previously disclosed, by reaction with an acid in the presence of HOBt » H 2 0, EDC » HC1 and a base, such as DIEA, in a polar aprotic solvent, such as CH 2 C1 2 , as in step a3 ⁇ 42* of Scheme XXII.
  • the phthalimide protecting group in the compounds of Formula XXVIId is removed as in step ag of Scheme XXIII by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90 °C to provide the compounds of Formula XXVIIId, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, Rl l is CH 2 NH 2 and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, XI and X2 are as previously disclosed.
  • a base such as Et 3 N
  • a non-reactive solvent such as CH 2 C1 2 at 0 °C as in step aii of Scheme XXIII.
  • step I of Scheme XXIV the compound of Formula V, wherein Y, Rl, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula Xlle, wherein Rl l is NHN(Phthalimide) and R8, R9, R12, R13, 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 180 °C to provide the corresponding compounds of Formula XXVIIe, wherein Rll is NHN(Phthalimide) and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, XI, X2, and X3 are as previously disclosed.
  • the phthalimide protecting group in the compounds of Formula XXVIIe is removed as in step ag of Scheme XXIV by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90 °C to provide the compounds of Formula XXVIIIe, wherein Rl 1 is NHNH 2 and Rl , R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, XI, X2, and X3 are as previously disclosed.
  • step I of Scheme XXV the compound of Formula V, wherein Y, Rl, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula Xllf, wherein Rll is ON(Phthalimide) and R8, R9, R10, R12, R13, 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 180 °C to provide the corresponding compounds of Formula XXVIIf, wherein Rll is ON(Phthalimide) and Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO, R12, R13, XI, X2, and X3 are as previously disclosed.
  • a solvent such as 1,2-dichlorobenzene
  • the phthalimide protecting group in the compounds of Formula XXVIIf is removed as in step ag of Scheme XXV by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90 °C to provide the compounds of Formula XXVIIIf, wherein Rl l is ONH 2 and Rl , R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed.
  • 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 Rl l is CH 2 NH(2-pyridine) and R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,24?ipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180 °C to provide the corresponding compounds of Formula One, wherein Rl l is CH 2 NH(2-pyridine), and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed.
  • a solvent such as 1,2-dichlorobenzene
  • the compounds of Formula One can be further elaborated by standard methods.
  • Rl 1 contains a thioether
  • the thioether can be oxidized to the sulfone by treatment with oxone in the presence of an acetone:water mixture at ambient temperature.
  • Rl l contains an oxalate ester
  • the compound of Formula One can be transformed into the corresponding oxalamide by reaction with an amine hydrochloride and a solution of trimethylaluminum in toluene in a non-reactive solvent such as CH 2 CI 2 .
  • a fluorobenzaldehyde of Formula ⁇ wherein RIO, XI, X2, and X3 are as previously disclosed can be converted to a (l,2,4-triazol-l-yl)benzaldehyde of Formula XXX, wherein Rll is a substituted or unsubstituted 1,2,4-triazol-l-yl 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 potassium carbonate, in a solvent such as DMF as in step aj.
  • a base such as potassium carbonate
  • step ak the (l,2,4-triazol-l-yl)benzaldehyde of Formula XXX is converted to a (l,2,4-triazol-l-yl)vinyl benzene of Formula XXXIa wherein Rl 1 is a substituted or unsubstituted 1,2,4-triazol-l-yl group, and R8, R10, XI, X2, and X3 are as previously disclosed by reaction with triphenyl phosphonium bromide in the presence of a base, such as potassium carbonate, in an aprotic solvent, such as 1,4-dioxane.
  • a base such as potassium carbonate
  • bromofluorobenzene is reacted with a substituted or unsubstituted 1,2,4-triazole in the presence of a base, such as potassium carbonate, in a solvent such as DMF to generate the (l,2,4-triazol-l-yl)bromobenzene.
  • a base such as potassium carbonate
  • a solvent such as DMF
  • step cl the (l,2,4-triazol-l-yl)bromobenzene is reacted with vinyl boronic anhydride pyridine complex in the presence of a catalyst, such
  • step Z a compound of Formula V, wherein Y is Br, Rl, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and a vinylbenzene of Formula XXXIa or XXXIb, wherein Rl 1 is a substituted or unsubstituted 1,2,4-triazol-l-yl group, and R8, R9, RIO, 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 180 °C to provide the molecules of Formula One, wherein Rl l is a substituted or unsubstituted 1,2,4-triazol-l-yl group, and Rl, R2, R3, R4, R5,
  • step am the 3-nitro-l,2,4-triazol-l-yl group is reduced to a 3-amino-l,2,4-triazol-l-yl group in the presence of zinc dust and ammonium chloride in a protic solvent, such as methanol.
  • a protic solvent such as methanol.
  • the 3-amino- 1,2,4- triazol-l-yl group is acylated with an acid chloride, such as cyclopropylcarbonyl chloride or acetyl chloride, in the presence of a base, such as triethylamine, in a solvent such as dichloromethane .
  • step ao of Scheme XXXI a bromophenyl methyl ketone of Formula XXXIV wherein RIO, XI, X2, and X3 are as previously disclosed is converted to an phenyl methyl ketone of the Formula XXXV wherein Rl l is a 1,2,4-triazol-l-yl 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.
  • a base such as cesium carbonate
  • a catalyst such as copper iodide
  • step ap the 1,2,4-triazolylacetophenone of Formula XXXV is converted to the trimethylsilyl enol ether of Formula XXXVI by treatment with trimethylsilyl triflluoromethanesulfonate in the presence of a base, such as triethylamine, in an aprotic solvent, such as dichloromethane.
  • a base such as triethylamine
  • step aq the silyl enol ether is reacted with a compound of Formula V, wherein Y is Br, Rl, R2, R3, R4, R5, R6, and R7 are as previously disclosed in the presence of CuCl and 2,2- bipyridyl in a solvent, such as 1,2-dichlorobenzene at a temperature of about 180 °C to generate a ketone of the Formula XXXVII, wherein Rl 1 is a 1,2,4-triazol-l-yl group, and Rl, R2, R3, R4, R5, R6, R7, R10, XI, X2, and X3 are as previously disclosed.
  • a solvent such as 1,2-dichlorobenzene
  • step ar the ketone of the Formula XXXVII is treated with methylmagnesium bromide in an aprotic solvent, such as THF to generate the tertiary alcohol.
  • the tertiary alcohol then undergoes an elimination reaction when treated with a catalytic amount of p-toluenesulfonic acid in a solvent, such as toluene, when heated to a temperature to allow azeotropic removal of water to produce compounds of Formula One wherein Rll is a 1,2,4-triazol-l-yl group, R8 is methyl, and Rl, R2, R3, R4, R5, R6, R7, R10, XI, X2, and X3 are as previously disclosed, as in step as.
  • step av the nitrogen atom is protected with a ieri-butyloxycarbonyl (BOC) group by reaction with di-ieri-butyl dicarbonate in the presence of a catalyst, such as DMAP, in a solvent, such as acetonitrile.
  • BOC ieri-butyloxycarbonyl
  • the bromide of Formula XL can be converted to the olefin of Formula XLI, wherein R8, XI, X2 and X3 are as previously disclosed, by reaction with potassium vinyl trifluoroborate in the presence of a palladium catalyst, such as PdCl 2 (dppf), and a base, such as K 2 CO 3 , in a polar aprotic solvent such as DMSO at 100 °C, as in step aw.
  • a palladium catalyst such as PdCl 2 (dppf)
  • a base such as K 2 CO 3
  • step ay the nitrogen atom is protected with a tert- butyloxycarbonyl (BOC) group by reaction with di-ieri-butyl dicarbonate in the presence of a catalyst, such as DMAP, in a solvent, such as acetonitrile.
  • a catalyst such as DMAP
  • R7, R8, XI, X2, and X3 are as previously disclosed is converted to a molecule of Formula XLIV, wherein 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.
  • step ba the indoline is treated with sodium nitrite (NaN0 2 ), in an acid, such as concentrated HC1, at a temperature around 5 °C, to form the nitrosoindole.
  • step bb the nitrosoindole is reacted with ammonium chloride in the presence of zinc powder in a protic solvent, such as methanol.
  • R5, R6, R7, R8, XI, X2, and X3 are as previously disclosed, by treatment with and acid, such as 3,3,3-trifluoropropanoic acid, PyBOP, and a base, such as DIEA, in a polar aprotic solvent, such as dichloromethane.
  • acid such as 3,3,3-trifluoropropanoic acid, PyBOP
  • base such as DIEA
  • a polar aprotic solvent such as dichloromethane
  • Compounds of the Formula XLVII can be transformed into compounds of the Formula XLVIII wherein Rl, R2, R3, R4, R5, R6, R7, R8, XI, X2, and X3 are as previously disclosed, by reaction with 4-nitrophenyl-2-((ieri-butoxycarbonyl)amino)acetate in the presence of potassium fluoride and a crown ether, such as 18-crown-6-ether, in a solvent, such as acetonitrile, as in step be.
  • Compounds of the Formula XLVIII can be transformed into compounds of the Formula XLIX, wherein Rl, R2, R3, R4, R5, R6, R7, R8, XI, X2, and X3 are as previously disclosed in two steps.
  • step bf the Boc group is removed by treatment with trifluoroacetic acid, in a solvent such as dichloromethane.
  • 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.
  • step I of Scheme XXXIX the compound of Formula V, wherein Y, Rl, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compound of Formula LIV, 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 180 °C to provide the corresponding compound of Formula LV, wherein Rl, R2, R3, R4, R5, R6, R7, R8, XI, X2, and X3 are as previously disclosed.
  • a solvent such as 1,2-dichlorobenzene
  • the compound of Formula LV can be further transformed into a compound of the Formula LVI, wherein Rl, R2, R3, R4, R5, R6, R7, R8, XI, X2, and X3 are as previously disclosed, in two steps.
  • step bl the ester is hydrolyzed to the acid in the presence of HC1 and acetic acid, at a temperature of about 100 °C.
  • step bm the acid is treated with an amine, such as 2,2,2-trifluoroethylamine, PyBOP, and a base, such as DIEA, in a polar aprotic solvent, such as dichloromethane.
  • a solvent such as N-methyl pyrrolidine
  • Step 1 Method B. l-(3,5-Dichlorophenyl)-2,2,2-trifluoroethanol (AI2).
  • 3,5-dichlorobenzaldehyde 10 g, 57 mmol
  • THF tetrahydrofuran
  • TBAF tetrabutylammonium fluoride
  • Step 2 l-(l-Bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (All). To a stirred solution of l-(3,5-dichlorophenyl)-2,2,2-trifluoroethanol (4.0 g, 16.3 mmol) in
  • Step 1 4-Vinylbenzoyl chloride (AI10). To a stirred solution of 4-vinylbenzoic acid (1 g, 6.75 mmol) in CH 2 C1 2 (20 mL) at 0 °C 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 °C for 6 h. After the reaction was deemed complete by TLC, the reaction mixture was concentrated under reduced pressure to give the crude acid chloride.
  • DMF N,N- dimethylformamide
  • N-Methyl-4-vinylbenzamide (AI9). To 1 M N-methylamine in THF (13.5 mL, 13.5 mmol) at 0 °C were added triethylamine (Et 3 N; 1.34 mL, 10.12 mmol) and the acid chloride from Step 1 above in THF (10 mL), and the reaction mixture was stirred at 25 °C for 3 h. After the reaction was deemed complete by TLC, the reaction mixture was quenched with water and then was extracted with EtOAc (3x).
  • EtOAc EtOAc
  • Step 1 4-Formyl-2-methylbenzoic acid (AI15). To a stirred solution of 4-bromo-2- methylbenzoic acid (10 g, 46.4 mmol) in dry THF (360 mL) at -78 °C was added n- butyllithium (n-BuLi, 1.6 M solution in hexane; 58.17 mL, 93.0 mmol) and DMF (8 mL). The reaction mixture was stirred at -78 °C for 1 h then was warmed to 25 °C and stirred for 1 h. The reaction mixture was quenched with 1 N HCl solution and extracted with EtOAc.
  • AI15 4-Formyl-2-methylbenzoic acid
  • Step 1 fert-Butyl 4-bromo-2-chlorobenzoate (AI18). To a stirred solution of 4- bromo-2-chlorobenzoic acid (5 g, 21.37 mmol) in THF (30 mL) was added di-ieri-butyl dicarbonate (25.5 g, 25.58 mmol), Et 3 N (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 °C for 18 h. The reaction mixture was diluted with EtOAc and washed with H 2 0. The combined organic layer was washed with brine, dried over Na 2 S0 4 and concentrated under reduced pressure.
  • AI18 fert-Butyl 4-bromo-2-chlorobenzoate
  • Step 2 fert-butyl 2-chloro-4-vinylbenzoate (AI17).
  • tert-butyl 4-bromo-2-chlorobenzoate 1.6 g, 5.50 mmol
  • toluene 20 mL
  • tetrakis(triphenylphospine)palladium(0) Pd(PPh 3 ) 4 ; (0.31 mg, 0.27 mmol)
  • K 2 C0 3 (2.27 g, 16.5 mmol
  • vinylboronic anhydride pyridine complex 2.0 g, 8.3 mmol
  • Example 7 Preparation of ethyl 4 ate (AI50) To a stirred solution of 4-bromo-2-fluorobenzoic acid (2.0 g, 9.17 mmol) in THF (16 mL), was added 1.0 M ethyl magnesium bromide in THF (32 mL, 32.0 mmol) dropwise at 0°C and the resultant reaction mixture was stirred at RT for 18h. The reaction mixture was quenched with 2 N HC1 and extracted with ethyl acetate.
  • AI50 ethyl 4 ate
  • reaction mixture was stirred at reflux for 18 h, cooled to 25 °C, quenched with IN HCl solution (50 mL) and extracted with CH 2 CI 2 (2 x 50 mL). The combined organic extracts were washed with brine, dried over Na 2 S0 4 , and concentrated under reduced pressure.
  • Example 106 Preparation of ethyl-(Z)-2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-en-l-yl
  • Example 109a Preparation of (£')-2-bromo- V-(piperidin-4-yl)-4-(4,4,4-trifluoro-3- (3,4,5-trichlorophenyl)b -l-en-l-yl)benzamide (AC114)
  • Example 109b Preparation of (£')- V-(l-acetylpiperidin-4-yl)-2-bromo-4-(4,4,4-trifluoro- 3-(3,4,5-trichlorophenyl)but-l-en-l-yl)benzamide (AC103)
  • Example 110 Preparation of (£)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-en-l-yl)- V-(l-(3,3,3-trifluoropropanoyl)piperidin-4-yl)benzamide
  • Example 112 Preparation of (£')-2-bromo-/V-(l-methylpiperidin-4-yl)-4-(4,4,4-trifluoro- 3-(3,4,5-trichlorophenyl)but-l-en-l-yl)benzamide (AC106)
  • Example 118 Preparation of (£)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut- l-en-l-yl)- V-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-2- (trifluoromethoxy)b
  • Example 23 Preparation of (£')-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l- en-l-yl)- V-(3,3,3-trifluoropropyl)-2,3-dihydro-lH-inden-l-amine (BC10)
  • Step 1 5-Bromo-indoline (Bill): To 5-Bromo-lH-indole (2.5 g, 12.82 mmol) in acetic acid (10.0 mL), NaCNBIL (2.38 g, 38.46 mmol) was added portion wise at 10 °C over the period of 20 min. After that the reaction mixture was stirred at RT for 3 h. The reaction mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with saturated NaHCC>3, water and brine solution. The combined ether layer was dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure to afford title compound as a pale yellow semi-solid (1.8 g, 71%).
  • Step 2 fert-Butyl-5-bromoindoline-l-carboxylate (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-ieri-butyl dicarbonate (3.98 g, 18.3 mmol) and the reaction was stirred at RT for 16 h. The reaction mixture was concentrated on reduced pressure to obtain a residue which was diluted with diethyl ether and washed with water and brine solution (2X). The combined ether layer was dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure to afford the crude product as an off-white solid, which was used in the next step without further purification (3.0 g).
  • Step 3 fert-Butyl-5-vinylindoline-l-carboxylate (BI10): A stirred solution of tert- butyl-5-bromoindoline-l-carboxylate (2.0 g, 6.73 mmol), potassium vinyl trifluoroborate (2.6 g, 20.20 mmol) and K 2 C0 3 (2.78 g, 20.2 mmol) in DMSO (50.0 mL) was degassed with argon for 20 min at RT. PdCl 2 (dppf) (0.49 g, 0.67mmol) was added at RT, then the reaction mixture was heated to 100 °C for 3 h.
  • DMSO DMSO
  • Step 2 5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l-enyl)-l- nitrosoindoline (BI16): To (£)- 5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l- enyl)indoline (0.2 g, 0.5 mmol) in concentrated HC1 (5.0 ml) at 5 °C, was added slowly NaN0 2 in water and the reaction was allowed to stir at RT for 2 h. The reaction mixture was diluted with DCM, and the DCM layer washed with water and brine solution.
  • Step 3 (£)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l-en-l- yl)indolin-l-amine (BI14): To (£)- 5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l- enyl)-l -nitrosoindoline (0.1 g, 0.2 mmol) in methanol(10.0 mL) was added zinc powder (77.5 mg) and NH 4 C1 (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 Na 2 S0 4 and concentrated under reduced pressure to afford the crude compound, which was purified by column chromatography (Si0 2 , 100-200 mesh; eluting with 2% ethyl acetate/ petroleum ether) to afford the title compound as a light brown gummy material (0.08 g): ESIMS m/z 404.86 ([M+H] + ).
  • Step 2 fert-Butyl-5-vinyl-lH-indole-l-carboxylate (BI17): To a stirred solution of 5-vinyl-lH-indole (0.7 g, 4.89 mmol) in acetonitrile (20 ml) was added DMAP (59.65 mg, 0.489 mmol) and di-ieri-butyl dicarbonate (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 Na 2 S0 4 and concentrated under reduced pressure to afford the crude compound.
  • DMAP 59.65 mg, 0.489 mmol
  • di-ieri-butyl dicarbonate 1.38 g, 6.36 mmol
  • Example 36 Preparation of (E)-tert- ⁇ ⁇ ty ⁇ (2-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4- trifluorobut-l-en-l-yl)- -indol-l-yl)-2-oxoethyl)carbamate (BI22)
  • Step 1 5-Bromo-3-hydroxyisoindoline-l-one (BI25): A mixture of Zn powder (1.73 g, 26.154 mmol), copper (II) sulfate pentahydrate (0.02 g ,0.08 mmol) and 2M aq NaOH (27 mL) were cooled to 0 °C. 5-Bromoisoindoline-l,3-dione (5 g, 22mmol) was added at the same temperature over the period of 30 min. The reaction mixture was stirred at 0 °C for 30 min and 3 h at RT. The reaction mixture was filtered and the filtrate was neutralized with concentrated HC1.
  • Step 2 6-Bromophthalazine-l(2H)-one (BI26): To a stirred solution of 5-bromo-3- hydroxyisoindoline-l-one (1.0 g, 4.40 mmol) in water, was added hydrazine hydrate (0.45 g , 8.80 mmol) and heated to 95°C for 5 h. The reaction mixture was cooled to RT, filtered and washed with diethyl ether and pentane (1: 1) to afford the title compound as a white solid that was used in the next step without further purification (0.5 g): ESIMS m/z 225.15 ([M+H] + ).
  • 6-vinylphthalazine-l(2H)-one (BI27): A solution of 6-bromophthalazine- l(2H)-one (0.25 g, 1.11 mmol), potassium vinyl trifluoroborate (0.446 g, 3.33 mmol) and K 2 CO 3 (0.46 g, 3.33 mmol) in DMSO (2 mL) was degassed with argon for 20 min at RT. PdCl 2 (dppf) (0.04 g, 0.055 mmol) was added at RT, and the reaction mixture was heated to 80 °C for 2 h. The reaction mixture was cooled to RT and filtered through celite bed under vacuum and washed with ethyl acetate.
  • Step 4 Ethyl-2-(l-oxo-6-vinylphthalazine-2(lH)-yl acetate (BI24): To a stirred solution of 6-vinylphthalazine-l(2H)-one (0.5 g, 2.90 mmol) in DMF (5.0 mL) was added Cs 2 CC>3 (0.94 g, 2.90 mmol) and the reaction was stirred for 10 min. Ethyl bromoacetate (0.48 g,2.90 mmol) was added to the reaction mixture at RT and the reaction was stirred for 8 h at RT.
  • 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 Na 2 S0 4 and concentrated under reduced pressure to afford crude product.
  • Example 39 Preparation of (£ ethyl 2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4- trifluorobut-l-en-l-yl)-l-oxophthalazin-2(lH)-yl)acetate (BI28)
  • Example 41 Preparation of (£')-2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut- l-en-l-yl)-l-oxophthalazin-2(lH)-yl)-N-(2,2,2-trifluoroethyl)acetamide (BC14)
  • Ethyl 2-(diphenylmethyleneamino)acetate (10.2 g, 38.2 mmol) was added to sodium hydride (NaH; 3.18 g, 133.52 mmol) in DMF (50 mL) at 0 °C, and the mixture was stirred for 30 min. To this was added 5-bromo-2,3-dichloropyridine (12.9 g, 57.23 mmol), and the reaction mixture was stirred for 3 h at ambient temperature. The reaction mixture was quenched with 2 N HCl solution and then stirred for 4 h at ambient temperature. The mixture was extracted with EtOAc.
  • Example 58 Preparation of (£)-(3-chloro-5-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-en-l-yl)pyridin-2-yl)methanamine (CI65)
  • Example 70 Preparation of (£)-2-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en- l-yl)phenoxy)isoindoline- -dione (CI77)
  • Step 1 (£)-l-(Pyridin-2-yl)- V-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l- enyl)-2-(trifluoromethyl)benzyl)methanamine.
  • (£)-(4-(4,4,4-Trifluoro-3-(3,4,5- trichlorophenyl)but-l-en-l-yl)-2-(trifluoromethyl)phenyl)methanamine (0.46 g, 1 mmol) was dissolved in CH 3 OH (3 mL). To this was added pyridine-2-carbaldehyde (0.107 g, 1 mmol).
  • Step 2 (£)- V-(Pyridin-2-ylmethyl)- V-(4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-enyl)-2-(trifluoromethyl)benzyl)cyclopropanecarboxamide.
  • Example 83 Preparation of (£)- V-((3-chloro-5-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)-but-l-en-l-yl)pyridin-2-yl)methyl)-3,3,3-trifluoropropanamide (CC44)
  • Example 84 Preparation of (£)-3,3,3-trifluoro- V-((4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-e -l-yl)naphthalen-l-yl)methyl)propanamide (CC46)

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Abstract

This document discloses molecules having the following formula ("Formula One") and processes associated therewith.

Description

PESTICIDAL COMPOSITIONS AND PROCESSES RELATED THERETO
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Patent Application Serial No. 61/739,042 filed December 19, 2012, the entire disclosure of which is hereby expressly incorporated by reference.
FIELD OF THE DISCLOSURE
The invention disclosed in this document is related to the field of processes to produce molecules that are useful as pesticides (e.g., acaricides, insecticides, molluscicides, and nematicides), such molecules, and processes of using such molecules to control pests.
BACKGROUND OF THE DISCLOSURE
Pests cause millions of human deaths around the world each year. Furthermore, there are more than ten thousand species of pests that cause losses in agriculture. The world-wide agricultural losses amount to billions of U.S. dollars each year.
Termites cause damage to all kinds of private and public structures. The world-wide termite damage losses amount to billions of U.S. dollars each year.
Stored food pests eat and adulterate stored food. The world-wide stored food losses amount to billions of U.S. dollars each year, but more importantly, deprive people of needed food.
There is an acute need for new pesticides. Certain pests are developing resistance to pesticides in current use. Hundreds of pest species are resistant to one or more pesticides. The development of resistance to some of the older pesticides, such as DDT, the carbamates, and the organophosphates, is well known. But resistance has even developed to some of the newer pesticides, for example, imidacloprid.
Therefore, for many reasons, including the above reasons, a need exists for new pesticides.
DEFINITIONS
The examples given in the definitions are generally non-exhaustive and must not be construed as limiting the invention disclosed in this document. It is understood that a substituent should comply with chemical bonding rules and steric compatibility constraints in relation to the particular molecule to which it is attached.
"Alkenyl" means an acyclic, unsaturated (at least one carbon-carbon double bond), branched or unbranched, substituent consisting of carbon and hydrogen, for example, vinyl, allyl, butenyl, pentenyl, and hexenyl. "Alkenyloxy" means an alkenyl further consisting of a carbon-oxygen single bond, for example, allyloxy, butenyloxy, pentenyloxy, hexenyloxy.
"Alkoxy" means an alkyl further consisting of a carbon-oxygen single bond, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and ieri-butoxy.
"Alkyl" means an acyclic, saturated, branched or unbranched, substituent consisting of carbon and hydrogen, for example, methyl, ethyl, (C3)alkyl which represents n-propyl and isopropyl), (C4)alkyl which represents n-butyl, sec-butyl, isobutyl, and ieri-butyl.
"Alkynyl" means an acyclic, unsaturated (at least one carbon-carbon triple bond), branched or unbranched, substituent consisting of carbon and hydrogen, for example, ethynyl, propargyl, butynyl, and pentynyl.
"Alkynyloxy" means an alkynyl further consisting of a carbon-oxygen single bond, for example, pentynyloxy, hexynyloxy, heptynyloxy, and octynyloxy.
"Aryl" means a cyclic, aromatic substituent consisting of hydrogen and carbon, for example, phenyl, naphthyl, and biphenyl.
"(Cx-Cy)" where the subscripts "x" and "y" are integers such as 1, 2, or 3, means the range of carbon atoms for a substituent - for example, (Ci-C4)alkyl means methyl, ethyl, n- propyl, isopropyl, n-butyl, sec -butyl, isobutyl, and ieri-butyl, each individually.
"Cycloalkenyl" means a monocyclic or polycyclic, unsaturated (at least one carbon- carbon double bond) substituent consisting of carbon and hydrogen, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, bicyclo[2.2.2]octenyl,
tetrahydronaphthyl, hexahydronaphthyl, and octahydronaphthyl.
"Cycloalkenyloxy" means a cycloalkenyl further consisting of a carbon-oxygen single bond, for example, cyclobutenyloxy, cyclopentenyloxy, norbornenyloxy, and bicyclo[2.2.2]octenyloxy.
"Cycloalkyl" means a monocyclic or polycyclic, saturated substituent consisting of carbon and hydrogen, for example, cyclopropyl, cyclobutyl, cyclopentyl, norbornyl, bicyclo[2.2.2]octyl, and decahydronaphthyl.
"Cycloalkoxy" means a cycloalkyl further consisting of a carbon-oxygen single bond, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, norbornyloxy, and
bicyclo[2.2.2]octyloxy.
"Halo" means fluoro, chloro, bromo, and iodo.
"Haloalkoxy" means an alkoxy further consisting of, from one to the maximum possible number of identical or different, halos, for example, fluoromethoxy, trifluoromethoxy, 2,2-difluoropropoxy, chloromethoxy, trichloromethoxy, 1,1,2,2- tetrafluoroethoxy, and pentafluoroethoxy.
"Haloalkyl" means an alkyl further consisting of, from one to the maximum possible number of, identical or different, halos, for example, fluoromethyl, trifluoromethyl, 2,2- difluoropropyl, chloromethyl, trichloromethyl, and 1,1,2,2-tetrafluoroethyl.
"Heterocyclyl" means a cyclic substituent that may be fully saturated, partially unsaturated, or fully unsaturated, where the cyclic structure contains at least one carbon and at least one heteroatom, where said heteroatom is nitrogen, sulfur, or oxygen. In the case of sulfur, that atom can be in other oxidation states such as a sulfoxide and sulfone. Examples of aromatic heterocyclyls include, but are not limited to, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl, benzoxazolyl, benzothienyl, benzothiazolyl, cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolinyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolinyl, thiazolyl, thienyl, triazinyl, and triazolyl. Examples of fully saturated heterocyclyls include, but are not limited to, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl and tetrahydropyranyl. Examples of partially unsaturated heterocyclyls include, but are not limited to, 1,2,3,4-tetrahydroquinolinyl, 4,5-dihydro-oxazolyl, 4,5- dihydro-lH-pyrazolyl, 4,5-dihydro-isoxazolyl, and 2,3-dihydro-[l,3,4]-oxadiazolyl.
Addition
Figure imgf000004_0001
thietanyl thietanyl-oxide thietanyl-dioxide.
DETAILED DESCRIPTION OF THE DISCLOSURE
This document discloses molecules having the following formula ("Formula One")
Figure imgf000005_0001
Formula One
wherein:
(a) Rl is selected from
(1) H, F, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, S(C C8)alkyl, S(halo(C C8)alkyl), S(0)(C C8)alkyl,
S(0)(halo(Ci-C8)alkyl), S(0)2(C C8)alkyl, S(0)2(halo(C C8)alkyl), N(R14)(R15),
(2) substituted (Ci-C8)alkyl, wherein said substituted (Ci-C8)alkyl has one or more substituents selected from CN and N02,
(3) substituted halo(Ci-C8)alkyl, wherein said substituted halo(d- C8)alkyl, has one or more substituents selected from CN and N02,
(4) substituted (Ci-Cs)alkoxy, wherein said substituted (Ci-C8)alkoxy has one or more substituents selected from CN and N02, and
(5) substituted halo(Ci-Cs)alkoxy, wherein said substituted halo(Ci- C8)alkoxy has one or more substituents selected from CN and N02;
(b) R2 is selected from
(1) H, F, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, S(C C8)alkyl, S(halo(C C8)alkyl), S(0)(C C8)alkyl, S(0)(halo(Ci-C8)alkyl), S(0)2(C C8)alkyl, S(0)2(halo(C C8)alkyl), N(R14)(R15),
(2) substituted (Ci-C8)alkyl, wherein said substituted (Ci-C8)alkyl has one or more substituents selected from CN and N02,
(3) substituted halo(Ci-C8)alkyl, wherein said substituted halo(d- C8)alkyl, has one or more substituents selected from CN and N02,
(4) substituted (Ci-Cs)alkoxy, wherein said substituted (Ci-C8)alkoxy has one or more substituents selected from CN and N02, and
(5) substituted halo(Ci-Cs)alkoxy, wherein said substituted halo(d-
C8)alkoxy has one or more substituents selected from CN and N02;
(c) R3 is selected from (1) H, F, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, S(C C8)alkyl, S(halo(C C8)alkyl), S(0)(C C8)alkyl, S(0)(halo(Ci-C8)alkyl), S(0)2(C C8)alkyl, S(0)2(halo(C C8)alkyl), N(R14)(R15),
(2) substituted (Ci-C8)alkyl, wherein said substituted (Ci-C8)alkyl has one or more substituents selected from CN and N02,
(3) substituted halo(Ci-C8)alkyl, wherein said substituted halo(d- C8)alkyl, has one or more substituents selected from CN and N02,
(4) substituted (Ci-C8)alkoxy, wherein said substituted (C C8)alkoxy has one or more substituents selected from CN and N02, and
(5) substituted halo(Ci-C8)alkoxy, wherein said substituted halo(Ci- C8)alkoxy has one or more substituents selected from CN and N02;
(d) R4 is selected from
(1) H, F, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, S(C C8)alkyl, S(halo(C C8)alkyl), S(0)(C C8)alkyl, S(0)(halo(Ci-C8)alkyl), S(0)2(C C8)alkyl, S(0)2(halo(C C8)alkyl), N(R14)(R15),
(2) substituted (Ci-C8)alkyl, wherein said substituted (Ci-C8)alkyl has one or more substituents selected from CN and N02,
(3) substituted halo(Ci-C8)alkyl, wherein said substituted halo(d- C8)alkyl, has one or more substituents selected from CN and N02,
(4) substituted (Ci-C8)alkoxy, wherein said substituted (Ci-C8)alkoxy has one or more substituents selected from CN and N02, and
(5) substituted halo(Ci-C8)alkoxy, wherein said substituted halo(Cr C8)alkoxy has one or more substituents selected from CN and N02;
(e) R5 is selected from
(1) H, F, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, S(C C8)alkyl, S(halo(C C8)alkyl), S(0)(C C8)alkyl, S(0)(halo(Ci-C8)alkyl), S(0)2(C C8)alkyl, S(0)2(halo(C C8)alkyl), N(R14)(R15),
(2) substituted (Ci-C8)alkyl, wherein said substituted (Ci-C8)alkyl has one or more substituents selected from CN and N02,
(3) substituted halo(Ci-C8)alkyl, wherein said substituted halo(d- C8)alkyl, has one or more substituents selected from CN and N02,
(4) substituted (Ci-C8)alkoxy, wherein said substituted (Ci-C8)alkoxy has one or more substituents selected from CN and N02, and (5) substituted halo(Ci-Cs)alkoxy, wherein said substituted halo(d- C8)alkoxy has one or more substituents selected from CN and N02;
(f) R6 is a (Ci-C8)haloalkyl;
(g) R7 is selected from H, F, CI, Br, I, OH, (C C8)alkoxy, and halo(C
C8)alkoxy;
(h) R8 is selected from H, (C C8)alkyl, halo(C C8)alkyl, OR14, and
N(R14)(R15);
(i) R9 is selected from H, F, CI, Br, I, (C C8)alkyl, halo(C C8)alkyl, (C
C8)alkoxy, halo(C C8)alkoxy, OR14, and N(R14)(R15);
(j) R10 is selected from
(1) H, F, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C
C8)alkoxy, halo(C C8)alkoxy, cyclo(C3-C6)alkyl, S(C C8)alkyl, S(halo(C C8)alkyl), S(0)(C C8)alkyl, S(0)(halo(C C8)alkyl), S(0)2(C C8)alkyl, S(0)2(halo(C C8)alkyl), NR14R15, C(=0)H, C(=0)N(R14)(R15), CN(R14)(R15)(=NOH), (C=0)0(C C8)alkyl, (C=0)OH, heterocyclyl, (C2-C8)alkenyl, halo(C2-C8)alkenyl, (C2-C8)alkynyl,
(2) substituted (Ci-C8)alkyl, wherein said substituted (Ci-C8)alkyl has one or more substituents selected from OH, (Ci-C8)alkoxy, S(Ci-C8)alkyl, S(0)(Ci-C8)alkyl, S(0)2(Ci-C8)alkyl, NR14R15, and
(3) substituted halo(Ci-C8)alkyl, wherein said substituted halo(d- C8)alkyl, has one or more substituents selected from (Ci-C8)alkoxy, S(Ci-C8)alkyl, S(0)(Cr C8)alkyl, S(0)2(C C8)alkyl, and N(R14)(R15);
(k) Rll is C(=X5)N(H)((substituted(C C8)alkyl)C(=X5)N(Rl la)(Rl la))
wherein each X5 is independently selected from O or S, and
wherein each Rlla is independently selected from H, (Ci-C8)alkyl, substituted (C C8)alkyl, halo(C C8)alkyl, substituted halo(CrC8)alkyl, cyclo(C3-C8)alkyl, substituted cyclo(C3-C8)alkyl, halocyclo(C3-C8)alkyl,
wherein each said substituted (Ci-C8)alkyl has one or more substituents selected from F, CI, Br, I, CN, N02, OC(=0)H, OH, (C C8)alkoxy, halo(C C8)alkyl, substituted halo(Ci-C8)alkyl, (C2-C8)alkenyl, substituted (C2-C8)alkenyl, substituted halo(C2- C8)alkenyl, (C2-C8)alkynyl, substituted (C2-C8)alkynyl, substituted halo(C2-C8)alkynyl, cyclo(C3-C8)alkyl, substituted cyclo(C3-C8)alkyl, halocyclo(C3-C8)alkyl,
C(X5)N(Rlla)(Rlla), S(C C8)alkyl, S(0)(C C8)alkyl, S(0)2(C C8)alkyl, OS(0)2aryl, N((Ci-C8)alkyl)2 (wherein each (Ci-C8)alkyl is independently selected), aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, wherein each said substituted aryl has one or more substituents selected from F, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, S(Ci-C8)alkyl, S(halo(C C8)alkyl), N((C C8)alkyl)2 (wherein each (C C8)alkyl is independently selected), and oxo,
wherein each said substituted heterocyclyl has one or more substituents selected from F, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, S(C C8)alkyl, S(halo(C C8)alkyl), N((C C8)alkyl)2 (wherein each (C C8)alkyl is independently selected), C(=0)(C C8)alkyl, C(=0)(C3-C6)cycloalkyl, S(=0)2(C C8)alkyl, NR14R15, and oxo, wherein each said substituted- aryl has one or more substituents selected from F, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C
C8)alkoxy, S(C C8)alkyl, S(halo(C C8)alkyl), N((C C8)alkyl)2 (wherein each (C C8)alkyl is independently selected), and oxo,
wherein said substituted halo(Ci-C8)alkyl, has one or more substituents selected from CN and N02,
wherein said substituted (C2-C8)alkenyl, has one or more substituents selected from CN and N02,
wherein said substituted halo(C2-C8)alkenyl, has one or more substituents selected from CN and N02,
wherein said substituted (C2-C8)alkynyl, has one or more substituents selected from CN and N02,
wherein said substituted halo(C2-C8)alkynyl, has one or more substituents selected from CN and N02,
wherein said substituted cyclo(C3-C8)alkenyl, has one or more substituents selected from CN and N02,
wherein said substituted halocyclo(C3-C8)alkenyl, has one or more substituents selected from CN and N02;
(1) R12 is selected from (v), H, F, CI, Br, I, CN, (C C8)alkyl, halo(C C8)alkyl, (Ci-C8)alkoxy, halo(Ci-C8)alkoxy, and cyclo(C3-C6)alkyl;
(m) R13 is selected from (v), H, F, CI, Br, I, CN, (C C8)alkyl, halo(C C8)alkyl, (Ci-C8)alkoxy, and halo(Ci-C8)alkoxy;
(n) each R14 is independently selected from H, (Ci-C8)alkyl, (C2-C8)alkenyl, substituted (Ci-C8)alkyl, halo(Ci-C8)alkyl, substituted halo(Ci-C8)alkyl), (Ci-C8)alkoxy, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (Ci-C8)alkyl-aryl, (Ci-C8)alkyl-(substituted-aryl), O- (Ci-C8)alkyl-aryl, 0-(Ci-C8)alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C C8)alkyl-heterocyclyl, (C C8)alkyl-(substituted-heterocyclyl), 0-(C C8)alkyl- heterocyclyl, 0-(C C8)alkyl-(substituted-heterocyclyl), N(R16)(R17), (C C8)alkyl- C(=0)N(R16)(R17), C(=0)(C C8)alkyl, C(=0)(halo(Ci-C8)alkyl),C(=0)(C3-C6)cycloalkyl, (Ci-C8)alkyl-C(=0)0(Ci-C8)alkyl, C(=0)H
wherein each said substituted (Ci-C8)alkyl has one or more substituents selected from CN, and N02,
wherein each said substituted halo(C]-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, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, S(Ci-C8)alkyl, S(halo(C C8)alkyl), N((C C8)alkyl)2 (wherein each (C C8)alkyl is independently selected), and oxo, and
wherein each said substituted-heterocyclyl has one or more substituents selected from F, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, (C3-C6)cycloalkyl S(C C8)alkyl, S(halo(C C8)alkyl), N((C C8)alkyl)2 (wherein each (Ci-C8)alkyl is independently selected), heterocyclyl, C(=0)(C C8)alkyl, C(=0)0(C C8)alkyl, and oxo, (wherein said alkyl, alkoxy, and heterocyclyl, may be further substituted with one or more of F, CI, Br, I, CN, and N02);
(o) each R15 is independently selected from H, (Ci-C8)alkyl, (C2-C8)alkenyl, substituted (C C8)alkyl, halo(C C8)alkyl, substituted halo(C C8)alkyl), (C C8)alkoxy, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (Ci-C8)alkyl-aryl, (Ci-C8)alkyl-(substituted-aryl), O- (C]-C8)alkyl-aryl, 0-(Ci-C8)alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (Ci-C8)alkyl-heterocyclyl, (C C8)alkyl-(substituted-heterocyclyl), 0-(C C8)alkyl- heterocyclyl, 0-(C C8)alkyl-(substituted-heterocyclyl), N(R16)(R17), (C C8)alkyl- C(=0)N(R16)(R17), C(=0)(C C8)alkyl, C(=0)(halo(C C8)alkyl), C(=0)(C3-C6)cycloalkyl, (Ci-C8)alkyl-C(=0)0(Ci-C8)alkyl, C(=0)H
wherein each said substituted (Ci-C8)alkyl has one or more substituents selected from CN, and N02,
wherein each said substituted halo(Ci-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, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, S(Ci-C8)alkyl, S(halo(C C8)alkyl), N((C C8)alkyl)2 (wherein each (C C8)alkyl is independently selected), and oxo, and wherein each said substituted-heterocyclyl has one or more substituents selected from F, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, (C3-C6)cycloalkyl S(C C8)alkyl, S(halo(C C8)alkyl), N((C C8)alkyl)2 (wherein each (Ci-C8)alkyl is independently selected), heterocyclyl, C(=0)(C C8)alkyl, C(=0)0(C C8)alkyl, and oxo, (wherein said alkyl, alkoxy, and heterocyclyl, may be further substituted with one or more of F, CI, Br, I, CN, and N02);
(p) each R16 is independently selected from H, (C]-C8)alkyl, substituted-(Cr C8)alkyl, halo(C]-C8)alkyl, substituted-halo(Ci-C8)alkyl, cyclo(C3-C6)alkyl, aryl, substituted- aryl, (C C8)alkyl-aryl, (C C8)alkyl-(substituted-aryl), 0-(C C8)alkyl-aryl, 0-(C C8)alkyl- (substituted-aryl), heterocyclyl, substituted-heterocyclyl, (Ci-C8)alkyl-heterocyclyl, (Cr C8)alkyl-(substituted-heterocyclyl), 0-(C C8)alkyl-heterocyclyl, 0-(C C8)alkyl- (substituted-heterocyclyl), 0-(Ci-C8)alkyl
wherein each said substituted (Ci-C8)alkyl has one or more substituents selected from CN, and N02,
wherein each said substituted halo(Ci-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, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, S(Ci-C8)alkyl, S(halo(C C8)alkyl), N((C C8)alkyl)2 (wherein each (C C8)alkyl is independently selected), and oxo, and
wherein each said substituted-heterocyclyl has one or more substituents selected from F, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, S(C C8)alkyl, S(halo(C C8)alkyl), N((C C8)alkyl)2 (wherein each (C C8)alkyl is independently selected), and oxo;
(q) each R17 is independently selected from H, (C C8)alkyl, substituted-(C
C8)alkyl, halo(Ci-C8)alkyl, substituted-halo(Ci-C8)alkyl, cyclo(C3-C6)alkyl, aryl, substituted- aryl, (Ci-C8)alkyl-aryl, (C C8)alkyl-(substituted-aryl), 0-(C C8)alkyl-aryl, 0-(C C8)alkyl- (substituted-aryl), heterocyclyl, substituted-heterocyclyl, (Ci-C8)alkyl-heterocyclyl, (Cr C8)alkyl-(substituted-heterocyclyl), 0-(C C8)alkyl-heterocyclyl, 0-(C C8)alkyl- (substituted-heterocyclyl), 0-(C C8)alkyl
wherein each said substituted (Ci-C8)alkyl has one or more substituents selected from CN, and N02,
wherein each said substituted halo(Ci-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, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, S(Ci-C8)alkyl, S(halo(C C8)alkyl), N((C C8)alkyl)2 (wherein each (C C8)alkyl is independently selected), and oxo, and
wherein each said substituted-heterocyclyl has one or more substituents selected from F, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, S(C C8)alkyl, S(halo(C C8)alkyl), N((C C8)alkyl)2 (wherein each (C C8)alkyl is independently selected), and oxo;
(r) XI is selected from N and CR12;
(s) X2 is selected from N, CR9, and CR13;
(t) X3 is selected from N and CR9; and
(v) R12 and R13 together form a linkage containing 3 to 4 atoms selected from C, N, O, and S, wherein said linkage connects back to the ring to form a 5 to 6 member saturated or unsaturated cyclic ring, wherein said linkage has at least one substituent X4 wherein X4 is selected from R14, N(R14)(R15), N(R14)(C(=0)R14), N(R14)(C(=S)R14),
N(R14)(C(=0)N(R14)(R14)), N(R14)(C(=S)N(R14)(R14)), N(R14)(C(=0)N(R14)((C2- C8)alkenyl)), N(R14)(C(=S)N(R14)((C2-C8)alkenyl)), wherein each R14 is independently selected.
In another embodiment of this invention Rl may be selected from any combination of one or more of the following - H, F, CI, 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, (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 R2 may be selected from any combination of one or more of the following - H, F, CI, 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, (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, CI, 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(Cs)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (Cs)alkoxy, (C6)alkoxy, (C7)alkoxy, (Cs)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(Cs)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(Cs)alkoxy.
In another embodiment of this invention R4 may be selected from any combination of one or more of the following - H, F, CI, 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(Cs)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (Cs)alkoxy, (C6)alkoxy, (C7)alkoxy, (Cs)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(Cs)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(Cs)alkoxy.
In another embodiment of this invention R5 may be selected from any combination of one or more of the following - H, F, CI, 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(Cs)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (Cs)alkoxy, (C6)alkoxy, (C7)alkoxy, (Cs)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(Cs)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(Cs)alkoxy.
In another embodiment of this invention R2 and R4 are selected from F, CI, Br, I, CN, and N02 and Rl, R3, and R5 are H.
In another embodiment of this invention R2, R3, and R4 are selected from F, CI, Br, I, CN, and N02 and Rl, and R5 are H.
In another embodiment of this invention R2, R3, and R4 are independently selected from F and CI and Rland R5 are H.
In another embodiment of this invention Rl is selected from CI and H.
In another embodiment of this invention R2 is selected from CF3, CH3, CI, F, and H. In another embodiment of this invention R3 is selected from OCH3, CH3, F, CI, or H. In another embodiment of this invention R4 is selected from CF3, CH3, CI, F, and H. In another embodiment of this invention R5 is selected from F, CI, and H.
In another embodiment of this invention R6 may be selected from any combination of one or more of the following - halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, and halo(C8)alkyl.
In another embodiment of this invention R6 is trifluoromethyl. In another embodiment of this invention R7 may be selected from any combination of one or more of the following - H, F, CI, Br, and I.
In another embodiment of this invention R7 is selected from H, OCH3, and OH.
In another embodiment of this invention R8 may be selected from any combination of one or more of the following - H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (Cs)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, and halo(C8)alkyl.
In another embodiment of this invention R8 is selected from CH3 and H.
In another embodiment of this invention R9 may be selected from any combination of one or more of the following - H, F, CI, Br, I, 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(Cs)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (Cs)alkoxy, (C6)alkoxy, (C7)alkoxy, (Cs)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(Cs)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(Cs)alkoxy.
In another embodiment of this invention R10 may be selected from any combination of one or more of the following - H, F, CI, Br, I, CN, 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(Cs)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (Cs)alkoxy, (C6)alkoxy, (C7)alkoxy, (Cs)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(Cs)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, halo(Cs)alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
In another embodiment of this invention R10 may be selected from any combination of one or more of the following - H, CI, Br, CH3, and CF3.
In another embodiment of this invention R10 is selected from Br, C(=NOH)NH2,
C(=0)H, C(=0)NH2, C(=0)OCH2CH3, C(=0)OH, CF3, CH2CH3, CH2OH, CH3, CI, CN, F, H, NH2, NHC(=0)H, NHCH3, N02, OCH3, OCHF2, and pyridyl.
In another embodiment of this invention Rl lis selected from
C(=0)N(H)C(H)(CH2OCH3)(C(=0)N(H)(CH2CF3),
C(=0)N(H)C(H)(CH2OCH3)(C(=0)N(H)(CH2CHF2),
C(=0)N(H)C(H)(CH2OCH3)(C(=0)N(H)(CH(CH3)CF3),
C(=0)N(H)C(H)(CH2OCH3)(C(=S)N(H)(CH2CF3),
C(=S)N(H)C(H)(CH2OCH3)(C(=S)N(H)(CH2CF3), C(=S)N(H)C(H)(CH2OCH3)(C(=0)N(H)(CH2CF3), and
C(=0)N(H)C(CH3)(CH2OCH3)(C(=0)N(H)(CH2CF3).
In another embodiment of this invention R12 may be selected from any combination of one or more of the following - H, F, CI, Br, I, 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(Cs)alkyl, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(Cs)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(Cs)alkoxy.
In another embodiment of this invention R12 is selected from CH3, and H.
In another embodiment of this invention R13 may be selected from any combination of one or more of the following - H, F, CI, Br, I, 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(Cs)alkyl, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(Cs)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(Cs)alkoxy.
In another embodiment of this invention R13 is selected from CH3, CI and H.
In another embodiment of this invention R12-R13 are a hydrocarbyl linkage containing CH=CHCH=CH.
In another embodiment of this invention R14 may be selected from any combination of one or more of the following - H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (Cs)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methyl-aryl, ethyl-aryl, (C3)alkyl-aryl, (C4)alkyl- aryl, (Cs)alkyl-aryl, (C6)alkyl-aryl, (C7)alkyl-aryl, (Cs)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), (Cs)alkyl- (substituted-aryl), O-methyl-aryl, O-ethyl-aryl, 0-(C3)alkyl-aryl, 0-(C4)alkyl-aryl, O- (C5)alkyl-aryl, 0-(C6)alkyl-aryl, 0-(C7)alkyl-aryl, 0-(C8)alkyl-aryl, 0-methyl-(substituted- aryl), O-ethyl-(substituted-aryl), 0-(C3)alkyl-(substituted-aryl), 0-(C4)alkyl-(substituted- aryl), 0-(C5)alkyl-(substituted-aryl), 0-(C6)alkyl-(substituted-aryl), 0-(C7)alkyl-(substituted- aryl), 0-(Cs)alkyl-(substituted-aryl), methyl-heterocyclyl, ethyl-heterocyclyl, (C3)alkyl- heterocyclyl, (C4)alkyl-heterocyclyl, (Cs)alkyl-heterocyclyl, (C6)alkyl-heterocyclyl,
(C7)alkyl-heterocyclyl, (Cs)alkyl-heterocyclyl, methyl-(substituted-heterocyclyl), ethyl- (substituted-heterocyclyl), (C3)alkyl-(substituted-heterocyclyl), (C4)alkyl-(substituted- heterocyclyl), (Cs)alkyl-(substituted-heterocyclyl), (C6)alkyl-(substituted-heterocyclyl), (C7)alkyl-(substituted-heterocyclyl), (C8)alkyl-(substituted-heterocyclyl), O-methyl- heterocyclyl, O-ethyl-heterocyclyl, 0-(C3)alkyl-heterocyclyl, 0-(C4)alkyl-heterocyclyl, O- (C5)alkyl-heterocyclyl, 0-(C6)alkyl-heterocyclyl, 0-(C7)alkyl-heterocyclyl, 0-(C8)alkyl- heterocyclyl, O-methyl-(substituted-heterocyclyl), O-ethyl-(substituted-heterocyclyl), O- (C3)alkyl-(substituted-heterocyclyl), 0-(C4)alkyl-(substituted-heterocyclyl), 0-(Cs)alkyl- (substituted-heterocyclyl), 0-(C6)alkyl-(substituted-heterocyclyl), 0-(C7)alkyl-(substituted- heterocyclyl), 0-(C8)alkyl-(substituted-heterocyclyl), methyl-C(=0)N(R16)(R17), ethyl- C(=0)N(R16)(R17), (C3)alkyl-C(=0)N(R16)(R17), (C4)alkyl-C(=0)N(R16)(R17), (C5)alkyl- C(=0)N(R16)(R17), (C6)alkyl-C(=0)N(R16)(R17), (C7)alkyl-C(=0)N(R16)(R17), and (C8)alkyl-C(=0)N(R16)(R17).
In another embodiment of this invention R14 may be selected from any combination of one or more of the following - H, CH3, CH2CF3, C]¾-halopyridyl, oxo-pyrrolidinyl, halophenyl, thietanyl, CH2-phenyl, CH2-pyridyl, thietanyl-dioxide, CH2-halothiazolyl, C((CH3)2)-pyridyl, N(H) (halophenyl), CH2-pyrimidinyl, CH2-tetrahydrofuranyl, CH2-furanyl, 0-CH2-halopyridyl, and CH2C(=0)N(H)(CH2CF3).
In another embodiment of this invention R15 may be selected from any combination of one or more of the following - H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (Cs)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methyl-aryl, ethyl-aryl, (C3)alkyl-aryl, (C4)alkyl- aryl, (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), O-methyl-aryl, O-ethyl-aryl, 0-(C3)alkyl-aryl, 0-(C4)alkyl-aryl, O- (C5)alkyl-aryl, 0-(C6)alkyl-aryl, 0-(C7)alkyl-aryl, 0-(C8)alkyl-aryl, 0-methyl-(substituted- aryl), O-ethyl-(substituted-aryl), 0-(C3)alkyl-(substituted-aryl), 0-(C4)alkyl-(substituted- aryl), 0-(C5)alkyl-(substituted-aryl), 0-(C6)alkyl-(substituted-aryl), 0-(C7)alkyl-(substituted- aryl), 0-(C8)alkyl-(substituted-aryl), methyl-heterocyclyl, ethyl-heterocyclyl, (C3)alkyl- heterocyclyl, (C4)alkyl-heterocyclyl, (Cs)alkyl-heterocyclyl, (C6)alkyl-heterocyclyl,
(C7)alkyl-heterocyclyl, (C8)alkyl-heterocyclyl, methyl-(substituted-heterocyclyl), ethyl- (substituted-heterocyclyl), (C3)alkyl-(substituted-heterocyclyl), (C4)alkyl-(substituted- heterocyclyl), (Cs)alkyl-(substituted-heterocyclyl), (C6)alkyl-(substituted-heterocyclyl), (C7)alkyl-(substituted-heterocyclyl), (C8)alkyl-(substituted-heterocyclyl), O-methyl- heterocyclyl, O-ethyl-heterocyclyl, 0-(C3)alkyl-heterocyclyl, 0-(C4)alkyl-heterocyclyl, O- (C5)alkyl-heterocyclyl, 0-(C6)alkyl-heterocyclyl, 0-(C7)alkyl-heterocyclyl, 0-(C8)alkyl- heterocyclyl, O-methyl-(substituted-heterocyclyl), O-ethyl-(substituted-heterocyclyl), O- (C3)alkyl-(substituted-heterocyclyl), 0-(C4)alkyl-(substituted-heterocyclyl), 0-(Cs)alkyl- (substituted-heterocyclyl), 0-(C6)alkyl-(substituted-heterocyclyl), 0-(C7)alkyl-(substituted- heterocyclyl), 0-(C8)alkyl-(substituted-heterocyclyl), methyl-C(=0)N(R16)(R17), ethyl- C(=0)N(R16)(R17), (C3)alkyl-C(=0)N(R16)(R17), (C4)alkyl-C(=0)N(R16)(R17), (C5)alkyl- C(=0)N(R16)(R17), (C6)alkyl-C(=0)N(R16)(R17), (C7)alkyl-C(=0)N(R16)(R17), and (C8)alkyl-C(=0)N(R16)(R17).
In another embodiment of this invention R15 may be selected from any combination of one or more of the following - H, C¾, CH2CF3, CH2-halopyridyl, oxo-pyrrolidinyl, halophenyl, thietanyl, CH2-phenyl, CH2-pyridyl, thietanyl-dioxide, CH2-halothiazolyl,
C((CH3)2)-pyridyl, N(H) (halophenyl), CH2-pyrimidinyl, CH2-tetrahydrofuranyl, CH2-furanyl, 0-CH2-halopyridyl, and CH2C(=0)N(H)(CH2CF3).
In another embodiment of this invention R16 may be selected from any combination of one or more of the following - H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (Cs)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methyl-aryl, ethyl-aryl, (C3)alkyl-aryl, (C4)alkyl- aryl, (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), O-methyl-aryl, O-ethyl-aryl, 0-(C3)alkyl-aryl, 0-(C4)alkyl-aryl, O-
(C5)alkyl-aryl, 0-(C6)alkyl-aryl, 0-(C7)alkyl-aryl, 0-(C8)alkyl-aryl, 0-methyl-(substituted- aryl), O-ethyl-(substituted-aryl), 0-(C3)alkyl-(substituted-aryl), 0-(C4)alkyl-(substituted- aryl), 0-(C5)alkyl-(substituted-aryl), 0-(C6)alkyl-(substituted-aryl), 0-(C7)alkyl-(substituted- aryl), 0-(C8)alkyl-(substituted-aryl), methyl-heterocyclyl, ethyl-heterocyclyl, (C3)alkyl- heterocyclyl, (C4)alkyl-heterocyclyl, (Cs)alkyl-heterocyclyl, (C6)alkyl-heterocyclyl,
(C7)alkyl-heterocyclyl, (C8)alkyl-heterocyclyl, methyl-(substituted-heterocyclyl), ethyl- (substituted-heterocyclyl), (C3)alkyl-(substituted-heterocyclyl), (C4)alkyl-(substituted- heterocyclyl), (Cs)alkyl-(substituted-heterocyclyl), (C6)alkyl-(substituted-heterocyclyl), (C7)alkyl-(substituted-heterocyclyl), (C8)alkyl-(substituted-heterocyclyl), O-methyl- heterocyclyl, O-ethyl-heterocyclyl, 0-(C3)alkyl-heterocyclyl, 0-(C4)alkyl-heterocyclyl, O- (C5)alkyl-heterocyclyl, 0-(C6)alkyl-heterocyclyl, 0-(C7)alkyl-heterocyclyl, 0-(C8)alkyl- heterocyclyl, O-methyl-(substituted-heterocyclyl), O-ethyl-(substituted-heterocyclyl), O- (C3)alkyl-(substituted-heterocyclyl), 0-(C4)alkyl-(substituted-heterocyclyl), 0-(Cs)alkyl- (substituted-heterocyclyl), 0-(C6)alkyl-(substituted-heterocyclyl), 0-(C7)alkyl-(substituted- heterocyclyl), and 0-(Cs)alkyl-(substituted-heterocyclyl).
In another embodiment of this invention R16 may be selected from any combination of one or more of the following - H, CH2CF3, cyclopropyl, thietanyl, thietanyl dioxide, and halophenyl.
In another embodiment of this invention R17 may be selected from any combination of one or more of the following - H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (Cs)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methyl-aryl, ethyl-aryl, (C3)alkyl-aryl, (C4)alkyl- aryl, (Cs)alkyl-aryl, (C6)alkyl-aryl, (C7)alkyl-aryl, (Cs)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), (Cs)alkyl- (substituted-aryl), O-methyl-aryl, O-ethyl-aryl, 0-(C3)alkyl-aryl, 0-(C4)alkyl-aryl, O- (C5)alkyl-aryl, 0-(C6)alkyl-aryl, 0-(C7)alkyl-aryl, 0-(C8)alkyl-aryl, 0-methyl-(substituted- aryl), O-ethyl-(substituted-aryl), 0-(C3)alkyl-(substituted-aryl), 0-(C4)alkyl-(substituted- aryl), 0-(C5)alkyl-(substituted-aryl), 0-(C6)alkyl-(substituted-aryl), 0-(C7)alkyl-(substituted- aryl), 0-(Cs)alkyl-(substituted-aryl), methyl-heterocyclyl, ethyl-heterocyclyl, (C3)alkyl- heterocyclyl, (C4)alkyl-heterocyclyl, (Cs)alkyl-heterocyclyl, (C6)alkyl-heterocyclyl, (C7)alkyl-heterocyclyl, (Cs)alkyl-heterocyclyl, methyl-(substituted-heterocyclyl), ethyl- (substituted-heterocyclyl), (C3)alkyl-(substituted-heterocyclyl), (C4)alkyl-(substituted- heterocyclyl), (Cs)alkyl-(substituted-heterocyclyl), (C6)alkyl-(substituted-heterocyclyl), (C7)alkyl-(substituted-heterocyclyl), (Cs)alkyl-(substituted-heterocyclyl), O-methyl- heterocyclyl, O-ethyl-heterocyclyl, 0-(C3)alkyl-heterocyclyl, 0-(C4)alkyl-heterocyclyl, O- (C5)alkyl-heterocyclyl, 0-(C6)alkyl-heterocyclyl, 0-(C7)alkyl-heterocyclyl, 0-(C8)alkyl- heterocyclyl, O-methyl-(substituted-heterocyclyl), O-ethyl-(substituted-heterocyclyl), O- (C3)alkyl-(substituted-heterocyclyl), 0-(C4)alkyl-(substituted-heterocyclyl), 0-(Cs)alkyl- (substituted-heterocyclyl), 0-(C6)alkyl-(substituted-heterocyclyl), 0-(C7)alkyl-(substituted- heterocyclyl), and 0-(Cs)alkyl-(substituted-heterocyclyl).
In another embodiment of this invention R17 may be selected from any combination of one or more of the following - H, CH2CF3, cyclopropyl, thietanyl, thietanyl dioxide, and halophenyl.
In another embodiment of this invention XI is CR12, X2 is CR13, and X3 is CR9. In another embodiment of this invention a heterocyclyl has preferably about 6 to 10 atoms in the ring structure, more preferably, 6 to 8 atoms. The molecules of Formula One will generally have a molecular mass of about 100 Daltons to about 1200 Daltons. However, it is generally preferred if the molecular mass is from about 120 Daltons to about 900 Daltons, and it is even more generally preferred if the molecular mass is from about 140 Daltons to about 600 Daltons.
The benzyl alcohol of Formula IV, wherein Rl, 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 Rl, R2, R3, R4, R5, and R6 are as previously disclosed, with a reducing agent, such as sodium borohydride (NaBH4), under basic conditions, such as aqueous sodium hydroxide (NaOH), in a polar pro tic solvent, such as methyl alcohol (CH3OH) at 0 °C. Alternatively, an aldehyde of Formula III, wherein Rl, R2, R3, R4, R5, and R7 are as previously disclosed, is allowed to react with
trifluorotrimethylsilane in the presence of a catalytic amount of tetrabutylammonium fluoride in a polar aprotic solvent, such as tetrahydrofuran (THF), as in step b of Scheme I. The compound of Formula IV can be transformed into the compound of Formula V, wherein Y is selected from Br, CI or I, and Rl, R2, R3, R4, R5, R6, and R7 are as previously disclosed, by reaction with a halogenating reagent, such as N-bromosuccinimide and triethyl phosphite in a non-reactive solvent, such as dichloromethane (CH2CI2) 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 = CI, as in step c of Scheme I.
Scheme I
Figure imgf000018_0001
Formation of the styrene coupling partners can be accomplished as in Schemes II, III IV and V. In Scheme II, a vinylbenzoic acid of Formula VI, wherein Rl l is (C=0)OH and R8, R9, RIO, R12, R13, XI, X2, and X3 are as previously disclosed, can be converted in two steps to the vinylbenzamide of Formula Vila, wherein Rl l is (C=0)N(R14)(R15), and R8, R9, R10, R12, R13, R14, R15, and X are as previously disclosed. As in step d of Scheme II, the benzoic acid of Formula VI is treated with oxalyl chloride in the presence of a catalytic amount of N,N-dimethylformamide (DMF) in a non-reactive solvent such as CH2CI2 to form the acid chloride, which is subsequently allowed to react with an amine (HN(R14)(R15)), wherein R14 and R15 are as previously disclosed, in the presence of a base, such as triethylamine, in a polar aprotic solvent, such as THF, to provide the vinyl benzamide of Formula Vila, wherein Rl l is (C=0)N(R14)(R15), and R8, R9, R10, R12, R13, R14, R15, XI, X2, and X3 are as previously disclosed, as in step e of Scheme II.
Scheme II
Figure imgf000019_0001
VI Vila
In Schemes III and IV, a halobenzoic acid of Formula VIII, wherein R18 is Br or I, Rl l is (C=0)OH and R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed can be converted to a vinylbenzoic acid ester of Formula Vllbl or Formula VIIb2, wherein R18 is Br or I, Rl l is (C=0)0(C C6 alkyl), and R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed. In step / 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 °C. The resulting formyl benzoic acid is allowed to react with an acid, such as sulfuric acid (H2SO4), in the presence of an alcohol, such as ethyl alcohol (EtOH), as in step g, to provide the formyl benzoic acid ethyl ester of Formula IX, wherein Rl l is (C=0)0(C C6 alkyl), and R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed. The vinyl benzoic acid ester of Formula Vllbl is accessed via reaction of the compounds of Formula IX, with a base, such as potassium carbonate (K2CO3), and methyl triphenyl phosphonium bromide in a polar aprotic solvent, such as 1 ,4-dioxane, at ambient temperature, as in step h of Scheme III. Scheme III
Figure imgf000020_0001
VIII IX Vllb l
In step i of Scheme IV, the halobenzoic acid of Formula VIII, wherein R18 is Br, Rl 1 is (C=0)OH, and R8, R9, RIO, R12, R13, XI, X2, and X3 are as previously disclosed, is treated with di-ieri-butyl dicarbonate in the presence of a base, such as triethylamine (Et3N) and a catalytic amount of 4-(dimethylamino)pyridine (DMAP) in a polar aprotic solvent, such as THF, at ambient temperature. The resulting benzoic acid ieri-butyl ester is allowed to react with vinyl boronic anhydride pyridine complex in the presence of a palladium catalyst, such a tetrakis(triphenylphospine)palladium(0) (Pd(PPh3)4), and a base, such as K2C03, in a non- reactive solvent such as toluene at reflux temperature, as in step j, to provide the vinyl benzoic acid ester of Formula VIIb2, wherein Rl 1 is (C=0)0(C C6 alkyl), and R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed.
Scheme IV
Figure imgf000020_0002
VIII VIIb2
In step k of Scheme V, the vinyl benzoic acid ester of Formula VIIb2, wherein R10 is Br, Rll is (C=0)0(C C6 alkyl), and R8, R9, R12, R13, XI, X2, and X3 are as previously defined, can be further transformed into the corresponding vinyl benzoic acid ester of Formula VIIb3, wherein R10 is CN, Rll is (C=0)0(C C6 alkyl), and R8, R9, R12, R13, XI, X2, and X3 are as previously disclosed, by reaction with copper(I) cyanide (CuCN) in a polar aprotic solvent, such as DMF, at 140 °C. Scheme V
Figure imgf000021_0001
VIIb2 VIIb3
Coupling of the compounds of Formula V with the compounds of Formula Vila, Vllbl, 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 disclosed, and the vinylbenzamide of Formula Vila, wherein Rll is
(C=0)N(R14)(R15), and R8, R9, R10, R12, R13, R14, R15, XI, X2, and X3 are as previously disclosed, are allowed to react in the presence of copper(I) chloride (CuCl) and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180 °C to provide the molecules of Formula One, wherein Rl l is (C=0)N(R14)(R15), and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, XI, X2, and X3 are as previously disclosed.
Scheme VI
Figure imgf000021_0002
In step I of Scheme VII, the compound of Formula V, wherein Y, Rl, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the vinylbenzoic acid ester of Formula Vllbl, wherein Rl l is (C=0)0(C C6 alkyl), and R8, R9, R10, R12, R13, 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 180 °C to provide the compounds of Formula Xa, wherein Rl 1 is (C=0)0(C C6 alkyl), and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed. The compounds of Formula Xa are then converted to the molecules of Formula One, wherein Rl 1 is
(C=0)N(R14)(R15), and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, XI, X2, and X3 are as previously disclosed, by either a two-step process as disclosed in steps m and n or in one step as disclosed in step o. In step m of Scheme VII, the ester of Formula Xa is saponified to the corresponding acid under acidic conditions, such as about 11 Normal (N) hydrochloric acid (HCl), in a polar aprotic solvent, such as 1,4-dioxane, at about 100 °C. The acid can subsequently be coupled to an amine (HN(R14)(R15)), wherein R14 and R15 are as previously disclosed using peptide coupling reagents, such as 1-hydroxybenzotriazole (HOBt), N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (EDOHC1), benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 2-chloro- 1,3-dimethylimidazolidinium hexafluorophosphate (CIP), l-hydroxy-7-azabenzotriazole (HOAt), or 0-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate (HBTU) in the presence of a base, such as N,N-diisopropylethylamine (DIEA) or 4- (dimethylamino)pyridine (DMAP) to give the molecules of Formula One, wherein Rl l is (C=0)N(R14)(R15), and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, XI, X2, and X3 are as previously disclosed. Alternatively, the ester of Formula Xa is allowed to react with an amine (HN(R14)(R15)) in the presence of a solution of trimethylaluminum in toluene in a non-reactive solvent, such as CH2CI2, at ambient temperature, as in step o of Scheme VII, to access the molecules of Formula One, wherein Rl l is (C=0)N(R14)(R15), and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, XI, X2, and X3 are as previously disclosed.
Scheme VII
Figure imgf000022_0001
Formula One In step I of Scheme VIII, the compound of Formula V, wherein Y, Rl, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the vinylbenzoic acid ester of Formula VIIb2 or VIIb3, wherein Rl l is (C=0)0(C C6 alkyl), and R8, R9, RIO, R12, R13, 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 180 °C to provide the compounds of Formula Xb, wherein Rl 1 is (C=0)OH, and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, XI, X2, and X3 are as previously disclosed. The compounds of Formula Xb are then converted to the molecules of Formula One, wherein Rl 1 is
(C=0)N(R14)(R15), and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, XI, X2, and X3 are as previously disclosed, in one step as disclosed in step n. In step n of
Scheme VIII, the acid of Formula Xb can be coupled to an amine (HN(R14)(R15)), wherein R14 and R15 are as previously disclosed, using peptide coupling reagents, such as 1- hydroxybenzotriazole (HOBt), N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (EDOHC1) , benzotriazol- 1 -yl-oxytripyrrolidinophosphonium
hexafluorophosphate (PyBOP), 2-chloro-l,3-dimethylimidazolidinium hexafluorophosphate (CIP), l-hydroxy-7-azabenzotriazole (HOAt), or 0-benzotriazole-N,N,N',N'-tetramethyl- uronium-hexafluoro-phosphate (HBTU) in the presence of a base, such as N,N- diisopropylethylamine (DIEA) or 4-(dimethylamino)pyridine (DMAP) to give the molecules of Formula One, wherein Rl l is (C=0)N(R14)(R15), and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, XI, X2, and X3 are as previously disclosed.
Scheme VIII
Figure imgf000024_0001
Formula One
In step j of Scheme IX, the halobenzoketone of Formula VHIb, wherein R18 is Br, R10 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, XI, X2, and X3 are as previously disclosed, is allowed to react with vinyl boronic anhydride pyridine complex in the presence of a palladium catalyst, such as Pd(PPh3)4, and a base, such as K2CO3, in a non-reactive solvent such as toluene at reflux temperature, to provide the vinyl benzoketone of Formula VIIb4, wherein R10 and Rl 1 together form a linkage, having 3-4 carbon atoms and an oxo substituent and with the ring carbon atoms form a 5- or 6-membered ring, and R8, R9, R12, R13, XI, X2, and X3 are as previously disclosed.
Scheme IX
Figure imgf000024_0002
Vlllb VIIb4
In step I of Scheme X, the compound of Formula V, wherein Y, Rl, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the vinylbenzoketone of Formula VIIb4 as previously disclosed, wherein R8, R9, R12, R13, 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 180 °C to provide the compounds of Formula Xc, wherein R10 and Rl 1 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 Rl, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, XI, X2, and X3 are as previously disclosed. The compounds of Formula Xc are then converted to the molecules of Formula Xd, wherein R10 and Rl 1 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 Rl, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, XI, X2, and X3 are as previously disclosed, in step p. In step p of Scheme X, the ketone of Formula Xc is allowed to react with hydroxylamine hydrochloride in the presence of sodium acetate and in a polar protic solvent, such as EtOH, at a temperature of about 78 °C, to give the molecules of Formula Xd as previously disclosed.
Scheme X
Figure imgf000025_0001
The compounds of Formula Xc are also converted to the molecules of Formula Xe, wherein R10 and Rl l 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 Rl, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, XI, X2, and X3 are as previously disclosed, as demonstrated in step q of Scheme XI. The ketone of Formula Xc is allowed to react with ammonium acetate in the presence of sodium cyanoborohydride and in a polar protic solvent, such as CH3OH, at a temperature of about 65 °C, to give the molecules of Formula Xe. heme XI
Figure imgf000026_0001
The compounds of Formula Xe are converted to the molecules of Formula One, wherein RIO and Rl l together form a linkage as previously disclosed in (u), and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, XI, X2, and X3 are as previously, in one step as disclosed in steps r or s. In step r of Scheme XII, the amine of Formula Xe is allowed to react with an isocyanate in a polar, aprotic solvent such as diethyl ether at ambient temperature to provide the molecules of Formula One as previously disclosed. In step s of Scheme XII, the amine of Formula Xe is coupled to an acid with ΗΟΒι·Η20 and EDOHC1 in the presence of a base, such as DIEA, in a non-reactive solvent, such as CH2CI2, to give the molecules of Formula One, as previously disclosed.
Scheme XII
Figure imgf000026_0002
In step t of Scheme XIII, the vinyl benzyl chloride of Formula XIa, wherein Rl 1 is - CH2C1 and R8, R9, R10, R12, R13, XI, X2, and X3 are as previously defined, can be transformed into the corresponding phthalimide-protected benzyl amine of Formula Xlla, wherein Rl l is CH2N(Phthalimide), and R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed, by reaction with potassium phthalimide in a polar aprotic solvent, such as DMF, at 70 °C. Scheme ΧΠΤ
Figure imgf000027_0001
Xla Xlla
In step u of Scheme XIV, the 4-methylbenzonitrile of Formula XHIa, wherein Rll is CH3 and R9, RIO, R12, R13, XI, X2, and X3 are as previously defined, can be transformed into the corresponding benzyl bromide of Formula XlVa, wherein Rl 1 is CH2Br and R8, R9, RIO, R12, R13, XI, X2, and X3 are as previously disclosed, by reaction with N- bromosuccinimide (NBS) and azobisisobutyronitrile (AIBN) in a non-reactive solvent, such as carbon tetrachloride at 77 °C. The nitrile group (CN) of Formula XlVa can be reduced to the corresponding aldehyde of Formula XVa, wherein Rl 1 is CH2Br and R9, RIO, R12, R13, XI, X2, and X3 are as previously defined via reaction with diisobutylaluminum hydride (DIBAL-H) in an aprotic solvent, such as toluene, at 0 °C, followed by quenching with 1.0 M hydrochloric acid (HC1) 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 Rl l is CH2N(Phthalimide) and R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed, by reaction with potassium phthalimide in a polar aprotic solvent, such as DMF, at 60 °C as in step t of Scheme XIV. In step w of Scheme XIV, the aldehyde of Formula XVIa can be converted to the olefin of Formula Xllb, wherein Rll is
CH2N(Phthalimide) and R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed, by reaction with methyl triphenyl phosphonium bromide in a polar aprotic solvent, such as 1,4-dioxane, in the presence of a base, such as K CO3, at ambient temperature.
Scheme XIV
Figure imgf000027_0002
XHIa XlVa XVa
Figure imgf000027_0003
XVIa XI lb The aldehyde of Formula XVa, wherein Rl l is CH2Br and R9, RIO, R12, R13, XI, X2, and X3 are as previously defined, can be reacted with a nucleophile, such as 2- aminopyridine, in a polar aprotic solvent, such as N,N-dimethylacetamide (DMA), in the presence of a base, such as K2CO3, at ambient temperature to provide the compound of Formula XVII, wherein Rl l is CH2NH(2-pyridine) and R9, RIO, R12, R13, XI, X2, and X3 are as previously disclosed, as in step x of Scheme XV. In step w of Scheme XV, the compound of Formula XVII can be converted to the olefin of Formula XVIII, wherein Rl l is CH2NH(2-pyridine) and R8, R9, RIO, R12, R13, XI, X2, and X3 are as previously disclosed.
Scheme XV
Figure imgf000028_0001
XVa XVII XVIII
In a two-step, one-pot reaction as in steps y and z of Scheme XVI, the compound of Formula XIX can be reacted with the compounds of Formula XX, wherein R10 and Rl l are CI, XI is N, and R9, R13, X2, and X3 are as previously disclosed, in the presence of a base, such as sodium hydride (NaH), and a polar aprotic solvent, such as DMF, at ambient temperature to provide the compounds of Formula XXI, wherein R10 is CI, Rl l is (CH)NH2C02CH2CH3, XI 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 HC1, at reflux temperature, to afford the compounds of Formula XXII, wherein R10 is CI, Rl 1 is CH2NH2 »HC1, XI is N, and R9, R13, X2, and X3 are as previously disclosed, as in step aa in Scheme XVI. The compounds of Formula XXII can be further transformed to the corresponding phthalimide-protected benzyl amines of Formula XXIIIa, wherein R10 is CI, Rl 1 is CH2N(Phthalimide), XI is N, and R9, R13, XI, X2, and X3 are as previously disclosed, by reaction with phthalic anhydride in the presence 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 R10 is CI, Rl 1 is CH2N(Phthalimide), XI 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 CO3, in a non-reactive solvent such as toluene at reflux temperature, as in step ac of Scheme XVI. Scheme XVI
Figure imgf000029_0001
xix xx xxi
Figure imgf000029_0002
XXII XXIIIa XIIc
In step u of Scheme XVII, the 4-methylnaphthonitrile of Formula XHIb, wherein X3 is CR9, RIO and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, Rl l is CH3, and R12, R13, XI and X2 are as previously defined, can be transformed into the corresponding naphthyl bromide of Formula XlVb, wherein X3 is CR9, RIO and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, Rl l is CH2Br, and R12, R13, XI 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 XlVb can be reduced to the corresponding aldehyde of Formula XVb, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring (or if desired a non- aromatic ring), Rl l is CH2Br, and R12, R13, XI and X2 are as previously defined via reaction with diisobutylaluminum hydride (DIBAL-H) in an aprotic solvent, such as toluene, at 0 °C, followed by quenching with 1.0 M HCl as in step v of Scheme XVII. The compound of Formula XVb can be further transformed to the corresponding phthalimide-protected benzyl amine of Formula XVIb, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, Rl l is CH2N(Phthalimide), and R12, R13, XI and X2 are as previously disclosed, by reaction with potassium phthalimide in a polar aprotic solvent, such as DMF, at 60 °C as in step t of Scheme XVII. In step w of Scheme XVII, the aldehyde of Formula XVIb can be converted to the olefin of Formula Xlld, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, Rl l is CH2N(Phthalimide), and R8, R12, R13, XI and X2 are as previously disclosed, by reaction with methyl triphenyl phosphonium bromide in a polar aprotic solvent, such as 1,4-dioxane, in the presence of a base, such as K2CO3, at ambient temperature.
Scheme XVII
Figure imgf000030_0001
Xlllb XlVb XVb
Figure imgf000030_0002
XVIb Xlld
The compound of Formula XXIV, wherein Rll is NHNH2»HC1 and R9, RIO, R12, R13, XI, X2, and X3 are as previously disclosed, can be transformed into the corresponding phthalimide-protected hydrazine of Formula XXV, wherein Rll is NHN(Phthalimide) and R9, RIO, R12, R13, XI, X2, and X3 are as previously disclosed, by reaction with phthalic anhydride in glacial acetic acid at reflux temperature as in step ad of Scheme XVIII. The bromide of Formula XXV can be converted to the olefin of Formula Xlle, wherein Rl 1 is NHN(Phthalimide) and R8, R9, R10, R13, XI, X2 and X3 are as previously disclosed, by reaction with vinyl boronic anhydride pyridine complex in the presence of a palladium catalyst, such as Pd(PPh3)4, and a base, such as K2CO3, in a polar aprotic solvent such as 1,2- dimethoxyethane at 150 °C under microwave conditions, as in step ae of Scheme XVIII.
Scheme XVIII
Figure imgf000030_0003
XXIV XXV Xlle In step af of Scheme ΧΓΧ, the compound of Formula XXVI, wherein Rl 1 is B(OH)2, and R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed, are allowed to react with 2-hydroxyisoindoline-l,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 Xllf , wherein Rl l is ON(Phthalimide) and R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed. Scheme XIX
Figure imgf000031_0001
XXVI Xllf
In step I of Scheme XX, the compound of Formula V, wherein Y, Rl, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula Xlla, wherein Rl 1 is CH2N(Phthalimide) and R8, R9, RIO, R12, R13, 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 180 °C to provide the corresponding compounds of Formula XXVIIa, wherein Rl l is CH2N(Phthalimide) and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIIa is removed as in step ag of Scheme XX by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90 °C to provide the compounds of Formula XXVIIIa, wherein Rl l is CH2NH2 and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed. The compounds of Formula XXVIIIa can be transformed into the compounds of Formula One, wherein Rl l is CH2N(C=0)(R14) and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed, by acylation with an anhydride, such as acetic anhydride, and a base, such as Et3N, in a non-reactive solvent such as CH2C12 at 0 °C as in step ahi of Scheme XX.
Scheme XX
XXVIIa
Figure imgf000031_0002
XXVIIIa Formula One In step I of Scheme XXI, the compound of Formula V, wherein Y, Rl, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula Xllb, wherein Rl l is CH2N(Phthalimide) and R8, R9, RIO, R12, R13, 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 180 °C to provide the corresponding compounds of Formula XXVIIb, wherein Rll is CH2N(Phthalimide) and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIIb is removed as in step ag of Scheme XXI by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90 °C to provide the compounds of Formula XXVIIIb, wherein Rl 1 is CH2NH2 and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed. The compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein Rl l is CH2N(C=0)(R14) and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed, by reaction with an acid in the presence of HOBt»H20, EDOHC1 and a base, such as DIEA, in a polar aprotic solvent, such as DMF, as in step αίΐ2α 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)(R14) and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed, by reaction with a thioacid in the presence of HOBt»H20, EDOHC1 and a base, such as DIEA, in a polar aprotic solvent, such as DMF, as in step a¾2 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=0)N(R14)(R15) and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, XI, 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 reaction with sodium borohydride. The second step (step ahy, 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 CH2C12 at ambient temperature 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=0)N(R14)(R15) and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed, by reaction with an isocyanate (step aii 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 CH2C12 at 0 °C.
In another embodiment, the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein Rl l is CH2N(C=S)N(R14)(R15) and Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO, R12, R13, XI, X2, and X3 are as previously disclosed, by reaction with an isothiocyanate in the presence of a base such as Et3N and in a non-reactive solvent such as CH2C12 at 0 °C, as in steps aj of Scheme XXI.
In another embodiment, the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein Rl l is CH2N(C=0)0(R14) and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed, by reaction with a dicarbonate, such as di-ieri-butyl dicarbonate in the presence of a base such as Et3N and in a non-reactive solvent such as CH2C12 at ambient temperature, as in steps ak of Scheme XXI.
In yet another embodiment, the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein Rl l is CH2N(C=0)(C=0)0(R14) and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed, by reaction with a chlorooxalic acid ester, such as 2-chloro-2-oxoacetate in the presence of a base such as Et3N and in a non-reactive solvent such as CH2C12 at 0 °C, as in steps al of Scheme XXI.
Figure imgf000033_0001
In step I of Scheme XXII, the compound of Formula V, wherein Y, Rl, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIIc, wherein R10 is CI, Rl l is CH2N(Phthalimide), XI is N, and R8, R9, R12, R13, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1 ,2-dichlorobenzene, at a temperature of about 180 °C to provide the corresponding compounds of Formula XXVIIc, wherein R10 is CI, Rl 1 is
CH2N(Phthalimide), XI is N, and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X2, and X3 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIIc is removed as in step ag of Scheme XXII by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90 °C to provide the compounds of Formula XXVIIIc, wherein R10 is CI, Rl l is CH2NH2, XI is N, and Rl , R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X2, and X3 are as previously disclosed. The compounds of Formula XXVIIIc can be transformed into the compounds of Formula One, wherein R10 is CI, Rl 1 is
CH2N(C=0)(R14), XI is N, and Rl , 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»HC1 and a base, such as DIEA, in a polar aprotic solvent, such as CH2C12, as in step a¾2* of Scheme XXII.
Figure imgf000034_0001
XXVIIIc Formula One
In step I of Scheme XXIII, the compound of Formula V, wherein Y, Rl , R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula Xlld, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring (or if desired a non-aromatic ring), Rl l is
CH2N(Phthalimide) and R8, R9, R12, R13, XI and X2 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1 ,2- dichlorobenzene, at a temperature of about 180 °C to provide the corresponding compounds of Formula XXVIId, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, Rl 1 is CH2N(Phthalimide) and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, XI and X2 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIId is removed as in step ag of Scheme XXIII by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90 °C to provide the compounds of Formula XXVIIId, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, Rl l is CH2NH2 and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, XI and X2 are as previously disclosed. The compounds of Formula XXVIIId can be transformed into the compounds of Formula One, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, Rl l is CH2N(C=0)(R14) and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, XI and X2 are as previously disclosed, by reaction with an acid in the presence of HOBt»H20, EDOHC1 and a base, such as DIEA, in a polar aprotic solvent, such as CH2C12, as in step ati2b of Scheme XXIII.
In another embodiment, the compounds of Formula XXVIIId can be transformed into the compounds of Formula One, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, Rl l is CH2N(C=0)N(R14)(R15) and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, XI and X2 are as previously disclosed, by reaction with an isocyanate in the presence of a base such as Et3N and in a non-reactive solvent such as CH2C12 at 0 °C as in step aii of Scheme XXIII.
Figure imgf000035_0001
V xiid XXVIId
Figure imgf000035_0002
XXVIIId Formula One In step I of Scheme XXIV, the compound of Formula V, wherein Y, Rl, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula Xlle, wherein Rl l is NHN(Phthalimide) and R8, R9, R12, R13, 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 180 °C to provide the corresponding compounds of Formula XXVIIe, wherein Rll is NHN(Phthalimide) and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, XI, X2, and X3 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIIe is removed as in step ag of Scheme XXIV by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90 °C to provide the compounds of Formula XXVIIIe, wherein Rl 1 is NHNH2 and Rl , R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, XI, X2, and X3 are as previously disclosed. The compounds of Formula XXVIIIe can be transformed into the compounds of Formula One, wherein Rl 1 is NHN(C=0)(R14) and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, XI, X2, and X3 are as previously disclosed, by reaction with an acid in the presence of HOBt»H20, EDOHC1 and a base, such as DIEA, in a polar aprotic solvent, such as CH2C12, as in step ati2b of Scheme XXIV.
Figure imgf000036_0001
XXVIIIe Formula One
In step I of Scheme XXV, the compound of Formula V, wherein Y, Rl, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula Xllf, wherein Rll is ON(Phthalimide) and R8, R9, R10, R12, R13, 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 180 °C to provide the corresponding compounds of Formula XXVIIf, wherein Rll is ON(Phthalimide) and Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO, R12, R13, XI, X2, and X3 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIIf is removed as in step ag of Scheme XXV by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90 °C to provide the compounds of Formula XXVIIIf, wherein Rl l is ONH2 and Rl , R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed. The compounds of Formula XXVIIIf can be transformed into the compounds of Formula One, wherein Rl 1 is ON(C=0)(R14) and Rl , R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, XI , X2, and X3 are as previously disclosed, by reaction with an acid in the presence of HOBt»H20, EDOHC1 and a base, such as DIEA, in a polar aprotic solvent, such as CH2C12, as in step a¾2* of Scheme XXV.
Figure imgf000037_0001
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 Rl l is CH2NH(2-pyridine) and R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,24?ipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180 °C to provide the corresponding compounds of Formula One, wherein Rl l is CH2NH(2-pyridine), and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, XI, X2, and X3 are as previously disclosed.
The compounds of Formula One can be further elaborated by standard methods. For example, when Rl 1 contains a thioether, the thioether can be oxidized to the sulfone by treatment with oxone in the presence of an acetone:water mixture at ambient temperature. When Rl l 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 CH2CI2.
Figure imgf000038_0001
V XVIII Formula One
In Scheme XXVII, a fluorobenzaldehyde of Formula ΧΧΓΧ, wherein RIO, XI, X2, and X3 are as previously disclosed can be converted to a (l,2,4-triazol-l-yl)benzaldehyde of Formula XXX, wherein Rll is a substituted or unsubstituted 1,2,4-triazol-l-yl 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 potassium carbonate, in a solvent such as DMF as in step aj. In step ak, the (l,2,4-triazol-l-yl)benzaldehyde of Formula XXX is converted to a (l,2,4-triazol-l-yl)vinyl benzene of Formula XXXIa wherein Rl 1 is a substituted or unsubstituted 1,2,4-triazol-l-yl group, and R8, R10, XI, X2, and X3 are as previously disclosed by reaction with triphenyl phosphonium bromide in the presence of a base, such as potassium carbonate, in an aprotic solvent, such as 1,4-dioxane.
Scheme XXVII
Figure imgf000038_0002
XXIX XXX XXXIa
In Scheme XXVIII, a bromofluorobenzene of Formula XXXII, wherein R10, XI, X2, and X3 are as previously disclosed can be converted to a (l,2,4-triazol-l-yl)vinylbenzene of Formula XXXIb, wherein Rll is a substituted or unsubstituted 1,2,4-triazol-l-yl group, and R8, R10, XI, X2, and X3 are as previously disclosed in two steps. In step al, the
bromofluorobenzene is reacted with a substituted or unsubstituted 1,2,4-triazole in the presence of a base, such as potassium carbonate, in a solvent such as DMF to generate the (l,2,4-triazol-l-yl)bromobenzene. In step cl, the (l,2,4-triazol-l-yl)bromobenzene is reacted with vinyl boronic anhydride pyridine complex in the presence of a catalyst, such
(ΡΡ1¾)4, and a base, such as potassium carbonate in a solvent such as toluene.
Scheme XXVIII
Figure imgf000039_0001
XXXIb
Coupling of the compounds of Formula V with compounds of Formula XXXIa and XXXIb can be accomplished as in Schemes ΧΧΓΧ. In step Z, a compound of Formula V, wherein Y is Br, Rl, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and a vinylbenzene of Formula XXXIa or XXXIb, wherein Rl 1 is a substituted or unsubstituted 1,2,4-triazol-l-yl group, and R8, R9, RIO, 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 180 °C to provide the molecules of Formula One, wherein Rl l is a substituted or unsubstituted 1,2,4-triazol-l-yl group, and Rl, R2, R3, R4, R5, R6, R7, R8, R10, XI, X2, and X3 are as previously disclosed.
Scheme XXIX
Figure imgf000039_0002
V XXXIa or XXXIb Formula One
In Scheme XXX, compounds of Formula XXXIII wherein Rl 1 is a 3-nitro- 1,2,4- triazol-l-yl group, and Rl, R2, R3, R4, R5, R6, R7, R8, R10, XI, X2, and X3 are as previously disclosed can be converted to compounds of Formula One, wherein Rl 1 is a 3- amido- 1,2,4-triazol-l-yl group, and Rl, R2, R3, R4, R5, R6, R7, R8, R10, XI, X2, and X3 are as previously disclosed by a two-step process. In step am, the 3-nitro-l,2,4-triazol-l-yl group is reduced to a 3-amino-l,2,4-triazol-l-yl group in the presence of zinc dust and ammonium chloride in a protic solvent, such as methanol. In step an, the 3-amino- 1,2,4- triazol-l-yl group is acylated with an acid chloride, such as cyclopropylcarbonyl chloride or acetyl chloride, in the presence of a base, such as triethylamine, in a solvent such as dichloromethane .
Scheme XXX
Figure imgf000040_0001
XXXIII Formula One
In step ao of Scheme XXXI, a bromophenyl methyl ketone of Formula XXXIV wherein RIO, XI, X2, and X3 are as previously disclosed is converted to an phenyl methyl ketone of the Formula XXXV wherein Rl l is a 1,2,4-triazol-l-yl 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 1,2,4-triazolylacetophenone of Formula XXXV is converted to the trimethylsilyl enol ether of Formula XXXVI by treatment with trimethylsilyl triflluoromethanesulfonate in the presence of a base, such as triethylamine, in an aprotic solvent, such as dichloromethane. In step aq, the silyl enol ether is reacted with a compound of Formula V, wherein Y is Br, Rl, R2, R3, R4, R5, R6, and R7 are as previously disclosed in the presence of CuCl and 2,2- bipyridyl in a solvent, such as 1,2-dichlorobenzene at a temperature of about 180 °C to generate a ketone of the Formula XXXVII, wherein Rl 1 is a 1,2,4-triazol-l-yl group, and Rl, R2, R3, R4, R5, R6, R7, R10, XI, X2, and X3 are as previously disclosed. In step ar, the ketone of the Formula XXXVII is treated with methylmagnesium bromide in an aprotic solvent, such as THF to generate the tertiary alcohol. The tertiary alcohol then undergoes an elimination reaction when treated with a catalytic amount of p-toluenesulfonic acid in a solvent, such as toluene, when heated to a temperature to allow azeotropic removal of water to produce compounds of Formula One wherein Rll is a 1,2,4-triazol-l-yl group, R8 is methyl, and Rl, R2, R3, R4, R5, R6, R7, R10, XI, X2, and X3 are as previously disclosed, as in step as. Scheme XXXI
Figure imgf000041_0001
XXXIV XXXV XXXVI
Figure imgf000041_0002
Formula One
In Scheme XXXII, a compound of Formula XXXVIII, wherein 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 Rl, R2, R3, R4, R5, R6, R7, R8, XI, X2, and X3 are as previously disclosed is converted to a molecule of Formula One, wherein RIO and Rl 1 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. Scheme XXXII
Figure imgf000042_0001
XXXVIII Formula One
In Scheme XXXIII, a compound of Formula ΧΧΧΓΧ, wherein XI, X2, and X3 are as previously disclosed is converted to a molecule of Formula XL, wherein XI, X2, and X3 are as previously disclosed, by treatment with a reducing agent, such as sodium
cyanoborohydride, in a solvent, such as acetic acid, as in step au. In step av, the nitrogen atom is protected with a ieri-butyloxycarbonyl (BOC) group by reaction with di-ieri-butyl dicarbonate in the presence of a catalyst, such as DMAP, in a solvent, such as acetonitrile. The bromide of Formula XL can be converted to the olefin of Formula XLI, wherein R8, XI, X2 and X3 are as previously disclosed, by reaction with potassium vinyl trifluoroborate in the presence of a palladium catalyst, such as PdCl2(dppf), and a base, such as K2CO3, in a polar aprotic solvent such as DMSO at 100 °C, as in step aw.
Scheme XXXIII
Figure imgf000042_0002
In Scheme XXXIV, a compound of Formula XXXIX, wherein XI, X2, and X3 are as previously disclosed is converted to a molecule of Formula XLII, wherein XI, X2, and X3 are as previously disclosed in two steps. In step ax, the olefin is formed by treatment of the bromide with potassium vinyl trifluoroborate in the presence of a palladium catalyst, such as PdCl2, and a ligand, such as triphenylphosphine, and a base, such as CS2CO3, in a solvent mixture such as THF/H20. In step ay, the nitrogen atom is protected with a tert- butyloxycarbonyl (BOC) group by reaction with di-ieri-butyl dicarbonate in the presence of a catalyst, such as DMAP, in a solvent, such as acetonitrile. Scheme XXXIV
Figure imgf000043_0001
XXXIX XLI I
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 compounds 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 °C to 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
Figure imgf000043_0002
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, wherein 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 HC1, at a temperature around 5 °C, to form the nitrosoindole. In step bb, the nitrosoindole is reacted with ammonium chloride in the presence of zinc powder in a protic solvent, such as methanol. In step be, compounds of the Formula XLV are transformed into compounds of the Formula XL VI, wherein X4 is N(R14)(C(=0)R14) and Rl, R2, R3, R4,
R5, R6, R7, R8, XI, X2, and X3 are as previously disclosed, by treatment with and acid, such as 3,3,3-trifluoropropanoic acid, PyBOP, and a base, such as DIEA, in a polar aprotic solvent, such as dichloromethane.
Scheme XXXVI
Figure imgf000044_0001
XLIIIa XLIV
Figure imgf000044_0002
In Scheme XXXVII, a compound of Formula XLIIIb, wherein Rl, R2, R3, R4, R5, R6, R7, R8, XI, X2, and X3 are as previously disclosed is converted to an indole of Formula XLVII, wherein 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 bd. Compounds of the Formula XLVII can be transformed into compounds of the Formula XLVIII wherein Rl, R2, R3, R4, R5, R6, R7, R8, XI, X2, and X3 are as previously disclosed, by reaction with 4-nitrophenyl-2-((ieri-butoxycarbonyl)amino)acetate in the presence of potassium fluoride and a crown ether, such as 18-crown-6-ether, in a solvent, such as acetonitrile, as in step be. Compounds of the Formula XLVIII can be transformed into compounds of the Formula XLIX, wherein Rl, R2, R3, R4, R5, R6, R7, R8, XI, X2, and X3 are as previously disclosed in two steps. In step bf, the Boc group is removed by treatment with trifluoroacetic acid, in a solvent such as 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. Scheme XXXVII
Figure imgf000045_0001
In Scheme XXXVIII, a compound of Formula L, wherein XI, X2, and X3 are as previously disclosed is converted to a compound of the Formula LI, wherein XI, 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 XI, X2, and X3 are as previously disclosed, by reaction with hydrazine, in a solvent such as water, at a temperature around 95 °C, as in step bi. In step bj, the olefin of the Formula LIII wherein XI, X2, and X3 are as previously disclosed is formed by treatment of the bromide with potassium vinyl
trifluoroborate in the presence of a palladium catalyst, such as PdCl2(dppf), and a base, such as K2CO3, in a solvent mixture such as DMSO. Compounds of the Formula LIV, wherein XI, X2, and X3 are as previously disclosed, can be formed from compounds of the Formula LIII by reaction with ethyl bromoacetate, in the presence of a base, such as CS2CO3, in a solvent, such as DMF.
Scheme XXXVIII
Figure imgf000046_0001
In step I of Scheme XXXIX, the compound of Formula V, wherein Y, Rl, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compound of Formula LIV, 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 180 °C to provide the corresponding compound of Formula LV, wherein Rl, R2, R3, R4, R5, R6, R7, R8, XI, X2, and X3 are as previously disclosed. The compound of Formula LV can be further transformed into a compound of the Formula LVI, wherein Rl, R2, R3, R4, R5, R6, R7, R8, XI, X2, and X3 are as previously disclosed, in two steps. In step bl, the ester is hydrolyzed to the acid in the presence of HC1 and acetic acid, at a temperature of about 100 °C. In step bm, the acid is treated with an amine, such as 2,2,2-trifluoroethylamine, PyBOP, and a base, such as DIEA, in a polar aprotic solvent, such as dichloromethane.
Scheme XXXIX
Figure imgf000047_0001
LV
Figure imgf000047_0002
LVI
In step bn of Scheme XL, carboxylic acids of the Formula LVII, wherein Rl 1 is C(=0)OH and R8, RIO, XI, X2, and X3 are as previously disclosed and compounds of the Formula V, wherein Y is Br and Rl, R2, R3, R4, R5, R6, and R7 are as previously disclosed are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as N-methyl pyrrolidine, at a temperature of about 150 °C to afford compounds of Formula LVIII, wherein Rl l is (C=0)OH and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, XI, X2, and X3 are as previously disclosed. Compounds of the Formula LVIII can be further transformed to the corresponding benzamides of Formula LIX, wherein Rl l is (C=0)N(R14)(R15), and Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, XI, 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. Scheme XL
Figure imgf000048_0001
LIX
EXAMPLES
The examples are for illustration purposes and are not to be construed as limiting the invention disclosed in this document to only the embodiments disclosed in these examples.
Starting materials, reagents, and solvents that were obtained from commercial sources were used without further purification. Anhydrous solvents were purchased as Sure/Seal™ from Aldrich and were used as received. Melting points were obtained on a Thomas Hoover Unimelt capillary melting point apparatus or an OptiMelt Automated Melting Point System from Stanford Research Systems and are uncorrected. Molecules are given their known names, named according to naming programs within ISIS Draw, ChemDraw, or ACD Name Pro. If such programs are unable to name a molecule, the molecule is named using conventional naming rules. ]H NMR spectral data are in ppm (δ) and were recorded at 300, 400, or 600 MHz, and 13C NMR spectral data are in ppm (δ) and were recorded at 75, 100, or 150 MHz, unless otherwise stated.
Example 1: Preparation of l-(l-bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (All)
Figure imgf000048_0002
Step 1 Method A. l-(3,5-Dichlorophenyl)-2,2,2-trifluoroethanol (AI2). To a stirred solution of l-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone (procured from Rieke Metals, UK; 5.0 grams (g), 20.5 millimoles (mmol)) in methyl alcohol (CH3OH; 100 milliliters (mL)) at 0 °C were added sodium borohydride (NaBH4; 3.33 g, 92.5 mL) and 1 Normal (N) aqueous sodium hydroxide solution (NaOH; 10 mL). The reaction mixture was warmed to 25 °C and stirred for 2 hours (h). After the reaction was deemed complete by thin layer chromatography (TLC), saturated (satd) aqueous (aq) ammonium chloride (NH4C1) solution was added to the reaction mixture, and the mixture was concentrated 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%): ]H NMR (400 MHz, CDC13) δ 7.41 (m, 3H), 5.00 (m, 2H), 2.74 (s, 1H); ESIMS m/z 242.97 ([M-H]").
Step 1 Method B. l-(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 tetrabutylammonium fluoride (TBAF). The reaction mixture was stirred at 25 °C for 8 h. After the reaction was deemed complete by TLC, the reaction mixture was diluted with 3 N hydrochloric acid (HCl) and then was stirred for 16 h. The reaction mixture was diluted with H20 and was extracted with ethyl acetate (EtOAc; 3 x). The combined organic extracts 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-l-(3,4,5-trichlorophenyl)ethanol (AI3)
Figure imgf000049_0001
The product was isolated as a pale yellow liquid (500 mg, 65%): ]H NMR (400 MHz, CDCI3) δ 7.45 (s, 2H), 5.00 (m, 1H), 2.80 (s, 1H); ESIMS m/z 278 ([M+H]+); IR (thin film) 3420, 1133, 718 cm"1.
l-(3,5-Dichloro-4-fluorophenyl)-2,2,2-trifluoroethanol (AI4)
Figure imgf000050_0001
The product was isolated as a pale yellow liquid (500 mg, 65%): ]H NMR (400 MHz, CDC13) δ 7.41 (s, 2H), 5.00 (m, IH), 2.80 (s, IH); ESIMS m/z 262 ([M+H]+); IR (thin film) 3420, 1133, 718 cm"1.
l-(3,4-Dichlorophenyl)-2,2,2-trifluoroethanol (AI5)
Figure imgf000050_0002
The product was isolated as a pale yellow liquid (500 mg, 65%): ]H NMR (400 MHz, CDCI3) δ 7.60 (s, IH), 7.51 (m, IH), 7.35 (m, IH), 5.01 (m, IH), 2.60 (s, IH); EIMS m/z 244 «M]+).
Step 2. l-(l-Bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (All). To a stirred solution of l-(3,5-dichlorophenyl)-2,2,2-trifluoroethanol (4.0 g, 16.3 mmol) in
dichloromethane (CH2CI2; 50 mL), were added N-bromosuccinimide (NBS; 2.9 g, 16.3 mmol) and triphenyl phosphite (5.06 g, 16.3 mmol), and the resultant reaction mixture was heated at reflux for 18 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to 25 °C and was concentrated under reduced pressure. Purification by flash column chromatography (Si02, 100-200 mesh; eluting with 100% pentane) afforded the title compound as a liquid (2.0 g, 40%): ]H NMR (400 MHz, CDC13) δ 7.41 (s, 3H), 5.00 (m, IH); EIMS m/z 306 ([M]+). The following compounds were made in accordance with the procedures disclosed in
Step 2 of Example 1.
5-(l-Bromo-2,2,2-trifluoroethyl)-l,2,3-trichlorobenzene (AI6)
Figure imgf000050_0003
The product was isolated as a colorless oil (300 mg, 60%): ]H NMR (400 MHz, CDCI3) δ 7.59 (s, 2H), 5.00 (m, IH); EIMS m/z 340.00 ([M]+).
5-(l-Bromo-2,2,2-trifluoroethyl)-l,3-dichloro-2-fluorobenzene (AI7)
Figure imgf000051_0001
The product was isolated as a colorless oil (320 mg, 60%)
CDC13) δ 7.45 (s, 2H), 5.00 (m, 2H); EIMS m/z 324.00 ([M]+).
4-(l-Bromo-2,2,2-trifluoroethyl)-l,2-dichlorobenzene (AI8)
Figure imgf000051_0002
The product was isolated as a colorless oil (300 mg, 60%): ]H NMR (400 MHz, CDCI3) δ 7.63 (s, 1H), 7.51 (m, 1H), 7.35 (m, 1H), 5.01 (m, 1H); EIMS m/z 306.00 ([M]+). Example 2: Preparation of jV-meth -4-vinylbenzamide (AI9)
Figure imgf000051_0003
Step 1. 4-Vinylbenzoyl chloride (AI10). To a stirred solution of 4-vinylbenzoic acid (1 g, 6.75 mmol) in CH2C12 (20 mL) at 0 °C 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 °C for 6 h. After the reaction was deemed complete by TLC, the reaction mixture was concentrated under reduced pressure to give the crude acid chloride.
Step 2. N-Methyl-4-vinylbenzamide (AI9). To 1 M N-methylamine in THF (13.5 mL, 13.5 mmol) at 0 °C were added triethylamine (Et3N; 1.34 mL, 10.12 mmol) and the acid chloride from Step 1 above in THF (10 mL), and the reaction mixture was stirred at 25 °C for 3 h. After the reaction was deemed complete by TLC, the reaction mixture was quenched with water and then was extracted with EtOAc (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%): ]H NMR (400 MHz, CDC13) δ 7.76 (d, J = 8.0 Hz, 2H), 7.45 ( d, / = 8.0 Hz, 2H), 6.79 (m, 1H), 6.20 (br s, 1H), 5.82 (d, J = 17.6 Hz, 1H), 5.39 (d, / = 10.8 Hz, 1H); ESIMS m/z 161.95 ([M+H]+).
The following compounds were made in accordance with the procedures disclosed in accordance with Example 2.
jV,jV-Dimethyl-4-vinylbenzamide (AI11)
Figure imgf000052_0001
The product was isolated as an off-white solid (650 mg, 60%): ]H NMR (400 MHz, CDC13) δ 7.42 (m, 4H), 6.71 (m, 1H), 5.80 (d, / = 17.6 Hz, 1H), 5.31 (d, / = 10.8 Hz, 1H), 3.05 (s, 3H), 3.00 (s, 3H); ESIMS m/z 176.01 ([M+H]+).
V-(2,2,3-Trifluoromethyl)-4-vin
Figure imgf000052_0002
The product was isolated as an off-white solid (900 mg, 60%): ]H NMR (400 MHz, CDCI3) δ 7.76 (d, J = 8.0 Hz, 2H), 7.45 ( d, / = 8.0 Hz, 2H), 6.79 (m, 1H), 6.20 (br s, 1H), 5.82 (d, J = 17.6 Hz, 1H), 5.39 (d, J = 10.8 Hz, 1H), 4.19 (m, 2H); ESIMS m/z 230.06 «M+H]+).
M orpholino(4- vinylphenyl)metha
Figure imgf000052_0003
The product was isolated as a white solid (850 mg, 60%): ESIMS m/z 218.12 «M+H]+).
Example 3: Preparation of ethyl 2-methyl-4-vinylbenzoate (AI14)
Figure imgf000052_0004
Step 1. 4-Formyl-2-methylbenzoic acid (AI15). To a stirred solution of 4-bromo-2- methylbenzoic acid (10 g, 46.4 mmol) in dry THF (360 mL) at -78 °C was added n- butyllithium (n-BuLi, 1.6 M solution in hexane; 58.17 mL, 93.0 mmol) and DMF (8 mL). The reaction mixture was stirred at -78 °C for 1 h then was warmed to 25 °C and stirred for 1 h. The reaction mixture was quenched with 1 N HCl solution and extracted with EtOAc. The combined EtOAc extracts were washed with brine and dried over Na2SC>4 and concentrated under reduced pressure. The residue was washed with n-hexane to afford the title compound as a solid (3.0 g, 40%): mp 196-198 °C; ]H NMR (400 MHz, DMSO-d6) δ 13.32 (br s, 1H), 10.05 (s, 1H), 7.98 (m, 1H), 7.84 (m, 2H), 2.61 (s, 3H); ESIMS m/z 163.00 ([M-H]").
Step 2. Ethyl 4-formyl-2-methylbenzoate (AI16). To a stirred solution of 4-formyl- 2-methylbenzoic acid (3 g, 18.2 mmol) in ethyl alcohol (EtOH; 30 mL) was added sulfuric acid (H2SO4, x M; 2 mL), and the reaction mixture was heated at 80 °C for 18 h. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was diluted with EtOAc and washed with H20. The combined 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%): ]H NMR (400 MHz, CDC13) δ 10.05 (s, 1H), 8.04 (m, 1H), 7.75 (m, 2H), 4.43 (m, 2H), 2.65 (s, 3H), 1.42 (m, 3H).
Step 3. ethyl 2-methyl-4-vinylbenzoate (AI14). To a stirred solution of ethyl 4- formyl-2-methylbenzoate (2.8 g, 4 mmol) in 1,4-dioxane (20 mL) were added potassium carbonate (K2C03; 3.01 g, 21.87 mmol) and methyltriphenyl phosphonium bromide (7.8 g, 21.87 mmol) at 25 °C. Then the reaction mixture was heated at 100 °C for 18 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to 25 °C and filtered, and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash chromatography (Si02, 100-200 mesh; eluting with 25-30% EtOAc in n- Hexane) to afford the title compound as a solid (2.0 g, 72%): ]H NMR (400 MHz, CDC13) δ 7.86 (m, 1H), 7.27 (m, 2H), 6.68 (dd, J =17.6, 10.8 Hz , 1H), 5.84 (d, J = 17.6 Hz, 1H), 5.39 (d, / = 10.8 Hz, 1H), 4.39 (m, 2H), 2.60 (s, 3H), 1.40 (m, 3H); ESIMS m/z 191.10 ([M-H]"); IR (thin film) 2980, 1716, 1257 cm"1.
Example 4: Preparation of tert- n X 2-chloro-4-vinylbenzoate (AI17)
Figure imgf000053_0001
Step 1. fert-Butyl 4-bromo-2-chlorobenzoate (AI18). To a stirred solution of 4- bromo-2-chlorobenzoic acid (5 g, 21.37 mmol) in THF (30 mL) was added di-ieri-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 °C for 18 h. The reaction mixture was diluted with EtOAc and washed with H20. The combined 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 in n-hexane) to afford the title compound as a liquid (3.2 g, 51%): ]H NMR (400 MHz, CDCI3) δ 7.62 (m, 2H), 7.44 (d, / = 8.4 Hz, 1H), 1.59 (s, 9H); ESIMS m/z 290.10 ([M+H]+); IR(thin film) 1728 cm"1.
The following compounds were made in accordance with the procedures disclosed in
Step 1 of Example 4. fert-Butyl 2-bromo-4-iodobenzoate (AI19)
Figure imgf000054_0001
The product was isolated as a colorless oil (1.2 g, 50%): ]H NMR (400 MHz, CDC13) δ 8.01 (s, 1H), 7.68 (d, / = 8.4 Hz, 1H), 7.41 (d, / = 8.0 Hz, 1H), 1.59 (s, 9H); ESIMS m/z 382.10 ([M+H]+); IR(thin film) 1727 cm"1.
fert-Butyl 4-bromo-2-(trifluoromethyl)benzoate(AI20)
Figure imgf000054_0002
The product was isolated as a colorless oil (1 g, 52%): ]H NMR (400 MHz, CDC13) δ 7.85 (s, 1H), 7.73 (d, / = 8.4 Hz, 1H), 7.62 (d, / = 8.4 Hz, 1H), 1.57 (s, 9H); ESIMS m/z 324.10 ([M+H]+); IR (thin film) 1725 cm"1.
Step 2. fert-butyl 2-chloro-4-vinylbenzoate (AI17). To a stirred solution of tert- butyl 4-bromo-2-chlorobenzoate (1.6 g, 5.50 mmol) in toluene (20 mL) was added tetrakis(triphenylphospine)palladium(0) (Pd(PPh3)4; (0.31 mg, 0.27 mmol), K2C03 (2.27 g, 16.5 mmol) and vinylboronic anhydride pyridine complex (2.0 g, 8.3 mmol) and the reaction mixture was heated to reflux for 16 h. The reaction mixture was filtered, and the filtrate was washed with 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 in n-hexane) afforded the title compound as a liquid (0.6 g, 46%): ]H NMR (400 MHz, CDCI3) δ 7.72 (d, 7 = 8.1 Hz, 1H), 7.44 (m, 1H), 7.31 ( d, / = 8.0 Hz, 1H), 6.69 (dd, J =17.6, 10.8 Hz , 1H) , 5.85 (d, J = 17.6 Hz, 1H), 5.40 (d, J = 10.8 Hz, 1H), 1.60 (s, 9H); ESIMS m/z 238.95 ([M+H]+); IR (thin film) 2931, 1725, 1134 cm"1.
The following compounds were made in accordance with the procedures disclosed in Step 2 of Example 4.
tert-Butyl 2-bromo-4-vinylbenzoat
Figure imgf000054_0003
The product was isolated as a colorless oil (lg, 52%): ]H NMR (400 MHz, CDC13) δ 7.68 (m, 2H), 7.36 ( d, / = 8.0 Hz, 1H), 6.68 (dd, J =17.6, 10.8 Hz , 1H), 5.84 (d, J = 17.6 Hz, 1H), 5.39 (d, / = 10.8 Hz, 1H), 1.60 (s, 9H); ESIMS m/z 282.10 ([M+H]+); IR (thin film) 2978, 1724, 1130 cm"1.
tert-Butyl 2-(trifluoromethyl)-4-vin lbenzoate (AI22)
Figure imgf000055_0001
The product was isolated as a colorless oil (1.2 g, 50%): ]H NMR (400 MHz, CDC13) δ 7.71 (d, J = 6.4 Hz, 2H), 7.59 (d, J = 7.6 Hz, 1H), 6.77 (dd, J = 17.6, 10.8 Hz , 1H), 5.89 (d, / = 17.6 Hz, 1H), 5.44 (d, / = 10.8 Hz, 1H), 1.58 (s, 9H); ESIMS m/z 272.20 ([M+H]+); IR (thin film) 2982, 1727, 1159 cm"1.
Example 5: Preparation of fert-bu l 2-cyano-4-vinylbenzoate (AI23)
Figure imgf000055_0002
To a stirred solution of ieri-butyl 2-bromo-4-vinylbenzoate (0.5 g, 1.77 mmol) in DMF (20 mL) was added copper(I) cyanide (CuCN; 0.23 g, 2.65 mmol), and the reaction mixture was heated at 140 °C for 3 h. The reaction mixture was cooled to 25 °C, diluted with 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 chromatography (Si02, 100-200 mesh; eluting with 15% EtOAc in n-hexane) to afford the title compound as a white solid (0.3 g, 72%): mp 51-53 °C; ]H NMR (400 MHz, CDC13) δ 8.03 (s, 1H), 7.77 (s, 1H), 7.64 (d, / = 8.4 Hz, 1H), 6.75 (dd, / = 17.6, 10.8 Hz , 1H), 5.93 (d, / = 17.6 Hz, 1H), 5.51 (d, / = 10.8 Hz, 1H), 1.65 (s, 9H); ESIMS m/z 229.84 ([M+H]+); IR (thin film) 2370, 1709, 1142 cm"1.
Example 6: Preparation of ethyl 2- romo-4-iodobenzoate (AI46)
Figure imgf000055_0003
To a stirred solution of 4-iodo-2-bromobenzoic acid (5 g, 15.29 mmol) in ethyl alcohol (EtOH; 100 mL) was added sulfuric acid (H2S04; 5 mL), and the reaction mixture was heated at 80 °C for 18 h. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was diluted with EtOAc (2x100 mL) and washed with H20 (100 mL). The combined EtOAc extracts were washed with brine, dried over Na2S04 and concentrated under reduced pressure to afford the compound as a pale yellow solid (5 g, 92%): ]H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J = 1.2 Hz, 1H), 7.71 (d, 7 = 7.6 Hz, 1H), 7.51 (d, 7 = 8.4 Hz, 1H), 4.41 (q, 7 = 7.2 Hz, 2H), 1.41 (t, 7 = 7.2 Hz, 3H).
The following compounds were made in accordance with the procedures disclosed in Example 6.
Ethyl 4-bromo-2-chlorobenzoate (AI47)
Figure imgf000056_0001
The title compound was isolated as an off-white solid (2.0 g, 80 %): ]H NMR (400 MHz, DMSO-d6) δ 8.25 (d, 7 = 1.2 Hz, 1H), 7.79 (d, 7 = 7.6 Hz, 1H), 7.65 (d, 7 = 8.4 Hz, 1H), 4.65 (q, 7 = 7.2 Hz, 2H), 1.56 (t, 7 = 7.2 Hz, 3H).
Ethyl 4-bromo-2-methylbenzoate (AI48)
Figure imgf000056_0002
The title compound was isolated as a pale yellow liquid (3.0 g, 83%): ]H NMR (400 MHz, CDC13) δ 7.79 (d, 7 = 8.4 Hz, 1H), 7.41 (s, 1H), 7.39 (d, 7 = 8.4 Hz, 1H), 4.42 (q, 7 = 7.2 Hz, 2H), 2.60 (s, 3H), 1.40 (t, 7 = 7.2 Hz, 3H)ESIMS m/z 229.11 ([M+H]+); IR (thin film) 1725 cm"1.
Ethyl 4-bromo-2-fluorolbenzoate (AI49)
Figure imgf000056_0003
The title compound was isolated as a colorless liquid (9.0 g, 79%): ]H NMR (400 MHz, DMSO-d6) δ 7.84 (t, 7 = 8.4 Hz, 1H), 7.76 (d, 7 = 2.0 Hz, 1H), 7.58 (d, 7 = 1.6 Hz, 1H), 4.34 (q, 7 = 7.2 Hz, 2H), 1.32 (t, 7 = 7.2 Hz, 3H); ESIMS m/z 246.99 ([M+H]+), IR (thin film) 1734 cm"1.
Example 7: Preparation of ethyl 4 ate (AI50)
Figure imgf000056_0004
To a stirred solution of 4-bromo-2-fluorobenzoic acid (2.0 g, 9.17 mmol) in THF (16 mL), was added 1.0 M ethyl magnesium bromide in THF (32 mL, 32.0 mmol) dropwise at 0°C and the resultant reaction mixture was stirred at RT for 18h. The reaction mixture was quenched with 2 N HC1 and extracted with ethyl acetate. The combined ethyl acetate layer was dried over anhydrous Na2S04 and concentrated under reduced pressure to afford crude 4- bromo-2-ethylbenzoic acid as a colorless liquid that was used in the next step without purification (0.4 g): ]H NMR (400 MHz, CDC13) δ 7.64 (d, J = 8.4 Hz, 1H), 7.47 (m, 1H), 7.43 (m, 1H), 2.95 (q, J = 4.0 Hz, 2H), 1.32 (t, J = 4.0 Hz, 3H); ESIMS m/z 228.97 ([M+H]+).
The title compound was synthesized from 4-bromo-2-ethylbenzoic acid in accordance to the procedure in Example 6, isolated as a colorless liquid (0.15 g, 68%): ]H NMR (400
MHz, DMSO-d6)5 7.90 (d, J = 8.4 Hz, 1H), 7.47 (m, 2H), 4.40 (q, J = 7.2 Hz, 2H), 3.06 (q, J = 7.6 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H), 1.26 (t, J = 7.6 Hz, 3H); ESIMS m/z 226.96 ([M-H]"); IR (thin film) 3443, 1686, 568 cm"1.
Example 8: Preparation of ethyl 2-bromo-4-vinylbenzoate (AI51)
Figure imgf000057_0001
To a stirred solution of ethyl 2-bromo-4-iodobenzoate (5 g, 14.3 mmol) in THF/water (100 mL, 9: 1) was added potassium vinyltrifluoroborate (1.89 g, 14.3 mmol), CS2CO3 (18.27 g, 56.07 mmol) and triphenylphosphine (0.22 g, 0.85 mmol) and the reaction mixture was degassed with argon for 20 min, then charged with PdCl2 (0.05 g,0.28 mmol). The reaction mixture was heated to reflux for 16 h. The reaction mixture was cooled to RT and filtered through a celite bed and washed with ethyl acetate. The filtrate was again extracted with ethyl acetate and the combined organic layers washed with water and brine, dried over 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 acetate/ petroleum ether) to afford the title compound as a light brown gummy material (2 g, 56%): 'H NMR (400 MHZ, CDCI3) δ 7.78 (d, 7 = 8.4 Hz, 1H), 7.71 (d, / = 1.2 Hz, 1H), 7.51 (d, / = 8.4 Hz, 1H), 6.69 (dd, J = 17.6, 10.8 Hz, 1H), 5.86 (d, / = 17.6 Hz, 1H), 5.42 (d, / = 11.2 Hz, 1H), 4.42 (q, / = 7.2Hz, 2H), 1.43 (t, / = 3.6 Hz, 3H); ESIMS m/z 255.18 ([M+H]+); IR (thin film) 1729 cm"1.
The following compounds were made in accordance with the procedures disclosed in
Example 8. Ethyl 2-methyl-4-vinylbenzoate (
Figure imgf000058_0001
The title compound was isolated as a colorless liquid (0.8 g, 80 %): ]H NMR (400 MHz, CDC13) δ 7.89 (d, / = 8.4 Hz, 1H), 7.27 (m, 2H), 6.79 (dd, / = 17.6, 10.8 Hz, 1H), 5.86 (d, / = 17.6 Hz, 1H), 5.42 (d, / = 11.2 Hz, 1H), 4.42 (q, / = 7.2 Hz, 2H), 2.60 (s, 3H), 1.43 (t, J = 1.2 Hz, 3H); ESIMS m/z 191.10 ([M+H]+); IR (thin film) 1717, 1257 cm"1.
Ethyl 2-fluoro-4-vinylbenzoate (A
Figure imgf000058_0002
The title compound was isolated as a pale yellow liquid (2.0 g, 50 %): H NMR (400
MHz, DMSO-d6) δ 7.87 (t, / = 8.0 Hz, 1H), 7.51(d, / = 16.0 Hz, 1H), 7.48 (d, / = 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, / = 7.2 Hz, 2H), 1.35 (t, / = 7.2 Hz, 3H); ESIMS m/z 195.19 ([M+H]+); IR (thin film) 1728 cm"1.
Example 9: Preparation of ethyl 2-chloro-4-vinylbenzoate (AI54)
Figure imgf000058_0003
To a stirred solution of ethyl 2-chloro-4-bromobenzoate (2 g, 7.63 mmol) in dimethylsulfoxide (20 mL) was added potassium vinyltrifluoroborate (3.06 g, 22.9 mmol) and potassium carbonate (3.16 g, 22.9 mmol). The reaction mixture was degassed with argon for 30 min. Bistriphenylphosphine(diphenylphosphinoferrocene)palladium dichloride (0.27 g, 0.38 mmol) was added and the reaction mixture was heated to 80 °C for 1 h. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (2 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%): ]H NMR (400 MHz, CDC13) δ 7.81 (d, J = 8.4 Hz, 1H), 7.46 (s, 1H), 7.33 (d, 7 = 8.4 Hz, 1H), 6.70 (dd, / = 17.6, 11.2 Hz, 1H), 5.87 (d, / = 17.6 Hz, 1H), 5.42 (d, / = 10.8 Hz, 1H), 4.41 (q, / = 7.2 Hz,2H), 1.43 (t, 7 = 7.2 Hz, 3H); ESIMS m/z 211.22 ([M+H]+); IR (thin film) 1729, 886 cm"1.
The following compounds were made in accordance with the procedures disclosed in Example 9. Ethyl 2-ethyl-4-vinylbenzoate (AI
Figure imgf000059_0001
The title compound was isolated as a color less liquid (1.0 g, 66 %): ]H NMR (300 MHz, CDC13) δ 7.85 (m, 1H), 7.29 (m, 2H), 6.76 (d, / = 10.8 Hz, 1H), 5.86 (d, / = 17.6 Hz, 1H), 5.36 (d, 7 = 10.5 Hz, 1H), 4.41 (q, / = 7.2 Hz, 2H), 3.10 (q, / = 7.2 Hz, 2H), 1.40 (t, / = 7.2 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H); ESIMS m/z 205.26 ([M+H]+); IR (thin film) 1720, 1607, 1263 cm"1 .
Methyl 2-methoxy-4-vinylbenzoate
Figure imgf000059_0002
The title compound was isolated as a pale yellow liquid (1.2 g, 75 %): ]H NMR (400
MHz, CDCI3) δ 7.79 (d, / = 8.0 Hz, 1H), 7.04 (d, / = 1.2 Hz, 1H), 6.97 (s, 1H), 6.74 (dd, / = 11.2, 11.2 Hz, 1H), 5.86 (d, / = 17.6 Hz, 1H), 5.39 (d, / = 17.6 Hz, 1H) 3.93 (s, 3H), 3.91 (s, 3H). ESIMS m/z 193.18 ([M+H]+); IR (thin film) 1732 cm"1 .
Example 10: Preparation of (£')-ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-l- enyl)-2-methylbenzoate (AI24)
Figure imgf000059_0003
To a stirred solution of ethyl 2-methyl-4-vinylbenzoate (2.0 g, 10.5 mmol) in 1,2- dichlorobenzene (25 mL) were added l-(l-bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (6.44 g, 21.0 mmol), copper(I) chloride (CuCl; 208 mg, 21 mmol) and 2,2bipyridyl (0.65 g, 4.1 mmol). The reaction mixture was degassed with argon for 30 min and then stirred at 180 °C for 24 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to 25 °C and filtered, and the filtrate was concentrated under reduced pressure.
Purification by flash chromatography (Si02, 100-200 mesh; eluting with 25-30% EtOAc in petroleum ether) afforded the title compound as a solid (1.7 g, 40%): ]H NMR (400 MHz, CDCI3) δ 7.91 (d, / = 8.0 Hz, 1H), 7.37 (m, 1H), 7.27-7.24 (m, 4H), 6.59 (d, / = 16.0 Hz, 1H), 6.59 (dd, / = 16.0, 8.0 Hz, 1H), 4.38 (q, / = 7.2 Hz, 2H), 4.08 (m, 1H), 2.62 (s, 3H), 1.42 (t, / = 7.2 Hz, 3H); ESIMS m/z 415.06 ([M-H]"); IR (thin film) 1717, 1255, 1114 cm"1.
Compounds AI25, AI57-AI68 and AC1-AC5 (Table 1) were made in accordance with the procedures disclosed in Example 10.
(£)-Ethyl 4 4,4,4 rifluoro-3-(3,4,5 richlorophenyl)but-l-enyl)-2-(trifluoromethyl)- benzoic acid (AI25)
Figure imgf000060_0001
The product was isolated as a pale brown gummy liquid (500 mg, 40%): ]H NMR (400 MHz, CDC13) δ 7.79 (d, J = 8.0 Hz, 1H), , 7.71 (m, 1H), 7.61 (d, J = 7.6 Hz, 1H),7.42 (s, 2H), 6.70 (d, J = 16.0 Hz, 1H), 6.57 (dd, J = 16.0, 8.0 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 4.19 (m, 1H), 1.40 (t, / = 7.6 Hz, 3H),; ESIMS m/z 502.99 ([M-H]"); IR (thin film) 1730, 1201, 1120, 749 cm"1.
(£)-Ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-l-enyl)-2-fluorobenzoate (AI57)
Figure imgf000060_0002
]H NMR (400 MHz, CDC13) δ 7.38 (s, 1H), 7.26 (s, 3H), 7.21 (d, J = 8.4 Hz, 1H), 7.16 (d, / = 11.6 Hz, 1H), 6.59 (d, / = 16.0 Hz, 1H), 6.47 (dd, / = ,16.0, 8.0 Hz, 1H), 4.41 (q, / = 6.8 Hz, 2H), 4.18 (m, 1H), 1.41 (t, / = 6.8 Hz, 3H); ESIMS m/z 419.33 ([M-H]"); IR (thin film) 1723, 1115, 802 cm"1.
(£ Ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-l-enyl)-2-bromobenzoate (AI58)
Figure imgf000060_0003
]H NMR (400 MHz, CDCI3) δ 7.79 (d, / = 8.0 Hz, 1H), 7.67 (s, 1H), 7.38 (m, 2H), 7.26 (m, 2H), 6.56 (d, / = 16.0 Hz, 1H), 6.45 (dd, / = 16.0, 7.6 Hz, 1H), 4.42 (q, / = 7.2 Hz, 2H), 4.39 (m, 1H), 1.42 (t, / = 7.2 Hz, 3H); ESIMS m/z 481.22 ([M-H]"); IR (thin film) 1727, 1114, 801, 685 cm"1. (£ Ethyl 2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl) but-l-enyl)benzoate (AI59)
Figure imgf000061_0001
]H NMR (400 MHz, CDC13) δ 7.79 (d, J = 8.0 Hz, 1H), 7.67 (d, 7 = 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, / = 6.8 Hz, 2H), 4.15 (m, 1H), 1.42 (t, / = 6.8 Hz, 3H); ESIMS m/z 514.74 ([M-H]"); IR (thin film) 1726, 1115, 808, 620 cm"1.
(£ Ethyl 2-methyl-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl) but-l-enyl)benzoate (AI60)
Figure imgf000061_0002
The title compound was isolated as a light brown gummy material: ]H NMR (400 MHz, CDCI3) δ 7.90 (d, J = 8.8 Hz, 1H), 7.34 (d, J = 6.0 Hz, 2H), 7.25 (d, J = 7.2 Hz, 2H), 6.59 (d, / = 16.0 Hz, 1H), 6.42 (dd, / = 16.0, 8.0 Hz, 1H), 4.38 (q, / = 7.2 Hz, 2H), 4.19 (m, 1H), 2.63 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H).
(£ Ethyl 2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl) but-l-enyl)benzoate (AI61)
Figure imgf000061_0003
]H NMR (400 MHz, CDCI3) δ 7.87 (d, J = 8.0 Hz, 1H), 7.46 (d, 7 = 1.6 Hz, 1H), 7.40 (s, 2H), 7.31 (d, / = 1.6 Hz, 1H), 6.57 (d, / = 16.0 Hz, 1H), 6.44 (dd, / = 16.0 Hz„ 8.0 Hz, 1H), 4.42 (q, / = 6.8 Hz, 2H), 4.15 (m, 1H), 1.42 (t, / = 6.8 Hz, 3H); ESIMS m/z 470.73 ([M- H]"); IR (thin film) 1726, 1115, 809, 3072 cm"1.
(£)-Ethyl 4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-enyl)-2- (trifluoromethyl)benzoate (AI62)
Figure imgf000062_0001
The title compound was isolated as a pale brown liquid (1.0 g, 46.3 %): ]H NMR (400 MHz, CDC13) δ 7.79 (d, / = 8.0 Hz, 1H), 7.71 (s, 1H), 7.61 (d, / = 7.6 Hz, 1H), 7.41 (s, 2H) 6.65 (d, / = 16.0 Hz, 1H), 6.49 (dd, / = 16.0, 8.0 Hz, 1H), 4.42 (q, / = 7.6 Hz, 2H), 4.15 (m, 1H), 1.42 (t, / = 7.6 Hz, 3H); ESIMS m/z 502.99 ([M-H]"); IR (thin film) 1730, 1202, 1120, 750 cm"1.
(£ Ethyl 2-chloro-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l-enyl)benzoate (AI63)
Figure imgf000062_0002
]H NMR (400 MHz, CDC13) δ 7.85 (d, J = 6.0 Hz, 1H), 7.46 (d, 7 = 1.8 Hz, 2H), 7.34
(m, 1H), 7.24 (m, 1H), 6.57 (d, / = 16.2 Hz, 1H), 6.45 (dd, / = 16.2, 7.2 Hz, 1H), 4.43 (q, / = 7.2 Hz, 2H), 4.13 (m, 1H), 1.41 (t, / = 7.2 Hz, 3H); ESIMS m/z 455.0 ([M+H]+); IR (thin film) 1728, 1115, 817 cm"1.
(£ Ethyl 2-fluoro-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l-enyl)benzoate (AI64)
Figure imgf000062_0003
]H NMR (400 MHz, CDC13) δ 7.93 (t, J = 7.6 Hz, 1H), 7.34 (d, J = 5.6 Hz, 2H), 7.21 (d, J = 8.0 Hz, 1H), 7.16 (d, 7 = 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, / = 7.6 Hz, 2H), 4.13 (m, 1H), 1.41 (t, / = 7.6 Hz, 3H); ESIMS m/z 436.81([M-H]"); IR (thin film) 1725 cm"1.
(£ Ethyl 2-bromo-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l-enyl)benzoate (AI65)
Figure imgf000062_0004
]H NMR (400 MHz, CDC13) δ 7.94 (d, J = 8.0 Hz, 1H), 7.67 (s, 1H), 7.36 (m, 3H), 6.56 (d, / = 15.6 Hz, 1H), 6.44 (dd, / = 15.6, 8.0 Hz, 1H), 4.42 (q, / = 6.8 Hz, 2H), 4.10 (m, 1H), 1.42 (t, / = 6.8 Hz, 3H); ESIMS m/z 498.74 ([M-H]"); IR (thin film) 1726, 1114, 820, 623 cm"1.
(£)-Ethyl 2-methyl-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l- enyl)benzoate (AI66)
Figure imgf000063_0001
The title compound was isolated as a brown semi- solid: ]H NMR (400 MHz, CDC13) δ 7.90 (d, / = 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, / = 16.0 Hz, 8.0 Hz, 1H), 4.38 (q, / = 7.2 Hz, 2H), 4.19 (m, 1H), 2.63 (s, 3H), 1.41 (t, / = 7.2 Hz, 3H); ESIMS m/z 432.90 ([M-H]"); IR (thin film) 1715 cm"1.
(£ Methyl 2-methoxy-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l- enyl)benzoate (AI67)
Figure imgf000063_0002
]H NMR (400 MHz, CDCI3) δ 7.80 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 6.0 Hz, 2H), 7.03 (d, J = 1.2 Hz, 1H), 6.92 (s, 1H), 6.59 (d, J = 15.6 Hz, 1H), 6.42 (dd, J = 15.6, 8.0 Hz, 1H), 4.13 (m, 1H), 3.93 (s, 3H), 3.88 (s, 3H); ESIMS m/z 437.29 ([M+H]+); IR (thin film) 1724 cm"1.
(£ Ethyl 2-ethyl-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l-enyl)benzoate (AI68)
Figure imgf000063_0003
]H NMR (400 MHz, CDCI3) δ 7.85 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 9.6 Hz, 2H), 7.26 (m, 1H), 7.24 (m, 1H), 6.60 (d, / = 15.6 Hz, 1H), 6.42 (dd, / = 15.6, 8.0 Hz, 1H), 4.38 (q, / = 7.2 Hz, 2H), 4.14 (m, 1H), 3.01 (q, J = 7.6 Hz 2H), 1.41 (t, / = 7.2 Hz, 3H), 1.26 (t, / = 7.6 Hz, 3H); ESIMS m/z 447.05 ([M-H]"); IR (thin film) 1715, 1115, 817 cm"1. Example 11: Preparation of (£')-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-l-enyl)-2- methylbenzoic acid (AI32)
Figure imgf000064_0001
To a stirred solution of (£)-ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-l-enyl)-
2-methylbenzoate (1.7 g, 4.0 mmol) in 1,4-dioxane (10 mL) was added U N HC1 (30 mL), and the reaction mixture was heated at 100 °C for 48 h. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was diluted with H20 and extracted with chloroform (CHCI3). 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 142-143 °C; ]H NMR (400 MHz, DMSO-rfe) δ 12.62 (br s, 1H), 7.81 (d, / = 8.0 Hz, 1H), 7.66 (s, 3H), 7.52-7.44 (m, 2H), 6.89 (dd, / = 16.0, 8.0 Hz, 1H), 6.78-6.74 (d, / = 16.0 Hz, 1H), 4.84 (m, 1H), 2.50 (s, 3H); ESIMS m/z 387.05 ([M-H] ); IR (thin film) 3448, 1701, 1109, 777 cm"1.
The following compounds were made in accordance with the procedures disclosed in
Example 11.
(£)-2-Methyl-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-enyl)benzoic acid (AI26)
Figure imgf000064_0002
The product was isolated as a pale brown gummy liquid (1 g, 46%): ]H NMR (400 MHz, CDCI3) δ 7.97 (d, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.65 (m, 1H), 7.41 (s, 2H), 6.68 (d, J = 16.0 Hz, 1H), 6.53 (dd, / = 16.0, 8.0 Hz, 1H), 4.16 (m, 1H), 2.50 (s, 3H); ESIMS m/z 422.67 ([M-H]").
(£)-2-Chloro-4-(4,4,4-trifluor -3-(3,4,5-trichlorophenyl)but-l-enyl)benzoic acid (AI27)
Figure imgf000064_0003
The product was isolated as an off-white semi- solid (1 g, 45%): ]H NMR (400 MHz, CDC13) δ 7.99 (d, / = 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, / = 15.6, 7.6 Hz, 1H), 4.14 (m, 1H); ESIMS m/z 442.72 ([M-H]"); IR (thin film) 3472, 1704, 1113, 808 cm"1.
(£)-2-Bromo-4-(4,4,4-trifluo -3-(3,4,5-trichlorophenyl)but-l-enyl)benzoic acid (AI28)
Figure imgf000065_0001
The product was isolated as a brown solid (1 g, 45%): mp 70-71 °C; ]H NMR (400 MHz, CDCI3) δ 7.99 (d, / = 8.0 Hz, 1H), 7.72 (s, 1H), 7.40 (m, 3H), 6.58 (d, / = 16.0 Hz, 1H), 6.48 (dd, / = 16.0, 8.0 Hz, 1H), 4.14 (m, 1H); ESIMS m/z 484.75 ([M-H]"); IR (thin film) 3468, 1700 cm"1.
(£)-2-Cyano-4-(4,4,4-trifluo -3-(3,4,5-trichlorophenyl)but-l-enyl)benzoic acid (AI29)
Figure imgf000065_0002
The product was isolated as an off-white solid (500 mg, 45%): mp 100-101 °C; ]H NMR (400 MHz, CDC13) δ 7.90 (s, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.65 (br s, 1H), 7.42 (s, 2H), 6.73 (d, / = 16.0 Hz, 1H), 6.58 (dd, / = 16.0, 8.0 Hz, 1H), 4.19 (m, 1H); ESIMS m/z 431.93 ([M-H]").
£)-4-(3-(3,4-Dichlorophenyl)-4,4,4-trifluorobut-l-enyl)-2-methylbenzoic acid (AI30)
Figure imgf000065_0003
The product was isolated as a pale brown liquid (500 mg, 46%): ]H NMR (400 MHz, CDCI3) δ 8.03 (m, 1H), 7.49 (m, 2H), 7.29 (m, 1H), 7.22 (m, 2H), 6.73 (d, J = 16.0 Hz, 1H), 6.58 (dd, / = 16.0, 7.8 Hz, 1H), 4.16 (m, 1H), 2.64 (s, 3H); ESIMS m/z 386.84 ([M-H]"); IR (thin film) 3428, 1690, 1113, 780 cm"1.
(£')-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l-enyl)-2-methylbenzoic acid (AI31)
Figure imgf000066_0001
The product was isolated as a white solid (500 mg, 50%): mp 91-93°C; ]H NMR (400 MHz, CDC13) δ 8.02 (d, / = 8.0 Hz, 1H), 7.35 (d, / = 5.6 Hz, 1H), 7.30 (m, 3H), 6.61 (d, J = 16.0 Hz, 1H), 6.48 (dd, J = 16.0, 8.0 Hz, 1H), 4.13 (m, 1H), 2.65 (s, 3H); ESIMS m/z 406.87 ([M-H]-).
(£')-4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-l-enyl)-2-(trifluoromethyl)benzoic acid (AI33)
Figure imgf000066_0002
The product was isolated as a white solid (500 mg, 45%): mp 142-143 °C; ]H NMR (400 MHz, CDCI3) δ 7.97 (d, / = 8.0 Hz, 1H), 7.77 (s, 1H), 7.65 (m, 1H), 7.41 (s, 2H), 6.68 (d, / = 16.0 Hz, 1H), 6.53 (dd, / = 16.0, 8.0 Hz, 1H), 4.16 (m, 1H); ESIMS m/z 474.87 ([M- H] ).
(£)-2-Bromo-4-(4,4,4-trifluor -3-(3,4,5-trichlorophenyl)but-l-enyl)benzoic acid (AI69)
Figure imgf000066_0003
The title compound was isolated as a brown solid (0.8 g, 28%): ]H NMR (400 MHz,
CDCI3) δ 13.42 (br, 1H), 7.98 (d, / = 1.5 Hz, 1H), 7.94 (m, 2H), 7.75 (d, / = 8.1 Hz, 1H), 7.65 (m, 1H), 7.06 (dd, J = 15.9, 9.0 Hz, 1H), 6.80 (d, J = 15.9 Hz, 1H), 4.91 (m, 1H);
ESIMS m/z 484.75 ([M-H]"); IR (thin film) 3469, 1700 cm"1.
(£')-2-Bromo-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluo robut-l-enyl)benzoic acid (AI70)
Figure imgf000066_0004
The title compound was isolated as a yellow liquid (0.3 g, crude): ]H NMR (300 MHz, CDC13) δ 7.79 (d, / = 8.1 Hz, 1H), 7.67 (s, 1H), 7.34 (m, 3H), 6.56 (d, / = 15.9 Hz, 1H), 6.45 (dd, / = 15.9, 7.6 Hz, 1H), 4.43 (m, 1H); ESIMS m/z 471.0 ([M-H]").
(£')-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l-enyl)-2-ethylbenzoic acid (AI71)
Figure imgf000067_0001
The title compound was isolated as a brown gummy material (0.2 g, crude): ]H NMR (300 MHz, DMSO-d6) δ 12.5 (br, 1H), 7.85 (d, / = 6.3 Hz, 2H), 7.75 (d, / = 8.1 Hz, 1H), 7.52 (m, 2H), 6.96 (dd, / = 8.7, 8.7 Hz, 1H), 6.78 (d, / = 15.6 Hz, 1H), 4.80 (m, 1H), 4.06 (q, / = 7.2 Hz, 2H), 1.33 (t, / = 7.2 Hz, 3H); ESIMS m/z 419.06 ([M-H]").
(£')-2-Chloro-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l-enyl)benzoic acid (AI72)
Figure imgf000067_0002
The title compound was isolated as a yellow liquid (0.7 g, 95%): ]H NMR (300 MHz, CDCI3) δ 7.85 (d, / = 6.0 Hz, 1H), 7.46 (d, / = 1.8 Hz, 1H), 7.41 (s, 3H), 6.57 (d, / = 16.0 Hz, 1H), 6.45 (dd, / = 16.0, 8.0 Hz, 1H), 4.16 (m, 1H); ESIMS m/z 455.0 ([M+H]+); IR (thin film) 1728, 1115, 817 cm"1.
(£')-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l-enyl)-2-methylbenzoic acid (AI73)
Figure imgf000067_0003
The title compound was isolated as a light brown gummy material (0.7 g, 38%): mp 91-93 °C; ]H NMR (400 MHz, CDC13) δ 8.02 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 5.6 Hz, 1H), 7.30 (m, 3H), 6.10 (d, / = 16.0 Hz, 1H), 6.46 (dd, / = 16.0, 8.0 Hz, 1H), 4.03 (m, 1H), 2.65 (s, 3H); ESIMS m/z 406.87 ([M-H]").
(£)-4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-l-enyl)-2-fluorobenzoic acid (AI74)
Figure imgf000068_0001
The title compound was isolated as a light brown liquid (0.3 g, crude): ESIMS m/z 393.15 ([M-H]").
')-2-Bromo-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-l-enyl)benzoic acid (AI75)
Figure imgf000068_0002
The title compound was isolated as a light brown liquid (0.35 g, crude): ESIMS m/z 451.91 ([M-H]").
Prophetically, compounds AI34, AI36-AI41, AI44-AI45 (Table 1) could be made in accordance with the procedures disclosed in Example 10, or Examples 10 and 11.
Example 12: Preparation of (£')-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-l-enyl)-2- methyl-N-(2,2,2-trifluoroethyl)benzamide (AC6)
Figure imgf000068_0003
To a stirred solution of (£)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-l-enyl)-2- methylbenzoic acid in DMF was added 2,2,2-trifluoroethylamine, 1-hydroxybenzotriazole hydrate (HOBt»H20), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC»HC1) and N,N-diisopropylethylamine (DIEA), and the reaction mixture was stirred at 25 °C for 18 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. Purification by flash column chromatography (Si02, 100-200 mesh; eluting with hexane:EtOAc afforded a white semi-solid (110 mg, 50%): ]H NMR (400 MHz, CDC13) 7.40 (m, 2H), 7.26 (m, 3H), 6.56 (d, / = 16.0 Hz, 1H), 6.48 (dd, / = 16.0, 8.0 Hz, 1H), 5.82 (br s, 1H), 4.08 (m, 3H), 2.52 (s, 3H); ESIMS m/z 468.40 ([M-H]"); IR (thin film) 1657, 1113, 804 cm"1. Compounds AC7-AC38, AC40-AC58, AC110-AC112, AC117, and AC118 (Table 1) were made in accordance with the procedures disclosed in Example 12.
Example 13: Preparation of 4-((£')-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-l-enyl)-2- methyl- V-((pyrimidin-5-yl)methyl)benzamide (AC39)
Figure imgf000069_0001
To a stirred solution of (pyrimidin-5-yl)methanamine (0.15 g, 1.43 mmol) in CH2CI2 (10 mL) was added drop wise trimethylaluminum (2 M solution in toluene; 0.71 mL, 1.43 mmol), and the reaction mixture was stirred at 25 °C for 30 min. A solution of ethyl 4-((£)-3- (3,5-dichlorophenyl)-4,4,4-trifluorobut-l-enyl)-2-methylbenzoate (0.3 g, 0.71 mmol) in CH2CI2 was added drop wise to the reaction mixture at 25 °C. The reaction mixture was stirred at reflux for 18 h, cooled to 25 °C, quenched with 0.5 N HCl solution (50 mL) and extracted with EtOAc (2 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 (S1O2, 100-200 mesh; eluting with 40% EtOAc in n- hexane) to afford the title compound (0.18 g, 55%): mp 141-144 °C;
]H (400 MHz, CDCI3) δ 9.19 (s, 1H), 8.79 (s, 2H), 7.37 (m, 2H), 7.23 (m, 2H),7.21 (m, 1H), 6.57 (d, / = 16.0 Hz, 1H), 6.40 (dd, / = 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 All '.83 ([M-H]").
Example 14: Preparation of (£)-2-chloro- V-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)- 4-(4,4,4-trifluoro-3-(3, -trichlorophenyl)but-l-en-l-yl)benzamide (AC64)
Figure imgf000069_0002
To a stirred solution of glycine amide (0.15 g, 0.58 mmol) in CH2CI2 (5 mL) was added trimethylaluminum (2 M solution in toluene; 1.45 mL, 2.91 mmol) dropwise, and the reaction mixture was stirred at 28 °C for 30 min. A solution of (£)-ethyl 2-chloro-4-(4,4,4- trifluoro-3-(3,4,5-trichlorophenyl)but-l-enyl)benzoate (0.3 g, 0.58 mmol) in CH2CI2 (5 mL) was added drop wise to the reaction mixture at 28 °C. The reaction mixture was stirred at reflux for 18 h, cooled to 25 °C, quenched with IN HCl solution (50 mL) and extracted with CH2CI2 (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 in n-hexane) to afford the title compound as yellow solid (0.15 g, 50%): mp 83-85 °C; ]H NMR (400 MHz, CDC13) δ 7.72 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.40 (s, 2H), 7.36 (d, J = 6.8 Hz, 1H), 7.05 (t, J = 5.2 Hz, 1H), 6.70 (t, 7 = 5.2 Hz, 1H), 6.57 (d, / = 15.6 Hz, 1H), 6.44 (dd, / = 15.6, 8.0 Hz, 1H), 4.23 (d, / = 5.6 Hz, 2H), 4.15 (m, 1H), 4.01 (m, 2H); ESIMS m/z 580.72 ([M-H]").
Compounds AC59-AC75 (Table 1) were made in accordance with the procedures disclosed in Example 14.
Example 15: Preparation of (£')-2-bromo-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4- trifluorobut-l-en-l-yl)- V-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide (AC79)
Figure imgf000070_0001
To a stirred solution of (£)-2-bromo-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4- trifluorobut-l-enyl)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-1- yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (364.5 mg, 0.701 mmol) and DIPEA (0.32 mL, 1.914 mmol), and the resultant reaction mixture was stirred at RT for 18 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, 100-200 mesh; eluting with 40% ethyl acetate/ petroleum ether) afforded the title compound as an off-white solid (121 mg, 31 %): ]H NMR (400 MHz, CDC13) δ 8.69 (t, / = 6.0 Hz, 1H), 8.58 (t, / = 6.0 Hz, 1H), 7.92 (s, 1H), 7.87 (d, / = 6.4 Hz, 2H), 7.62 (d, / = 8.4 Hz, 1H), 7.45 (d, / = 8.4 Hz, 1H), 7.0 (m, 1H), 6.76 (d, / = 15.6 Hz, 1H), 4.83 (t, / = 8.0 Hz, 1H), 3.98 (m, 4H); ESIMS m/z 610.97 ([M+H]+); IR (thin film) 3303, 1658, 1166, 817 cm"1.
Compounds AC76-AC80, AC96-AC102, and AC113 (Table 1) were made in accordance with the procedures disclosed in Example 15.
Example 16: Preparation of (£')-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-l-en-l-yl)- A7-(l,l-dioxidothietan-3-yl)-2-fluorobenzamide (AC83)
Figure imgf000071_0001
To a stirred solution of (£)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-l-enyl)-2- fluoro-N-(thietan-3-yl)benzamide (100 mg, 0.2159 mmol) in acetone/ water (1 : 1, 5.0 mL) was added oxone (266 mg, 0.4319 mmol) and the resultant reaction mixture was stirred at RT for 4h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined ethyl acetate layer was dried over anhydrous Na2S04 and concentrated under reduced pressure. Purification by flash column chromatography (Si02, 100-200 mesh; eluting with 30% ethyl acetate/ pet ether) afforded the title compound as an off white solid (70.0 mg, 66 %): ]H NMR (400 MHz, CDC13) δ 8.07 (t, J = 8.4 Hz, 1H), 7.39 (t, 7 = 1.6 Hz, 1H), 7.31 (d, / = 1.2 Hz, 1H), 7.26 (m, 2H), 7.23 (m, 2H), 7.19 (d, / = 1.6 Hz, 1H), 6.60 (d, / = 16.8 Hz, 1H), 6.49 (dd, / = 16.8, 7.6 Hz, 1H), 4.90 (m, 1H), 4.64 (m, 2H), 4.14 (m, 2H),; ESIMS m/z 493.83 ([M-H]"); IR (thin film) 1527, 1113, 801, 1167, 1321 cm"1.
Compounds AC81-AC87 (Table 1) were made in accordance with the procedures disclosed in Example 16.
Example 17: Preparation of (£')- V-((5-cyclopropyl-l,3,4-oxadiazol-2-yl)methyl)-4-(3- (3,5-dichlorophenyl)-4 4,4-trifluorobut-l-en-l-yl)-2-methylbenzamide (AC89)
Figure imgf000071_0002
A solution of (E)-N-(2-(2-(cyclopropanecarbonyl)hydrazinyl)-2-oxoethyl)-4-(3-(3,5- dichlorophenyl)-4,4,4-trifluorobut-l-enyl)-2-methylbenzamide (200 mg, 0.379 mmol) in POCI3 (2.0 mL) was stirred at RT for 10 min, then the resultant reaction mixture was heated to 50 °C for lh. The reaction mixture was quenched with ice water at 0 °C and extracted with ethyl acetate. The combined ethyl acetate layer was washed with saturated NaHCC>3 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 compound as a light brown gummy material (70.0 mg, 36 %): ]H NMR (400 MHz, CDC13) δ 7.43 (m, 2H), 7.27 (m, 2H), 7.23 (m, 2H), 6.58 (d, J = 16.0 Hz, 1H), 6.41 (dd, / = 16.0, 7.6 Hz, 1H), 4.79 (d, / = 5.6 Hz, 2H), 4.14 (m, 1H), 2.48 (s, 3H), 2.18 (m, 1H), 1.16 (m, 4H); ESIMS mJz 509.89 ([M+H]+); IR (thin film) 1666, 1166, 1112, 800 cm"1.
Example 18: Preparation of (£)-2-bromo- V-(2-thioxo-2-((2,2,2- trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en-l- yl)benzothioamide (AC90)
Figure imgf000072_0001
To a stirred solution of (£)-2-bromo-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)- 4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en-l-yl)benzamide (400 mg, 0.638 mmol) in 5 mL of THF at RT was added 2,4-bis(4-methoxyphenyl)-l,3,2,4-dithiadiphosphetane-2,4- disulfide (Lawesson's reagent) (336 mg, 0.830 mmol) in one portion. The resulting reaction mixture was stirred for 18 h. TLC showed the reaction was not complete, therefore additional Lawesson's reagent (168 mg, 0.415 mmol) was added and reaction stirred for 48 h. After the reaction was deemed complete by TLC, the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (Si02, 230-400 mesh; eluting with 20% EtOAc in hexanes) afforded the title compound as a yellow glassy oil (188 mg, 44.7%): ]H
NMR (400 MHz, CDC13) δ 8.34 (m, 1H), 8.27 (m, 1H), 7.60 (d, / = 1.6 Hz, 1H), 7.49 (d, / = 8.0 Hz, 2H), 7.40 (s, 2H), 7.36 (dd, / = 8.2, 1.7 Hz, 1H), 6.53 (d, / = 16.0 Hz, 1H), 6.38 (dd, / = 15.9, 7.9 Hz, 1H), 4.89 (d, / = 8.4, 5.5 Hz, 2H), 4.48 (qd, / = 9.0, 6.0 Hz, 2H), 4.11 (m, 1H); ESIMS m/z 656.9 ([M-H]").
Example 19: Preparation of (£)-2-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-en-l-yl)phenylthioamido)-A7-(2,2,2-trifluoroethyl)acetamide
(AC91)
Figure imgf000072_0002
To a stirred solution of (E)-2-bromo-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)- 4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en-l-yl)benzamide (400 mg, 0.638mmol) in 5 mL of THF at RT was added Lawesson's reagent (64.5 mg, 0.160 mmol) in one portion. The resulting reaction mixture was stirred for 18 h, after which time, the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (Si02, 230-400 mesh; eluting with 20% EtOAc in hexanes) afforded the title compounds as a yellow oil (18.5 mg, 4.51%): ]H NMR (400 MHz, CDC13) δ 8.18 (t, 7 = 5.0 Hz, 1H), 7.58 (d, 7 = 1.6 Hz, 1H), 7.47 (d, 7 = 8.0 Hz, 1H), 7.40 (s, 2H), 7.34 (dd, 7 = 8.1, 1.6 Hz, 1H), 6.52 (m, 2H), 6.37 (dd, 7 = 15.9, 7.9 Hz, 1H), 4.54 (d, 7 = 4.9 Hz, 2H), 4.12 (m, 1H), 3.99 (qd, 7 = 8.9, 6.5 Hz, 2H); ESIMS m/z 640.9 ([M-H] ).
The following compound was made in accordance with the procedures disclosed in Example 19.
(£)-2-Bromo-N-(2-thioxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3- (3,4,5-trichloropheny
Figure imgf000073_0001
The product was isolated as a colorless oil (17.9 mg, 4.36%): ]H NMR (400 MHz, CDCI3) δ 9.16 (d, 7 = 6.1 Hz, 1H), 7.65 (d, 7 = 1.6 Hz, 1H), 7.57 (d, 7 = 8.0 Hz, 1H), 7.41 (m, 3H), 7.21 (t, 7 = 5.6 Hz, 1H), 6.55 (d, 7 = 15.9 Hz, 1H), 6.41 (dd, 7 = 15.9, 7.8 Hz, 1H), 4.59 (d, 7 = 5.6 Hz, 2H), 4.45 (qd, 7 = 9.0, 6.0 Hz, 2H), 4.12 (q, 7 = 7.2 Hz, 1H); ESIMS m/z 640.9 ([M-H] ).
Example 106: Preparation of ethyl-(Z)-2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-en-l-yl
Figure imgf000073_0002
The title compound was made in accordance with the procedure disclosed in Example
88 and was isolated as a yellow viscous oil (416 mg, 23%): ]H NMR (400 MHz, CDC13) δ 7.80 (d, 7 = 8.0 Hz, 1H), 7.40 (d, 7 = 1.7 Hz, 1H), 7.35 (s, 2H), 7.12 (dd, 7 = 8.0, 1.7 Hz, 1H), 6.86 (d, 7 = 11.4 Hz, 1H), 6.23 - 5.91 (m, 1H), 4.42 (q, 7 = 7.1 Hz, 2H), 4.33 - 4.10 (m, 1H), 1.42 (t, 7 = 7.2 Hz, 3H); 19F NMR (376 MHz, CDC13) δ -69.34 (d, 7 = 8.3 Hz); EIMS m/z 514.10 ([M]"); IR (thin film) 2983, 1727, 1247, 1204, 1116 cm"1.
Example 107 : Preparation of (Z)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-en-l-yl)benzoic acid (AI77)
Figure imgf000074_0001
To a stirred solution of (Z)-ethyl 2-bromo-4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-en-l-yl)benzoate (360 mg, 0.70 mmol) in C¾CN (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 CH2CI2 and aq. 10 %
Na2S203. Organic phase was washed once with aq. 10% Na2S203 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 CH2CI2 ) as the eluting solvents afforded the title compound as a yellow foam (143 mg, 42%): mp 54-64°C; ]H NMR (400 MHz, CDC13) δ 11.36 (s, 1H), 7.99 (d, 7 = 8.0 Hz, 1H), 7.43 (s, 1H), 7.30 (s, 2H), 7.14 (d, 7 = 7.9 Hz, 1H), 6.85 (d, 7 = 11.4 Hz, 1H), 6.15 (t, 7 = 10.9 Hz, 1H), 4.36 - 4.09 (m, 1H);19F NMR (376 MHz,
Figure imgf000074_0002
Example 108 : Preparation of (Z)-2-bromo- V-(2-oxo-2-((2,2,2- trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en-l- yl)benzamide (AC95)
Figure imgf000074_0003
To a stirred solution of (Z)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l- en-l-yl)benzoic acid (200 mg, 0.41 mmol) in anhydrous THF (5.0 mL) was added DCI (82 mg, 0.51 mmol). The mixture was heated in a 50 °C oil bath for 1.5 h, treated with 2-amino- N-(2,2,2-trifluoroethyl)acetamide hydrochloride (109 mg, .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 (IX). 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°C: ]H NMR (400 MHz, CDC13) δ 7.58 (d, 7 = 7.9 Hz, 1H), 7.44 - 7.29 (m, 3H), 7.14 (dd, 7 = 7.9, 1.6 Hz, 1H), 6.86 (d, 7 = 11.4 Hz, 1H), 6.76 (t, / = 5.9 Hz, 1H), 6.59 (br s, 1H), 6.21 - 6.04 (m, 1H), 4.23 (d, / = 5.5 Hz, 1H), 3.98 (qd, / = 9.0, 6.5 Hz, 2H); 19F NMR (376 MHz, CDC13) δ -69.31, -72.3; EIMS m/z 626.9 ([M+l]+).
Compound F13A in Table 1A was made in accordance with the procedures disclosed in Example 108.
Example 109a: Preparation of (£')-2-bromo- V-(piperidin-4-yl)-4-(4,4,4-trifluoro-3- (3,4,5-trichlorophenyl)b -l-en-l-yl)benzamide (AC114)
Figure imgf000075_0001
( Keri-Butyl 4-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l- enyl)benzamido)piperidine-l-carboxylate (0.75 g, 1.11 mmol) was added to dioxane HCl (10 mL) at 0 °C and was stirred for 18 h. The reaction mixture was concentrated under reduced pressure and triturated with diethylether to afford the compound as a light brown solid (0.6 g, 88%).
Example 109b: Preparation of (£')- V-(l-acetylpiperidin-4-yl)-2-bromo-4-(4,4,4-trifluoro- 3-(3,4,5-trichlorophenyl)but-l-en-l-yl)benzamide (AC103)
Figure imgf000075_0002
To a stirred solution of (£)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-enyl)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 chloride (0.014, 0.18 mmol) was added and stirred for 16 h at RT. The reaction mixture was diluted with DCM and washed with saturated NaHCC>3 solution and brine solution. The combined DCM layer was dried over Na2SC>4 and concentrated under reduced pressure to afford crude compound. The crude compound was washed with 5% diethyl ether / n-pentane to afford the title compound as a white solid (0.054 g, 50%). Example 110: Preparation of (£)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-en-l-yl)- V-(l-(3,3,3-trifluoropropanoyl)piperidin-4-yl)benzamide
(AC104)
Figure imgf000076_0001
To a stirred solution of 3,3,3-trifluoropropanoic acid (0.02g, 0.16 mmol) in DCM
(10.0 mL), (£)-2-bromo-N<piperidin-4-yl)-4 4,4,4-trifluoro-3 3,4,5-trichlorophenyl)but-l- 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 HC1 and saturated NaHCC^ solution, the separated DCM layer was dried over anhydrous 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% methanol in DCM) to afford the title compound as an off white gummy material (0.035 g, 29.%).
Example 111: Preparation of (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-en-l-yl)-N-(l-(2,2,2-trifluoroethyl)piperidin-4-yl)benzamide (AC105)
Figure imgf000076_0002
To a stirred solution of (£)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-enyl)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 h at RT. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCC>3 solution and brine solution. The combined ethyl acetate layer was dried over Na2S04 and concentrated under reduced pressure to afford the title compound as a brown solid (0.05 g, 44%). Example 112: Preparation of (£')-2-bromo-/V-(l-methylpiperidin-4-yl)-4-(4,4,4-trifluoro- 3-(3,4,5-trichlorophenyl)but-l-en-l-yl)benzamide (AC106)
Figure imgf000077_0001
A solution of (£')-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-enyl)benzamide (0.1 g, 0.16 mmol), formaldehyde (30% in water) (0.1 mL, 0.16 mmol) and acetic acid (0.01 mL) in methanol (5.0 mL) was stirred at RT for 30 min. After that NaBFLCN (0.01 g, 0.16 mmol) was added at 0°C and the reaction was stirred for 8 h at RT. The solvent was removed under reduced pressure to obtain residue which was diluted with ethyl acetate and washed with saturated aq. NaHCC>3 solution 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 a pale yellow gummy material (0.06 g, 59%).
Example 113: Preparation of ((£')-2-bromo-/V-(l-(cyanomethyl)piperidin-4-yl)-4-(4,4,4- trifluoro-3-(3,4,5-trichl rophenyl)but-l-en-l-yl)benzamide (AC107)
Figure imgf000077_0002
To a stirred solution of (£)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-enyl)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 h at 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 (0.125 g, 46.8%).
Example 114: Preparation of (£')-2-bromo-/V-(l-(oxetan-3-yl)piperidin-4-yl)-4-(4,4,4- trifluoro-3-(3,4,5-trichlorophenyl)but-l-en-l-yl)benzamide (AC108)
Figure imgf000078_0001
A solution of (£')-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-enyl)benzamide (0.2 g, 0.35 mmol), oxetan-3-one (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 °C slowly lot wise over the period of 10 min and the reaction was stirred for 8 h at RT. The solvent was removed under reduced pressure to obtain a residue which was diluted with ethyl acetate and washed with saturated NaHCC>3 solution 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 (£')-2-bromo-/V-(l-(2-hydroxyethyl)piperidin-4-yl)-4- (4,4,4-trifluoro-3-(3,4 5-trichlorophenyl)but-l-en-l-yl)benzamide (AC109)
Figure imgf000078_0002
To a stirred solution of (£)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-enyl)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 h at 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 (£ 2-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-en-l-yl)benzamido)acetic acid (AI78)
Figure imgf000079_0001
To a stirred solution of (E)-tert-buty\ 2-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-enyl)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 n-pentane to afford the title compound as an off-white solid (310 mg, 78%): ]H NMR (400 MHz, CDC13) δ 13.0 (s, 1H), 8.75 (t, / = 5.7 Hz, 1H), 7.93 (m, 2H), 7.62 (d, / = 7.5 Hz, 1H), 7.40 (d, / = 8.1 Hz, 1H), 6.96 (dd, / = 15.3, 9.3 Hz, 1H), 6.78 (d, / = 15.3 Hz, 1H), 4.83 (m, 1H), 3.90 (d, / = 5.7 Hz, 2H); ESIMS m/z 543.61([M+H]+); IR (thin film) 3429, 1635, 1114, 772 cm"1.
Example 117: Preparation of (£')- V-((6-chloropyridin-3-yl)methyl)-4-(3-(3,5- dichlorophenyl)-4,4,4-trifl robut-l-en-l-yl)-2-methylbenzothioamide (AC115)
Figure imgf000079_0002
To the stirred solution of (£')-N-((6-chloropyridin-3-yl)methyl)-4-(3-(3,5- dichlorophenyl)-4,4,4-trifluorobut-l-enyl)-2-methylbenzamide (0.06 g, 0.117 mmol) in toluene (3 mL) was added Lawesson's reagent (0.14 g, 0.351 mmol) and the reaction was irradiated at 100 C for 1 h, then cooled to RT and concentrated under reduced pressure to provide crude compound. The crude product was purified by preparative HPLC to afford the product as yellow color solid (0.03 g, 49%).
Example 118: Preparation of (£)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut- l-en-l-yl)- V-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-2- (trifluoromethoxy)b
Figure imgf000079_0003
Step 1. 2-(Trifluoromethoxy)-4-vinylbenzoic acid (AI79): To a stirred solution of 4-bromo-2-(trifluoromethoxy)benzoic acid (1 g, 3.67 mmol) in DMSO (20 mL) was added potassium vinyltrifluoroborate (1.47 g, 11.02 mmol) and potassium carbonate (1.52 g, 11.02 mmol). The reaction mixture was degassed with argon for 30 min.
Bistriphenylphosphine(diphenylphosphinoferrocene)palladium dichloride (0.13 g, 0.18 mmol) was added and the reaction mixture was heated to 80 °C for 1 h. The reaction mixture was diluted with water (lOOmL), 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%): ]H NMR (400 MHz, CDC13) δ 8.05 (d, 7 = 8.1 Hz, 1H), 7.44 (d, / = 1.8 Hz, 1H), 7.35 (s, 1H), 6.78 (dd, 7 =17.4.1, 11.1 Hz, 1H), 5.92 (d, / = 17.4 Hz, 1H), 5.51 (d, / = 10.8 Hz, 1H); ESIMS m/z 232.97 ([M+H]+).
Step 2. (£)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l-enyl)-2- (trifluoromethoxy)benzoic acid (AI80): To a stirred solution of 2-(trifluoromethoxy)-4- vinylbenzoic acid (0.356 g, 1.53 mmol) in IN methyl pyrrolidine (5.0 mL) was added 1-(1- bromo-2,2,2-trifluoroethyl)-3,5-dichloro 4-fluorobenzene (1.0 g, 3.07 mmol), copper(I) chloride (CuCl; 0.03 g, 0.307 mmol) and 2,2 bipyridyl (0.095 g, 0.614 mmol). The reaction mixture was stirred at 150 °C for 1 h. After the reaction was complete by TLC, the reaction mixture was diluted with water (lOOmL) and extracted with ethyl acetate (2X 50 mL). The combined organic layers were washed with brine, dried over Na2S04 and concentrated under reduced pressure to obtain the crude compound which was purified by flash column chromatography to afford the product as pale yellow gummy material (0.3 g, 21%): ]H NMR (400 MHz, CDCI3) δ 8.08 (d, / = 8.0 Hz, 1H), 7.45 (d, / = 1.6 Hz, 1H), 7.35 (s, 3H), 6.63 (d, J = 16.0 Hz, 1H), 6.50 (dd, J = 16.0, 8.0 Hz, 1H), 4.15 (m, 1H); ESIMS m/z 474.81 ([M-H]").
Step 3. (£)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l-enyl)- V-(2- oxo-2-(2,2,2-trifluoroethylamino)ethyl)-2-(trifluoromethoxy)benzamide (AC116) : A mixture of (£')-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l-enyl)-2- (trifluoromethoxy)benzoic acid (0.25 g, 0.52 mmol), 2-amino-N-(2,2,2- trifluoroethyl)acetamide (0.158 g, 0.62 mmol), PyBOP (0.40 g, 0.78 mmol) and DIPEA (0.134 g, 1.04 mmol) in 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, 100-200 mesh; eluting with 20% ethyl acetate/ pet ether) afforded the title compound as a pale yellow gummy material (0.15 g, 47 %). Example 20: Preparation of 5-vinyl- -dihydro-lH-inden-l-one (BI1)
Figure imgf000081_0001
To a stirred solution of 5-bromo-2,3-dihydro-lH-inden- l-one (5 g, 23.7 mmol) in toluene were added vinylboronic anhydride pyridine complex (8.55 g, 35.54 mmol), Pd(PPh3)4 (0.1 g, 0.094 mmol), K2C03 (22.88 g, 165.83 mmol). The resultant reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to 25 °C and filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc and washed with H20 and brine. The combined organic 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 compound as a solid (1.8 g, 48%): ]H NMR (400 MHz, CDC13) δ 7.74 (d, J = 7.2 Hz, 1H), 7.49 (br s, 1H), 7.44 (d, J = 7.2 Hz, 1H), 6.82 (m, 1H), 5.90 (d, J = 7.4 Hz, 1H), 5.42 (d, J = 6.4 Hz, 1H), 3.20 (m, 2H), 2.70 (m, 2H); ESIMS m/z 159.06 ([M+H]").
The following compound was made in accordance with the procedures disclosed in Example 20.
6-Vinyl-3,4-dihydronaphthalen-l(2 -one (BI2)
Figure imgf000081_0002
The product was isolated as an off-white solid (5 g, 48%): ]H NMR (400 MHz, DMSO-d6) δ 7.85 (d, / = 8.4 Hz, 1H), 7.48 (m, 2H), 6.82 (m, 1H), 6.02 (d, / = 7.4 Hz, 1H), 5.44 (d, / = 6.4 Hz, 1H), 2.95 (m, 2H), 2.60 (m, 2H), 2.00 (m, 2H); ESIMS m/z 173.14 ([M- H]~); IR (thin film) 1681 cm"1.
Example 21: Preparation of (£')-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-enyl)- 2,3-dihydro-lH-inden-l-one (
Figure imgf000081_0003
5-(l-Bromo-2,2,2-trifluoroethyl)-l ,2,3-trichlorobenzene (4 g, 11.7 mmol), 5-vinyl- 2,3-dihydro-lH-inden- l-one (0.92 g, 5.8 mmol), CuCl (0.115 g, 1.171 mmol) and 2,2- bipyridyl (0.053 g, 0.34 mmol) in 1,2-dichlorobenzene (25 mL) were heated at 180 °C for 16 h. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by flash column chromatography (Si02, 5% EtOAc in petroleum ether) to afford the title compound as a liquid (1.28 g, 25%): ]H NMR (400 MHz, CDC13) δ 7.76 (d, 7 = 7.4 Hz, 1H), 7.52 (m, 3H), 6.68 (d, 7 = 7.4 Hz, 1H), 6.52 (m, 1H), 4.18 (m, 1H), 3.18 (m,
2H), 2.75 (m, 2H); ESIMS m/z 419.14 ([M+H]"); IR (thin film) 1708.94, 1113.60, 807.77 cm"
1
The following compound was made in accordance with the procedures disclosed in Example 21.
(E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l-en-l-yl)-2,3-dihydro-lH- inden-l-one (BI4)
Figure imgf000082_0001
The product was isolated as a brown semi- solid (1.2 g, 16%): ]H NMR (400 MHz, CDCI3) δ 7.76 (d, 7 = 7.4 Hz, 1H), 7.54 (m, 3H), 7.30 (s, 1H), 6.68 (d, 7 = 7.4 Hz, 1H), 6.52 (m, 1H), 4.18 (m, 1H), 3.18 (m, 2H), 2.75 (m, 2H); ESIMS m/z 400.84 ([M-H]"); IR (thin film) 815, 1113, 1709 cm"1.
(£)-6-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-l-enyl)-3,4-dihydronaphthalen- l(2H)-one (BI5)
Figure imgf000082_0002
The product was isolated as a pale yellow semi solid (1.2 g, 30%): ]H NMR (400 MHz, CDCI3) δ 8.20 (d, 7 = 8.0 Hz, 1H), 7.42 (s, 2H), 7.35 (m, 1H), 7.24 (m, 2H), 6.62 (d, 7 = 16 Hz, 1H), 6.46 (m, 1H), 4.18 (m, 1H), 2.95 (m, 2H), 2.65 (m, 2H), 2.19 (m, 2H); ESIMS m/z 432.94 ([M-H]"); IR (thin film) 1680, 1113, 808 cm"1.
Example 22: Preparation of (£')-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l- en-l-yl)-2-fluoro-2,3-dihydr -lH-inden-l-one (BI6)
Figure imgf000082_0003
To a stirred solution of (£')-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l- enyl)-2,3-dihydro-lH-inden-l-one (0.5 g, 1.24 mmol) in acetonitrile (20 mL), was added Selectfluor® (0.52 g, 1.48 mmol) and the reaction was heated to reflux temperature for 16 h. The reaction mixture was cooled to 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 product 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%): ]H NMR (400 MHz, CDC13) δ 7.80 (m, IH), 7.48 (m, 2H), 7.32 (m, 2H), 6.65 (d, / = 16.0 Hz, IH), 6.54 (dd, J = 16.0, 8.0 Hz, IH), 5.38 (m, IH), 4.18 (m, IH), 3.62 (m, IH), 3.32 (m, IH); ESIMS m/z 419.06 ([M-H]"); IR (thin film) 1728, 1114, 817 cm"1.
Example 23: Preparation of (£')-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l- en-l-yl)- V-(3,3,3-trifluoropropyl)-2,3-dihydro-lH-inden-l-amine (BC10)
Figure imgf000083_0001
To a stirred solution of (£')-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l- enyl)-2,3-dihydro-lH-inden-l-one (0.15 g, 0.35 mmol) in DCE (10 mL), was added trifluoropropyl amine (0.048 g, 0.42 mmol) and sodium cyanoborohydride (0.055 g, 0.875 mmol) in cooling and the reaction mixture was stirred at 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 colorless gummy material (0.042g, 24%): ]H NMR (400 MHz, CDC13) δ 7.38-7.20 (m, 5H), 6.62 (d, J = 16.0 Hz, IH), 6.34 (dd, J = 16.0, 8.0 Hz, IH), 5.83 (br, IH), 5.52 (m, IH), 4.12 (m, IH), 3.02 (m, 3H), 2.82 (m, IH), 2.50 (m, 2H), 1.82 (m, IH), 1.42 (m, IH); ESIMS m/z 497.98 ([M-H]"); IR (thin film) 3027, 1654, 815 cm"1.
Example 24: Preparation of 6-((£')-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-enyl)- 3,4-dihydronaphthalen-l(2H)-one oxime (BI5a)
Figure imgf000084_0001
To a stirred solution of ((£)-6-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-enyl)- 3,4-dihydronaphthalen-l(2H)-one (0.4 g, 0.92 mmol) in EtOH (50 mL) were added hydroxylamine hydrochloride (0.128 g, 1.85 mmol) and sodium acetate (0.23 g, 2.77 mmol), and the reaction mixture was heated at reflux for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with 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 155-158 °C; ]H NMR (400 MHz, CDC13) δ 7.89 (d, / = 8.4 Hz, 1H), 7.41 (s, 2H), 7.24 (m, 1H), 7.17 (m, 1H), 6.57 (d, / = 16 Hz, 1H), 6.46 (dd, / = 16.0, 8.0 Hz, 1H), 4.13 (m, 1H), 2.82 (m, 4H), 2.04 (m, 2H); ESIMS m/z 445.95 ([M-H]").
Example 25: Preparation of (£')-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-enyl)- 2,3-dihydro-lH-inden-l-amine (BI5b)
Figure imgf000084_0002
To a stirred solution of (£')-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-enyl)-2,3- dihydro-lH-inden-l-one (1 g, 2.39 mmol) in CH3OH (10 mL) were added ammonium acetate (1.84 g, 23.9 mmol) and sodium cyanoborohydride (NaCNB¾; 0.44 g, 7.17 mmol,) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with H20 and extracted with EtOAc . The combined 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): ]H NMR (400 MHz,
DMSO- ) δ 7.85 (s, 2H), 7.40 (s, 1H), 7.30 (s, 2H), 6.71 (s, 2H), 4.78 (m, 1H), 4.2 (m, 1H), 2.80 (m, 1H), 2.73 (m, 1H), 1.60 (m, 2H); ESIMS m/z 419.02 ([M+H]+); IR (thin film) 2924, 1552, 1112, 807 cm"1. The following compound was made in accordance with the procedures disclosed in Example 25.
(£)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l-en-l-yl)-2,3-dihydro-lH- inden-l-amine (BI7)
Figure imgf000085_0001
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 ([Μ-Η]").
(£)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l-en-l-yl)-2-fluoro-2,3- dihydro-lH-inden-l-amine (BI8)
Figure imgf000085_0002
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 ([Μ-Η]").
(£')-6-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-enyl)-l,2,3,4-tetrahydronaphthalen 1-amine (BI9)
Figure imgf000085_0003
The product was isolated as a pale yellow liquid (500 mg crude).
Example 26: Preparation of (£)-l-methyl-3-(5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)- but-l-enyl)-2,3-dihydro-lH-inden-l-yl)thiourea (BC1)
Figure imgf000086_0001
To a stirred solution of (£')-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-enyl)-2,3- dihydro-lH-inden-1 -amine (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 °C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (Si02, 20% EtOAc in petroleum ether). The title compound was isolated as a liquid (65 mg, 50%): ]H NMR (400 MHz, CDC13) δ 7.39 (s, 2H), 7.25 - 7.18 (m, 3H), 6.58 (d, / = 16.0 Hz, 1H), 6.30 (dd, / = 16.0, 8.4 Hz, 1H), 5.91 - 5.70 (br, 2H), 4.05 (m, 1H), 3.05 - 2.80 (m, 6H), 2.70 (m, 1H), 1.81 (m, 1H); ESIMS m/z 492.17 ([M+H]+); IR (thin film) 3211, 1569, 1113, 806 cm"1.
Compounds BC2 - BC3 in Table 1 were made in accordance with the procedures disclosed in Example 26.
Example 27: Preparation of (£)-3,3,3-trifluoro- V-(5-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-enyl)-2,3-dihydro-lH-inden-l-yl)propanamide (BC4)
Figure imgf000086_0002
To a stirred solution of (£')-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-enyl)-2,3- dihydro-lH-inden-1 -amine (0.1 g, 0.23 mmol) in CH2C12 (10 mL) were added
trifluoropropionic acid (0.044 g, 0.34 mmol), EDC'HCl (0.038 g, 0.35 mmol), HOBf H20 (0.07 g, 0.46 mmol) and DIEA (0.074 g, 0.57 mmol), and the reaction mixture was stirred for 16 h at 25 °C. The reaction mixture was diluted with CH2C12 and washed with H20. The combined organic layer was washed with brine, dried over anhydrous Na2S04, and concentrated under reduced 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%): ]H NMR (400 MHz, CDC13) δ 7.39 (s, 2H), 7.25-7.20 (m, 3H), 6.34 (d, / = 16.0 Hz, 1H), 6.30 (dd, J = 16.0, 8.0 Hz, 1H), 5.81 (br, 1H), 5.48 (m, 1H), 4.10 (m, 1H), 3.10 (m, 2H), 2.86-3.07 (m, 2H), 2.86 (m, 1H), 1.81 (m, 1H); ESIMS mJz 529.02 ([M+H]+); IR (thin film) 3283, 1652, 1241, 811 cm"1.
Compounds BC5 - BC9, BC11 in Table 1 were made in accordance with the procedures disclosed in Example 27.
Example 28: Preparation of fert-butyl 5-vinylindoline-l-carboxylate (BI10)
Figure imgf000087_0001
Step 1. 5-Bromo-indoline (Bill): To 5-Bromo-lH-indole (2.5 g, 12.82 mmol) in acetic acid (10.0 mL), NaCNBIL (2.38 g, 38.46 mmol) was added portion wise at 10 °C over the period of 20 min. After that the reaction mixture was stirred at RT for 3 h. The reaction mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with saturated NaHCC>3, 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. fert-Butyl-5-bromoindoline-l-carboxylate (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-ieri-butyl dicarbonate (3.98 g, 18.3 mmol) and the reaction was stirred at RT for 16 h. The reaction mixture was concentrated on reduced pressure to obtain a residue which was diluted with diethyl ether and washed with water and brine solution (2X). The combined ether layer was dried over anhydrous Na2S04 and concentrated under reduced pressure to afford the crude product as an off-white solid, which was used in the next step without further purification (3.0 g).
Step 3. fert-Butyl-5-vinylindoline-l-carboxylate (BI10): A stirred solution of tert- butyl-5-bromoindoline-l-carboxylate (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. PdCl2(dppf) (0.49 g, 0.67mmol) was added at RT, then the reaction mixture was heated to 100 °C for 3 h. The reaction mixture was cooled to RT and filtered through a celite bed under vacuum and washed with diethyl ether. The reaction mixture was extracted with diethyl ether. The combined diethyl ether layer was dried over Na2S04 and concentrated under reduced pressure to afford crude product. 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 an off-white solid (1.2 g, 73%): Mp 85.5 - 88.6 °C; ]H NMR (400 MHz, CDC13) δ 7.23 (m, 3H), 6.69 (dd, / = 17.4, 10.8 Hz, 1H), 5.64 (d, J = 10.5 Hz, 1H), 5.13 (d, J = 10.5 Hz, 1H), 4.00 (t, J = 9.0 Hz, 2H), 3.10 (t, J = 9.0 Hz, 2H), 1.55 (bs, 9H).
Example 29: Preparation of (E)-tert-butyl 5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4- trifluorobut-l-en-l-yl)indoline-l-carboxylate (BI13)
Figure imgf000088_0001
To a stirred solution of ieri-butyl-5-vinylindoline-l-carboxylate (1.28 g, 5.23mmol) inl,2-dichlorobenzene (10.0 mL), was added 5-(l-bromo-2,2,2-trifluoroethyl)-l,3-dichloro-2- fluorobenzene (3.4 g ,10 mmol), CuCl (103 mg, 1.05 mmol) and 2,2-bipyridyl (0.326 g, 2.092 mmol) and the resultant reaction mixture was degassed with argon for 30 min and heated to 150 °C for 1 h. The reaction mixture was cooled to RT and filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography (Si02, 100-200 mesh; 2% ethyl acetate/ petroleum ether) to afford the title compound as a pale yellow gummy solid (0.3 g, 61%): ]H NMR (400 MHz, CDC13) δ 7.34
(d, / = 6.0 Hz, 2H), 7.22 (s, 2H), 7.16 (d, / = 8.4 Hz, 1H), 6.52 (d, / = 16.0 Hz, 1H), 6.21 (dd, / = 16.0, 7.6 Hz, 1H), 4.07 (m, 3H), 3.10 (t, / = 8.4 Hz, 2H), 1.55 (s, 9H); ESIMS m/z 433.79 ([M-H]"); IR (thin film) 1168, 858 cm"1.
Example 30: Preparation of (£')-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l- en-l-yl)indolin-l-amine (BI14)
Figure imgf000088_0002
Step 1. (E)- 5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l-enyl)indoline (BI15) To a stirred solution of (£')-ieri-butyl-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4- trifluorobut-l-enyl)indoline-l-carboxylate (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 reaction mixture was diluted with DCM, washed with saturated aq NaHCC>3 , 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): ]H NMR (400 MHz, CDC13) δ 7.33 (d, J = 6.4 Hz, 2H), 7.21 (s, 1H), 7.02 (d, / = 8.0 Hz, 1H), 6.57 (d, / = 8.4 Hz, 1H), 6.49 (d, / = 15.6 Hz, 1H), 6.21(dd, .7 = 15.6, 8.4 Hz, 1H), 4.07 (m, 1H), 3.61 (t, J = 8.4 Hz, 2H), 3.05 (t, J = 8.4 Hz, 2H); ESIMS m/z 389.89 ([M+H]+); IR (thin film) 3385, 1112, 816 cm"1.
Step 2. 5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l-enyl)-l- nitrosoindoline (BI16): To (£)- 5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l- enyl)indoline (0.2 g, 0.5 mmol) in concentrated HC1 (5.0 ml) at 5 °C, was added slowly NaN02 in water and the reaction was allowed to stir at RT for 2 h. The reaction mixture 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 reduced pressure to afford the crude product as a pale yellow solid that was used in the next step without further purification (0.2 g): ]H NMR (400 MHz, CDC13) δ 7.33 (d, J = 8.4 Hz, 1H), 7.39 (m, 4H), 6.61 (d, / = 16.0 Hz, 1H), 6.35 (dd, 7 =16.0, 8.4 Hz, 1H), 4.07 (m, 3H), 3.23 (t, / = 8.4 Hz, 2H); ESIMS m/z 418.82 ([M+H]+); IR (thin film) 1488, 1112, 860 cm"1.
Step 3. (£)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l-en-l- yl)indolin-l-amine (BI14): To (£)- 5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l- enyl)-l -nitrosoindoline (0.1 g, 0.2 mmol) in methanol(10.0 mL) was added zinc powder (77.5 mg) and NH4C1 (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 compound, 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+H]+).
Example 31: Preparation of (£)-N-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4- trifluorobut-l-en-l-yl)indolin-l-yl)-3,3,3-trifluoropropanamide (BC12)
Figure imgf000089_0001
To a stirred solution of (£)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l- enyl)indoline-l- amine (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 reaction was stirred at RT for 18 h. The reaction mixture was diluted 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/ petroleum ether) to afford the title compound as a light brown gummy material (0.12 g, 33%): ]H NMR (400 MHz, CDC13) δ 7.32, (d, / = 6.0 Hz, 2H) 7.28 (m, 1H), 7.20 (d, / = 8.0, 1H), 7.14 (d, J = 8.8, 1H ), 6.70 (d, J = 8.0 Hz, 1H), 6.60 (m, 2H), 4.15 (m, 1H), 3.85 (m, 1H), 3.65 (m, 1H), 3.46 (m, 2H), 3.19 (m, 2H); ESIMS m/z 514.86 ([M+H]+); IR (thin film) 3428, 1112, 857 cm-
Example 32: Preparation of fert-butyl-5-vinyl-lH-indole-l-carboxylate (BI17)
Figure imgf000090_0001
Step 1. 5-Vinyl-lH-indole (BI18): A mixture of 5-bromo-lH-indole (2.5 g, 12.82 mmol), potassium vinyltrifluoroborate (2.57 g ,19.2 mmol), Cs2CC>3 (12.53 g, 38.46 mmol) and triphenylphosphine (201 mg, 0.769 mmol) in THF/water (9: 1, 75 ml) was degassed with argon for 20 min, then charged with PdCl2 (45.3 mg,0.256 mmol). The reaction mixture was heated to reflux for 16 h, then cooled to RT, filtered through celite bed and washed with ethyl acetate. The filtrate was again extracted with ethyl acetate, and the combined organic layer washed with water and brine, dried over Na2S04 and concentrated under reduced pressure to afford the crude compound. The crude compound 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%): ]H NMR (400 MHz, CDC13) δ 8.20 (br, 1H), 7.68 (s, 1H), 7.45 (s, 2H), 7.21 (m, 1H), 6.90 (dd, 7 =16.0, 10.8 Hz, 1H), 6.55 (m, 1H), 5.75 (d, / = 10.5 Hz, 1H), 5.21 (d, / = 10.5 Hz, 1H); ESIMS m/z 142.05 ([M-H]").
Step 2. fert-Butyl-5-vinyl-lH-indole-l-carboxylate (BI17): To a stirred solution of 5-vinyl-lH-indole (0.7 g, 4.89 mmol) in acetonitrile (20 ml) was added DMAP (59.65 mg, 0.489 mmol) and di-ieri-butyl dicarbonate (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, 100-200 mesh; 2% ethyl acetate/ petroleum ether) to afford the title compound as an off-white semi-solid (0.7 g, 59%): ]H NMR (400 MHz, CDC13) δ 8.15 (d, J = 8.0 Hz, 1H), 7.60 (s, 2H), 7.30 (d, / = 8.4 Hz, 1H), 7.21 (m, 1H), 6.90 (dd, 7 =16.0, 10.8 Hz, 1H), 6.59 (s, 1H), 5.75 (d, / = 10.5 Hz, 1H), 5.21 (d, / = 10.5 Hz, 1H), 1.65 (s, 9H); ESIMS m/z 242.10 ([M-H]"); IR (thin film) 1630 cm"1.
Example 33: Preparation of {E)-tert-huty\ 5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4- trifluorobut-l-en-l-yl)-
Figure imgf000091_0001
To a stirred solution of ieri-butyl 5-vinyl-lH-indole-l-carboxylate (0.65 g, 2.67 mmol), in 1,2-dichlorobenzene (10.0 mL) was added 5-(l-bromo-2,2,2-trifluoroethyl)-l,3- dichloro-2-fluorobenzene (1.74 g, 5.37 mmol), CuCl (53 mg, 0.537 mmol) and 2,2-bipyridyl (167 mg, 1.07 mmol). The resultant reaction mixture was degassed with argon for 30 min and heated to 150 °C for 2 h. The reaction mixture was cooled to RT and filtered, and the filtrate concentrated under reduced pressure. The crude compound 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 (0.25 g, 10%): ]H NMR (400 MHz, CDC13) δ 8.20 (d, / = 8.0 Hz, 1H), 7.60 (m, 2H), 7.39 (m, 3H), 6.69 (d, J = 16.0 Hz, 1H), 6.55 (d, J = 10.5 Hz, 1H), 6.36 (dd, J = 16.0, 8.0 Hz, 1H), 4.10 (m, 1H), 1.65 (s, 9H); ESIMS m/z 485.91 ([M-H]"); IR (thin film) 1165, 854 cm"1.
Example 34: Preparation of (£')-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l- en-l-yl)-lH-indole (BI20)
Figure imgf000091_0002
To a stirred solution of (E)-tert-buty\ 5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4- trifluorobut-l-enyl)-lH-indole-l-carboxylate (0.2 g, 0.40 mmol) in DCM (10.0 mL) was added TFA (70 mg, 0.61 mmol) and the reaction was stirred at RT for 2 h. The reaction mixture was diluted with DCM and washed with saturated NaHCC>3 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 °C; ]H NMR (400 MHz, CDC13) δ 11.19 (br, 1H), 8.20 (d, / = 8.0 Hz, 1H), 7.60 (m, 2H), 7.39 (m, 3H), 6.69 (d, / = 16.0 Hz, 1H), 6.55 (d, / = 10.5 Hz, 1H), 6.36 (dd, J =16.0, 8.0 Hz, 1H), 4.82 (m, 1H); ESIMS m/z 387.98 ([M+H]+).
Example 35: Preparation of 4 rbonyl)amino)acetate (BI21)
Figure imgf000092_0001
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 HC1 (2.05 g,10.785 mmol) and the reaction was stirred 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): ]H NMR (400 MHz, CDC13) δ 8.29 (d, J = 9.2 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 5.07 (br, 1H), 4.20 (s, 2H), 1.47 (s, 9H); ESIMS m/z 296.27 ([M+H]+).
Example 36: Preparation of (E)-tert-\ \\ty\ (2-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4- trifluorobut-l-en-l-yl)- -indol-l-yl)-2-oxoethyl)carbamate (BI22)
Figure imgf000092_0002
To a stirred solution of (£)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l- enyl)-lH-indole (0.1 g, 0.258 mmol) in acetonitrile (5.0 mL) was added 4-nitrophenyl 2-(tert- butoxycarbonylamino) acetate (0.114 g, 0.387 mmol), potassium fluoride (0.03 g, 0.516 mmol), 18-crown-6-ether (0.075 g, 0.283 mmol) and DIEA (0.0332 g, 0.258 mmol) and the reaction was stirred at RT for 16 h. The reaction 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+H]+).
Example 37: Preparation of (£)- V-(2-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4- trifluorobut-l-en-l-yl)-lH-indol-l-yl)-2-oxoethyl)-3,3,3-trifluoropropanamide (BC13)
Figure imgf000093_0001
Step 1. (£)-2-amino-l-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l- enyl)-lH-indol-l-yl)ethanone (BI23): To a stirred solution of (E)-tert-b ty\ 2-(5-(3-(3,5- dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l-enyl)-lH-indol-l-yl)-2-oxoethylcarbamate (0.05 g, 0.09 mmol) in DCM (5.0 mL) was added TFA (0.01 mL) and the reaction was stirred at RT for 16 h. The reaction mixture was diluted with DCM and washed with saturated NaHCC>3 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 further purification (50 mg).
Step 2. (£)- V-(2-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l-en-l-yl)- lH-indol-l-yl)-2-oxoethyl)-3,3,3-trifluoropropanamide (BC13): To a stirred solution of (£')-2-amino-l-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l-enyl)-lH-indol-l-yl) 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 diluted with DCM, and the DCM layer was washed with water and saturated brine solution .The separated DCM layer was dried over anhydrous 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 °C; ]H NMR (400 MHz, CDC13) δ 8.33 (br, 1H), 7.59 (s, 1H), 7.45 (m, 4H), 6.72 (d, / = 3.6 Hz, 3H) , 6.39 (m, 1H ), 4.71 (t, / = 7.2 Hz, 2H), 4.15 (m, 1H), 3.51 (m, 1H), 3.28 (m, 1H); ESIMS m/z 553.06 ([M-H]").
Example 38: Preparation of ethyl 2-(l-oxo-6-vinylphthalazin-2(lH)-yl)acetate (BI24)
Figure imgf000093_0002
Step 1. 5-Bromo-3-hydroxyisoindoline-l-one (BI25): A mixture of Zn powder (1.73 g, 26.154 mmol), copper (II) sulfate pentahydrate (0.02 g ,0.08 mmol) and 2M aq NaOH (27 mL) were cooled to 0 °C. 5-Bromoisoindoline-l,3-dione (5 g, 22mmol) was added at the same temperature over the period of 30 min. The reaction mixture was stirred at 0 °C for 30 min and 3 h at RT. The reaction mixture was filtered and the filtrate was neutralized with concentrated HC1. The reaction mixture was diluted with ethanol and extracted with ethyl acetate. 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°C; ]H NMR (400 MHz, DMSO-d6) δ 9.03 (br, 1H), 7.81 (m, 2H), 7.69 (m, 1H), 6.44 (m, 1H), 5.88 (d, J = 9.3 Hz, 1H); ESIMS m/z 225.83 ([M-H]"); IR (thin film) 1684, 3246, 606 cm"1.
Step 2. 6-Bromophthalazine-l(2H)-one (BI26): To a stirred solution of 5-bromo-3- hydroxyisoindoline-l-one (1.0 g, 4.40 mmol) in water, was added hydrazine hydrate (0.45 g , 8.80 mmol) and heated to 95°C for 5 h. The reaction mixture was cooled to RT, filtered and washed with diethyl ether and pentane (1: 1) to afford the title compound as a white solid that was used in the next step without further purification (0.5 g): ESIMS m/z 225.15 ([M+H]+).
Step 3. 6-vinylphthalazine-l(2H)-one (BI27): A solution of 6-bromophthalazine- l(2H)-one (0.25 g, 1.11 mmol), potassium vinyl trifluoroborate (0.446 g, 3.33 mmol) and K2CO3 (0.46 g, 3.33 mmol) in DMSO (2 mL) was degassed with argon for 20 min at RT. PdCl2(dppf) (0.04 g, 0.055 mmol) was added at RT, and the reaction mixture was heated to 80 °C for 2 h. The reaction mixture was cooled to RT 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 concentrated under reduced pressure to afford the crude product. The crude compound 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%): ]H NMR (400 MHz, DMSO-d6) δ 13.61 (br, 1H), 8.33 (m, 1H), 8.19 (m, 1H), 8.01 (m, 2H), 6.97 (m, 1H), 6.15 (m, 1H), 5.56 (d, / = 10.8 Hz, 1H); ESIMS m/z 172.93 ([M+H] +); IR (thin film) 1748, 1655, 3241 cm"1.
Step 4. Ethyl-2-(l-oxo-6-vinylphthalazine-2(lH)-yl acetate (BI24): To a stirred solution of 6-vinylphthalazine-l(2H)-one (0.5 g, 2.90 mmol) in DMF (5.0 mL) was added Cs2CC>3 (0.94 g, 2.90 mmol) and the reaction was stirred for 10 min. Ethyl bromoacetate (0.48 g,2.90 mmol) was added to the reaction mixture at RT and the reaction was stirred for 8 h at 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 purified by column chromatography (Si02, 100-200 mesh; 25% ethyl acetate/ petroleum ether) to afford the title compound as a brown solid (0.34 g, 45%): ]H NMR (400 MHz, DMSO-d6) δ 8.45 (m, 1H), 8.24 (m, 1H), 8.04 (m, 2H), 7.01 (m, 1H), 6.17 (d, / = 2.1 Hz, 1H), 5.56 (d, / = 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 (£ ethyl 2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4- trifluorobut-l-en-l-yl)-l-oxophthalazin-2(lH)-yl)acetate (BI28)
Figure imgf000095_0001
To a stirred solution of ethyl-2-(l-oxo-6-vinylphthalazine-2(lH)-yl acetate (0.07 g, 0.27 mmol) in 1,2-dichlorobenzene (1.0 mL) was added 5-(l-bromo-2,2,2-trifluoroethyl)-l,3- dichloro-2fluorobenzene (0.17 g, 0.54 mmol), CuCl (0.005 g, 0.05 mmol) and 2,2-bipyridyl (0.016 g, 0.10 mmol) and the resultant reaction mixture was degassed with argon for 30 min and heated to 180 °C for 12 h. The reaction mixture was cooled to RT and filtered and the filtrated was concentrated 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%): ]H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 8.4 Hz, 1H), 7.84 (d, 7 = 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 (£')-2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut- l-en-l-yl)-l-oxophthalazin-2(lH)-yl)acetic acid (BI29)
Figure imgf000095_0002
A solution of (£')-ethyl-2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l- enyl)-l-oxophthalazin-2(lH)-yl) acetate (0.04 g, 0.07mmol) in HQ (0.5 mL) and acetic acid (0.5 mL) was heated to 100 °C for 3 h. The solvent was removed under reduced pressure and the residue diluted with water. The aqueous layer was extracted with ethyl acetate and the separated ethyl acetate layer dried over anhydrous Na2S04 and concentrated under reduced pressure to afford the crude compound. The crude compound was triturated with diethyl ether-pentane mixture to afford the title compound as a brown solid (0.03 g): ]H NMR (400 MHz, DMSO-d6) δ 13.0 (br s, 1H), 8.43 (m, 1H), 8.23 (d, / = 8.1 Hz, 1H), 8.14 (m, 2H), 7.91 (m, 2H), 7.16 (dd, / =16.0, 8.0 Hz, 1H), 6.99 (d, / = 16.0 Hz, 1H), 4.96 (m, 3H),; ESIMS m/z 473.0 ([M-H]"); IR (thin film) 1629, 1168, 817 cm"1.
Example 41: Preparation of (£')-2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut- l-en-l-yl)-l-oxophthalazin-2(lH)-yl)-N-(2,2,2-trifluoroethyl)acetamide (BC14)
Figure imgf000096_0001
To a stirred solution of (£)-2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l- enyl)-l-oxophthalazin-2(lH)-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 reaction was stirred for 18 h. The reaction mixture was diluted with DCM and washed with 3N HC1 (2 x 20 mL), NaHC03 (2 x 20 mL) and brine solution (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 chromatography (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 °C; ]H NMR (400 MHz, CDC13) δ 8.83 (t, / = 6.6 Hz, 1H), 8.42 (t, / = 14.7 Hz, 1H), 8.22 (d, / = 8.1 Hz, 1H), 8.13 (t, / = 6.3 Hz, 1H), 7.98-7.86 (m, 2H), 7.16 - 7.07 (m, 1H), 7.01 - 6.93 (m, 1H), 4.96 - 4.81 (m, 3H), 4.00 - 3.88 (m, 2H); ESIMS m/z 554.0 ([M-H]").
Example 42: Preparation of 2-(4-vinylbenzyl)isoindoline-l,3-dione (CI1)
Figure imgf000096_0002
To a stirred solution of l-(chloromethyl)-4-vinylbenzene (10 g, 66 mmol) in DMF
(100 mL) was added potassium phthalimide (13.3 g, 72.1 mmol), and the resultant reaction mixture was heated at 70 °C for 16 h. The reaction mixture was diluted with H20 and extracted with CHCI3. The combined CHCI3 layer was washed with brine, dried over Na2S04 and concentrated under reduced pressure. Recrystallization from CH3OH afforded the title compound as an off-white solid (8 g, 46%): ]H NMR (400 MHz, CDC13) δ 7.83 (m, 2H), 7.71 (m, 2H), 7.39 (m, 4H), 6.65 (dd, / = 17.6, 10.8 Hz, 1H), 5.72 (d, / = 17.6 Hz, 1H), 5.21 (d, J = 10.8 Hz , 1H), 4.82 (s, 2H); GCMS m/z 263.2 ([M]+); IR (thin film) 3420, 1133, 718 cm"1. Example 43: Preparation of (£')-2-(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-l-en-l- yl)benzyl)isoindoline-l,3-
Figure imgf000097_0001
Using the procedure of Example 10 with 2-(4-vinylbenzyl)isoindoline-l,3-dione and l-(l-bromoethyl)-3,5-dichlorobenzene as the starting materials, the title compound was isolated as an off-white solid (0.3 g, 40-50%): mp 142-145 °C; ]H NMR (400 MHz, CDC13) δ 7.86 (m, 2H), 7.74 (m, 2H ), 7.42 (m, 2H), 7.36 (m,3H), 7.27 (m, 2H), 6.58 (d, / = 16.0 Hz, 1H), 6.32 (dd, / = 16.0, 8.0 Hz, 1H), 4.82 (s, 2H), 4.05 (m, 1H); ESIMS m/z 488.17 ([M-H]").
The following compound was made in accordance with the procedures disclosed in Example 43.
(£)-2 4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-l-en-l-yl)benzyl)isoindoline-l,3- dione (CI3)
Figure imgf000097_0002
The title compound was isolated as an off white solid (0.3 g, 56%): mp 145-146 °C; ]H NMR (400 MHz, CDC13) δ 7.86 (m, 2H), 7.74 ( m, 2H ), 7.42-7.31 (m, 6H), , 6.58 (d, J = 16.0 Hz, 1H), 6.53 (dd, / = 16.0, 8.0 Hz, 1H), 4.82 (s, 2H), 4.05 (m, 1H); ESIMS m/z 522.2 ([M-H]"); IR (thin film) 1716, 1110, 712 cm"1.
Prophetically, compounds CI4-CI5 (Table 1) could be made in accordance with the procedures disclosed in Example 43.
Example 44: Preparation of (£)-(4-(3,5-dichlorophenyl)-4,4,4-trifluorobut-l-en-l- yl)phenyl)methanamine (CI
Figure imgf000097_0003
To a stirred solution of (£)-2-(4-(3-(3,5-dichlorophenyl)but-l-en-l-yl)benzyl)- isoindoline-l,3-dione (1.2 g, 2.45 mmol) in EtOH was added hydrazine hydrate (0.61 g, 12 mmol), and the resultant reaction mixture was heated at 90 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2CI2, washed with brine, dried over Na2S04, 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.
(£')-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-l-en-l-yl)phenyl)methanamine (CI7)
Figure imgf000098_0001
The title compound was isolated and used without further purification.
Prophetically, compounds CI8-CI9 (Table 1) could be made in accordance with the procedures disclosed in Example 44.
Example 45: Preparation of 4-(bromomethyl)-3-chlorobenzonitrile (CI10)
N
Figure imgf000098_0002
To a stirred solution of 3-chloro-4-methylbenzonitrile (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 azobisisobutyronitrile (AIBN; 0.3 g, 1.8 mmol), and the resultant reaction mixture was heated at reflux for 4 h. The reaction mixture was cooled to ambient temperature, washed with H20, and extracted with CH2C12. The combined CH2C12 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 in n-Hexane) to afford the title compound as a white solid (4.8 g, 68%): mp 87-88 °C; ]H NMR (400 MHz, CDC13) δ 7.71 (s, 1H), 7.59 ( s, 2H ), 4.60 (s, 2H); ESIMS m/z 229.77 ([M+H]+); IR (thin film) 2235, 752, 621 cm"1.
The following compounds were made in accordance with the procedures disclosed in Example 45.
4-(Bromomethyl)-3-(trifluoromethyl)benzonitrile (CI11)
N
Figure imgf000098_0003
The title compound was isolated as an off-white gummy material (5 g, 66%)
NMR (400 MHz, CDC13) δ 7.96 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 4.62 (s, 2H); ESIMS m/z 262.11 ([M-H]"); IR (thin film) 2236, 1132, 617 cm"1.
3-Bromo-4-(bromomethyl)benzonitrile (CI12)
N
Figure imgf000099_0001
The title compound was isolated as an off-white solid(5 g, 67%): mp 82-83 °C; ]H NMR (400 MHz, CDC13) δ 7.90 (s, 1H), 7.61 (m, 2H ), 4.62 (s, 2H); EIMS m/z 272.90; IR (thin film) 2229, 618 cm"1.
4-(Bromomethyl)-3-fluorobenzonitrile (CI13)
Figure imgf000099_0002
The title compound was isolated as an off-white solid (2 g, 60%): mp 79-81 °C; ]H
NMR (400 MHz, CDC13) δ 7.54 (t, J = 8.0 Hz, 1H), 7.48 (dd, J = 8.0 Hz, 8.0, 1H), 7.38 (dd, J = 5 Hz, 1H ), 4.5 (s, 2H); EIMS m/z 215.
Example 46: Preparation of 4-(bromomethyl)-3-chlorobenzaldehyde (CI14)
Figure imgf000099_0003
To a stirred solution of 4-(bromomethyl)-3-chlorobenzonitrile (4.8 g, 17 mmol) in toluene (50 mL) at 0 °C was added dropwise diisobutylaluminum hydride (DIBAL-H, 1.0 M solution in toluene; 23.9 mL), and the reaction mixture was stirred at 0 °C for 1 h. 10 M HCl in 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 CHCI3. The combined organic layer was dried over Na2SC>4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (Si02, 100-200 mesh; 5% EtOAc in n-Hexane) to afford the title compound as a white solid (3.8 g, 80%): mp 64-66 °C; ]H NMR (400 MHz, CDC13) δ 10.00 (s, 1H), 7.92 (s, 1H), 7.78 (d, / = 8.0 Hz, 1H), 7.64 (d, / = 8.0 Hz, 1H), 4.60 (s, 2H); ESIMS m/z 232.78 ([M+H]+). The following compounds were made in accordance with the procedures disclosed in Example 46.
4-(Bromomethyl)-3-(trifluoromethyl)benzaldehyde (CI15)
Figure imgf000100_0001
The title compound was isolated as a pale yellow low-melting solid (5 g, 60%): ]H NMR (400 MHz, CDC13) δ 10.09 (s, IH), 8.19 (s, IH), 8.09 (m, IH), 7.81 (m, IH), 4.61 (s, 2H); ESIMS m/z 265.04 ([M-H]"); IR (thin film) 1709, 1126, 649 cm"1.
3- Bromo-4-(bromomethyl)benzaldeh
Figure imgf000100_0002
The title compound was isolated as a pale yellow solid (5 g, 62%): mp 94-95 °C; ]H NMR (400 MHz, CDC13) δ 9.96 (s, IH), 8.05 (s, IH), 7.81 (d, / = 8.0 Hz, IH), 7.62 (d, / = 8.0 Hz, IH), 4.60 (s, 2H); EIMS m/z 275.90.
4- (Bromomethyl)-3-fluorobenzaldehyde (CI17)
Figure imgf000100_0003
The title compound was isolated as an off-white solid (5 g, 61%): mp 43-45 °C; ]H NMR (400 MHz, CDC13) δ 9.1 (s, IH), 7.54 (t, / = 8 Hz, IH), 7.48 (d, / = 8 Hz, IH), 7.38 (d, / = 5 Hz, IH ), 4.5 (s, 2H); EIMS m/z 216.
Example 47: Preparation of 3-chloro-4-((l,3-dioxoisoindolin-2-yl)methyl)benzaldehyde (CI18)
Figure imgf000100_0004
To a stirred solution of 4-(bromomethyl)-3-chlorobenzaldehyde (3.8 g, 14 mmol) in DMF (40 mL) was added potassium pthalimide (3.54 g, 19.14 mmol), and the mixture was heated at 60°C for 6 h. The reaction mixture was cooled to ambient temperature and diluted with 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 °C; ]H NMR (400 MHz, CDC13) δ 9.95 (s, IH), 8.21 (s, IH), 7.91 (m, 3H), 7.80 (m, 2H), 7.20 (m, IH), 5.05 (s, 2H); ESIMS m/z 298.03 ([M-H] ).
The following compounds were made in accordance with the procedures disclosed in Example 47.
4-((l,3-Dioxoisoindolin-2-yl)-3-(trifluoromethyl)benzaldehyde (CI19)
Figure imgf000101_0001
The title compound was isolated as an off white solid (1 g, 62%): mp 142-143 °C; ]H
NMR (400 MHz, CDC13) δ 10.05 (s, IH), 8.15 (s, IH), 7.91 (m, 2H), 7.80 (m, 3H), 7.27 (m, IH), 5.19 (s, 2H); ESIMS m/z 332.03 ([M-H]").
3-Bromo-4-((l,3-dioxoisoindolin-2-yl)methyl)benzaldehyde (CI20)
Figure imgf000101_0002
The title compound was isolated as an off-white solid (0.5 g, 64%): mp 159-161 °C; ]H NMR (400 MHz, CDC13) δ 9.95 (s, IH), 8.21 (s, IH), 7.91 (m, 3H), 7.80 (m, 2H), 7.20 (m, IH), 5.05 (s, 2H); ESIMS m/z 314.00 ([M-CHO]").
4-((l,3-Dioxoisoindolin-2-yl)-3-fluorobenzaldehyde (CI21)
Figure imgf000101_0003
The title compound was isolated as a white solid (2 g, 60%): mp 154-156 °C; ]H NMR (400 MHz, CDC13) δ 9.95 (s, 1H), 7.9 (m, 2H), 7.75 (m, 2H), 7.6 (m, 2H), 7.5 (t, / = 7.6 Hz, 1H), 5.05 (s, 2H); EIMS m/z 283.1.
Example 48: Preparation of 2-(2-chloro-4-vinylbenzyl)isoindoline-l,3-dione (CI22)
Figure imgf000102_0001
To a stirred solution of 3-chloro-4-((l,3-dioxoisoindolin-2-yl)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 °C for 18 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (Si02, 100-200 mesh; 20% EtOAc in n-Hexane) to afford the title compound as a white solid (1.94 g, 70%): mp 141-143 °C; ]H NMR (400 MHz, CDC13) δ 7.85 (m, 2H), 7.70 (m, 2H), 7.41 (m, 1H), 7.21 (m, 2H), 6.71 (dd, / = 17.6, 10.8 Hz, 1H), 5.72 (d, J = 17.6 Hz, 1H), 5.23 (d, J = 10.8 Hz, 1H), 4.92 (s, 2H); ESIMS m/z 298.10 ([M-H] )·
The following compounds were made in accordance with the procedures disclosed in Example 48.
2-(2-(Trifluoromethyl)-4-vinylbenzyl)isoindoline-l,3-dione (CI23)
Figure imgf000102_0002
The title compound was isolated as a light brown solid (0.5 g, 60%): mp 134-135 °C; ]H NMR (400 MHz, CDC13) δ 7.92 (m, 2H), 7.80 (m, 2H), 7.71 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.16 (d, / = 8.0 Hz, 1H), 6.65 (m, 1H), 5.80 (d, / = 17.8 Hz, 1H), 5.19 (d, / = 10.8 Hz, 1H), 5.09 (s, 2H); ESIMS m/z 332.10 ([M+H]+).
2-(2-Bromo-4-vinylbenzyl)isoindoline-l,3-dione (CI24)
Figure imgf000103_0001
The title compound was isolated as an off white solid (0.5 g, 62%): mp 126-128 °C; ]H NMR (400 MHz, CDC13) δ 7.92 (m, 2H), 7.79 (m, 2H), 7.62 (s, 1H), 7.21 (m, 1H), 7.16 (d, / = 8.0 Hz, 1H), 6.62 (m, 1H), 5.72 (d, / = 17.8 Hz, 1H), 5.15 (d, / = 10.8 Hz, 1H), 4.95 (s, 2H); EIMS m/z 341.10.
2-(2-Fluoro-4-vinylbenzyl)isoindoli -l,3-dione (CI25)
Figure imgf000103_0002
The title compound was isolated as a white solid (0.5 g, 61%): mp 140-142 °C; ]H NMR (400 MHz, CDC13) δ 7.85 (m, 2H), 7.72 (m, 2H), 7.25 (m, 1H), 7.11 (m, 2H), 6.63 (m 1H), 5.80 (d, J = 17.6 Hz, 1H), 5.28 (d, J = 10.8 Hz, 1H), 4.92 (s, 2H); EIMS m/z 282.08. Example 49: Preparation of (£)-2-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4- trifluorobut-l-en-l-yl)benzyl)isoindoline-l,3-dione (CI26)
Figure imgf000103_0003
To a stirred solution of 2-(2-chloro-4-vinylbenzyl)isoindoline-l,3-dione (2.0 g, 6.51 mmol) in 1,2-dichlorobenzene (25 mL) were added l-(l-bromo-2,2,2-trifluoroethyl)-3,5- dichlorobenzene (3.48 g, 11.36 mmol), CuCl (112 mg, 1.13 mmol) and 2,2- bipyridyl (0.35 g). The resultant reaction mixture was degassed with argon for 30 min and then was stirred at 180 °C for 24 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (Si02, 100-200 mesh; 25-30% EtOAc in n-hexane) to afford the title compound as solid (1.3 g, 50%): mp 141-143 °C; ]H NMR (400 MHz, CDC13) δ 7.92 (m, 2H), 7.79 (m, 2H), 7.42 (m, 2H), 7.24 (m, 2H), 7.20 (m, 2H), 6.54 (d, / = 16.0 Hz, 1H), 6.34 (dd, / = 16.0, 8.0 Hz, 1H), 5.00 (s, 2H), 4.10 (m, 1H); ESIMS m/z 524.07 ([M+H]+).
The following compounds were made in accordance with the procedures disclosed in
Example 49.
(£)-2-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en-l- yl)benzyl)isoindoline-l,3-di
Figure imgf000104_0001
The title compound was isolated as a pale white solid (0.2 g, 55%): mp 128-129 °C;
]H NMR (400 MHz, CDC13) δ 7.92 (m, 2H), 7.79 (m, 2H), 7.42 (m, 3H), 7.22 (m, 2H), 6.52 (d, / = 16.0 Hz, 1H), 6.32 (dd, / = 16.0, 8.0 Hz, 1H), 5.00 (s, 2H), 4.05 (m, 1H); ESIMS m/z 557.99 ([M+H]+).
(£)-2-(2-Chloro-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-l-en-l- yl)benzyl)isoindoline-l,3-d
Figure imgf000104_0002
The title compound was isolated as an off white solid (0.2 g, 54%): mp 177-180 °C; ]H NMR (400 MHz, CDCI3) δ 7.90 (m, 2H), 7.77 (m, 2H), 7.42 (s, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.21 (m, 2H), 6.52 (d, / = 16.0 Hz, 1H), 6.32 (dd, / = 16.0, 8.0 Hz, 1H), 5.00 (s, 2H), 4.05 (m, 1H); ESIMS m/z 540.08 ([M-H]"); IR (thin film) 1716 cm"1.
(£)-2-(2-Chloro-4-(3-(3,4-dichlorophenyl)-4,4,4-trifluorobut-l-en-l- yl)benzyl)isoindoline-l,3-dione (CI29)
Figure imgf000105_0001
The title compound was isolated as an off-white solid (0.2 g, 59%): ]H NMR (400 MHz, CDC13) δ 7.89 (m, 2H), 7.76 (m, 2H), 7.47 (m, 3H), 7.21 ( m, 3H), 6.50 (d, / = 16.0 Hz, IH), 6.32 (dd, / = 16.0, 7.6 Hz, IH), 4.97 (s, 2H), 4.11 (m, IH); ESIMS m/z 522.27 ([M- H]~); IR (thin film) 3064, 1717, 1111, 715 cm"1.
(£)-2-(4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-l-en-l-yl)-2-(trifluoromethyl)- benzyl)isoindoline-l,3-dione
Figure imgf000105_0002
The title compound was isolated as an off-white solid (0.2 g, 54%): mp 141-142 °C; ]H NMR (400 MHz, CDC13) 7.94 (m, 2H), 7.80 (m, 2H), 7.69 (s, IH), 7.44 ( m, IH), 7.38 (m, IH), 7.24 (m, 2H), 7.19 ( m, IH ), 6.60 (d, / = 16.0 Hz, IH), 6.39 (dd, / = 16.0, 7.6 Hz, IH), 5.10 (s, 2H), 4.11 (m, IH); ESIMS m/z 556.00 ([M-H]").
(£)-2-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-l-en-l-yl)-2-(trifluoromethyl)- benzyl)isoindoline-l,3-dione
Figure imgf000105_0003
The title compound was isolated as an off-white solid (0.2 g, 56%): mp 130-132 °C; ]H NMR (400 MHz, CDC13) δ 7.94 (m, 2H), 7.80 (m, 2H), 7.69 (s, IH), 7.44 (m, 3H), 7.19 (m, IH), 6.61 (d, / = 16.0 Hz, IH), 6.38 (dd, / = 16.0, 7.6 Hz, IH), 5.10 (s, 2H), 4.12 (m, IH); ESIMS m/z 589.57 ([M-2H]").
(£)-2-(2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en-l-yl)benzyl)- isoindoline-l,3-dione (CI32)
Figure imgf000106_0001
The title compound was isolated as a pale yellow solid (0.2 g, 55%): mp 160-162 °C; ]H NMR (400 MHz, CDC13) δ 7.92 (m, 2H), 7.80 (m, 2H), 7.62 (s, IH), 7.39 (s, 2H), 7.24 (m, IH), 7.16 (m, IH), 6.52 (d, / = 16.0 Hz, IH), 6.32 (dd, / = 16.0, 8.0 Hz, IH), 4.98 (s, 2H), 4.12 (m, IH); ESIMS m/z 599.78 ([M-H]").
(£)-2-(2-Fluoro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en-l-yl)benzyl)- isoindoline-l,3-dione (CI33)
Figure imgf000106_0002
The title compound was isolated as an off-white solid (0.2 g, 55%): mp 72-74 °C; ]H
NMR (400 MHz, CDC13) δ 7.88 (m, 2H), 7.74 (m, 2H), 7.38 (s, 2H), 7.34 (m, IH), 7.18 (m, 2H), 6.54 (d, J = 16.0 Hz, IH), 6.32 (dd, J = 16.0, 8.0 Hz, IH), 4.91 (s, 2H), 4.08 (m, IH); ESIMS m/z 539.89 ([M-H]"); IR (thin film)1773 cm"1.
Prophetically, compounds CI34-CI41 (Table 1) could be made in accordance with the procedures disclosed in Example 49.
Example 50: Preparation of (£')-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut- l-en-l-yl)phenyl)methana
Figure imgf000106_0003
To a stirred solution of (£')-2-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut- l-en-l-yl)benzyl)isoindoline-l,3-dione (0.4 g, 0.76 mmol) in EtOH was added hydrazine hydrate (0.38 g, 7.6 mmol), and the resultant reaction mixture was heated at 80 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2CI2, washed with brine, dried over Na2SC>4, and concentrated under reduced pressure to afford the title compound as a gummy liquid (0.3 g), which was carried on to the next step without further purification.
The following compounds were made in accordance with the procedures disclosed in Example 50.
(£)-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en-l-yl)phenyl)- methanamine (CI43)
Figure imgf000107_0001
The product obtained in this reaction was carried on to the next step without further purification.
(£)-(2-Chloro-4-(3-(3,4-dichlorophenyl)-4,4,4-trifluorobut-l-en-l-yl)phenyl)- methanamine (CI44)
Figure imgf000107_0002
The product obtained in this reaction was carried on to the next step without further purification.: ]H NMR (400 MHz, CDC13) δ 7.48 (d, J = 8.4 Hz, 2H), 7.39 (m, 2H), 7.23 (m, 2H), 6.52 (d, / = 16.0 Hz, 1H), 6.38 (dd, / = 16.0, 7.6 Hz, 1H), 4.12 (m, 1H), 3.90 (s, 2H); ESIMS m/z 391.90 ([M-H]"); IR (thin film) 3370, 3280, 1111, 817 cm"1.
(£)-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-l-en-l-yl)-2-(trifluoromethyl)- phenyl)methanamine (CI45
Figure imgf000107_0003
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.
Figure imgf000108_0001
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.
(£)-(2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en-l-yl)phenyl)- methanamine (CI47)
Figure imgf000108_0002
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.
(£)-(2-Fluoro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en-l-yl)phenyl)- methanamine (CI48)
Figure imgf000108_0003
The title compound was isolated as a gummy material: ]H NMR (400 MHz, CDC13) δ 7.40 (s, 2H), 7.33 (t, 7 = 7.6 Hz, IH), 7.13 (m, 2H), 6.56 (d, / = 16.0 Hz, IH), 6.33 (dd, / =
16.0, 7.6 Hz, IH), 4.08 (m, IH), 3.90 (s, 2H); ESIMS m/z 413.84 ([M+H]+); IR (thin film)
3368, 3274, 1114, 808 cm"1.
Prophetically, compounds CI49-CI57 (Table 1) could be made in accordance with the procedures disclosed in Example 50.
Example 51: Preparation of 3-chloro-4-((pyridin-2-ylamino)methyl)benzaldehyde
(CI58)
Figure imgf000108_0004
To a stirred solution of 4-(bromomethyl)-3-chlorobenzaldehyde (2 g, 9 mmol) in N,N- dimethylacetamide (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 in n-Hexane) to afford the title compound as off-white solid (1.05 g, 50%): mp 122-123 °C; ]H NMR (400 MHz, CDC13) δ 9.94 (s, 1H), 8.11 (s, 1H), 7.88 (s, 1H), 7.72 (d, J = 4.8 Hz, 1H), 7.62 (d, J = 5.7 Hz, 1H), 7.4 (m, 1H), 6.64 (d, J = 3.9 Hz, 1H), 6.38 (d, J = 6.3 Hz, 1H), 5.04 (br s, 1H), 4.71 (s, 2H); ESIMS m/z 246.97 ([M+H]+). Example 52: Preparation of A -(2 idin-2-amine (CI59)
Figure imgf000109_0001
To a stirred solution of 3-chloro-4-((pyridin-2-ylamino)methyl)benzaldehyde (1 g, 4. mmol) in 1,4-dioxane (20 mL) were added K2C03 (0.84 g, 6.09 mmol) and methyl triphenyl phosphonium bromide (2.17 g, 6.09 mmol) at ambient temperature. Then the resultant reaction mixture was heated at 100 °C for 18 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (Si02, 100-200 mesh; 10% EtOAc in n-Hexane) to afford the title compound as a white solid (0.5 g, 50%): mp 119-121 °C; ]H NMR (400 MHz, CDC13) δ 8.12 (s, 1H),
7.42 - 7.40 (m, 3H), 7.26 (s, 1H), 6.66 (m, 2H), 6.36 (d, J = 6.3 Hz, 1H), 5.75 (d, J = 13.2
Hz, 1H), 4.92 (br s, 1H), 4.60 (s, 2H); ESIMS m/z 245.05 ([M+H]+).
Example 53: Preparation of ethyl 2-amino-2-(5-bromo-3-chloropyridin-2-yl)acetate
(CI60)
Figure imgf000109_0002
Ethyl 2-(diphenylmethyleneamino)acetate (10.2 g, 38.2 mmol) was added to sodium hydride (NaH; 3.18 g, 133.52 mmol) in DMF (50 mL) at 0 °C, and the mixture was stirred for 30 min. To this was added 5-bromo-2,3-dichloropyridine (12.9 g, 57.23 mmol), and the reaction mixture was stirred for 3 h at ambient temperature. The reaction mixture was quenched with 2 N HCl solution and then stirred for 4 h at ambient temperature. The mixture was extracted with EtOAc. The combined EtOAc layer was washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure. Purification by flash column chromatography (20-30% EtOAc in hexane) afforded the title compound as a liquid (1.3 g, 20%): ]H NMR (400 MHz, CDC13) δ 8.52 (s, 1H), 7.89 (s, 1H ), 5.09 (slH), 4.23 (m, 2H), 2.27 (br s, 2H), 1.26 (m, 3H); ESIMS m/z 293.05 ([M+H]+); IR (thin film) 3381, 3306, 1742, 759, 523 cm"1.
Example 54: Preparation of (5-bromo-3-chloropyridin-2-yl)methanamine hydrochloride (CI61)
Figure imgf000110_0001
A stirred solution of ethyl 2-amino-2-(5-bromo-3-chloropyridin-2-yl)acetate (0.5 g, 1.7 mmol) in 3 N HCl (25 mL) was heated at reflux for 4 h. The reaction mixture was washed with diethyl ether and H20. The combined ether layer was concentrated under reduced pressure to afford the title compound as an off-white solid (400 mg, 65%): ]H NMR (400 MHz, CDCI3) δ 8.78 (s, 1H), 8.70 (br s, 2H), 8.45 (s, 1H), 4.56 (m, 2H); ESIMS m/z 221.15 «M+H]+).
Example 55: Preparation of 2-((5-bromo-3-chloropyridin-2-yl)methyl)isoindoline-l,3- dione (CI62)
Figure imgf000110_0002
To a stirred solution of (5-bromo-3-chloropyridin-2-yl)methanamine hydrochloride
(0.3 g, 1.4 mmol) in toluene (40 mL) was added 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 residue was diluted with H20 and extracted with EtOAc . The combined EtOAc layer was washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure. The residue was purified by column chromatography (20-30% EtOAc in hexane) to afford the title compound as a white solid (0.25 g, 65%): ]H NMR (400 MHz, CDC13) δ 8.78 (s, 1H), 8.45 (s, 1H), 7.88 (m, 2H), 7.74 ( m, 2H), 4.56 (m, 2H); ESIMS mJz 349 ([M-H]"); IR (thin film) 3307, 1665, 1114, 813 cm"1.
Example 56: Preparation of 2-((3-chloro-5-vinylpyridin-2-yl)methyl)isoindoline-l,3- dione (CI63)
Figure imgf000111_0001
To a stirred solution of 2-((5-bromo-3-chloropyridin-2-yl)methyl)isoindoline-l,3- dione (0.23 g, 0.65 mmol) in toluene (10 mL) were added Pd(PPh3)4 (3.7 mg, 0.003 mmol), K2CO3 (0.269 g, 1.95 mmol) and vinyl boronic anhydride pyridine complex (0.78 g, 3.28 mmol), and the reaction mixture was heated at reflux for 16 h. The reaction mixture was filtered, and the filtrate was washed with 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%): ]H NMR
(400 MHz, CDCI3) δ 8.30 (s, 1H), 7.91 (m, 2H), 7.77 (m, 3H), 7.72 (m, 1H), 6.63 (m, 5.79 (d, / = 16.0 Hz, 1H), 5.39 (d, / = 16.0 Hz, 1H), 5.12 (s, 2H); ESIMS mJz 299.20 «M+H]+).
Example 57: Preparation of (£)-2-((3-chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichloro- phenyl)but-l-en-l-yl)pyridin-2-yl)methyl)isoindoline-l,3-dione (CI64)
Figure imgf000111_0002
To a stirred solution of 2-((3-chloro-5-vinylpyridin-2-yl)methyl)isoindoline-l,3-dione (0.35 g, 1.17 mmol) in 1 ,2-dichlorobenzene (10 mL) were added 5-(l-bromo-2,2,2- trifluoroethyl)-l,2,3-trichlorobenzene (0.8 g, 2.3 mmol), CuCl (23 mg, 0.12 mmol), 2,2- bipyridyl (0.073 g, 0.234 mmol), and the reaction mixture was heated at 180 °C for 16 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (20-30% EtOAc in hexane) to afford the title compound as a liquid (0.4 g, 50%): mp 79-82 °C; ]H NMR (400 MHz, CDC13) δ 8.27 (s, 1H), 7.91 (m, 2H), 7.77 (m, 3H), 7.36 (s, 2H), 6.51 (d, / = 15.6 Hz, 1H), 6.32 (dd, / = 15.6, 8.0 Hz, 1H), 5.30 (s, 2H), 4.13 (m, 1H); ESIMS m/z 559 ([M+H]+).
Example 58: Preparation of (£)-(3-chloro-5-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-en-l-yl)pyridin-2-yl)methanamine (CI65)
Figure imgf000112_0001
To a stirred solution of (£)-2-((3-chloro-5-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-en-l-yl)pyridin-2-yl)methyl)isoindoline-l,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 CH2CI2. 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 purification.
Example 59: Preparation of 4-(bromomethyl)-l-naphthonitrile (CI66)
Figure imgf000112_0002
To a stirred solution of 4-methyl-l-naphthonitrile (5 g, 30 mmol) in CC14 (50 mL) under argon atmosphere was added NBS (6.06 g, 34.09 mmol), and the reaction mixture was degassed for 30 min. AIBN (0.3 g, 2.1 mmol) was added, and the resultant reaction mixture was heated at reflux for 4 h. The reaction mixture was cooled to ambient temperature, diluted with H20 and extracted with CH2C12 (3 x 100 mL). The combined CH2C12 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; 5% EtOAc in n-Hexane) to afford the title compound as a white solid (3.8 g, 52%): mp 131-133 °C; ]H NMR (400 MHz, CDCI3) δ 8.33 (m, 1H), 8.24 (m, 1H), 7.88 (d, / = 8.0 Hz, 1H), 7.78 (m, 2H), 7.62 (d, / = 8.0 Hz, 1H), 4.95 (s, 2H); ESIMS m/z 245.92 ([M+H]+); IR (thin film) 2217 cm"1.
Example 60: Preparation of 4-(bromomethyl)-l-naphthaldehyde (CI67)
Figure imgf000113_0001
To a stirred solution of 4-(bromomethyl)-l-naphthonitrile (8 g, 33mmol) in toluene (100 mL) at 0 °C was added dropwise DIBAL-H (1.0 M solution in toluene; 43 mL), and the reaction mixture was stirred at 0 °C for 1 h. 3 N HC1 in H20 (50 mL) was added to the mixture until it became a white slurry and then additional 1 N HC1 (20 mL) was added. The organic layer was collected and the aqueous layer was extracted with EtOAc (3 xlOO 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 °C; ]H NMR (400 MHz, CDC13) δ 10.41 (s, 1H), 9.35 (m, 1H), 8.22 (m, 1H), 7.90 (d, / = 8.0 Hz, 1H), 7.75 (m, 3H), 4.95 (s, 2H); ESIMS m/z 248.88 ([M+H]+).
Example 61: Preparation of 4-((l,3-dioxoisoindolin-2-yl)methyl)-l-naphthaldehyde (CI68)
Figure imgf000113_0002
To a stirred solution of 4-(bromomethyl)-l-naphthaldehyde (7 g, 28. mmol) in DMF
(100 mL) was added potassium phthalimide (7.3 g, 39.5 mmol), and the mixture was heated at 85 °C for 2 h. The reaction mixture was cooled to ambient temperature and diluted with H20 (100 mL). The obtained solid was separated by filtration and dried under vacuum to afford the title compound as a white solid (8.8 g, 98%): mp 190-192 °C; ]H NMR (400 MHz, CDCI3) δ 10.39 (s, 1H), 9.25 (m, 1H), 8.41 (m, 1H), 8.10 (d, / = 8.0 Hz, 1H), 7.95 (m, 4H), 7.80 (m, 4H), 7.61 (m, 4H), 5.39 (s, 2H); ESIMS m/z 316.09 ([M+H]+); IR (thin film) 1708 cm"1.
Example 62: Preparation of 2-((4-vinylnaphthalen-l-yl)methyl) isoindoline-l,3-dione (CI69)
Figure imgf000114_0001
To a stirred solution of 4-((l,3-dioxoisoindolin-2-yl)methyl)-l-naphthaldehyde (9 g, 28.5 mmol) in 1,4-dioxane (100 mL) were added K2CO3 (6 g, 42.8 mmol) and methyl triphenyl phosphonium bromide (15.3 g, 35.7 mmol) at ambient temperature. The reaction mixture was heated at 100 °C for 14 h and then was cooled to ambient temperature. The reaction mixture was filtered, and the obtained filtrate was concentrated under reduced pressure. Purification by flash chromatography (Si02, 100-200 mesh; 20% EtOAc in petroleum ether) afforded the title compound as a white solid (6 g, 67%): mp 146-147 °C; ]H NMR (400 MHz, CDC13) δ 8.35 (m, 2H), 7.95 (m, 4H), 7.65 (m, 4H), 7.39 (m, 1H), 5.81 (m, 1H), 5.45 (m, 1H), 5.21 (s, 2H); ESIMS mJz 314.13 ([M+H]+).
Example 63: Preparation of (£')-2-((4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en- l-yl)naphthalen-l-yl)methyl)isoindoline-l,3-dione (CI70)
Figure imgf000114_0002
To a stirred solution of 2-((4-vinylnaphthalen-l-yl)methyl)isoindoline-l,3-dione (1.5 g, 4.79 mmol) in 1,2-dichlorobenzene (15 mL) were added l-(l-bromo-2,2,2-trifluoroethyl)- 3,4,5-trichlorobenzene (3.2 g, 9.5 mmol), CuCl (24 mg, 0.24 mmol) and 2,2-bipyridyl (0.149 g, 0.95 mmol), and the resultant reaction mixture was degassed with argon for 30 min and then stirred at 180 °C for 14 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (Si02, 100-200 mesh; 25-30% EtOAc in petroleum ether) afforded the title compound as an off-white solid (1.5 g, 56%): mp 158-160 °C; ]H NMR (400 MHz, CDC13) δ 8.40 (m, 1H), 7.89 (m, 2H), 7.74 (m, 2H), 7.64 (m, 2H), 7.58 (m, 2H), 7.46 (s, 2H), 7.36 (m, 2H), 6.31 (m, 1H), 5.30 (s, 2H), 4.21 (m, 1H); ESIMS m/z 572.08 ([M-H]").
Example 64: Preparation of (£)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en-l- yl)naphthalen-l-yl)methanamine (CI71)
Figure imgf000115_0001
To a stirred solution of (£)-2-((4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en-l- yl)naphthalen-l-yl)methyl)isoindoline-l,3-dione (0.4 g, 0.7 mmol) in EtOH was added hydrazine hydrate (0.18 g, 3.5 mmol), and the resultant reaction mixture was heated at 80 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2CI2, and the solution was washed with brine, dried over Na2SC>4, and concentrated under reduced pressure. The title compound was isolated as a gummy liquid (150 mg, 50%). The product obtained in this reaction was carried on to the next step without further purification.
Example 65: Preparation of 2-((4-bromophenyl)amino)isoindoline-l,3-dione (CI72)
Figure imgf000115_0002
To a stirred solution of (4-bromophenyl)hydrazine hydrochloride (0.5 g, 2.2 mmol) in glacial acetic acid (8 mL) was added phthalic anhydride (0.398 g, 2.690 mmol), and the reaction mixture was stirred at 130 °C for 1 h under a nitrogen atmosphere. The reaction mixture was quenched with satd aq. NaHCC>3 solution and filtered to give a solid. Purification by column chromatography (Si02, 0-10% EtOAc in petroleum ether) afforded the title compound as a solid (60 mg, 84%): mp 205-206 °C; ]H NMR (400 MHz, CDC13) δ 8.71 (s, 1H), 7.99 (m, 4H), 7.32 (d, / = 8.8 Hz, 2H), 6.79 (d, / = 8.8 Hz, 2H); ESIMS m/z 314.95 ([M-H] ).
Example 66: Preparation of 2-((4-vinylphenyl)amino)isoindoline-l,3-dione (CI73)
Figure imgf000115_0003
To a solution of 2-(4-bromophenylamino)isoindoline-l,3-dione (2 g, 6. mmol) in 1,2- dimethoxyethane (20 mL) and H20 (4 mL) were added vinyl boronic 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 °C 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 °C; ]H NMR (400 MHz, CDC13) δ 8.65 (s, 1H), 7.94 (m, 4H), 7.29 (d, / = 8.4 Hz, 2H), 6.72 (d, 7 = 8.4 Hz, 2H), 6.61 (m, 1H), 5.61 (d, / = 17.6 Hz, 1H), 5.05 (d, / = 11.2 Hz, 1H); ESIMS m/z 263.18 ([M-H] ).
Example 67: Preparation of (£)-2-((4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en- l-yl)phenyl)amino)isoin
Figure imgf000116_0001
To a stirred solution of 2-(4-vinylphenylamino)isoindoline-l,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-(l-bromo-2,2,2-trifluoroethyl)-l,2,3-trichlorobenzene (0.77 g, 2.27 mmol). The reaction mixture was degassed with argon for 30 min and was heated at 180 °C for 2 h. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (Si02, 0-30% EtOAc in petroleum ether) to afford the title compound as a solid (450 mg, 75%): mp 187-189 °C; ]H NMR (400 MHz, CDC13) δ 8.75 (s, 1H), 7.96 (m, 4H), 7.82 (s, 2H), 7.37 (d, / = 8.8 Hz, 1H), 6.73 (d, / = 8.4 Hz, 2H), 6.61 (m, 2H), 6.58 (m, 1H), 4.59 (m, 1H); ESIMS m/z 523.05 ([M-H]").
Example 68: Preparation of (£)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en-l- yl)phenyl)hydrazine (CI75)
Figure imgf000116_0002
To a stirred solution of (£)-2-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l- enyl)phenylamino)isoindoline-l,3-dione (0.16 g, 0.31 mmol) in EtOH (5 mL), was added hydrazine hydrate (0.076 g, 1.52 mmol), and the reaction mixture was heated at 85 °C for 1 h. The reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a solid (0.08 g, 66%) which was carried on to the next step without further purification. Example 69: Preparation of 2-(4-vinylphenoxy)isoindoline-l,3-dione (CI76)
Figure imgf000117_0001
To a stirred solution of 4-vinylphenylboronic acid (2 g, 13 mmol), 2- hydroxyisoindoline-l,3-dione (3.63 g, 24.53 mmol), and CuCl (1.214 g 12.26 mmol) in 1,2- dichloroethane (50 mL) was added pyridine (1.065 g, 13.48 mmol), and the resultant reaction mixture was stirred at ambient temperature for 48 h. The reaction mixture was diluted with H20 and extracted with CHCI3. The combined CHCI3 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 °C; ]H NMR (400 MHz, CDC13) δ 7.93 (d, J = 2.0 Hz, 2H), 7.82 (d, J = 3.2 Hz, 2H), 7.38 (d, J = 2.0 Hz, 2H), 7.14 (d, J = 2.0 Hz, 2H), 6.70 (m, 1H), 5.83 (d, / = 16.0 Hz, 1H), 5.22 (d, / = 10.8 Hz, 1H); ESIMS m/z 266.12 ([M+H]+). Example 70: Preparation of (£)-2-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en- l-yl)phenoxy)isoindoline- -dione (CI77)
Figure imgf000117_0002
To a stirred solution of 2-(4-vinylphenoxy)isoindoline-l,3-dione (0.3g, 1.1 mmol) in 1,2-dichlorobenzene (10 mL) was added l-(l-bromoethyl)-3,4,5-trichlorobenzene (769 mg, 2.26 mmol), CuCl (22 mg, 0.22mmol) and 2,2-bipyridyl (35 mg, 0.44 mmol), and the resultant reaction mixture was degassed with argon for 30 min and heated to 180 °C for 24 h. The reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by column
chromatography (Si02, 100-200 mesh; 20% EtOAc in petroleum ether) to afford the title compound as a solid (0.29 g, 50%): ]H NMR (400 MHz, CDC13) δ 7.90 (m, 1H), 7.62 (m, 2H), 7.50 (m, 1H), 7.40 (s, 2H), 7.12 (s, 1H), 6.90 (m, 2H), 6.60 (m, 2H), 6.20 (m,lH), 4.08 (m, 1H); ESIMS m/z 524.09 ([M-H]").
Example 71: Preparation of (£')-0-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en- l-yl)phenyl)hydroxylamine (CI78)
Figure imgf000118_0001
To a stirred solution of (£)-2-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l- enyl)phenoxy)isoindoline-l,3-dione (0.2 g, 0.4 mmol) in EtOH was added hydrazine hydrate (0.1 g, 1.9 mmol), and the resultant reaction mixture was heated at 90 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2CI2. 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%): ]H NMR (400 MHz, CDC13) δ 7.40 (s, 2H), 6.98 (s, 1H), 6.82 (s, 2H), 6.48 (m, 1H), 6.20 (m, 1H), 5.02 (s, 1H), 4.08 (m, 1H); ESIMS m/z 394.94 ([M-H]").
Example 72: Preparation of (£)- V-(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-l- enyl)benzyl)acetamide (CC
Figure imgf000118_0002
To a stirred solution of (£)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-l- en-l-yl)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 (Si02, 100-200 mesh; 30-50% ethyl acetate in hexane) afforded the title compound as an off- white solid (0.2 g, 60%) mp 107-109 °C; ]H NMR (400 MHz, CDC13) δ 7.37 (m, 3H), 7.28 (m, 4H), 6.60 (d, / = 16.0 Hz, 1H), 6.36 (dd, / = 16.0, 8.0 Hz, 1H), 5.75 (br s, 1H), 4.46 (d, J = 6 Hz, 2H), 4.01 (m, 1H), 2.11 (s, 3H); ESIMS m/z 402.00 ([M+H]+).
Compounds CC2 - CC6 in Table 1 were made in accordance with the procedures disclosed in Example 72. In addition, compound DC56 in Table 1 was made from compound DC55 in accordance with the procedures disclosed in Example 72.
Example 73: Preparation of (£ N-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4- trifluorobut-l-en-l-yl)benzyl)acetamide (CC7)
Figure imgf000119_0001
To a stirred solution of (£)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-l- en-l-yl)phenyl)methanamine (0.3 g, 0.8 mmol) in DMF (5 mL) was added 2,2,2-trifluoro- propanoic acid (97 mg, 0.76 mmol), HOBfH20 (174 mg, 1.14 mmol) and EDOHCl (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 mixture was diluted with H20 and extracted with EtOAc. The combined EtOAc layer was washed with brine, dried over Na2S04, and concentrated under reduced pressure. Purification by flash column
chromatography (Si02, 100-200 mesh; ethyl acetate in hexane (30-50% afforded the title compound as an off-white solid (0.2 g, 60%): mp 127-128 °C; ]H NMR (400 MHz, CDC13) δ 7.42 (m, 4H), 7.24 (m, 2H), 6.53 (d, / = 16.0 Hz, 1H), 6.36 (dd, / = 16.0, 8.0 Hz, 1H) , 5.86 (br s, 1H), 4.51 (d, / = 6.0 Hz, 2H), 4.05 (m, 1H), 2.02 (s, 3H); ESIMS m/z 436.03 ([M+H]+).
Compounds CC8 - CC28 in Table 1 were made in accordance with the procedures disclosed in Example 73.
Example 74 : Preparation of (£)- V-(pyridin-2-ylmethyl)- V-(4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-enyl)-2-(trifluoromethyl)benzyl)cyclopropanecarboxamide (CC29)
Figure imgf000119_0002
Step 1 : (£)-l-(Pyridin-2-yl)- V-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l- enyl)-2-(trifluoromethyl)benzyl)methanamine. (£)-(4-(4,4,4-Trifluoro-3-(3,4,5- trichlorophenyl)but-l-en-l-yl)-2-(trifluoromethyl)phenyl)methanamine (0.46 g, 1 mmol) was dissolved in CH3OH (3 mL). To this was added pyridine-2-carbaldehyde (0.107 g, 1 mmol). The reaction mixture was stirred for 1 h. After 1 h, NaBH4 (0.076 g, 2 mmol) was added and left at ambient temperature for 3 h. The reaction mixture was concentrated to give an oily residue. Purification by flash column chromatography (Si02, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a pale yellow liquid (0.22 g, 40%): ]H NMR (400 MHz, CDCI3) δ 8.58 (d, /= 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, / = 16.0 Hz, 1H), 6.38 (dd, / = 16.0, 8.0 Hz, 1H), 4.10 (m, 1H), 4.02 (s, 2H), 3.96 (s, 2H); ESIMS m/z 552.95 ([M+H]+); IR (thin film) 3338, 1114, 808 cm"1.
Step 2 : (£)- V-(Pyridin-2-ylmethyl)- V-(4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-enyl)-2-(trifluoromethyl)benzyl)cyclopropanecarboxamide. (£)-l- (Pyridin-2-yl)-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en-l-yl)-2- (trifluoromethyl)benzyl)methanamine (0.27 g, 0.05 mmol) was taken up in CH2CI2 (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 cyclopropylcarbonyl chloride (0.08 mL, 0.075 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 h and then was washed with H20 and satd aq NaHCC>3 solution. The organic layer was dried over anhydrous Na2S04 and evaporated to obtain pale yellow gummy material (0.15 g, 50%): ]H NMR (400 MHz, CDC13) δ 8.58 (d, J = 4.6 Hz, 1H), 7.74 (m, 1H), 7.62 (m, 2H), 7.52 (m, 1H), 7.4 (s, 2H), 7.3 (m, 1H), 7.2 (m, 2H), 6.60 (d, J = 16.0 Hz, 1H), 6.38 (dd, J = 16.0, 8.0 Hz, 1H), 5.02 (s, 1H), 4.8 (s, 1H), 4.8 (d, / = 10 Hz, 2H), 4.10 (m, 1H), 1.8 (m, 1H), 1.2 (m, 2H), 0.6 (m, 2H); ESIMS m/z 620.86 ([M-H] ); IR (thin film) 1645, 1115, 808 cm"1. Example 75: Preparation of (£)- V-(2-chloro-4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-en-l-yl)benzyl)-3-(methylsulfonyl)propanamide (CC30)
Figure imgf000120_0001
(£')-N-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en-l-yl)benzyl)-3- (methylthio)propanamide (0.15 g, 0.28 mmol) was treated with oxone (0.175 g, 0.569 mmol) in 1 : 1 acetone: water (20mL) for 4 h at ambient temperature. The acetone was evaporated to obtain a white solid (0.095 g, 60%): mp 101-104 °C; ]H NMR (400 MHz, CDC13) δ 7.41 (m, 4H), 7.24 (m, 1H), 6.53 (d, / = 16.0 Hz, 1H), 6.35 (dd, / = 16.0, 8.0 Hz, 1H), 6.12 (br s, 1H), 4.53 (m, 2H), 4.10 (m, 1H), 3.42 (m, 2H), 2.91 (s, 3H), 2.78 (m, 2H); ESIMS m/z 559.75 ([M-H] ).
Example 76: Preparation of (£)-l-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4- trifluorobut-l-en-l-yl)benzyl)-3-ethylurea (CC31)
Figure imgf000121_0001
To a stirred solution of (£)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-l- en-l-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2CI2 (5 mL) at 0 °C were added Et3N (0.141 mL, 1 mmol) and ethylisocyanate (0.053 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0 °C. The reaction mixture was diluted with CH2CI2. The organic layer was washed with ¾0 and brine, dried over Na2S04, and concentrated under reduced pressure. Purification by column chromatography (S1O2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.141 g, 60%): mp 177-178 °C; ]H NMR (400 MHz, CDCI3) δ 7.58 (m, 2H), 7.41 (m, 3H), 7.24 (m, 1H), 6.53 (d, / = 16.0 Hz, 1H), 6.35 (dd, / = 16.0, 8.0 Hz, 1H), 4.70 (br s, 1H), 4.43 (s, 2H), 4.08 (m, 1H), 3.21 (m, 2H), 1.25 (m, 3H); ESIMS m/z 463 ([M-H]").
Compounds CC32 - CC35 in Table 1 were made in accordance with the procedures disclosed in Example 76.
Example 77: Preparation of (£)-3-(2-chloro-4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-en-l-yl)benzyl)-l,l-dimethylurea (CC36)
Figure imgf000121_0002
To a stirred solution of (£)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut- l-en-l-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2CI2 (5 mL) at 0 °C 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 °C. The reaction mixture was diluted with CH2CI2. The organic layer was washed with ¾0 and brine, dried over Na2S04, and concentrated under reduced pressure. Purification by column chromatography (S1O2, 100-200 mesh; 30- 50% EtOAc in hexane) afforded the title compound as a solid (0.15 g, 60%): ]H NMR (400 MHz, CDCI3) δ 7.39 (m, 4H), 7.28 (m, 1H), 6.54 (d, / = 16.0 Hz, 1H), 6.34 (dd, / = 16.0, 8.0 Hz, 1H), 4.97 (br s, 1H), 4.38 (d, J = 6.0 Hz, 2H), 4.10 (m, 1H), 2.9 (s, 3H), 2.7 (s, 3H); ESIMS m/z 497 ([M-H]"); IR (thin film) 3350, 1705, 1114, 808 cm"1.
Example 78: Preparation of (£ l-(2-chloro-4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-en-l-yl)benzyl)-3-ethylthiourea (CC37)
Figure imgf000122_0001
To a stirred solution of (£)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut- l-en-l-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2CI2 (5 mL) at 0 °C 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 CH2CI2. The organic layer was washed with H2O and brine, dried over Na2S04, and concentrated under reduced pressure. Purification by column chromatography (S1O2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.14 g, 60%): mp 88-91 °C; ]H NMR (400 MHz, CDCI3) δ 7.49 (d, / = 8 Hz, 1H), 7.41 (d, J = 7.2 Hz, 2H), 7.26 (m, 2H), 6.50 (d, / = 16 Hz, 1H), 6.35 (dd, J = 16.0, 8.0 Hz, 1H), 6.0 (br s, 1H), 5.73 (br s, 1H), 4.80 (br s, 2H), 4.09 (m, 1H), 1.23 (m, 3H); ESIMS m/z 515.01 ([M+H]+).
Compound CC38 in Table 1 was made in accordance with the procedures disclosed in Example 78.
Example 79: Preparation of (E)-tert-\ \\ty\ (2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4- trifluorobut-l-en-l-yl)benzyl)-3-ethylurea (CC39)
Figure imgf000122_0002
To a stirred solution of (£)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut- l-en-l-yl)phenyl)methanamine (0.2 g, 0.5 mmol in CH2CI2 (5 mL) at 0 °C were added Et3N (0.141 mL, 1 mmol) and di-ieri-butyl dicarbonate (0.163 mL, 0.75 mmol), and the reaction mixture was stirred for 4 h at ambient temperature. The reaction mixture was diluted with CH2CI2. The organic layer was washed with ¾0 and brine, dried over Na2S04, and concentrated under reduced pressure. Purification by column chromatography (S1O2, 100-200 mesh; 10-20% EtOAc in hexane) afforded the title compound as a white solid (0.147 g, 60%): ]H NMR (400 MHz, CDC13) δ 7.39 (m, 4H), 7.28 (m, 1H), 6.54 (d, / = 16.0 Hz, 1H), 6.34 (dd, 7 = 16.0, 8.0 Hz, 1H), 4.97 (br s, 1H), 4.38 (d, / = 6.0 Hz, 2H), 4.10 (m, 1H), 1.53 (s, 9H); ESIMS m/z 526.09 ([M-H]"); IR (thin film) 3350, 1705, 1114, 808 cm"1.
Compound CC40 in Table 1 was made in accordance with the procedures disclosed in Example 79. Example 80: Preparation of (£ methyl 2-((2-chloro-4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-en-l-yl)benzyl)amino)-2-oxoacetate (CC41)
Figure imgf000123_0001
To a stirred solution of (£)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut- l-en-l-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2CI2 (5 mL) at 0 °C were added Et3N (0.141 mL, 1 mmol) and methyl 2-chloro-2-oxoacetate (0.09 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0 °C. The reaction mixture was diluted with CH2CI2. The organic layer was washed with ¾0 and brine, dried over Na2S04, and concentrated under reduced pressure. Purification by column chromatography (S1O2, 100-200 mesh; 20% EtOAc in hexane) afforded the title compound as a solid (0.12 g, 50%): ]H NMR (400 MHz, CDC13) δ 7.48 (m, 1H). 7.43 (m, 3H), 7.38 (m, 1H), 7.23 (s, 1H), 6.55 (d, / = 16.0 Hz, 1H), 6.36 (dd, / = 16.0, 8.0 Hz, 1H), 4.60 (d, / = 4.4 Hz, 2H), 4.18 (m, 1H), 3.85 (s, 3H); ESIMS m/z 512.22 ([M-H]"); IR (thin film) 1740, 1701, 1114, 808 cm"1.
Example 81: Preparation of (£)- V1-(2-chloro-4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l- -l-yl)benzyl)- V2-(2,2,2-trifluoroethyl)oxalamide (CC42)
Figure imgf000123_0002
To a stirred solution of 2,2,2-trifluoroethylamine hydrochloride (0.1 g, 0.77 mmol) in CH2CI2 (10 mL) was added dropwise trimethylaluminum (2 M solution in toluene; 0.39 mL, 0.77 mmol), and the reaction mixture was stirred at 25 °C for 30 min. A solution of (£)- methyl 2-((2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en-l-yl)benzyl)-2- oxoacetate (0.2 g, 0.38 mmol) in CH2CI2 (5 mL) was added dropwise to the reaction mixture at 25 °C. The reaction mixture was stirred at reflux for 18 h, cooled to 25 °C, quenched with 0.5 N HC1 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 (S1O2, 100-200 mesh; 20%-40% EtOAc in n-hexane) to afford the title compound (0.13 g, 60%): mp 161-163 °C; ]H NMR (400 MHz, DMSO-d6) δ 9.45 (br s, 2H), 7.90 (s, 2H), 7.75 (s, 1H), 7.46 (s, 1H), 7.28 (s, IH), 6.93 (m, IH), 6.75 (m, IH), 4.80 (m, IH), 4.40 (s, 2H), 3.90 (s, 2H); ESIMS m/z 578.96 ([M-H]").
Example 82: Preparation of (£)- V-(2-chloro-4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-en-l-yl)benzyl)pyridin-2-amine (CC43)
Figure imgf000124_0001
To a stirred solution of N-(2-chloro-4-vinylbenzyl)pyridin-2-amine (0.3 g, 1.22 mmol) in 1 ,2-dichlorobenzene (5 mL) were added 5-(l-bromo-2,2,2-trifluoroethyl)-l,2,3- trichlorobenzene (0.83 g, 2.44 mmol), CuCl (24 mg, 0.24 mmol) and 2,2-bipyridyl (76 mg, 0.48 mmol). The resultant reaction mixture was degassed with argon for 30 min and then stirred at 180 °C for 24 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (Si02, 100-200 mesh; 15% EtOAc in n-hexane) afforded the title compound as an off-white solid (0.2 g, 35%): mp 140- 142 °C; ]H NMR (400 MHz, CDC13) δ 8.11 (d, / = 4.0 Hz, IH), 7.40 (m, 5H), 7.22 (m, IH), 6.61 (m, 2H), 6.35 (m, 2H), 4.94 (br s, IH), 4.61 (d, / = 6.4 Hz, 2H), 4.11 (m, IH); ESIMS m/z 505.39 ([M+H]+).
Example 83: Preparation of (£)- V-((3-chloro-5-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)-but-l-en-l-yl)pyridin-2-yl)methyl)-3,3,3-trifluoropropanamide (CC44)
Figure imgf000124_0002
To a stirred solution of (£)-(3-chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but- l-en-l-yl)pyridin-2-yl)methanamine (0.1 g, 0.2 mmol) in CH2CI2 (5 mL) were added 3,3,3- trifluoropropanoic acid (45 mg, 0.350 mmol), EDOHC1 (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 reaction mixture was diluted with CH2C12 and washed with H20. The combined CH2C12 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%): ]H NMR (400 MHz, CDC13) δ 8.41 (s, IH), 7.77 (s, IH), 7.47 (br s, 1H), 7.40 (s, 2H), 6.58 (d, / = 16.0 Hz, 1H), 6.45 (dd, / = 16.0, 8.0 Hz, 1H), 4.68 (d, J = 4.0 Hz, 2H), 4.14 (m, 1H), 3.24 (q, / = 10.8 Hz, 2H); ESIMS m/z 536.88 ([M-H] ); IR (thin film) 3320, 1674, 1114, 808.
Compound CC45 in Table 1 was made in accordance with the procedures disclosed in Example 83.
Example 84: Preparation of (£)-3,3,3-trifluoro- V-((4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-e -l-yl)naphthalen-l-yl)methyl)propanamide (CC46)
Figure imgf000125_0001
To a stirred solution of (£)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en-l- yl)naphthalen-l-yl)methanamine (0.1 g, 0.22 mmol) in CH2CI2 (8 mL) were added 3,3,3- trifluoropropanoic acid (0.032 g, 0.24 mmol), HOBf H20 (52 mg, 0.33 mmol), EDOHC1 (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 concentrated under reduced pressure. Purification by flash column chromatography (Si02, 100-200 mesh; 15% EtOAc in n-hexane) afforded the title compound as a gummy material (60 mg, 50%): mp 151-153 °C; ]H NMR (400 MHz, CDC13) δ 8.06 (m, 1H), 7.61 (m, 4H), 7.48 (s, 2H), 7.44 (d, / = 8.0 Hz, 1H), 7.38 (m, 1H), 6.42 (m, 1H), 5.92 (br s, 1H), 4.92 (m, 2H), 4.24 (m, 1H), 3.12 (m, 2H); ESIMS m/z 554.04 ([M-H]").
Compounds CC47 - CC48 in Table 1 were made in accordance with the procedures disclosed in Example 84.
Example 85: Preparation of (£ l-ethyl-3-((4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-e -l-yl)naphthalen-l-yl)methyl)urea (CC49)
Figure imgf000125_0002
To a stirred solution of (£)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en-l- yl)naphthalen-l-yl)methanamine (0.1 g, 0.22 mmol) in CH2C12 at 0 °C 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 reaction mixture was diluted with CH2C12. 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% EtOAc in hexane) afforded the title compound as a solid (0.07 g, 60%): mp 84-87 °C; ]H NMR (400 MHz, CDC13) δ 8.06 (m, 1H), 7.98 (m, 1H), 7.61 (m, 3H), 7.48 (s, 2H), 7.44 (d, / = 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, / = 4.6 Hz, 3H); ESIMS m/z 515.33 ([M+H]+).
Example 86: Preparation of (£)- V'-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en- l-yl)phenyl)cyclopropanecarbohydrazide (CC50)
Figure imgf000126_0001
To a stirred solution of (£)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en-l- yl)phenyl)hydrazine (0.1 g, 0. 3 mmol) in CH2C12 (10 mL) was added DIEA (65 mg, 0.51 mmol), HOBfH20 (59 mg, 0.38 mmol), EDOHC1 (73 mg, 0.38 mmol) and
cyclopropanecarbonyl chloride (0.024 g, 0.28 mmol), and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with satd aq NaHCC>3 solution and extracted with CH2C12. The combined CH2C12 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 solid (65 mg, 55%): mp 138-140 °C; ]H NMR (400 MHz, CDC13) δ 9.81 (s, 1H), 7.90 (s, 1H), 7.84 (s, 2H), 7.34 (d, / = 8.4 Hz, 2H), 6.65 (d, / = 15.6 Hz, 1H), 6.61 (m, 1H), 6.57 (s, 1H), 6.48 (dd, / = 15.6, 8.8 Hz, 1H), 4.74 (m, 1H), 1.64 (m, 1H), 0.75 (m, 4H); ESIMS m/z 461.32 ([M-H]").
Compound CC51 in Table 1 was made in accordance with the procedures disclosed in Example 86.
Example 87: Preparation of (£)- V-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en- l-yl)phenoxy)cyclopropanecarboxamide (CC52)
Figure imgf000126_0002
To a stirred solution of (£)-0-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en-l- yl)phenyl)hydroxylamine (0.15 g, 0.38 mmol) in CH2C12 (5 mL) was added EDC'HCl (0.109 g, 0.569 mmol), HOBfH20 (0.087 g, 0.569 mmol), DIEA (0.097 g, 0.758 mmol) and cyclopropanecarboxylic acid (0.049 g, 0.569 mmol). The resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with H20 and extracted with CHCI3 (35 mL) The combined CHCI3 layer was washed with brine, dried over Na2S04 and concentrated under reduced pressure. Purification by flash column
chromatography (Si02; 20% EtOAc in hexane) afforded the title compound as a brown liquid (0.06 g, 34%): ]H NMR (400 MHz, CDC13) δ 7.40 (s, 2H), 7.18 (s, 1H), 7.08 (s, 1H), 6.85 (m, 1H), 6.45 (m, 1H), 6.65 (m, 1H), 6.20 (m, 1H), 5.55 (s, 1H), 4.08 (m, 1H), 1.90 (m, 1H), 1.30 - 1.10 (m, 4H); ESIMS m/z 464.87 ([M-H]").
Compound CC53 in Table 1 was made in accordance with the procedures disclosed in
Example 87.
Example 88: Preparation of (Z)-3,3,3-trifluoro- V-(4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-en- -yl)benzyl)propanamide (CC54)
Figure imgf000127_0001
A silicon borate vial was charged with (£')-3,3,3-trifluoro-N-(4-(4,4,4-trifluoro-3-
(3,4,5-trichlorophenyl)but-l-en-l-yl)benzyl)propanamide (133 mg, 0.269 mmol) and dimethyl sulfoxide (DMSO; 10 mL). The mixture was placed within 0.6 to 1 meter (m) of a bank of eight 115 watt Sylvania FR48T12/350BL/VHO/180 Fluorescent Tube Black Lights and four 115 watt Sylvania (daylight) F48T12/D/VHO Straight T12 Fluorescent Tube Lights for 72 h. The mixture was concentrated in vacuo and purified by reverse phase
chromatography to give the title compound as a colorless oil (11 mg, 8%): ]H NMR (300 MHz, CDCI3) δ 7.28 (s, 2H), 7.25 (m, 2H), 7.10 (d, 7 = 8.0 Hz, 2H), 6.89 (d, 7 = 11.4 Hz, 1H), 6.07 (br s, 1H), 6.01 (m, 1H), 4.51 (d, 7 = 5.8 Hz, 2H), 4.34 (m, 1H), 3.12 (q, 7 = 7.5 Hz, 2H); 13C NMR (101 MHz, CDC13) δ 162.44, 137.20, 135.38, 135.23, 134.82, 134.68, 131.71, 129.00, 128.80, 128.69, 128.10, 127.96, 122.63,76.70, 47.33 (q, 7 = 28 Hz), 43.59, 42.12 (q, 7 = 30 Hz); ESIMS m/z 504 ([M+H]+).
Compounds DC46, AC93. AC94 in Table 1 were made in accordance with the procedures disclosed in Example 88.
Example 89: Preparation of l-(l-bromo-2,2,2-trifluoroethyl)-3-chlorobenzene (DI2)
Figure imgf000128_0001
The title compound was synthesized in two steps via l-(3-chlorophenyl)-2,2,2- trifluoroethanol (DIl, prepared as in Step 1, Method B in Example 1); isolated as a colorless viscous oil (1.5 g, 75%): ]H NMR (400 MHz, CDC13) δ 7.50 (s, IH), 7.42-7.35 (m, 3H), 5.02 (m, IH), 2.65 (br s, IH)) and Step 2 in Example 1 and isolated (0.14 g, 22%): ]H NMR (400 MHz, CDC13) δ 7.50 (br s, IH), 7,42-7.35 (m, 3H), 5.07 (m, IH).
The following compounds were made in accordance with the procedures disclosed in Example 89.
(l-Bromo-2,2,2-trifluoroethyl)benzene (DI4)
Figure imgf000128_0002
DI3 DI4
2,2,2-Trifluoro-l-phenylethanol (DI3) was isolated (10 g, 80%): ]H NMR (300 MHz, CDCI3) δ 7.48 (m, 2H), 7.40 (m, 3H), 5.02 (m, IH), 2.65 (d, / = 7.1 Hz, IH). The title compound (DI4) was isolated as a liquid (8.0 g, 60%): ]H NMR (400 MHz, CDC13) δ 7.50 (m, 2H), 7.40 (m, 3H), 5.00 (q, / = 7.5 Hz, IH).
l-(l-Bromo-2,2,2-trifluoroethyl)-3,5-dimethylbenzene (DI20)
Figure imgf000128_0003
DI19 DI20
l-(3,5-Dimethylphenyl)-2,2,2-trifluoroethanol (DI19) was isolated an off white solid ]H NMR (400 MHz, CDC13) δ 7.05 (s, 2H), 7.02 (s, IH), 4.95 (m, IH), 2.32 (s, 6H); ESIMS mJz 204 ([M]"). The title compound (DI20) was isolated (3.0 g, 51%).
l-(l-Bromo-2,2,2-trifluoroethyl)-2,4-dichlorobenzene (DI22)
Figure imgf000129_0001
DI21 DI22
l-(2,4-Dichlorophenyl)-2,2,2-trifluoroethanol (DI21) was isolated as an off white powder (5.3 g, 61%): mp 49-51 °C; ]H NMR (400 MHz, CDC13) δ 7.62-7.66 (d, IH), 7.42- 7.44 (d, IH), 7.32-7.36 (d, IH), 5.6 (m, IH), 2.7 (s, IH); ESIMS m/z 244 ([M]+). The title compound (DI22) was isolated (3.2 g, 50%): ]H NMR (400 MHz, CDC13) δ 7.62-7.72 (m, IH), 7.4-7.42 (m, IH), 7.3-7.38 (m, IH), 5.7-5.8 (m, IH).
l-(l-Bromo-2,2,2-trifluoroethyl)-2,3-dichlorobenzene (DI24)
Figure imgf000129_0002
l-(2,3-Dichlorophenyl)-2,2,2-trifluoroethanol (DI23) was isolated as a pale yellow oil
(5.2 g, 60%): ]H NMR (400 MHz, CDC13) δ 7.62-7.64 (d, IH), 7.52-7.54 (m, IH), 7.29-7.33 (t, IH), 5.6-5.76 (m, IH), 2.7 (s, IH); ESIMS m/z 243.9 ([M]+). The title compound (DI24) was isolated as an oil (8.7 g, 60%): ]H NMR (400 MHz, CDC13) δ 7.62-7.71 (m, IH), 7.44- 7.52 (m, IH), 7.27-7.3 (s, IH), 5.81-5.91 (m, IH).
2-(l-Bromo-2,2,2-trifluoroethyl)-l,4-dichlorobenzene (DI26)
Figure imgf000129_0003
l-(2,5-Dichlorophenyl)-2,2,2-trifluoroethanol (DI25) was isolated as a yellow oil (4.1 g, 60%): ]H NMR (400 MHz, CDC13) δ 7.68-7.7 (s, IH), 7.3-7.37 (m, 2H), 5.51-5.6 (m, IH), 2.7 (s, IH); ESIMS m/z 244 ([M]+)). The title compound (DI26) was isolated (3.0 g, 60%): ]H NMR (400 MHz, CDCI3) δ 7.7-7.78 (m, IH), 7.3-7.4 (m, 2H), 5.7-5.8 (m, IH). l-(l-Bromo-2,2,2-trifluoroethyl)-3,5-bis(trifluoromethyl)benzene (DI28)
Figure imgf000130_0001
l-(3,5-Bis(trifluoromethyl)phenyl)-2,2,2-trifluoroethanol (DI27) was isolated (3.8 g, 60%): ]H NMR (400 MHz, CDC13) δ 7.98 (m, 3H), 5.25 (m, IH), 3.2 (br, IH); ESIMS m/z 312.2 ([M]+). The title compound (DI28) was prepared and carried on crude.
l-(l-Bromo-2,2,2-trifluoroethyl)-2,3,5-trichlorobenzene (DI30)
Figure imgf000130_0002
2,2,2-Trifluoro-l-(2,3,5-trichlorophenyl)ethanol (DI29) was isolated as a white solid (4.0 g, 60%): mp 113-115 °C; ]H NMR (400 MHz, CDC13) δ 7.62 (d, IH), 7.50 (d, IH), 5.60- 5.70 (m, IH), 2.75 (s, IH); ESIMS m/z 278.0 ([M+]). The title compound (DI30) was isolated (2.9 g, 60%): ]H NMR (400 MHz, CDC13) δ 7.70 (d, IH), 7.50 (d, IH), 5.72-5.82 (m, IH). l-(l-Bromo-2,2,2-trifluoroethyl)-3-chloro-5-(trifluorometh l)benzene (DI32)
Figure imgf000130_0003
l-(3-Chloro-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroethanol (DI31) was isolated as a pale yellow oil (2.0 g, 50%): ]H NMR (400 MHz, CDC13) δ 7.51 (m, 3H), 5.08 (m, IH), 2.81 (s, IH); ESIMS m/z 278.1 ([M]+). The title compound (DI32) was isolated oil (2.0 g, 40%): ESIMS m/z 342 ([M]+).
5-(l-Bromo-2,2,2-trifluoroethyl)-l,3-dichloro-2-methoxybenzene (DI34)
Figure imgf000130_0004
l-(3,5-Dichloro-4-methoxyphenyl)-2,2,2-trifluoroethanol (DI33) was isolated as an off white solid (0.8 g, 60%); mp 92-95 °C: ]H NMR (400 MHz, CDC13) δ 7.41 (s, 2H), 5.00 (m, IH), 3.89 (s, 3H), 2.64 (m, IH); ESIMS m/z 274 ([M]+). The title compound (DI34) was isolated as a colorless liquid (0.6 g, 57%).
Example 90: Prepar ifluorobenzene (DI36)
Figure imgf000131_0001
The title compound was synthesized in two steps via l-(3,5-difluorophenyl)-2,2,2- trifluoroethanol (DI35, prepared as in Step 1, Method A in Example 1; isolated as a colorless oil (0.2 g, 75%): ]H NMR (400 MHz, CDC13) δ 7.05 (m, 2H), 6.88 (m, IH), 5.06 (m, IH), 2.66 (s, IH); ESIMS m/z 212 ([M]+) and Step 2 in Example 1 and isolated (3.2 g, 50%); ]H NMR (400 MHz, CDC13) δ 7.05 (m, 2H), 6.86 (m, IH), 5.03 (q, J = 7.4 Hz, IH).
The following compounds were made in accordance with the procedures disclosed in
Example 90.
l-(l-Bromo-2,2,2-trifluoroethyl)-4-chlorobenzene (DI38)
Figure imgf000131_0002
DI37 DI38
l-(4-Chlorophenyl)-2,2,2-trifluoroethanol (DI37) was isolated as a colorless oil (5.0 g, 99%): ]H NMR (400 MHz, CDC13) δ 7.44-7.38 (m, 4H), 5.05 (m, IH), 2.55 (s, IH);
ESIMS m/z 210 ([M]+). The title compound (DI38) was isolated (3.0 g, 46 %): ]H NMR (400 MHz, CDCI3) δ 7.45 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 5.10 (q, / = 7.2 Hz, IH). l-(l-Bromo-2,2,2-trifluoroethyl)-4-methoxybenzene (DI40)
Figure imgf000131_0003
DI39 DI40
2,2,2-Trifluoro-l-(4-methoxyphenyl)ethanol (DI39) was isolated as a pale yellow liquid: ]H NMR (400 MHz, CDC13) δ 7.41 (d, J = 8.8 Hz, 2H), 6.95 (m, J = 8.8 Hz, 2H), 5.00 (m, IH), 3.82 (s, 3H), 2.44 (s, IH); ESIMS m/z 206.1 ([M]+). The title compound (DI40) was isolated (3.8 g, 62%). l-(l-Bromo-2,2,2-trifluoroethyl)-4-fluorobenzene (DI42)
Figure imgf000132_0001
DI41 DI42
2,2,2-Trifluoro-l-(4-fluorophenyl)ethanol (DI41) was isolated as a colorless oil (5 g, 99%): ]H NMR (400 MHz, CDC13) δ 7.48-7.45 (m, 2H), 7.13-7.07 (m, 2H), 5.06 (m, IH), 2.53 (s, IH); ESIMS m/z 194 ([M]+). The title compound (DI42) was prepared and carried on as crude intermediate.
l-(l-Bromo-2,2,2-trifl roethyl)-4-methylbenzene (DI44)
Figure imgf000132_0002
DI43 DI44
2,2,2-Trifluoro-l-(p-tolyl)ethanol (DI43) was isolated as colorless oil (5.0 g, 99%): ]H NMR (400 MHz, CDC13) δ 7.37 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 5.02 (m, IH), 2.46 (m, IH), 2.37 (s, 3H); ESIMS m/z 190 ([M]+). The title compound (DI44) was isolated (3.0 g, 45%).
l-(l-bromo-2,2,2-trifluoroethyl)-3-fluorobenzene (DI46)
Figure imgf000132_0003
DI45 DI46
2,2,2-Trifluoro-l-(3-fluorophenyl)ethanol (DI45) was isolated as a colorless viscous oil (2.8 g, 93%): ]H NMR (400 MHz, CDC13) δ 7.41 (m, IH), 7.25 (m, 2H), 7.14 (m, IH), 5.06 (m, IH), 2.60 (s, IH); ESIMS m/z 194 ([M]+). The title compound (DI46) was isolated (2.0 g, 61%).
l-(l-Bromo-2,2,2-trifluoroethyl)-2-fluorobenzene (DI48)
Figure imgf000132_0004
DI47 DI48 2,2,2-Trifluoro-l-(2-fluorophenyl)ethanol (DI47) was isolated as a colorless oil (2.5 g, 99%): ]H NMR (400 MHz, CDC13) δ 7.40 (m, 1H), 7.43 (m,lH), 7.24 (m, 1H), 7.13 (m, 1H), 5.42 (m, 1H), 2.65 (s, 1H); ESIMS m/z 194 ([M]+). The title compound (DI48) was isolated (2.0 g, 61%): ]H NMR (400 MHz, CDC13) δ 7.61 (m, 1H), 7.40 (m, 1H), 7.23 (m, 1H), 7.10 (m, 1H), 5.40 (m, 1H); GCMS m/z 255 ([M-H]").
Example 91: Preparation of 4-(lH-l,2,4-triazol-l-yl)benzaldehyde (DI5)
Figure imgf000133_0001
To a stirring solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K2CO3 (13.3 g, 96.7 mmol) and 1,2,4- triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120 °C for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with H20 and extracted with EtOAc (3 xlOO mL). The combined 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 °C: ]H NMR (400 MHz, CDC13) δ 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J = 8.0 Hz, 2H), 7.92 (d, J = 8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]+).
The following compound was made in accordance with the procedures disclosed in Example 91.
5-Formyl-2-(lH-l,2,4-triazol-l-yl)benzonitrile (DI49)
Figure imgf000133_0002
The title compound was isolated (2.8 g, 60%); ]H NMR (400 MHz, CDC13) δ 10.10 (s, 1H), 8.98 (s, 1H), 8.35 (s, 1H), 8.30 (d, 1H), 8.22 (s, 1H), 8.07 (d, 1H); IR (thin film) 3433, 3120, 1702, 1599, 1510 cm"1.
2-Chloro-4-(lH-l,2,4-triazol-l-yl)benzaldehyde (DI50)
Figure imgf000133_0003
The title compound was isolated as an off white solid (3.0 g, 40%): mp 149-151 °C; ]H NMR (400 MHz, CDC13) δ 10.05 (s, IH), 8.74 (s, IH), 8.17 (s, IH), 8.10 (s, IH), 7.90 (m, 2H) ; ESIMS m/z 208.10 ([M+H]+).
5-Methyl-4-(lH-l,2,4-triazol-l-yl)benzaldehyde (DI51)
Figure imgf000134_0001
The title compound was isolated as a white solid (0.5 g, 74 %): mp 109-111 °C; ]H
NMR (400 MHz, D6-DMSO ) δ 10.06 (s, IH), 9.00 (s, IH), 8.30 (s, IH), 7.99 (s, IH), 7.92 / = 9.2 Hz, IH), 7.69 (d, / = 9.2 Hz, IH), 2.30 (s, 3H); ESIMS m/z 188.13 ([M+H]+).
Example 92: Preparation of 5-formyl-2-(3-nitro-lH-l,2,4-triazol-l-yl)benzonitrile (DI52)
Figure imgf000134_0002
To a stirring solution of 2-fluoro-5-formylbenzonitrile (0.5 g, 3.3 mmol) in DMF (25 mL) were added K2CO3 (0.68 g, 4.95 mmol) and 3-nitro-l,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 Na2SC>4 and concentrated under reduced pressure to afforded the title compound as a pale yellow solid (0.36 g, 45%): mp 170-172 °C; ]H NMR (300 MHz, DMSO-d6) δ 10.12 (s, IH), 9.61 (s, IH), 8.69 (s, IH), 8.45 (d, J = 9.3 Hz, IH), 8.23 (d, J = 9.3 Hz, IH); ESIMS m/z 242.3 ([M-H]"); IR (thin film) 2238, 1705, 1551, 1314 cm"1.
Example 93: Preparation of 4-(3-methyl-lH-l,2,4-triazol-l-yl)benzaldehyde (DI53)
Figure imgf000134_0003
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-l,2,4-trizole (3.34 g, 40.32 mmol) and the resultant reaction mixture was stirred at RT for 4 h. After completion 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 Na2SC>4 and concentrated under reduced pressure to afforded the title compound as a white solid (4.1 g, 60%): mp 125-128°C; ]H NMR (400 MHz, CDC13) δ 10.05 (s, IH), 8.76 (s, IH), 8.02 (d, 2H), 7.85 (d, 2H), 2.50 (s, 3H); ESIMS m/z 188.04 ([M+H]+).
The following compound was made in accordance with the procedures disclosed in Example 93.
4-(lH-l,2,4-triazol-l-yl)-3-(trifluoromethyl)benzaldehyde (DI54)
Figure imgf000135_0001
The title compound was isolated as white solid (1.05 g, 60%): mp 81-83 °C; ]H NMR (400 MHz, CDCI3) δ 10.15 (s, IH), 8.43 (s, IH), 8.37 (s, IH), 8.25 (d, / = 7.2 Hz, IH), 8.18 (s, IH), 7.79 (d, / = 7.2 Hz, IH); ESIMS m/z 241.0 ([M]+).
4-(3-nitro-lH-l,2,4-triazol-l-yl)benzaldehyde (DI55)
Figure imgf000135_0002
The title compound was isolated as pale yellow solid (0.10 g, 23%): mp 159-161 °C; ]H NMR (400 MHz, CDCI3) δ 10.10 (s, IH), 8.89 (s, IH), 8.15 (m, 2H), 8.00 (m, 2H); ESIMS m/z 217.11 ([M-H]").
3-bromo-4-(lH-l,2,4-triazol-l-yl)benzaldehyde (DI56)
Figure imgf000135_0003
The title compound was isolated as white solid (3.2 g, 51%): mp 126-128 °C; ]H NMR (400 MHz, CDC13) δ 10.04 (s, IH), 8.69 (s, IH), 8.27 (M, IH, 8.18 (s, IH) 7.99 (d, / = 9.2 Hz, IH), 7.76 (d, / = 9.2 Hz, IH); ESIMS m/z 250.9 ([M]+).
5-formyl-2-(3-methyl-lH-l,2,4-triazol-l-yl)benzonitrile (DI57)
Figure imgf000136_0001
The title compound was isolated as white solid (0.13 g, 30%): mp 147-149 °C; ]H NMR (400 MHz, CDC13) δ 10.07 (s, 1H), 8.89 (s, 1H), 8.32 (d, / = 1.8 Hz, 1H), 8.24 (dd, / = 8.6, 1.3 Hz, 1H), 8.06 (d, / = 8.6 Hz, 1H), 2.54 (s, 3H); ESIMS m/z 213.09 ([M+H]+); IR (thin film) 2239, 1697 cm"1.
3-nitro-4-(lH-l,2,4-triazol-l-yl)benzaldehyde (DI58)
Figure imgf000136_0002
The title compound was isolated as pale yellow solid (3.0 g, 60 %): mp 116-118 °C; ]H NMR (400 MHz, CDC13) δ 10.15 (s, 1H), 8.48 (s, 1H), 8.46 (s, 1H), 8.26 (d, / = 6.9 Hz, 1H), 8.16 (s, 1H), 7.83 (d, J = 6.9 Hz, 1H); ESIMS m/z 219.00 ([M+H]+).
Example 94: Preparation of l-(4-vinylphenyl)-lH-l,2,4-triazole (DI59)
Figure imgf000136_0003
To a stirred solution of 4-[l,2,4]triazol-l-yl-benzaldehyde (9.0 g, 52 mmol) in 1,4- dioxane (100 mL), were added K2CO3 (10.76 g, 78 mmol) and methyl triphenyl phosphonium bromide (22.2 g, 62.4 mmol) at room temperature. The resultant reaction mixture was heated to 70 °C for 18 h. After completion of the reaction (TLC), the reaction mixture was cooled to room temperature and filtered and the obtained filtrate was concentrated under reduced pressure. 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+H]+).
The following compound was made in accordance with the procedures disclosed in Example 94.
l-(2-Methyl-4-vinylphenyl)-lH-l,2,4-triazole (DI60)
Figure imgf000137_0001
The title compound was isolated as an off white solid (1.5 g, 76%): ]H NMR (400
MHz, CDC13) δ 8.25 (s, 1H), 8.11 (s, 1H), 7.35 (m, 2H), 7.27 (d, / = 8.7 Hz, 1H), 6.74 (m, 1H), 5.82 (d, / = 17.3 Hz, 1H), 5.36 (d, / = 10.0 Hz, 1H), 2.25 (s, 3H); ESIMS m/z 186.14 «M+H]+).
2-(lH-l,2,4-Triazol-l-yl)-5-vinylb
Figure imgf000137_0002
The title compound was isolated as an off-white solid (1.40 g, 71%): mp 126-129 °C; ]H NMR (400 MHz, CDC13) δ 8.76 (s, 1H), 8.18 (s, 1H), 7.82-7.84 (m, 1H), 7.72-7.80 (m, 2H), 6.70-6.80 (dd, / = 17.6, 10.8 Hz, 1H), 5.90-5.95 (d, / = 17.6 Hz, 1H), 5.50-5.70 (d, J = 10.8 Hz, 1H); ESIMS m/z 197.03 ([M+H]+).
Example 95: Preparation of 2-(3-nitro-lH-l 2 4-triazol-l-yl)-5-vinylbenzonitrile (DI62)
Figure imgf000137_0003
To a stirred solution of 5-formyl-2-(3-nitro-lH-l,2,4-triazol-l-yl)benzonitrile (0.36 g, 1.49 mmol) in 1,4-dioxane (25 mL), were added K2CO3 (0.3 g, 2.2 mmol) and methyl triphenyl phosphonium bromide (0.63 g, 1.79 mmol). The resultant reaction mixture was heated to 100 °C for 18 h. After completion of the reaction (TLC), the reaction mixture was cooled to room temperature and filtered and the obtained filtrate was concentrated under reduced pressure. Purification by flash chromatography (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 °C; ]H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.34 (m, 1H), 7.98 (d, / = 7.8 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 6.87 (m, 1H), 6.20 (d, / = 15.7 Hz, 1H), 5.56 (d, / = 11.8 Hz, 1H); ESIMS m/z 240.27 ([M-H]"); IR (thin film) 2240, 1514, 1312 cm"1.
The following compound was made in accordance with the procedures disclosed in Example 95.
l-(3-chloro-4-vinylphenyl)-lH-l,2,4-triazole (DI63)
Figure imgf000138_0001
The title compound was isolated as an off-white solid (2.3 g, 80%): mp 134-137 °C; ]H NMR (400 MHz, CDC13) δ 8.56 (s, 1H), 8.11 (s, 1H), 7.76 (s, 1H), 7.70 (d, / = 9.0 Hz, 1H), 7.57 (d, J = 9.0 Hz, 1H), 7.10 (m, 1H), 5.80 (d, J = 17.2 Hz, 1H), 5.47 (d, J = 12.4 Hz, 1H); ESIMS m/z 206.04 ([M+H]+.
3-methyl-l-(4-vinylphenyl)-lH-l,2, -triazole (DI64)
Figure imgf000138_0002
The title compound was isolated as a white solid (0.6 g, 60%): mp 109-111 °C; ]H
NMR (400 MHz, CDC13) δ 8.42 (s, 1H), 7.40-7.60 (m, 4H), 6.70-7.00 (dd, / = 17.6, 10.8 Hz, 1H), 5.80 (d, / = 17.6 Hz, 1H), 5.30 (d, / = 17.6 Ηζ,ΙΗ), 2.50 (s, 3H); ESIMS m/z 186.20 «M+H]+).
l-(2-(trifluoromethyl)-4-vinylphen -lH-l,2,4-triazole (DI65)
Figure imgf000138_0003
The title compound was isolated as a colorless oil (0.6 g, 60%): ]H NMR (400 MHz,
CDCI3) δ 8.32 (s, 1H), 8.14 (s, 1H), 7.84 (s, 1H), 7.72 (d, / = 8.0 Hz, 1H), 7.50 (d, / = 7.6 Hz, 1H), 6.70-6.90 (dd, / = 17.6, 10.8 Hz, 1H), 5.90-6.00 (d, / = 17.6 Hz, 1H), 5.50-5.80 (d, / = 10.8 Hz 1H); ESIMS m/z 240.16 ([M+H]+).
3-nitro-l-(4-vinylphenyl)-lH-l,2,4
Figure imgf000138_0004
The title compound was isolated as a pale yellow solid (61 mg, 20%): mp 137-139 °C; ]H NMR (400 MHz, CDC13) δ 8.60 (s, 1H), 7.68 (d, J = 7.7 Hz, 2H),7.60 (d, J = 8.3 Hz, 2H), 6.77 (dd, / = 17.7, 10.8, 1H), 5.87 (d, / = 17.7 Hz, 1H), 5.42 (d, / = 10.8 Hz, 1H); ESIMS m/z 217.28 ([M+H]+).
l-(2-bromo-4-vinylphenyl)-lH-l,2,4-triazole (DI67)
Figure imgf000139_0001
The title compound was isolated as a white solid (1.2 g, 40%): mp 75-77 °C; ]H NMR (400 MHz, CDC13) δ 8.48 (s, IH), 8.12 (s, IH), 7.75 (s, IH) 7.42 (s, 2H), 6.70 (m, IH), 5.83 (d, / = 18 Hz, IH), 5.42 (d, / = 12 Hz, IH); ESIMS m/z 249.1 ([M]+).
2-(3-methyl-lH-l,2,4-triazol-l-yl)- -vinylbenzonitrile (DI68)
Figure imgf000139_0002
The title compound was isolated as an off-white solid (0.6 g, 60%): mp 96-97 °C; ]H NMR (400 MHz, CDC13) δ 8.66 (s, IH), 7.80 (s, IH), 7.74 (m, 2H), 6.73 (dd, / = 17.6 Hz, 10.8 Hz, IH), 5.88 (d, / = 17.6 Hz, IH), 5.49 (d, / = 10.8 Hz, IH), 2.52 (s, 3H); ESIMS m/z 211.10 ([M+H]+); IR (thin film) 2229 cm"1.
l-(2-nitro-4-vinylphenyl)-lH-l,2,4
Figure imgf000139_0003
The title compound was isolated as a yellow solid (1.78 g, 60%): mp 102-104 °C; ]H NMR (400 MHz, CDC13) δ 8.40 (s, IH), 8.12 (s, IH), 8.02 (s, IH), 7.72-7.76 (d, J = 8.0 Hz, IH), 7.52-7.56 (d, / = 17.6 Hz, IH), 6.70-6.82 (dd, / = 17.6, 10.8 Hz, IH), 5.85-6.00 (d, / = 17.6 Hz, IH), 5.50-5.60 (d, / = 10.8, Hz IH); ESIMS m/z 217.0 ([M+H]+).
Example 96: Preparation of 3-methyl-2-(lH-l,2,4-triazol-l-yl)-5-vinylbenzonitrile (DI70)
Figure imgf000139_0004
Step 1. 5-Bromo-2-fluoro-3-methylbenzaldehyde: To a stirred solution of di- isopropyl amine (4.01 g, 39.88 mmol) in THF (20 mL) was added n-butyl lithium (1.6 M in hexane) (19.9 mL, 31.91 mmol) at -78 °C slowly dropwise over the period of 10 min, the reaction mixture was stirred at -78°C for 30 min. A solution of 4-bromo-l-fluoro-2- methylbenzene (5.0 g, 26.6 mmol) in THF (30.0 mL) was added at -78°C, and the reaction mixture was stirred for 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 mixture was quenched with IN HC1 solution (aq) at 0°C. The aqueous layer was extracted with diethyl ether, washed with water and saturated brine solution. The combined organic layer was dried over anhydrous 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- 50°C: ]H NMR (400 MHz, CDC13) δ 8.33 (s, 1H), 8.22 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 6.75 (dd, J = 17.6, 10.8 Hz, 1H), 5.92 (dd, J = 17.6, 10.8 Hz, 1H), 5.52 (d, J = 17.6 Hz, 1H), 2.21 (s, 3H); ESIMS m/z 211.35 ([M-H]").
Step 2. ((£')-5-Bromo-2-fluoro-3-methylbenzaldehyde oxime: To a stirred solution of 5-bromo-2-fluoro-3-methylbenzaldehyde (3.5 g, 16.2 mmol) in ethanol (50.0 mL) were added sodium acetate (2.0 g, 24.3 mmol) and hydroxylamine hydrochloride (1.69 g, 24.3 mmol) at 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 °C; ]H NMR (400 MHz, CDC13) δ 8.32 (s, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.51 (s, 1H), 7.34 (d, J = 2.4 Hz, 1H), 2.25 (s, 3H); ESIMS m/z 232.10 ([M+H]+).
Step 3. 5-Bromo-2-fluoro-3-methylbenzonitrile: A stirred solution of (£)-5-bromo- 2-fluoro-3-methylbenzaldehyde oxime (0.5 g, 2.2 mmol) in acetic anhydride (5.0 mL) was heated to reflux for 18 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined ethyl acetate layer was washed with brine and dried over Na2S04 and concentrated under reduced pressure to afford the crude compound as a light brown gummy material (0.4 g, crude): ESIMS m/z 213.82 ([M+H]+).
Step 4. 5-Bromo-3-methyl-2-(lH-l,2,4-triazol-l-yl)benzonitrile (DI71) : To a stirred solution of 5-bromo-2-fluoro-3-methylbenzonitrile (1.0 g, 47.716 mmol), in DMF (10.0 mL) was added potassium carbonate (1.95 g, 14.14 mmol) followed by 1H-1,2,4- triazole (0.811 g, 9.433 mmol) at RT. The reaction mixture was heated to 140 °C for 18 h. The reaction mixture was cooled to RT, diluted with water and extracted with ethyl acetate (2 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 compound as a pink solid (0.6 g, 49 %): ]H NMR (400 MHz, CDC13) δ 8.39 (s, 1H), 8.23 (s, 1H), 7.91 (d, / = 2.4 Hz, 2H), 2.21 (s, 3H), ESIMS m/z 262.57 ([M+H]+); IR (thin film) 2231, 554 cm"1.
Step 5. 3-Methyl-2-(lH-l,2,4-triazol-l-yl)-5-vinylbenzonitrile (DI70) : A mixture of 5-bromo-3-methyl-2-(lH-l,2,4-triazol-l-yl)benzonitrile (0.6 g, 2.3 mmol), potassium carbonate (0.95 g, 6.87 mmol), vinyl boronic anhydride (0.82 g, 3.43 mmol) and
triphenylphosphine (0.13 g, 0.114 mmol) in toluene (20.0 mL) were stirred and degassed with argon for 30 min. The reaction mixture was heated to reflux for 18 h. The reaction mixture was cooled to RT, diluted with water and extracted with ethyl acetate (2 x 100 mL). The combined ethyl acetate layer was washed with brine, dried over Na2SC>4 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 acetate/ pet ether) to afford the title compound as a pink solid (0.25 g, 52 %): ]H NMR (400 MHz, CDC13) δ 8.33 (s, 1H), 8.22 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 6.75 (dd, / = 17.6, 10.8 Hz, 1H), 5.92 (d, / = 17.6, 1H), 5.52 (d, / = 10.8 Hz, 1H), 2.21 (s, 3H), ESIMS m/z 211.35 ([M+H]+); IR (thin film) 2236, 1511 cm"1.
The following compound was made in accordance with the procedures disclosed in Steps 4 and 5 of Example 96.
l-(2-fluoro-4-vinylphenyl)-lH-l,2, -triazole (DI72)
Figure imgf000141_0001
l-(4-Bromo-2-fluorophenyl)-lH-l,2,4-triazole (DI73) was isolated as a pale yellow solid (3.0 g, 75%): mp 113-116 °C; ]H NMR (400 MHz, CDC13) δ 8.69 (s, 1H), 8.13 (m, 2H), 7.50 (m, 1H), 7.21 (m, 1H); ESIMS m/z 241.93 ([M]+). The title compound (DI72) was isolated as a yellow solid (1.0 g, 71%): mp 67-70 °C; ]H NMR (400 MHz, CDC13) δ 8.67 (s, 1H), 8.13 (s, 1H), 7.94 (m, 1H), 7.41 (m, 1H), 7.24 (s, 1H), 6.75 (dd, J = 17.6, 10.8 Hz, 1H ), 5.81 (d, J = 17.6 Hz, 1H), 5.37 (d, J = 10.8 Hz, 1H); ESIMS m/z 190.00 ([M+H]+).
Example 119: Preparation of l-(l-( -vinylphenyl)-lH-l,2,4-triazol-5-yl)ethanone (DI78)
Figure imgf000141_0002
To a stirred solution of l-(4-vinyl-phenyl)-lH-[l,2,4]triazole (1 g, 5.8 mmol) in 25 mL of THF, was added n-BuLi (0.37 g, 5.8 mmol) at -78 °C and stirred for 30 min. To this N- methoxy-N-methyl acetamide in THF (0.66 g, 6.4 mmol) was added and the resultant reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with a saturated aqueous NH4C1 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 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 (280 mg, 23%): mp 97-98 °C; ]H NMR (400 MHz, CDC13) δ 8.10 (s, 1H), 7.50 (d, 2H), 7.38 (d, 2H), 6.68 (dd, 1H), 5.85 (d, 1H), 5.38 (d, 1H), 2.75 (s, 3H); ESIMS m/z 214.14 ([M+H]+).
Example 120: Preparation of cyclopropyl(l-(4-vinylphenyl)-lH-l,2,4-triazol-5- yl)methanone (DI79)
Figure imgf000142_0001
To a stirred solution of l-(4-vinyl-phenyl)-lH-[l,2,4]triazole (1 g, 5.8 mmol) in 25 mL of THF, was added n-BuLi (0.37 g, 5.8 mmol) at -78 °C and stirred for 30 min. To this N- methoxy N-methylcyclopropoxide in THF (0.82 g, 6.4 mmol) was added and the resultant reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with a saturated aqueous NH4CI solution and extracted 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,
30%): mp 90-91 °C; ]H NMR (400 MHz, CDC13) δ 8.12 (s, 1H), 7.50 (d, / = 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, / = 10.7 Hz, 1H), 3.22 (m, 1H), 1.27(m, 2H), 1.18 (m, 2H); ESIMS m/z 240.18 ([M+H]+); IR (thin film) 2922, 1630 cm"1.
Example 121: Preparation of 5-(methylthio)-l-(4-vinylphenyl)-lH-l,2,4-triazole (DI80)
Figure imgf000142_0002
To a stirred solution of l-(4-vinyl-phenyl)-lH-[l,2,4]triazole (1 g, 5.8 mmol) in 50 mL of THF, was added n-BuLi (0.41 g, 6.4 mmol) at -78 °C and stirred for 30 min. To this dimethyldisulfide in THF (0.6 g, 6.43 mmol) was added and the resultant reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with a saturated aqueous NH4CI 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 °C; ]H NMR (400 MHz, CDC13) δ 7.96 (s, 1H), 7.05 (m, 4H), 6.75 (dd, / = 16.4, 10.7 Hz, 1H), 5.81 (d, J = 16.4 Hz, 1H), 5.35 (d, J = 10.7 Hz, 1H), 2.73 (s, 3H); ESIMS m/z 218.09 «M+H]+).
Example 122: Preparation of 5-methyl-l-(4-vinylphenyl)-lH-l,2,4-triazole (DI81)
Figure imgf000143_0001
To a stirred solution of l-(4-vinyl-phenyl)-lH-[l,2,4]triazole (0.5 g, 2.9 mmol) in 10 mL of THF, was added n-BuLi (0.22 g, 3.5 mmol) at -78 °C and stirred for 30 min. To this methyl iodide in THF (0.50 g, 3.5 mmol) was added and the resultant reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with a saturated aqueous NH4CI 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%): ]H NMR (400 MHz,
CDCI3) δ 7.93 (s, 1H), 7.55 (d, / = 9 Hz, 2H), 7.42 (d, / = 9 Hz, 2H), 6.76 (dd, / = 18, 11 Hz, 1H), 5.83 (d, / = 18 Hz, 1H), 5.38 (d, J = 11 Hz, 1H), 2.55 (s, 3H); ESIMS m/z 186.13 ([M+H]+); IR (thin film) 1517, 1386, 1182, 847 cm"1.
Example 97: Preparation of (E)-l-(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-l-en-l- yl)phenyl)-lH-l,2,4-triazole DC1)
Figure imgf000143_0002
To a stirred solution of l-(l-bromo-2,2,2-trifluoro-ethyl)-3,5-dichloro-benzene (2.0 g, 6.51 mmol) in 1,2-dichlorobenzene (25 mL), were added l-(4-vinyl-phenyl)-lH- [l,2,4]triazole (2.22 g, 13.0 mmol), CuCl (64 mg, 0.65 mmol) and 2,2 -bipyridyl (0.2 g, 1.3 mmol). The resultant reaction mixture was degassed with argon for 30 min, then stirred at 180 °C for 24 h. After completion of reaction (TLC), the reaction mixture was cooled to RT and filtered and the filtrate concentrated under reduced pressure. Purification by flash chromatography (Si02, 100-200 mesh; 25-30% EtOAc in petroleum ether) afforded the title compound as an off-white solid (0.8 g, 32%): mp 93-97 °C; ]H NMR (300 MHz, CDC13) δ 8.56 (s, 1H), 8.11 (s, 1H), 7.68 (d, / = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.38 (t, 7 = 1.8 Hz, 1H), 7.29 (s, 2H), 6.62 (d, / = 15.6 Hz, 1H), 6.42 (dd, / = 15.6, 8.2 Hz, 1H), 4.15 (m, 1H); ESIMS m/z 398.05 ([M+H]+).
Compounds DC2-DC37, DC44, DC45, DC47-49, DC50, DC51, DC54, DC58,
DC60, DC62, and DC63-DC67 in Table 1 were made in accordance with the procedures disclosed in Example 97.
Example 98: Preparation of (£)-2-(3-nitro-lH-l,2,4-triazol-l-yl)-5-(4,4,4-trifluoro-3- (3,4,5-trichlorophenyl)bu -l-en-l-yl)benzonitrile (DC40)
Figure imgf000144_0001
To a stirred solution of 2-(3-nitro-lH-l,2,4-triazol-l-yl)-5-vinylbenzonitrile (0.9 g, 3.7 mmol) in 1,2- dichlorobenzene (10 mL), were added 5-(l-bromo-2,2,2-trifluoroethyl)- 1,2,3-trichlorobenzene (2.5 g, 7.5 mmol), CuCl (73 mg, 0.74 mmol) and 2,2-bipyridyl (0.23 g, 1.49 mmol) and the resultant reaction mixture was degassed with argon for 30 min and then stirred at 180°C for 14 h. After completion of the reaction (TLC), the reaction mixture was cooled to RT 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 an off white solid (0.9 g, 50%): mp 70-73 °C; ]H NMR (300 MHz, CDCI3) δ 8.86 (s, 1H), 7.88 (m, 3H), 7.44 (s, 2H), 6.67 (d, / = 16.0 Hz, 1H), 6.56 (dd, J = 16.0, 7.6 Hz, 1H), 4.19 (m, 1H); ESIMS m/z 436.11 ([M-2H]").
Example 99: Preparation of (E)-2-(3-amino-lH-l,2,4-triazol-l-yl)-5-(4,4,4-trifluoro-3- (3,4,5-trichlorophenyl)bu -l-en-l-yl)benzonitrile (DC41)
Figure imgf000144_0002
To a stirred solution of (E)-2-(3-nitro-lH-l,2,4-triazol-l-yl)-5-(4,4,4-trifluoro-3- (3,4,5-trichlorophenyl)but-l-enyl)benzonitrile (0.6 g, 1.2 mmol) in MeOH (10 mL), were added Zn dust (0.39g, 5.98 mmol) and sat. aq NH4C1 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 compound as a solid (0.5 g, 89%): mp 72-75 °C; ]H NMR (300 MHz, DMSO-rfe) δ 8.72 (s, 1H), 8.26 (s, 1H), 8.01 (d, / = 8.4 Hz, 1H), 7.91 (s, 2H), 7.77 (d, J = 8.4 Hz, 1H), 6.42 (dd, / = 15.6, 9.2 Hz, 1H), 6.83 (d, / = 15.6 Hz, 1H), 5.87 (s, 2H), 4.89 (m, 1H); ESIMS m/z 469.95 ([M-H]").
Compound DC38 in Table 1 was made in accordance with the procedures disclosed in Example 99. Also, compound DC55 in Table 1 was made from compound DC54 in accordance with the procedures disclosed in Example 99, with the exception of using ammonium formate in place of ammonium chloride.
Example 100: Preparation of (E)- V-(l-(2-cyano-4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-en-l-yl)phenyl)-lH-l,2,4-triazol-3-yl)-N- (cyclopropanecarbonyl)cyclopropanecarboxamide (DC42)
Figure imgf000145_0001
To a stirred solution of (E)-2-(3-amino-lH-l,2,4-triazol-l-yl)-5-(4,4,4-trifluoro-3- (3,4,5-trichlorophenyl)but-l-enyl)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 h at RT. The reaction mixture was diluted with DCM and washed with water and brine and dried over Na2SC>4. Concentration under reduced pressure and purification by preparative HPLC afforded the title compound as a solid (0.09g, 79%): mp 104-107 °C; ]H NMR (300 MHz, CDC13) δ 8.78 (s, 2H), 7.83 (s, 1H), 7.80 (m, 2H), 7.42 (s, 2H) , 6.65 (d, J = 16.4 Hz, 1H), 6.51 (dd, / = 7.6, 8.0 Hz, 1H), 4.17 (m, 1H), 2.16 (m, 2H), 1.25 (m, 4H), 1.00 (m, 4H); ESIMS m/z 609.98 ([M+H]+); IR (thin film) 2234, 1714, 1114, 807 cm"1.
Example 101: Preparation of (E)- V-(l-(2-cyano-4-(4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-en-l-yl)phenyl)-lH-l,2,4-triazol-3-yl)cyclopropanecarboxamide (DC43)
Figure imgf000145_0002
To a stirred solution of (£')-2-(3-amino-lH-l,2,4-triazol-l-yl)-5-(4,4,4-trifluoro-3- (3,4,5-trichlorophenyl)but-l-enyl)benzonitrile (0.15 g,0.31 mmol) in DCM at 0 °C, were added triethylamine (0.1 g, 1 mmol) and cyclopropylcarbonyl chloride (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 compound as a solid (66 mg, 34%): mp 109-112 °C; ]H NMR (300 MHz, DMSO-d6) δ 10.94 (br s, 1H), 8.36 (s, 1H), 8.08 (m, 7 = 8.4 Hz, 1H), 7.91 (s, 2H), 7.84 (d, 7 = 8.4 Hz, 1H), 7.13 (dd, 7 = 15.6, 9.2 Hz, 1H), 6.87 (d, 7 = 15.6 Hz, 1H), 4.92 (m, 1H), 1.99 (br s, 1H), 0.82 (s, 4H); ESIMS m/z 540.04 ([M+H]+); IR (thin film) 3233, 2233, 1699, 1114, 807cm"1.
Compound DC39 in Table 1 was made in accordance with the procedures disclosed in Example 101.
Example 102: Preparation of l-(4-(lH-l,2,4-triazol-l-yl)phenyl)ethanone (DI74)
Figure imgf000146_0001
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 Cul (1.4 g, 10.1 mmol) and the resultant reaction mixture was refluxed for 48 h. After completion of the reaction (by TLC), the reaction mixture was cooled to RT 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 pressure. Purification by washing with diethyl ether afforded the title compound as a solid (5 g, 96%): ]H NMR (400 MHz, CDC13) δ 8.71 (s, 1H), 8.16, (s, 1H), 8.13 (d, 7 = 8.6 Hz, 2H), 7.83 (d, 7 = 8.6 Hz, 2H), 2.66 (s, 3H); ESIMS m/z 186.02 ([M-H]").
Example 103: Preparation of l-(4-(lH-l,2,4-triazol-l-yl)phenyl)-3-(3,5-dichlorophenyl)- 4,4,4-trifluorobutan-l-one (
Figure imgf000146_0002
Step 1. l-(4-(l-(trimethylsilyloxy)vinyl)phenyl)-lH-l,2,4-triazole (DI76) To a stirred solution of l-(4-(lH-l,2,4-triazol-l-yl)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 reaction mixture was stirred for 1 h. The reaction mixture was quenched with a mixture of sat aq sodium bicarbonate solution and ether. The ether layer and was separated, washed with brine, dried over Na2S04 and concentrated under reduced pressure to afford the title compound (5.5 g) which was taken directly to next step.
Step 2. l-(4-(lH-l,2,4-triazol-l-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4- trifluorobutan-l-one (DI75): To a stirred solution of l-(4-(l-
(trimethylsilyloxy)vinyl)phenyl)-lH-l,2,4-triazole (6g, 23 mmol) and l-(l-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 mixture was heated to 180 °C for 18 h. After completion of the reaction (by TLC), the reaction mixture was absorbed onto silica gel and purified by column chromatography (Si02; 10% EtOAc in petroleum ether) to afford title compound as a solid (3 g, 31 ): ]H NMR (400 MHz, CDC13) δ 8.67 (s, 1H), 8.15 (s, 1H), 8.10 (d, / = 8.3 Hz, 2H), 7.82 (d, / = 8.3 Hz, 2H), 7.33 (m, 1H), 7.30 (m, 2H), 4.20 (m, 1H), 3.63 (m, 2H); ESIMS m/z 412. 14 ([M-H]").
Example 104: Preparation of 2-(4-(lH-l,2,4-triazol-l-yl)phenyl)-4-(3,5-dichlorophenyl)- 5,5,5-trifluoropentan-2-ol (D
Figure imgf000147_0001
To a solution of l-(4-(lH-l,2,4-triazol-l-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4- trifluorobutan-l-one (300 mg, 0.726 mmol ) in THF cooled to 0 °C was added
methylmagnesium bromide (450 mg, 5 mmol) drop wise. The reaction was stirred for 3 h at 0 °C, then the reaction mixture was quenched with sat aq NH4CI 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 petroleum ether) afforded the title compound as a solid (100 mg, 32%): ]H NMR (400 MHz, CDC13) δ two diastereoisomers 8.58 (s, 1H, minor), 8.48 (s, 1H, major), 8.13 (s, 1H, minor), 8.09 (s, 1H, major), 7.70 (d, / = 9.0 Hz, 2H, minor), 7.53 (d, J = 9.0 Hz, 2H, minor), 7.40 (d, J = 9.0 Hz, 2H, major), 7.31 (m, 1H, minor), 7.27 (d, J = 9.0 Hz, 2H, major), 7.20 (m, 2H, minor), 7.01 (m, 1H, major), 6.75 (m, 2H, major), 350 (m, 1H), 2.50 (m, 2H), 1.56 (s, 3H, major), 1.54 (s, 3H, minor); ESIMS mJz 430.05 ([M+H]+).
Example 105: Preparation of (E)-l-(4-(4-(3,5-dichlorophenyl)-5,5,5-trifluoropent-2-en- 2-yl)phenyl)-lH-l,2,4-triazol
Figure imgf000148_0001
To a solution of 2-(4-(lH-l,2,4-triazol-l-yl)phenyl)-4-(3,5-dichlorophenyl)-5,5,5- trifluoropentan-2-ol (100 mg, 0.233 mmol) in toluene was added a catalytic amount of p- toluenesulfonic acid (PTSA) and the water was removed by azeotropic distillation over the course of 12 h. The reaction mixture was cooled to room temperature and dissolved in ethyl acetate. The solution was washed with sat aq NaHCC>3 solution and brine, dried over Na2S04 and concentrated under reduced pressure. Purification by column chromatography (Si02, 100-200 mesh; 20 -25 EtOAc in petroleum ether) afforded the title compound as a solid (30 mg, 31%).
Example 123: Preparation of (£')-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-l-en-l-yl)- 2-(lH-l,2,4-triazol-l-yl)benzaldehyde (DC52)
Figure imgf000148_0002
To a stirred solution of (£)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-l-en-l-yl)-2- (lH-l,2,4-triazol-l-yl)benzonitrile (0.3 g, 0.71 mmol) in toluene (10 mL) at -78 °C was added dropwise diisobutylaluminum hydride (DIBAL-H, 1.0 M solution in toluene; 0.85 mL), and the reaction mixture was stirred at -78 °C for 20 min. The reaction mixture was quenched with the addition of 1 N HC1 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 purified 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 (£')-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-l-en-l-yl)- /V-methyl-2-(lH-l,2,4-triazol-l-yl)aniline (DC57)
Figure imgf000149_0001
To a stirred solution of (£)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut- l-en-l-yl)-2- (lH-l ,2,4-triazol-l-yl)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%).
Example 125: Preparation of (£')-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-l-en-l-yl)- 2-(lH-l,2,4-triazol-l-yl)ben
Figure imgf000149_0002
A solution of (£ ethyl 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-l-en- l-yl)-2-(lH- l,2,4-triazol- l-yl)benzoate (0.2 g, 0.4 mmol) in 6 N HCl (10 mL) was stirred at 100 °C for 18 h. The reaction was cooled to RT, resulting in a white solid precipitate. The precipitate was filtered to afford the title compound as a white solid (0.12 g, 60%).
Example 126: Preparation of (Z)-5-((£')-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-l-en- l.yl). V'-hydroxy-2-(lH-l,2, -triazol-l-yl)benzimidamide (DC59)
Figure imgf000149_0003
A solution of (E)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-l-en-l-yl)-2-(lH-l,2,4- triazol- l-yl)benzonitrile (0.3 g, 0.71 mmol), sodium acetate (0.087 g, 1.065 mmol) and hydroxylammonium chloride (0.072 g, 1.065 mmol) in 9: 1 ethanol/water mixture (10 mL) was stirred at 70 °C for 8 h. The reaction was cooled to RT, 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 pressure to afford the title compound as an off white solid. Example 127: Preparation of (£)-l-(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3- methoxybut-l-en-l-yl)ph
Figure imgf000150_0001
Step 1. (£)-3-(4-(lH-l,2,4-triazol-l-yl)phenyl)-l-(3,5-dichlorophenyl)prop-2-en-l- one: To a solution of l-(3,5-dichlorophenyl)ethanone (0.5 g, 2.6 mmol) in ethanol (20 mL) was added 4-(lH-l,2,4-triazol-l-yl)benzaldehyde (0.46 g, 2.65 mmol) and the reaction was cooled to 0 °C. Sodium hydroxide (0.22 g, 5.29 mmol) in water (10 mL) was then added and the reaction was allowed to stir for 2 h at 0 °C. The reaction was extracted with EtOAc and the combined organic layers were dried over Na2S04 and concentrated under reduced pressure to afford the title compound (0.149 g, 17%): ); ESIMS m/z 430.05 ([M+H]+) 344.08 Step 2. (£)-4-(4-(lH-l,2,4-triazol-l-yl)phenyl)-2-(3,5-dichlorophenyl)-l,l,l- trifluorobut-3-en-2-ol (DC69): To a solution of (£)-3-(4-(lH-l,2,4-triazol-l-yl)phenyl)-l- (3,5-dichlorophenyl)prop-2-en-l-one (1 g, 3 mmol) in THF (150 mL) was added
trifluoromethyltrimethylsilane (0.517 g, 3.644 mmol) and tetra-n-butylammonium fluoride (TBAF) (1.0 M, 1 mL) at 0 °C. The reaction was slowly warmed to RT and allowed to stir for 2 h. The reaction was then cooled to 0 °C and 5 M HC1 solution was added and the reaction was stirred for an additional 4 h at RT. The reaction was extracted with DCM and the combined organic 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%).
Step 3. (£)-l-(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-methoxybut-l-en-l- yl)phenyl)-lH-l,2,4-triazole (DC70): To a solution of (£')-4-(4-(lH-l,2,4-triazol-l- yl)phenyl)-2-(3,5-dichlorophenyl)-l,l,l-trifluorobut-3-en-2-ol (0.15 g, 0.36 mmol) in THF (5 mL) was added NaH (60%, 10 mg, 0.44 mmol) at 0 °C. The reaction was allowed to stir at 0 °C for 30 min, then methyl iodide (61 mg, 0.44 mmol) was added slowly and the reaction was warmed to RT and allowed to stir for 4 h. The reaction was quenched with aq NH4C1 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%). Prophetic Example CI: Preparation of tert-butyl (3-methoxy-l-oxo-l-((2,2,2- trifluoroethyl)amino)propan-2-yl)carbamate (CI)
Figure imgf000151_0001
Prophetically, 2-((ieri-butoxycarbonyl)amino)-3-methoxypropanoic acid
reacted with 2,2,2-trifluoroethanamine in the presence of N-(3-dimethylaminopropyl)-N'- ethyl-carbodiimide hydrochloride (EDC»HC1) and 4-(dimethylamino)pyridine (DMAP) in CH2C12 to furnish the title molecule (/. Am. Chem. Soc. 2006, 128, 14640-14648).
Prophetic Example C2: Preparation 3-methoxy-l-oxo-l-((2,2,2- trifluoroethyl)amino)propan-2- cetate (C2)
Figure imgf000151_0002
Prophetically, ieri-butyl (3-methoxy- 1 -oxo- 1 -((2,2,2-trifluoroethyl)amino)propan-2- yl)carbamate can be reacted with trifluoroacetic acid in CH2CI2 to furnish the title molecule (/. Am. Chem. Soc. 2006, 128, 14640-14648).
Prophetic Example Fl: Preparation of (£')-2-bromo- V-(3-methoxy-l-oxo-l-((2,2,2- trifluoroethyl)amino)propan-2-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en-l- yl)benzamide (Fl)
Figure imgf000151_0003
Prophetically, (£)-2-bromo-4-(4,4,4-trifluoro-3 -(3 ,4,5 -trichlorophenyl)but- 1 -en- 1 - yl)benzoic acid can be reacted with 3-methoxy-l-oxo-l-((2,2,2-trifluoroethyl)amino)propan- 2-aminium 2,2,2-trifluoroacetate in the presence of N-(3-dimethylaminopropyl)-N'-ethyl- carbodiimide hydrochloride (EDC»HC1), 4-(dimethylamino)pyridine (DMAP) and triethylamine to furnish the title molecule.
The following prophetic molecules could be made in accordance with the procedures disclosed in Prophetic Example Fl:
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
The following prophetic molecules could be made in accordance with the procedures disclosed in this application:
Figure imgf000159_0001
Figure imgf000159_0002
Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F61 F F F H Br 0 CH(CH2OCH3) 0 CH2CH3
F62
F F F H CI 0 CH(CH2OCH3) 0 CH2CH3
F63 F F F H CF3 0 CH(CH2OCH3) 0 CH2CH3
F64 F F F H CH3 0 CH(CH2OCH3) 0 CH2CH3
F65 F F F H Br 0 CH(CH2OH) 0 CH2CF3
F66 F F F H CI 0 CH(CH2OH) 0 CH2CF3
F67 F F F H CF3 0 CH(CH2OH) 0 CH2CF3
F68 F F F H CH3 0 CH(CH2OH) 0 CH2CF3
F69 F F F H Br 0 CH(CH2SH) 0 CH2CF3
F70 F F F H CI 0 CH(CH2SH) 0 CH2CF3
F71 F F F H CF3 0 CH(CH2SH) 0 CH2CF3
F72 F F F H CH3 0 CH(CH2SH) 0 CH2CF3
F73 F F F H Br 0 CH(CH2SCH3) 0 CH2CF3
F74 F F F H CI 0 CH(CH2SCH3) 0 CH2CF3
F75
F F F H CF3 0 CH(CH2SCH3) 0 CH2CF3
F76 F F F H CH3 0 CH(CH2SCH3) 0 CH2CF3
F77 F F F H Br 0 CH(CH2N(CH3)2) 0 CH2CF3
F78 F F F H CI 0 CH(CH2N(CH3)2) 0 CH2CF3
F79 F F F H CF3 0 CH(CH2N(CH3)2) 0 CH2CF3
F80 F F F H CH3 0 CH(CH2N(CH3)2) 0 CH2CF3
F81 F F F H Br 0 CH(CH2N02) 0 CH2CF3
F82 F F F H CI 0 CH(CH2N02) 0 CH2CF3
F83 F F F H CF3 0 CH(CH2N02) 0 CH2CF3
F84
F F F H CH3 0 CH(CH2N02) 0 CH2CF3
F85 F F F H Br 0 CH(CF3) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F86 F F F H CI 0 CH(CF3) 0 CH2CF3
F87 F F F H CF3 0 CH(CF3) 0 CH2CF3
F88 F F F H CH3 0 CH(CF3) 0 CH2CF3
F89 F F F H Br 0 CH(CH2CH=CH2) 0 CH2CF3
F90 F F F H CI 0 CH(CH2CH=CH2) 0 CH2CF3
F91 F F F H CF3 0 CH(CH2CH=CH2) 0 CH2CF3
F92 F F F H CH3 0 CH(CH2CH=CH2) 0 CH2CF3
F93 F F F H Br 0 CH(CH2CH≡CH) 0 CH2CF3
F94 F F F H CI 0 CH(CH2CH≡CH) 0 CH2CF3
F95 F F F H CF3 0 CH(CH2CH≡CH) 0 CH2CF3
F96 F F F H CH3 0 CH(CH2CH≡CH) 0 CH2CF3
F97 F F F H Br 0 CH(CN) 0 CH2CF3
F98 F F F H CI 0 CH(CN) 0 CH2CF3
F99 F F F H CF3 0 CH(CN) 0 CH2CF3
F100 F F F H CH3 0 CH(CN) 0 CH2CF3
F101 CI CI H CI Br 0 CH(CH2OCH3) 0 CH2CF3
F102 CI CI H CI CI 0 CH(CH2OCH3) 0 CH2CF3
F103 CI CI H CI CF3 0 CH(CH2OCH3) 0 CH2CF3
F104 CI CI H CI CH3 0 CH(CH2OCH3) 0 CH2CF3
F105 CI CI H CI Br 0 CH(CH2OCH3) s CH2CF3
F106 CI CI H CI CI 0 CH(CH2OCH3) s CH2CF3
F107 CI CI H CI CF3 0 CH(CH2OCH3) s CH2CF3
F108 CI CI H CI CH3 0 CH(CH2OCH3) s CH2CF3
F109 CI CI H CI Br s CH(CH2OCH3) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F110 CI CI H CI CI S CH(CH2OCH3) 0 CH2CF3
Fill CI CI H CI CF3 s CH(CH2OCH3) 0 CH2CF3
F112 CI CI H CI CH3 s CH(CH2OCH3) 0 CH2CF3
F113 CI CI H CI Br 0 CH(CH2OCH3) 0 CH2CHF2
F114 CI CI H CI CI 0 CH(CH2OCH3) 0 CH2CHF2
F115 CI CI H CI CF3 0 CH(CH2OCH3) 0 CH2CHF2
F116 CI CI H CI CH3 0 CH(CH2OCH3) 0 CH2CHF2
F117 CI CI H CI Br 0 CH(CH2OCH3) 0 CH2CH2F
F118 CI CI H CI CI 0 CH(CH2OCH3) 0 CH2CH2F
F119 CI CI H CI CF3 0 CH(CH2OCH3) 0 CH2CH2F
F120 CI CI H CI CH3 0 CH(CH2OCH3) 0 CH2CH2F
F121 CI CI H CI Br 0 CH(CH2OCH3) 0 CH2CH3
F122 CI CI H CI CI 0 CH(CH2OCH3) 0 CH2CH3
F123 CI CI H CI CF3 0 CH(CH2OCH3) 0 CH2CH3
F124 CI CI H CI CH3 0 CH(CH2OCH3) 0 CH2CH3
F125 CI CI H CI Br 0 CH(CH2OH) 0 CH2CF3
F126 CI CI H CI CI 0 CH(CH2OH) 0 CH2CF3
F127 CI CI H CI CF3 0 CH(CH2OH) 0 CH2CF3
F128 CI CI H CI CH3 0 CH(CH2OH) 0 CH2CF3
F129 CI CI H CI Br 0 CH(CH2SH) 0 CH2CF3
F130 CI CI H CI CI 0 CH(CH2SH) 0 CH2CF3
F131 CI CI H CI CF3 0 CH(CH2SH) 0 CH2CF3
F132 CI CI H CI CH3 0 CH(CH2SH) 0 CH2CF3
F133 CI CI H CI Br 0 CH(CH2SCH3) 0 CH2CF3
F134 CI CI H CI CI 0 CH(CH2SCH3) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F135
CI CI H CI CF3 0 CH(CH2SCH3) 0 CH2CF3
F136
CI CI H CI CH3 0 CH(CH2SCH3) 0 CH2CF3
F137
CI CI H CI Br 0 CH(CH2N(CH3)2) 0 CH2CF3
F138 CI CI H CI CI 0 CH(CH2N(CH3)2) 0 CH2CF3
F139 CI CI H CI CF3 0 CH(CH2N(CH3)2) 0 CH2CF3
F140 CI CI H CI CH3 0 CH(CH2N(CH3)2) 0 CH2CF3
F141
CI CI H CI Br 0 CH(CH2N02) 0 CH2CF3
F142
CI CI H CI CI 0 CH(CH2N02) 0 CH2CF3
F143
CI CI H CI CF3 0 CH(CH2N02) 0 CH2CF3
F144
CI CI H CI CH3 0 CH(CH2N02) 0 CH2CF3
F145
CI CI H CI Br 0 CH(CF3) 0 CH2CF3
F146 CI CI H CI CI 0 CH(CF3) 0 CH2CF3
F147
CI CI H CI CF3 0 CH(CF3) 0 CH2CF3
F148 CI CI H CI CH3 0 CH(CF3) 0 CH2CF3
F149
CI CI H CI Br 0 CH(CH2CH=CH2) 0 CH2CF3
F150 CI CI H CI CI 0 CH(CH2CH=CH2) 0 CH2CF3
F151
CI CI H CI CF3 0 CH(CH2CH=CH2) 0 CH2CF3
F152
CI CI H CI CH3 0 CH(CH2CH=CH2) 0 CH2CF3
F153
CI CI H CI Br 0 CH(CH2CH≡CH) 0 CH2CF3
F154
CI CI H CI CI 0 CH(CH2CH≡CH) 0 CH2CF3
F155
CI CI H CI CF3 0 CH(CH2CH≡CH) 0 CH2CF3
F156
CI CI H CI CH3 0 CH(CH2CH≡CH) 0 CH2CF3
F157
CI CI H CI Br 0 CH(CN) 0 CH2CF3
F158 CI CI H CI CI 0 CH(CN) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F159 CI CI H CI CF3 0 CH(CN) 0 CH2CF3
F160 CI CI H CI CH3 0 CH(CN) 0 CH2CF3
F161 OC 0 CH(CH2OCH3) 0 CH2CF3
H H H Br
F3
F162 OC 0 CH(CH2OCH3) 0 CH2CF3
H H H CI
F3
F163 OC 0 CH(CH2OCH3) 0 CH2CF3
H H H CF3
F3
F164 OC 0 CH(CH2OCH3) 0 CH2CF3
H H H CH3
F3
F165 OC 0 CH(CH2OCH3)
H H H Br s CH2CF3
F3
F166 OC 0 CH(CH2OCH3) s CH2CF3
H H H CI
F3
F167 OC 0 CH(CH2OCH3)
H H H CF3 s CH2CF3
F3
F168 OC 0 CH(CH2OCH3)
H H H CH3 s CH2CF3
F3
F169 OC s CH(CH2OCH3) 0 CH2CF3
H H H Br
F3
F170 OC s CH(CH2OCH3) 0 CH2CF3
H H H CI
F3
F171 OC s CH(CH2OCH3) 0 CH2CF3
H H H CF3
F3
F172 OC s CH(CH2OCH3) 0 CH2CF3
H H H CH3
F3
F173 OC 0 CH(CH2OCH3) 0 CH2CHF2
H H H Br
F3
F174 OC 0 CH(CH2OCH3) 0 CH2CHF2
H H H CI
F3
F175 OC 0 CH(CH2OCH3) 0 CH2CHF2
H H H CF3
F3
F176 OC 0 CH(CH2OCH3) 0 CH2CHF2
H H H CH3
F3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F177 OC 0 CH(CH2OCH3) 0 CH2CH2F
H H H Br
F3
F178 OC 0 CH(CH2OCH3) 0 CH2CH2F
H H H CI
F3
F179 OC 0 CH(CH2OCH3) 0 CH2CH2F
H H H CF3
F3
F180 OC 0 CH(CH2OCH3) 0 CH2CH2F
H H H CH3
F3
F181 OC 0 CH(CH2OCH3) 0 CH2CH3
H H H Br
F3
F182 OC 0 CH(CH2OCH3) 0 CH2CH3
H H H CI
F3
F183 OC 0 CH(CH2OCH3) 0 CH2CH3
H H H CF3
F3
F184 OC 0 CH(CH2OCH3) 0 CH2CH3
H H H CH3
F3
F185 OC 0 CH(CH2OH) 0 CH2CF3
H H H Br
F3
F186 OC 0 CH(CH2OH) 0 CH2CF3
H H H CI
F3
F187 OC 0 CH(CH2OH) 0 CH2CF3
H H H CF3
F3
F188 OC 0 CH(CH2OH) 0 CH2CF3
H H H CH3
F3
F189 OC 0 CH(CH2SH) 0 CH2CF3
H H H Br
F3
F190 OC 0 CH(CH2SH) 0 CH2CF3
H H H CI
F3
F191 OC 0 CH(CH2SH) 0 CH2CF3
H H H CF3
F3
F192 OC 0 CH(CH2SH) 0 CH2CF3
H H H CH3
F3
F193 OC 0 CH(CH2SCH3) 0 CH2CF3
H H H Br
F3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F194 OC 0 CH(CH2SCH3) 0 CH2CF3
H H H CI
F3
F195 OC 0 CH(CH2SCH3) 0 CH2CF3
H H H CF3
F3
F196 OC 0 CH(CH2SCH3) 0 CH2CF3
H H H CH3
F3
F197 OC 0 CH(CH2N(CH3)2) 0 CH2CF3
H H H Br
F3
F198 OC 0 CH(CH2N(CH3)2) 0 CH2CF3
H H H CI
F3
F199 OC 0 CH(CH2N(CH3)2) 0 CH2CF3
H H H CF3
F3
F200 OC 0 CH(CH2N(CH3)2) 0 CH2CF3
H H H CH3
F3
F201 OC 0 CH(CH2N02) 0 CH2CF3
H H H Br
F3
F202 OC 0 CH(CH2N02) 0 CH2CF3
H H H CI
F3
F203 OC 0 CH(CH2N02) 0 CH2CF3
H H H CF3
F3
F204 OC 0 CH(CH2N02) 0 CH2CF3
H H H CH3
F3
F205 OC 0 CH(CF3) 0 CH2CF3
H H H Br
F3
F206 OC 0 CH(CF3) 0 CH2CF3
H H H CI
F3
F207 OC 0 CH(CF3) 0 CH2CF3
H H H CF3
F3
F208 OC 0 CH(CF3) 0 CH2CF3
H H H CH3
F3
F209 OC 0 CH(CH2CH=CH2) 0 CH2CF3
H H H Br
F3
F210 OC 0 CH(CH2CH=CH2) 0 CH2CF3
H H H CI
F3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F211 OC 0 CH(CH2CH=CH2) 0 CH2CF3
H H H CF3
F3
F212 OC 0 CH(CH2CH=CH2) 0 CH2CF3
H H H CH3
F3
F213 OC 0 CH2CF3
H H H Br CH(CH2CH≡CH) 0
F3
F214 OC 0
H H H CI CH(CH2CH≡CH) 0 CH2CF3
F3
F215 OC 0
H H H CF3 CH(CH2CH≡CH) 0 CH2CF3
F3
F216 OC 0 0 CH2CF3
H H H CH3 CH(CH2CH≡CH)
F3
F217 OC 0 CH(CN) 0 CH2CF3
H H H Br
F3
F218 OC 0 CH(CN) 0 CH2CF3
H H H CI
F3
F219 OC 0 CH(CN) 0 CH2CF3
H H H CF3
F3
F220 OC 0 CH(CN) 0 CH2CF3
H H H CH3
F3
F221 H F H Br Br 0 CH(CH2OCH3) 0 CH2CF3
F222 H F H Br CI 0 CH(CH2OCH3) 0 CH2CF3
F223 H F H Br CF3 0 CH(CH2OCH3) 0 CH2CF3
F224 H F H Br CH3 0 CH(CH2OCH3) 0 CH2CF3
F225 H F H Br Br 0 CH(CH2OCH3) s CH2CF3
F226 H F H Br CI 0 CH(CH2OCH3) s CH2CF3
F227 H F H Br CF3 0 CH(CH2OCH3) s CH2CF3
F228 H F H Br CH3 0 CH(CH2OCH3) s CH2CF3
F229 H F H Br Br s CH(CH2OCH3) 0 CH2CF3
F230 H F H Br CI s CH(CH2OCH3) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F231 H F H Br CF3 s CH(CH2OCH3) 0 CH2CF3
F232 H F H Br CH3 s CH(CH2OCH3) 0 CH2CF3
F233 H F H Br Br 0 CH(CH2OCH3) 0 CH2CHF2
F234 H F H Br CI 0 CH(CH2OCH3) 0 CH2CHF2
F235 H F H Br CF3 0 CH(CH2OCH3) 0 CH2CHF2
F236 H F H Br CH3 0 CH(CH2OCH3) 0 CH2CHF2
F237 H F H Br Br 0 CH(CH2OCH3) 0 CH2CH2F
F238 H F H Br CI 0 CH(CH2OCH3) 0 CH2CH2F
F239 H F H Br CF3 0 CH(CH2OCH3) 0 CH2CH2F
F240 H F H Br CH3 0 CH(CH2OCH3) 0 CH2CH2F
F241 H F H Br Br 0 CH(CH2OCH3) 0 CH2CH3
F242 H F H Br CI 0 CH(CH2OCH3) 0 CH2CH3
F243 H F H Br CF3 0 CH(CH2OCH3) 0 CH2CH3
F244 H F H Br CH3 0 CH(CH2OCH3) 0 CH2CH3
F245 H F H Br Br 0 CH(CH2OH) 0 CH2CF3
F246 H F H Br CI 0 CH(CH2OH) 0 CH2CF3
F247 H F H Br CF3 0 CH(CH2OH) 0 CH2CF3
F248 H F H Br CH3 0 CH(CH2OH) 0 CH2CF3
F249 H F H Br Br 0 CH(CH2SH) 0 CH2CF3
F250 H F H Br CI 0 CH(CH2SH) 0 CH2CF3
F251 H F H Br CF3 0 CH(CH2SH) 0 CH2CF3
F252 H F H Br CH3 0 CH(CH2SH) 0 CH2CF3
F253 H F H Br Br 0 CH(CH2SCH3) 0 CH2CF3
F254 H F H Br CI 0 CH(CH2SCH3) 0 CH2CF3
F255 H F H Br CF3 0 CH(CH2SCH3) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F256 H F H Br CH3 0 CH(CH2SCH3) 0 CH2CF3
F257
H F H Br Br 0 CH(CH2N(CH3)2) 0 CH2CF3
F258 H F H Br CI 0 CH(CH2N(CH3)2) 0 CH2CF3
F259 H F H Br CF3 0 CH(CH2N(CH3)2) 0 CH2CF3
F260 H F H Br CH3 0 CH(CH2N(CH3)2) 0 CH2CF3
F261 H F H Br Br 0 CH(CH2N02) 0 CH2CF3
F262 H F H Br CI 0 CH(CH2N02) 0 CH2CF3
F263 H F H Br CF3 0 CH(CH2N02) 0 CH2CF3
F264
H F H Br CH3 0 CH(CH2N02) 0 CH2CF3
F265 H F H Br Br 0 CH(CF3) 0 CH2CF3
F266 H F H Br CI 0 CH(CF3) 0 CH2CF3
F267 H F H Br CF3 0 CH(CF3) 0 CH2CF3
F268 H F H Br CH3 0 CH(CF3) 0 CH2CF3
F269 H F H Br Br 0 CH(CH2CH=CH2) 0 CH2CF3
F270 H F H Br CI 0 CH(CH2CH=CH2) 0 CH2CF3
F271 H F H Br CF3 0 CH(CH2CH=CH2) 0 CH2CF3
F272 H F H Br CH3 0 CH(CH2CH=CH2) 0 CH2CF3
F273 H F H Br Br 0 CH(CH2CH≡CH) 0 CH2CF3
F274 H F H Br CI 0 CH(CH2CH≡CH) 0 CH2CF3
F275 H F H Br CF3 0 CH(CH2CH≡CH) 0 CH2CF3
F276 H F H Br CH3 0 CH(CH2CH≡CH) 0 CH2CF3
F277 H F H Br Br 0 CH(CN) 0 CH2CF3
F278 H F H Br CI 0 CH(CN) 0 CH2CF3
F279 H F H Br CF3 0 CH(CN) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F280 H F H Br CH3 0 CH(CN) 0 CH2CF3
F281 H CH3 CI H Br 0 CH(CH2OCH3) 0 CH2CF3
F282 H CH3 CI H CI 0 CH(CH2OCH3) 0 CH2CF3
F283 H CH3 CI H CF3 0 CH(CH2OCH3) 0 CH2CF3
F284 H CH3 CI H CH3 0 CH(CH2OCH3) 0 CH2CF3
F285 H CH3 CI H Br 0 CH(CH2OCH3) s CH2CF3
F286 H CH3 CI H CI 0 CH(CH2OCH3) s CH2CF3
F287 H CH3 CI H CF3 0 CH(CH2OCH3) s CH2CF3
F288 H CH3 CI H CH3 0 CH(CH2OCH3) s CH2CF3
F289 H CH3 CI H Br s CH(CH2OCH3) 0 CH2CF3
F290 H CH3 CI H CI s CH(CH2OCH3) 0 CH2CF3
F291 H CH3 CI H CF3 s CH(CH2OCH3) 0 CH2CF3
F292 H CH3 CI H CH3 s CH(CH2OCH3) 0 CH2CF3
F293 H CH3 CI H Br 0 CH(CH2OCH3) 0 CH2CHF2
F294 H CH3 CI H CI 0 CH(CH2OCH3) 0 CH2CHF2
F295 H CH3 CI H CF3 0 CH(CH2OCH3) 0 CH2CHF2
F296 H CH3 CI H CH3 0 CH(CH2OCH3) 0 CH2CHF2
F297 H CH3 CI H Br 0 CH(CH2OCH3) 0 CH2CH2F
F298 H CH3 CI H CI 0 CH(CH2OCH3) 0 CH2CH2F
F299 H CH3 CI H CF3 0 CH(CH2OCH3) 0 CH2CH2F
F300 H CH3 CI H CH3 0 CH(CH2OCH3) 0 CH2CH2F
F301 H CH3 CI H Br 0 CH(CH2OCH3) 0 CH2CH3
F302 H CH3 CI H CI 0 CH(CH2OCH3) 0 CH2CH3
F303 H CH3 CI H CF3 0 CH(CH2OCH3) 0 CH2CH3
F304 H CH3 CI H CH3 0 CH(CH2OCH3) 0 CH2CH3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F305 H CH3 CI H Br 0 CH(CH2OH) 0 CH2CF3
F306 H CH3 CI H CI 0 CH(CH2OH) 0 CH2CF3
F307 H CH3 CI H CF3 0 CH(CH2OH) 0 CH2CF3
F308 H CH3 CI H CH3 0 CH(CH2OH) 0 CH2CF3
F309 H CH3 CI H Br 0 CH(CH2SH) 0 CH2CF3
F310 H CH3 CI H CI 0 CH(CH2SH) 0 CH2CF3
F311 H CH3 CI H CF3 0 CH(CH2SH) 0 CH2CF3
F312 H CH3 CI H CH3 0 CH(CH2SH) 0 CH2CF3
F313 H CH3 CI H Br 0 CH(CH2SCH3) 0 CH2CF3
F314 H CH3 CI H CI 0 CH(CH2SCH3) 0 CH2CF3
F315 H CH3 CI H CF3 0 CH(CH2SCH3) 0 CH2CF3
F316 H CH3 CI H CH3 0 CH(CH2SCH3) 0 CH2CF3
F317
H CH3 CI H Br 0 CH(CH2N(CH3)2) 0 CH2CF3
F318 H CH3 CI H CI 0 CH(CH2N(CH3)2) 0 CH2CF3
F319 H CH3 CI H CF3 0 CH(CH2N(CH3)2) 0 CH2CF3
F320 H CH3 CI H CH3 0 CH(CH2N(CH3)2) 0 CH2CF3
F321 H CH3 CI H Br 0 CH(CH2N02) 0 CH2CF3
F322 H CH3 CI H CI 0 CH(CH2N02) 0 CH2CF3
F323 H CH3 CI H CF3 0 CH(CH2N02) 0 CH2CF3
F324
H CH3 CI H CH3 0 CH(CH2N02) 0 CH2CF3
F325 H CH3 CI H Br 0 CH(CF3) 0 CH2CF3
F326 H CH3 CI H CI 0 CH(CF3) 0 CH2CF3
F327 H CH3 CI H CF3 0 CH(CF3) 0 CH2CF3
F328 H CH3 CI H CH3 0 CH(CF3) 0 CH2CF3
F329 H CH3 CI H Br 0 CH(CH2CH=CH2) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F330 H CH3 CI H CI 0 CH(CH2CH=CH2) 0 CH2CF3
F331 H CH3 CI H CF3 0 CH(CH2CH=CH2) 0 CH2CF3
F332 H CH3 CI H CH3 0 CH(CH2CH=CH2) 0 CH2CF3
F333 H CH3 CI H Br 0 CH(CH2CH≡CH) 0 CH2CF3
F334 H CH3 CI H CI 0 CH(CH2CH≡CH) 0 CH2CF3
F335 H CH3 CI H CF3 0 CH(CH2CH≡CH) 0 CH2CF3
F336 H CH3 CI H CH3 0 CH(CH2CH≡CH) 0 CH2CF3
F337 H CH3 CI H Br 0 CH(CN) 0 CH2CF3
F338 H CH3 CI H CI 0 CH(CN) 0 CH2CF3
F339 H CH3 CI H CF3 0 CH(CN) 0 CH2CF3
F340 H CH3 CI H CH3 0 CH(CN) 0 CH2CF3
F341 H CI CH3 H Br 0 CH(CH2OCH3) 0 CH2CF3
F342 H CI CH3 H CI 0 CH(CH2OCH3) 0 CH2CF3
F343 H CI CH3 H CF3 0 CH(CH2OCH3) 0 CH2CF3
F344 H CI CH3 H CH3 0 CH(CH2OCH3) 0 CH2CF3
F345 H CI CH3 H Br 0 CH(CH2OCH3) s CH2CF3
F346 H CI CH3 H CI 0 CH(CH2OCH3) s CH2CF3
F347 H CI CH3 H CF3 0 CH(CH2OCH3) s CH2CF3
F348 H CI CH3 H CH3 0 CH(CH2OCH3) s CH2CF3
F349 H CI CH3 H Br s CH(CH2OCH3) 0 CH2CF3
F350 H CI CH3 H CI s CH(CH2OCH3) 0 CH2CF3
F351 H CI CH3 H CF3 s CH(CH2OCH3) 0 CH2CF3
F352 H CI CH3 H CH3 s CH(CH2OCH3) 0 CH2CF3
F353 H CI CH3 H Br 0 CH(CH2OCH3) 0 CH2CHF2 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F354 H CI CH3 H CI 0 CH(CH2OCH3) 0 CH2CHF2
F355
H CI CH3 H CF3 0 CH(CH2OCH3) 0 CH2CHF2
F356 H CI CH3 H CH3 0 CH(CH2OCH3) 0 CH2CHF2
F357 H CI CH3 H Br 0 CH(CH2OCH3) 0 CH2CH2F
F358 H CI CH3 H CI 0 CH(CH2OCH3) 0 CH2CH2F
F359 H CI CH3 H CF3 0 CH(CH2OCH3) 0 CH2CH2F
F360 H CI CH3 H CH3 0 CH(CH2OCH3) 0 CH2CH2F
F361 H CI CH3 H Br 0 CH(CH2OCH3) 0 CH2CH3
F362
H CI CH3 H CI 0 CH(CH2OCH3) 0 CH2CH3
F363 H CI CH3 H CF3 0 CH(CH2OCH3) 0 CH2CH3
F364 H CI CH3 H CH3 0 CH(CH2OCH3) 0 CH2CH3
F365 H CI CH3 H Br 0 CH(CH2OH) 0 CH2CF3
F366 H CI CH3 H CI 0 CH(CH2OH) 0 CH2CF3
F367 H CI CH3 H CF3 0 CH(CH2OH) 0 CH2CF3
F368 H CI CH3 H CH3 0 CH(CH2OH) 0 CH2CF3
F369 H CI CH3 H Br 0 CH(CH2SH) 0 CH2CF3
F370 H CI CH3 H CI 0 CH(CH2SH) 0 CH2CF3
F371 H CI CH3 H CF3 0 CH(CH2SH) 0 CH2CF3
F372
H CI CH3 H CH3 0 CH(CH2SH) 0 CH2CF3
F373 H CI CH3 H Br 0 CH(CH2SCH3) 0 CH2CF3
F374 H CI CH3 H CI 0 CH(CH2SCH3) 0 CH2CF3
F375 H CI CH3 H CF3 0 CH(CH2SCH3) 0 CH2CF3
F376 H CI CH3 H CH3 0 CH(CH2SCH3) 0 CH2CF3
F377
H CI CH3 H Br 0 CH(CH2N(CH3)2) 0 CH2CF3
F378 H CI CH3 H CI 0 CH(CH2N(CH3)2) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F379 H CI CH3 H CF3 0 CH(CH2N(CH3)2) 0 CH2CF3
F380 H CI CH3 H CH3 0 CH(CH2N(CH3)2) 0 CH2CF3
F381 H CI CH3 H Br 0 CH(CH2N02) 0 CH2CF3
F382 H CI CH3 H CI 0 CH(CH2N02) 0 CH2CF3
F383 H CI CH3 H CF3 0 CH(CH2N02) 0 CH2CF3
F384 H CI CH3 H CH3 0 CH(CH2N02) 0 CH2CF3
F385 H CI CH3 H Br 0 CH(CF3) 0 CH2CF3
F386 H CI CH3 H CI 0 CH(CF3) 0 CH2CF3
F387
H CI CH3 H CF3 0 CH(CF3) 0 CH2CF3
F388 H CI CH3 H CH3 0 CH(CF3) 0 CH2CF3
F389 H CI CH3 H Br 0 CH(CH2CH=CH2) 0 CH2CF3
F390 H CI CH3 H CI 0 CH(CH2CH=CH2) 0 CH2CF3
F391 H CI CH3 H CF3 0 CH(CH2CH=CH2) 0 CH2CF3
F392 H CI CH3 H CH3 0 CH(CH2CH=CH2) 0 CH2CF3
F393 H CI CH3 H Br 0 CH(CH2CH≡CH) 0 CH2CF3
F394 H CI CH3 H CI 0 CH(CH2CH≡CH) 0 CH2CF3
F395 H CI CH3 H CF3 0 CH(CH2CH≡CH) 0 CH2CF3
F396 H CI CH3 H CH3 0 CH(CH2CH≡CH) 0 CH2CF3
F397 H CI CH3 H Br 0 CH(CN) 0 CH2CF3
F398 H CI CH3 H CI 0 CH(CN) 0 CH2CF3
F399 H CI CH3 H CF3 0 CH(CN) 0 CH2CF3
F400 H CI CH3 H CH3 0 CH(CN) 0 CH2CF3
F401 H CH3 F CH3 Br 0 CH(CH2OCH3) 0 CH2CF3
F402 H CH3 F CH3 CI 0 CH(CH2OCH3) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F403 H CH3 F CH3 CF3 0 CH(CH2OCH3) 0 CH2CF3
F404 H CH3 F CH3 CH3 0 CH(CH2OCH3) 0 CH2CF3
F405 H CH3 F CH3 Br 0 CH(CH2OCH3) s CH2CF3
F406 H CH3 F CH3 CI 0 CH(CH2OCH3) s CH2CF3
F407 H CH3 F CH3 CF3 0 CH(CH2OCH3) s CH2CF3
F408 H CH3 F CH3 CH3 0 CH(CH2OCH3) s CH2CF3
F409 H CH3 F CH3 Br s CH(CH2OCH3) 0 CH2CF3
F410 H CH3 F CH3 CI s CH(CH2OCH3) 0 CH2CF3
F411 H CH3 F CH3 CF3 s CH(CH2OCH3) 0 CH2CF3
F412 H CH3 F CH3 CH3 s CH(CH2OCH3) 0 CH2CF3
F413 H CH3 F CH3 Br 0 CH(CH2OCH3) 0 CH2CHF2
F414 H CH3 F CH3 CI 0 CH(CH2OCH3) 0 CH2CHF2
F415 H CH3 F CH3 CF3 0 CH(CH2OCH3) 0 CH2CHF2
F416 H CH3 F CH3 CH3 0 CH(CH2OCH3) 0 CH2CHF2
F417 H CH3 F CH3 Br 0 CH(CH2OCH3) 0 CH2CH2F
F418 H CH3 F CH3 CI 0 CH(CH2OCH3) 0 CH2CH2F
F419 H CH3 F CH3 CF3 0 CH(CH2OCH3) 0 CH2CH2F
F420 H CH3 F CH3 CH3 0 CH(CH2OCH3) 0 CH2CH2F
F421 H CH3 F CH3 Br 0 CH(CH2OCH3) 0 CH2CH3
F422 H CH3 F CH3 CI 0 CH(CH2OCH3) 0 CH2CH3
F423 H CH3 F CH3 CF3 0 CH(CH2OCH3) 0 CH2CH3
F424 H CH3 F CH3 CH3 0 CH(CH2OCH3) 0 CH2CH3
F425 H CH3 F CH3 Br 0 CH(CH2OH) 0 CH2CF3
F426 H CH3 F CH3 CI 0 CH(CH2OH) 0 CH2CF3
F427 H CH3 F CH3 CF3 0 CH(CH2OH) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F428 H CH3 F CH3 CH3 0 CH(CH2OH) 0 CH2CF3
F429 H CH3 F CH3 Br 0 CH(CH2SH) 0 CH2CF3
F430 H CH3 F CH3 CI 0 CH(CH2SH) 0 CH2CF3
F431 H CH3 F CH3 CF3 0 CH(CH2SH) 0 CH2CF3
F432 H CH3 F CH3 CH3 0 CH(CH2SH) 0 CH2CF3
F433 H CH3 F CH3 Br 0 CH(CH2SCH3) 0 CH2CF3
F434 H CH3 F CH3 CI 0 CH(CH2SCH3) 0 CH2CF3
F435 H CH3 F CH3 CF3 0 CH(CH2SCH3) 0 CH2CF3
F436 H CH3 F CH3 CH3 0 CH(CH2SCH3) 0 CH2CF3
F437 H CH3 F CH3 Br 0 CH(CH2N(CH3)2) 0 CH2CF3
F438 H CH3 F CH3 CI 0 CH(CH2N(CH3)2) 0 CH2CF3
F439 H CH3 F CH3 CF3 0 CH(CH2N(CH3)2) 0 CH2CF3
F440 H CH3 F CH3 CH3 0 CH(CH2N(CH3)2) 0 CH2CF3
F441 H CH3 F CH3 Br 0 CH(CH2N02) 0 CH2CF3
F442
H CH3 F CH3 CI 0 CH(CH2N02) 0 CH2CF3
F443 H CH3 F CH3 CF3 0 CH(CH2N02) 0 CH2CF3
F444 H CH3 F CH3 CH3 0 CH(CH2N02) 0 CH2CF3
F445 H CH3 F CH3 Br 0 CH(CF3) 0 CH2CF3
F446 H CH3 F CH3 CI 0 CH(CF3) 0 CH2CF3
F447
H CH3 F CH3 CF3 0 CH(CF3) 0 CH2CF3
F448 H CH3 F CH3 CH3 0 CH(CF3) 0 CH2CF3
F449 H CH3 F CH3 Br 0 CH(CH2CH=CH2) 0 CH2CF3
F450 H CH3 F CH3 CI 0 CH(CH2CH=CH2) 0 CH2CF3
F451
H CH3 F CH3 CF3 0 CH(CH2CH=CH2) 0 CH2CF3
F452 H CH3 F CH3 CH3 0 CH(CH2CH=CH2) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F453 H CH3 F CH3 Br 0 CH(CH2CH≡CH) 0 CH2CF3
F454 H CH3 F CH3 CI 0 CH(CH2CH≡CH) 0 CH2CF3
F455 H CH3 F CH3 CF3 0 CH(CH2CH≡CH) 0 CH2CF3
F456 H CH3 F CH3 CH3 0 CH(CH2CH≡CH) 0 CH2CF3
F457 H CH3 F CH3 Br 0 CH(CN) 0 CH2CF3
F458 H CH3 F CH3 CI 0 CH(CN) 0 CH2CF3
F459 H CH3 F CH3 CF3 0 CH(CN) 0 CH2CF3
F460 H CH3 F CH3 CH3 0 CH(CN) 0 CH2CF3
F461 H CI H Br Br 0 CH(CH2OCH3) 0 CH2CF3
F462 H CI H Br CI 0 CH(CH2OCH3) 0 CH2CF3
F463 H CI H Br CF3 0 CH(CH2OCH3) 0 CH2CF3
F464 H CI H Br CH3 0 CH(CH2OCH3) 0 CH2CF3
F465 H CI H Br Br 0 CH(CH2OCH3) s CH2CF3
F466 H CI H Br CI 0 CH(CH2OCH3) s CH2CF3
F467 H CI H Br CF3 0 CH(CH2OCH3) s CH2CF3
F468 H CI H Br CH3 0 CH(CH2OCH3) s CH2CF3
F469 H CI H Br Br s CH(CH2OCH3) 0 CH2CF3
F470 H CI H Br CI s CH(CH2OCH3) 0 CH2CF3
F471 H CI H Br CF3 s CH(CH2OCH3) 0 CH2CF3
F472 H CI H Br CH3 s CH(CH2OCH3) 0 CH2CF3
F473 H CI H Br Br 0 CH(CH2OCH3) 0 CH2CHF2
F474 H CI H Br CI 0 CH(CH2OCH3) 0 CH2CHF2
F475 H CI H Br CF3 0 CH(CH2OCH3) 0 CH2CHF2
F476 H CI H Br CH3 0 CH(CH2OCH3) 0 CH2CHF2 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F477 H CI H Br Br 0 CH(CH2OCH3) 0 CH2CH2F
F478 H CI H Br CI 0 CH(CH2OCH3) 0 CH2CH2F
F479 H CI H Br CF3 0 CH(CH2OCH3) 0 CH2CH2F
F480 H CI H Br CH3 0 CH(CH2OCH3) 0 CH2CH2F
F481 H CI H Br Br 0 CH(CH2OCH3) 0 CH2CH3
F482 H CI H Br CI 0 CH(CH2OCH3) 0 CH2CH3
F483 H CI H Br CF3 0 CH(CH2OCH3) 0 CH2CH3
F484 H CI H Br CH3 0 CH(CH2OCH3) 0 CH2CH3
F485
H CI H Br Br 0 CH(CH2OH) 0 CH2CF3
F486 H CI H Br CI 0 CH(CH2OH) 0 CH2CF3
F487 H CI H Br CF3 0 CH(CH2OH) 0 CH2CF3
F488 H CI H Br CH3 0 CH(CH2OH) 0 CH2CF3
F489 H CI H Br Br 0 CH(CH2SH) 0 CH2CF3
F490 H CI H Br CI 0 CH(CH2SH) 0 CH2CF3
F491 H CI H Br CF3 0 CH(CH2SH) 0 CH2CF3
F492 H CI H Br CH3 0 CH(CH2SH) 0 CH2CF3
F493 H CI H Br Br 0 CH(CH2SCH3) 0 CH2CF3
F494 H CI H Br CI 0 CH(CH2SCH3) 0 CH2CF3
F495
H CI H Br CF3 0 CH(CH2SCH3) 0 CH2CF3
F496 H CI H Br CH3 0 CH(CH2SCH3) 0 CH2CF3
F497 H CI H Br Br 0 CH(CH2N(CH3)2) 0 CH2CF3
F498 H CI H Br CI 0 CH(CH2N(CH3)2) 0 CH2CF3
F499 H CI H Br CF3 0 CH(CH2N(CH3)2) 0 CH2CF3
F500 H CI H Br CH3 0 CH(CH2N(CH3)2) 0 CH2CF3
F501 H CI H Br Br 0 CH(CH2N02) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F502 H CI H Br CI 0 CH(CH2N02) 0 CH2CF3
F503 H CI H Br CF3 0 CH(CH2N02) 0 CH2CF3
F504 H CI H Br CH3 0 CH(CH2N02) 0 CH2CF3
F505 H CI H Br Br 0 CH(CF3) 0 CH2CF3
F506 H CI H Br CI 0 CH(CF3) 0 CH2CF3
F507 H CI H Br CF3 0 CH(CF3) 0 CH2CF3
F508 H CI H Br CH3 0 CH(CF3) 0 CH2CF3
F509 H CI H Br Br 0 CH(CH2CH=CH2) 0 CH2CF3
F510 H CI H Br CI 0 CH(CH2CH=CH2) 0 CH2CF3
F511 H CI H Br CF3 0 CH(CH2CH=CH2) 0 CH2CF3
F512 H CI H Br CH3 0 CH(CH2CH=CH2) 0 CH2CF3
F513 H CI H Br Br 0 CH(CH2CH≡CH) 0 CH2CF3
F514 H CI H Br CI 0 CH(CH2CH≡CH) 0 CH2CF3
F515 H CI H Br CF3 0 CH(CH2CH≡CH) 0 CH2CF3
F516 H CI H Br CH3 0 CH(CH2CH≡CH) 0 CH2CF3
F517 H CI H Br Br 0 CH(CN) 0 CH2CF3
F518 H CI H Br CI 0 CH(CN) 0 CH2CF3
F519 H CI H Br CF3 0 CH(CN) 0 CH2CF3
F520 H CI H Br CH3 0 CH(CN) 0 CH2CF3
F521 H H Br Br Br 0 CH(CH2OCH3) 0 CH2CF3
F522 H H Br Br CI 0 CH(CH2OCH3) 0 CH2CF3
F523 H H Br Br CF3 0 CH(CH2OCH3) 0 CH2CF3
F524 H H Br Br CH3 0 CH(CH2OCH3) 0 CH2CF3
F525 H H Br Br Br 0 CH(CH2OCH3) s CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F526 H H Br Br CI 0 CH(CH2OCH3) S CH2CF3
F527 H H Br Br CF3 0 CH(CH2OCH3) s CH2CF3
F528 H H Br Br CH3 0 CH(CH2OCH3) s CH2CF3
F529 H H Br Br Br s CH(CH2OCH3) 0 CH2CF3
F530 H H Br Br CI s CH(CH2OCH3) 0 CH2CF3
F531 H H Br Br CF3 s CH(CH2OCH3) 0 CH2CF3
F532 H H Br Br CH3 s CH(CH2OCH3) 0 CH2CF3
F533 H H Br Br Br 0 CH(CH2OCH3) 0 CH2CHF2
F534 H H Br Br CI 0 CH(CH2OCH3) 0 CH2CHF2
F535 H H Br Br CF3 0 CH(CH2OCH3) 0 CH2CHF2
F536 H H Br Br CH3 0 CH(CH2OCH3) 0 CH2CHF2
F537 H H Br Br Br 0 CH(CH2OCH3) 0 CH2CH2F
F538 H H Br Br CI 0 CH(CH2OCH3) 0 CH2CH2F
F539 H H Br Br CF3 0 CH(CH2OCH3) 0 CH2CH2F
F540 H H Br Br CH3 0 CH(CH2OCH3) 0 CH2CH2F
F541 H H Br Br Br 0 CH(CH2OCH3) 0 CH2CH3
F542 H H Br Br CI 0 CH(CH2OCH3) 0 CH2CH3
F543 H H Br Br CF3 0 CH(CH2OCH3) 0 CH2CH3
F544 H H Br Br CH3 0 CH(CH2OCH3) 0 CH2CH3
F545 H H Br Br Br 0 CH(CH2OH) 0 CH2CF3
F546 H H Br Br CI 0 CH(CH2OH) 0 CH2CF3
F547 H H Br Br CF3 0 CH(CH2OH) 0 CH2CF3
F548 H H Br Br CH3 0 CH(CH2OH) 0 CH2CF3
F549 H H Br Br Br 0 CH(CH2SH) 0 CH2CF3
F550 H H Br Br CI 0 CH(CH2SH) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F551 H H Br Br CF3 0 CH(CH2SH) 0 CH2CF3
F552
H H Br Br CH3 0 CH(CH2SH) 0 CH2CF3
F553 H H Br Br Br 0 CH(CH2SCH3) 0 CH2CF3
F554 H H Br Br CI 0 CH(CH2SCH3) 0 CH2CF3
F555 H H Br Br CF3 0 CH(CH2SCH3) 0 CH2CF3
F556 H H Br Br CH3 0 CH(CH2SCH3) 0 CH2CF3
F557 H H Br Br Br 0 CH(CH2N(CH3)2) 0 CH2CF3
F558 H H Br Br CI 0 CH(CH2N(CH3)2) 0 CH2CF3
F559 H H Br Br CF3 0 CH(CH2N(CH3)2) 0 CH2CF3
F560 H H Br Br CH3 0 CH(CH2N(CH3)2) 0 CH2CF3
F561 H H Br Br Br 0 CH(CH2N02) 0 CH2CF3
F562 H H Br Br CI 0 CH(CH2N02) 0 CH2CF3
F563 H H Br Br CF3 0 CH(CH2N02) 0 CH2CF3
F564 H H Br Br CH3 0 CH(CH2N02) 0 CH2CF3
F565
H H Br Br Br 0 CH(CF3) 0 CH2CF3
F566 H H Br Br CI 0 CH(CF3) 0 CH2CF3
F567 H H Br Br CF3 0 CH(CF3) 0 CH2CF3
F568 H H Br Br CH3 0 CH(CF3) 0 CH2CF3
F569 H H Br Br Br 0 CH(CH2CH=CH2) 0 CH2CF3
F570 H H Br Br CI 0 CH(CH2CH=CH2) 0 CH2CF3
F571 H H Br Br CF3 0 CH(CH2CH=CH2) 0 CH2CF3
F572 H H Br Br CH3 0 CH(CH2CH=CH2) 0 CH2CF3
F573 H H Br Br Br 0 CH(CH2CH≡CH) 0 CH2CF3
F574 H H Br Br CI 0 CH(CH2CH≡CH) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F575 H H Br Br CF3 0 CH(CH2CH≡CH) 0 CH2CF3
F576 H H Br Br CH3 0 CH(CH2CH≡CH) 0 CH2CF3
F577 H H Br Br Br 0 CH(CN) 0 CH2CF3
F578 H H Br Br CI 0 CH(CN) 0 CH2CF3
F579 H H Br Br CF3 0 CH(CN) 0 CH2CF3
F580 H H Br Br CH3 0 CH(CN) 0 CH2CF3
F581 H H CI N02 Br 0 CH(CH2OCH3) 0 CH2CF3
F582 H H CI N02 CI 0 CH(CH2OCH3) 0 CH2CF3
F583 H H CI N02 CF3 0 CH(CH2OCH3) 0 CH2CF3
F584 H H CI N02 CH3 0 CH(CH2OCH3) 0 CH2CF3
F585 H H CI N02 Br 0 CH(CH2OCH3) s CH2CF3
F586 H H CI N02 CI 0 CH(CH2OCH3) s CH2CF3
F587 H H CI N02 CF3 0 CH(CH2OCH3) s CH2CF3
F588 H H CI N02 CH3 0 CH(CH2OCH3) s CH2CF3
F589 H H CI N02 Br s CH(CH2OCH3) 0 CH2CF3
F590 H H CI N02 CI s CH(CH2OCH3) 0 CH2CF3
F591 H H CI N02 CF3 s CH(CH2OCH3) 0 CH2CF3
F592 H H CI N02 CH3 s CH(CH2OCH3) 0 CH2CF3
F593 H H CI N02 Br 0 CH(CH2OCH3) 0 CH2CHF2
F594 H H CI N02 CI 0 CH(CH2OCH3) 0 CH2CHF2
F595 H H CI N02 CF3 0 CH(CH2OCH3) 0 CH2CHF2
F596 H H CI N02 CH3 0 CH(CH2OCH3) 0 CH2CHF2
F597 H H CI N02 Br 0 CH(CH2OCH3) 0 CH2CH2F
F598 H H CI N02 CI 0 CH(CH2OCH3) 0 CH2CH2F Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F599 H H CI N02 CF3 0 CH(CH2OCH3) 0 CH2CH2F
F600 H H CI N02 CH3 0 CH(CH2OCH3) 0 CH2CH2F
F601 H H CI N02 Br 0 CH(CH2OCH3) 0 CH2CH3
F602 H H CI N02 CI 0 CH(CH2OCH3) 0 CH2CH3
F603 H H CI N02 CF3 0 CH(CH2OCH3) 0 CH2CH3
F604 H H CI N02 CH3 0 CH(CH2OCH3) 0 CH2CH3
F605 H H CI N02 Br 0 CH(CH2OH) 0 CH2CF3
F606 H H CI N02 CI 0 CH(CH2OH) 0 CH2CF3
F607
H H CI N02 CF3 0 CH(CH2OH) 0 CH2CF3
F608 H H CI N02 CH3 0 CH(CH2OH) 0 CH2CF3
F609 H H CI N02 Br 0 CH(CH2SH) 0 CH2CF3
F610 H H CI N02 CI 0 CH(CH2SH) 0 CH2CF3
F611 H H CI N02 CF3 0 CH(CH2SH) 0 CH2CF3
F612 H H CI N02 CH3 0 CH(CH2SH) 0 CH2CF3
F613 H H CI N02 Br 0 CH(CH2SCH3) 0 CH2CF3
F614 H H CI N02 CI 0 CH(CH2SCH3) 0 CH2CF3
F615 H H CI N02 CF3 0 CH(CH2SCH3) 0 CH2CF3
F616 H H CI N02 CH3 0 CH(CH2SCH3) 0 CH2CF3
F617
H H CI N02 Br 0 CH(CH2N(CH3)2) 0 CH2CF3
F618 H H CI N02 CI 0 CH(CH2N(CH3)2) 0 CH2CF3
F619 H H CI N02 CF3 0 CH(CH2N(CH3)2) 0 CH2CF3
F620 H H CI N02 CH3 0 CH(CH2N(CH3)2) 0 CH2CF3
F621 H H CI N02 Br 0 CH(CH2N02) 0 CH2CF3
F622
H H CI N02 CI 0 CH(CH2N02) 0 CH2CF3
F623 H H CI N02 CF3 0 CH(CH2N02) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F624 H H CI N02 CH3 0 CH(CH2N02) 0 CH2CF3
F625 H H CI N02 Br 0 CH(CF3) 0 CH2CF3
F626 H H CI N02 CI 0 CH(CF3) 0 CH2CF3
F627 H H CI N02 CF3 0 CH(CF3) 0 CH2CF3
F628 H H CI N02 CH3 0 CH(CF3) 0 CH2CF3
F629 H H CI N02 Br 0 CH(CH2CH=CH2) 0 CH2CF3
F630 H H CI N02 CI 0 CH(CH2CH=CH2) 0 CH2CF3
F631 H H CI N02 CF3 0 CH(CH2CH=CH2) 0 CH2CF3
F632 H H CI N02 CH3 0 CH(CH2CH=CH2) 0 CH2CF3
F633 H H CI N02 Br 0 CH(CH2CH≡CH) 0 CH2CF3
F634 H H CI N02 CI 0 CH(CH2CH≡CH) 0 CH2CF3
F635 H H CI N02 CF3 0 CH(CH2CH≡CH) 0 CH2CF3
F636 H H CI N02 CH3 0 CH(CH2CH≡CH) 0 CH2CF3
F637 H H CI N02 Br 0 CH(CN) 0 CH2CF3
F638 H H CI N02 CI 0 CH(CN) 0 CH2CF3
F639 H H CI N02 CF3 0 CH(CN) 0 CH2CF3
F640 H H CI N02 CH3 0 CH(CN) 0 CH2CF3
F641 H H F CN Br 0 CH(CH2OCH3) 0 CH2CF3
F642 H H F CN CI 0 CH(CH2OCH3) 0 CH2CF3
F643 H H F CN CF3 0 CH(CH2OCH3) 0 CH2CF3
F644 H H F CN CH3 0 CH(CH2OCH3) 0 CH2CF3
F645 H H F CN Br 0 CH(CH2OCH3) s CH2CF3
F646 H H F CN CI 0 CH(CH2OCH3) s CH2CF3
F647 H H F CN CF3 0 CH(CH2OCH3) s CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F648 H H F CN CH3 0 CH(CH2OCH3) S CH2CF3
F649 H H F CN Br s CH(CH2OCH3) 0 CH2CF3
F650 H H F CN CI s CH(CH2OCH3) 0 CH2CF3
F651 H H F CN CF3 s CH(CH2OCH3) 0 CH2CF3
F652 H H F CN CH3 s CH(CH2OCH3) 0 CH2CF3
F653 H H F CN Br 0 CH(CH2OCH3) 0 CH2CHF2
F654 H H F CN CI 0 CH(CH2OCH3) 0 CH2CHF2
F655 H H F CN CF3 0 CH(CH2OCH3) 0 CH2CHF2
F656 H H F CN CH3 0 CH(CH2OCH3) 0 CH2CHF2
F657 H H F CN Br 0 CH(CH2OCH3) 0 CH2CH2F
F658 H H F CN CI 0 CH(CH2OCH3) 0 CH2CH2F
F659 H H F CN CF3 0 CH(CH2OCH3) 0 CH2CH2F
F660 H H F CN CH3 0 CH(CH2OCH3) 0 CH2CH2F
F661 H H F CN Br 0 CH(CH2OCH3) 0 CH2CH3
F662 H H F CN CI 0 CH(CH2OCH3) 0 CH2CH3
F663 H H F CN CF3 0 CH(CH2OCH3) 0 CH2CH3
F664 H H F CN CH3 0 CH(CH2OCH3) 0 CH2CH3
F665 H H F CN Br 0 CH(CH2OH) 0 CH2CF3
F666 H H F CN CI 0 CH(CH2OH) 0 CH2CF3
F667 H H F CN CF3 0 CH(CH2OH) 0 CH2CF3
F668 H H F CN CH3 0 CH(CH2OH) 0 CH2CF3
F669 H H F CN Br 0 CH(CH2SH) 0 CH2CF3
F670 H H F CN CI 0 CH(CH2SH) 0 CH2CF3
F671 H H F CN CF3 0 CH(CH2SH) 0 CH2CF3
F672 H H F CN CH3 0 CH(CH2SH) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F673 H H F CN Br 0 CH(CH2SCH3) 0 CH2CF3
F674
H H F CN CI 0 CH(CH2SCH3) 0 CH2CF3
F675 H H F CN CF3 0 CH(CH2SCH3) 0 CH2CF3
F676 H H F CN CH3 0 CH(CH2SCH3) 0 CH2CF3
F677 H H F CN Br 0 CH(CH2N(CH3)2) 0 CH2CF3
F678 H H F CN CI 0 CH(CH2N(CH3)2) 0 CH2CF3
F679 H H F CN CF3 0 CH(CH2N(CH3)2) 0 CH2CF3
F680 H H F CN CH3 0 CH(CH2N(CH3)2) 0 CH2CF3
F681 H H F CN Br 0 CH(CH2N02) 0 CH2CF3
F682 H H F CN CI 0 CH(CH2N02) 0 CH2CF3
F683 H H F CN CF3 0 CH(CH2N02) 0 CH2CF3
F684 H H F CN CH3 0 CH(CH2N02) 0 CH2CF3
F685
H H F CN Br 0 CH(CF3) 0 CH2CF3
F686 H H F CN CI 0 CH(CF3) 0 CH2CF3
F687
H H F CN CF3 0 CH(CF3) 0 CH2CF3
F688 H H F CN CH3 0 CH(CF3) 0 CH2CF3
F689 H H F CN Br 0 CH(CH2CH=CH2) 0 CH2CF3
F690 H H F CN CI 0 CH(CH2CH=CH2) 0 CH2CF3
F691 H H F CN CF3 0 CH(CH2CH=CH2) 0 CH2CF3
F692
H H F CN CH3 0 CH(CH2CH=CH2) 0 CH2CF3
F693 H H F CN Br 0 CH(CH2CH≡CH) 0 CH2CF3
F694 H H F CN CI 0 CH(CH2CH≡CH) 0 CH2CF3
F695 H H F CN CF3 0 CH(CH2CH≡CH) 0 CH2CF3
F696 H H F CN CH3 0 CH(CH2CH≡CH) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F697 H H F CN Br 0 CH(CN) 0 CH2CF3
F698 H H F CN CI 0 CH(CN) 0 CH2CF3
F699 H H F CN CF3 0 CH(CN) 0 CH2CF3
F700 H H F CN CH3 0 CH(CN) 0 CH2CF3
F701 H CI OCF3 CI Br 0 CH(CH2OCH3) 0 CH2CF3
F702 H CI OCF3 CI CI 0 CH(CH2OCH3) 0 CH2CF3
F703 H CI OCF3 CI CF3 0 CH(CH2OCH3) 0 CH2CF3
F704 H CI OCF3 CI CH3 0 CH(CH2OCH3) 0 CH2CF3
F705 H CI OCF3 CI Br 0 CH(CH2OCH3) s CH2CF3
F706 H CI OCF3 CI CI 0 CH(CH2OCH3) s CH2CF3
F707 H CI OCF3 CI CF3 0 CH(CH2OCH3) s CH2CF3
F708 H CI OCF3 CI CH3 0 CH(CH2OCH3) s CH2CF3
F709 H CI OCF3 CI Br s CH(CH2OCH3) 0 CH2CF3
F710 H CI OCF3 CI CI s CH(CH2OCH3) 0 CH2CF3
F711 H CI OCF3 CI CF3 s CH(CH2OCH3) 0 CH2CF3
F712 H CI OCF3 CI CH3 s CH(CH2OCH3) 0 CH2CF3
F713 H CI OCF3 CI Br 0 CH(CH2OCH3) 0 CH2CHF2
F714 H CI OCF3 CI CI 0 CH(CH2OCH3) 0 CH2CHF2
F715 H CI OCF3 CI CF3 0 CH(CH2OCH3) 0 CH2CHF2
F716 H CI OCF3 CI CH3 0 CH(CH2OCH3) 0 CH2CHF2
F717 H CI OCF3 CI Br 0 CH(CH2OCH3) 0 CH2CH2F
F718 H CI OCF3 CI CI 0 CH(CH2OCH3) 0 CH2CH2F
F719 H CI OCF3 CI CF3 0 CH(CH2OCH3) 0 CH2CH2F
F720 H CI OCF3 CI CH3 0 CH(CH2OCH3) 0 CH2CH2F
F721 H CI OCF3 CI Br 0 CH(CH2OCH3) 0 CH2CH3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F722 H CI OCF3 CI CI 0 CH(CH2OCH3) 0 CH2CH3
F723 H CI OCF3 CI CF3 0 CH(CH2OCH3) 0 CH2CH3
F724 H CI OCF3 CI CH3 0 CH(CH2OCH3) 0 CH2CH3
F725 H CI OCF3 CI Br 0 CH(CH2OH) 0 CH2CF3
F726 H CI OCF3 CI CI 0 CH(CH2OH) 0 CH2CF3
F727 H CI OCF3 CI CF3 0 CH(CH2OH) 0 CH2CF3
F728 H CI OCF3 CI CH3 0 CH(CH2OH) 0 CH2CF3
F729 H CI OCF3 CI Br 0 CH(CH2SH) 0 CH2CF3
F730 H CI OCF3 CI CI 0 CH(CH2SH) 0 CH2CF3
F731 H CI OCF3 CI CF3 0 CH(CH2SH) 0 CH2CF3
F732 H CI OCF3 CI CH3 0 CH(CH2SH) 0 CH2CF3
F733 H CI OCF3 CI Br 0 CH(CH2SCH3) 0 CH2CF3
F734
H CI OCF3 CI CI 0 CH(CH2SCH3) 0 CH2CF3
F735 H CI OCF3 CI CF3 0 CH(CH2SCH3) 0 CH2CF3
F736 H CI OCF3 CI CH3 0 CH(CH2SCH3) 0 CH2CF3
F737 H CI OCF3 CI Br 0 CH(CH2N(CH3)2) 0 CH2CF3
F738 H CI OCF3 CI CI 0 CH(CH2N(CH3)2) 0 CH2CF3
F739 H CI OCF3 CI CF3 0 CH(CH2N(CH3)2) 0 CH2CF3
F740 H CI OCF3 CI CH3 0 CH(CH2N(CH3)2) 0 CH2CF3
F741
H CI OCF3 CI Br 0 CH(CH2N02) 0 CH2CF3
F742 H CI OCF3 CI CI 0 CH(CH2N02) 0 CH2CF3
F743 H CI OCF3 CI CF3 0 CH(CH2N02) 0 CH2CF3
F744 H CI OCF3 CI CH3 0 CH(CH2N02) 0 CH2CF3
F745
H CI OCF3 CI Br 0 CH(CF3) 0 CH2CF3
F746 H CI OCF3 CI CI 0 CH(CF3) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F747 H CI OCF3 CI CF3 0 CH(CF3) 0 CH2CF3
F748 H CI OCF3 CI CH3 0 CH(CF3) 0 CH2CF3
F749 H CI OCF3 CI Br 0 CH(CH2CH=CH2) 0 CH2CF3
F750 H CI OCF3 CI CI 0 CH(CH2CH=CH2) 0 CH2CF3
F751 H CI OCF3 CI CF3 0 CH(CH2CH=CH2) 0 CH2CF3
F752 H CI OCF3 CI CH3 0 CH(CH2CH=CH2) 0 CH2CF3
F753 H CI OCF3 CI Br 0 CH(CH2CH≡CH) 0 CH2CF3
F754 H CI OCF3 CI CI 0 CH(CH2CH≡CH) 0 CH2CF3
F755 H CI OCF3 CI CF3 0 CH(CH2CH≡CH) 0 CH2CF3
F756 H CI OCF3 CI CH3 0 CH(CH2CH≡CH) 0 CH2CF3
F757 H CI OCF3 CI Br 0 CH(CN) 0 CH2CF3
F758 H CI OCF3 CI CI 0 CH(CN) 0 CH2CF3
F759 H CI OCF3 CI CF3 0 CH(CN) 0 CH2CF3
F760 H CI OCF3 CI CH3 0 CH(CN) 0 CH2CF3
F761 H CI CN CI Br 0 CH(CH2OCH3) 0 CH2CF3
F762 H CI CN CI CI 0 CH(CH2OCH3) 0 CH2CF3
F763 H CI CN CI CF3 0 CH(CH2OCH3) 0 CH2CF3
F764 H CI CN CI CH3 0 CH(CH2OCH3) 0 CH2CF3
F765 H CI CN CI Br 0 CH(CH2OCH3) s CH2CF3
F766 H CI CN CI CI 0 CH(CH2OCH3) s CH2CF3
F767 H CI CN CI CF3 0 CH(CH2OCH3) s CH2CF3
F768 H CI CN CI CH3 0 CH(CH2OCH3) s CH2CF3
F769 H CI CN CI Br s CH(CH2OCH3) 0 CH2CF3
F770 H CI CN CI CI s CH(CH2OCH3) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F771 H CI CN CI CF3 s CH(CH2OCH3) 0 CH2CF3
F772 H CI CN CI CH3 s CH(CH2OCH3) 0 CH2CF3
F773 H CI CN CI Br 0 CH(CH2OCH3) 0 CH2CHF2
F774 H CI CN CI CI 0 CH(CH2OCH3) 0 CH2CHF2
F775 H CI CN CI CF3 0 CH(CH2OCH3) 0 CH2CHF2
F776 H CI CN CI CH3 0 CH(CH2OCH3) 0 CH2CHF2
F777 H CI CN CI Br 0 CH(CH2OCH3) 0 CH2CH2F
F778 H CI CN CI CI 0 CH(CH2OCH3) 0 CH2CH2F
F779 H CI CN CI CF3 0 CH(CH2OCH3) 0 CH2CH2F
F780 H CI CN CI CH3 0 CH(CH2OCH3) 0 CH2CH2F
F781 H CI CN CI Br 0 CH(CH2OCH3) 0 CH2CH3
F782 H CI CN CI CI 0 CH(CH2OCH3) 0 CH2CH3
F783 H CI CN CI CF3 0 CH(CH2OCH3) 0 CH2CH3
F784 H CI CN CI CH3 0 CH(CH2OCH3) 0 CH2CH3
F785 H CI CN CI Br 0 CH(CH2OH) 0 CH2CF3
F786 H CI CN CI CI 0 CH(CH2OH) 0 CH2CF3
F787 H CI CN CI CF3 0 CH(CH2OH) 0 CH2CF3
F788 H CI CN CI CH3 0 CH(CH2OH) 0 CH2CF3
F789 H CI CN CI Br 0 CH(CH2SH) 0 CH2CF3
F790 H CI CN CI CI 0 CH(CH2SH) 0 CH2CF3
F791 H CI CN CI CF3 0 CH(CH2SH) 0 CH2CF3
F792 H CI CN CI CH3 0 CH(CH2SH) 0 CH2CF3
F793 H CI CN CI Br 0 CH(CH2SCH3) 0 CH2CF3
F794 H CI CN CI CI 0 CH(CH2SCH3) 0 CH2CF3
F795 H CI CN CI CF3 0 CH(CH2SCH3) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F796 H CI CN CI CH3 0 CH(CH2SCH3) 0 CH2CF3
F797
H CI CN CI Br 0 CH(CH2N(CH3)2) 0 CH2CF3
F798 H CI CN CI CI 0 CH(CH2N(CH3)2) 0 CH2CF3
F799 H CI CN CI CF3 0 CH(CH2N(CH3)2) 0 CH2CF3
F800 H CI CN CI CH3 0 CH(CH2N(CH3)2) 0 CH2CF3
F801 H CI CN CI Br 0 CH(CH2N02) 0 CH2CF3
F802 H CI CN CI CI 0 CH(CH2N02) 0 CH2CF3
F803 H CI CN CI CF3 0 CH(CH2N02) 0 CH2CF3
F804
H CI CN CI CH3 0 CH(CH2N02) 0 CH2CF3
F805 H CI CN CI Br 0 CH(CF3) 0 CH2CF3
F806 H CI CN CI CI 0 CH(CF3) 0 CH2CF3
F807 H CI CN CI CF3 0 CH(CF3) 0 CH2CF3
F808 H CI CN CI CH3 0 CH(CF3) 0 CH2CF3
F809 H CI CN CI Br 0 CH(CH2CH=CH2) 0 CH2CF3
F810 H CI CN CI CI 0 CH(CH2CH=CH2) 0 CH2CF3
F811 H CI CN CI CF3 0 CH(CH2CH=CH2) 0 CH2CF3
F812 H CI CN CI CH3 0 CH(CH2CH=CH2) 0 CH2CF3
F813 H CI CN CI Br 0 CH(CH2CH≡CH) 0 CH2CF3
F814 H CI CN CI CI 0 CH(CH2CH≡CH) 0 CH2CF3
F815 H CI CN CI CF3 0 CH(CH2CH≡CH) 0 CH2CF3
F816 H CI CN CI CH3 0 CH(CH2CH≡CH) 0 CH2CF3
F817 H CI CN CI Br 0 CH(CN) 0 CH2CF3
F818 H CI CN CI CI 0 CH(CN) 0 CH2CF3
F819 H CI CN CI CF3 0 CH(CN) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F820 H CI CN CI CH3 0 CH(CN) 0 CH2CF3
F821 H CH3 H Br Br 0 CH(CH2OCH3) 0 CH2CF3
F822 H CH3 H Br CI 0 CH(CH2OCH3) 0 CH2CF3
F823 H CH3 H Br CF3 0 CH(CH2OCH3) 0 CH2CF3
F824 H CH3 H Br CH3 0 CH(CH2OCH3) 0 CH2CF3
F825 H CH3 H Br Br 0 CH(CH2OCH3) s CH2CF3
F826 H CH3 H Br CI 0 CH(CH2OCH3) s CH2CF3
F827 H CH3 H Br CF3 0 CH(CH2OCH3) s CH2CF3
F828 H CH3 H Br CH3 0 CH(CH2OCH3) s CH2CF3
F829 H CH3 H Br Br s CH(CH2OCH3) 0 CH2CF3
F830 H CH3 H Br CI s CH(CH2OCH3) 0 CH2CF3
F831 H CH3 H Br CF3 s CH(CH2OCH3) 0 CH2CF3
F832 H CH3 H Br CH3 s CH(CH2OCH3) 0 CH2CF3
F833 H CH3 H Br Br 0 CH(CH2OCH3) 0 CH2CHF2
F834 H CH3 H Br CI 0 CH(CH2OCH3) 0 CH2CHF2
F835 H CH3 H Br CF3 0 CH(CH2OCH3) 0 CH2CHF2
F836 H CH3 H Br CH3 0 CH(CH2OCH3) 0 CH2CHF2
F837 H CH3 H Br Br 0 CH(CH2OCH3) 0 CH2CH2F
F838 H CH3 H Br CI 0 CH(CH2OCH3) 0 CH2CH2F
F839 H CH3 H Br CF3 0 CH(CH2OCH3) 0 CH2CH2F
F840 H CH3 H Br CH3 0 CH(CH2OCH3) 0 CH2CH2F
F841 H CH3 H Br Br 0 CH(CH2OCH3) 0 CH2CH3
F842 H CH3 H Br CI 0 CH(CH2OCH3) 0 CH2CH3
F843 H CH3 H Br CF3 0 CH(CH2OCH3) 0 CH2CH3
F844 H CH3 H Br CH3 0 CH(CH2OCH3) 0 CH2CH3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F845 H CH3 H Br Br 0 CH(CH2OH) 0 CH2CF3
F846 H CH3 H Br CI 0 CH(CH2OH) 0 CH2CF3
F847 H CH3 H Br CF3 0 CH(CH2OH) 0 CH2CF3
F848 H CH3 H Br CH3 0 CH(CH2OH) 0 CH2CF3
F849 H CH3 H Br Br 0 CH(CH2SH) 0 CH2CF3
F850 H CH3 H Br CI 0 CH(CH2SH) 0 CH2CF3
F851 H CH3 H Br CF3 0 CH(CH2SH) 0 CH2CF3
F852 H CH3 H Br CH3 0 CH(CH2SH) 0 CH2CF3
F853 H CH3 H Br Br 0 CH(CH2SCH3) 0 CH2CF3
F854 H CH3 H Br CI 0 CH(CH2SCH3) 0 CH2CF3
F855 H CH3 H Br CF3 0 CH(CH2SCH3) 0 CH2CF3
F856 H CH3 H Br CH3 0 CH(CH2SCH3) 0 CH2CF3
F857
H CH3 H Br Br 0 CH(CH2N(CH3)2) 0 CH2CF3
F858 H CH3 H Br CI 0 CH(CH2N(CH3)2) 0 CH2CF3
F859 H CH3 H Br CF3 0 CH(CH2N(CH3)2) 0 CH2CF3
F860 H CH3 H Br CH3 0 CH(CH2N(CH3)2) 0 CH2CF3
F861 H CH3 H Br Br 0 CH(CH2N02) 0 CH2CF3
F862 H CH3 H Br CI 0 CH(CH2N02) 0 CH2CF3
F863 H CH3 H Br CF3 0 CH(CH2N02) 0 CH2CF3
F864
H CH3 H Br CH3 0 CH(CH2N02) 0 CH2CF3
F865 H CH3 H Br Br 0 CH(CF3) 0 CH2CF3
F866 H CH3 H Br CI 0 CH(CF3) 0 CH2CF3
F867 H CH3 H Br CF3 0 CH(CF3) 0 CH2CF3
F868 H CH3 H Br CH3 0 CH(CF3) 0 CH2CF3
F869 H CH3 H Br Br 0 CH(CH2CH=CH2) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F870 H CH3 H Br CI 0 CH(CH2CH=CH2) 0 CH2CF3
F871 H CH3 H Br CF3 0 CH(CH2CH=CH2) 0 CH2CF3
F872 H CH3 H Br CH3 0 CH(CH2CH=CH2) 0 CH2CF3
F873 H CH3 H Br Br 0 CH(CH2CH≡CH) 0 CH2CF3
F874 H CH3 H Br CI 0 CH(CH2CH≡CH) 0 CH2CF3
F875 H CH3 H Br CF3 0 CH(CH2CH≡CH) 0 CH2CF3
F876 H CH3 H Br CH3 0 CH(CH2CH≡CH) 0 CH2CF3
F877 H CH3 H Br Br 0 CH(CN) 0 CH2CF3
F878 H CH3 H Br CI 0 CH(CN) 0 CH2CF3
F879 H CH3 H Br CF3 0 CH(CN) 0 CH2CF3
F880 H CH3 H Br CH3 0 CH(CN) 0 CH2CF3
F881 H H F CH3 Br 0 CH(CH2OCH3) 0 CH2CF3
F882 H H F CH3 CI 0 CH(CH2OCH3) 0 CH2CF3
F883 H H F CH3 CF3 0 CH(CH2OCH3) 0 CH2CF3
F884 H H F CH3 CH3 0 CH(CH2OCH3) 0 CH2CF3
F885 H H F CH3 Br 0 CH(CH2OCH3) s CH2CF3
F886 H H F CH3 CI 0 CH(CH2OCH3) s CH2CF3
F887 H H F CH3 CF3 0 CH(CH2OCH3) s CH2CF3
F888 H H F CH3 CH3 0 CH(CH2OCH3) s CH2CF3
F889 H H F CH3 Br s CH(CH2OCH3) 0 CH2CF3
F890 H H F CH3 CI s CH(CH2OCH3) 0 CH2CF3
F891 H H F CH3 CF3 s CH(CH2OCH3) 0 CH2CF3
F892 H H F CH3 CH3 s CH(CH2OCH3) 0 CH2CF3
F893 H H F CH3 Br 0 CH(CH2OCH3) 0 CH2CHF2 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F894 H H F CH3 CI 0 CH(CH2OCH3) 0 CH2CHF2
F895
H H F CH3 CF3 0 CH(CH2OCH3) 0 CH2CHF2
F896 H H F CH3 CH3 0 CH(CH2OCH3) 0 CH2CHF2
F897 H H F CH3 Br 0 CH(CH2OCH3) 0 CH2CH2F
F898 H H F CH3 CI 0 CH(CH2OCH3) 0 CH2CH2F
F899 H H F CH3 CF3 0 CH(CH2OCH3) 0 CH2CH2F
F900 H H F CH3 CH3 0 CH(CH2OCH3) 0 CH2CH2F
F901 H H F CH3 Br 0 CH(CH2OCH3) 0 CH2CH3
F902
H H F CH3 CI 0 CH(CH2OCH3) 0 CH2CH3
F903 H H F CH3 CF3 0 CH(CH2OCH3) 0 CH2CH3
F904 H H F CH3 CH3 0 CH(CH2OCH3) 0 CH2CH3
F905 H H F CH3 Br 0 CH(CH2OH) 0 CH2CF3
F906 H H F CH3 CI 0 CH(CH2OH) 0 CH2CF3
F907 H H F CH3 CF3 0 CH(CH2OH) 0 CH2CF3
F908 H H F CH3 CH3 0 CH(CH2OH) 0 CH2CF3
F909 H H F CH3 Br 0 CH(CH2SH) 0 CH2CF3
F910 H H F CH3 CI 0 CH(CH2SH) 0 CH2CF3
F911 H H F CH3 CF3 0 CH(CH2SH) 0 CH2CF3
F912
H H F CH3 CH3 0 CH(CH2SH) 0 CH2CF3
F913 H H F CH3 Br 0 CH(CH2SCH3) 0 CH2CF3
F914 H H F CH3 CI 0 CH(CH2SCH3) 0 CH2CF3
F915 H H F CH3 CF3 0 CH(CH2SCH3) 0 CH2CF3
F916 H H F CH3 CH3 0 CH(CH2SCH3) 0 CH2CF3
F917
H H F CH3 Br 0 CH(CH2N(CH3)2) 0 CH2CF3
F918 H H F CH3 CI 0 CH(CH2N(CH3)2) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F919 H H F CH3 CF3 0 CH(CH2N(CH3)2) 0 CH2CF3
F920 H H F CH3 CH3 0 CH(CH2N(CH3)2) 0 CH2CF3
F921 H H F CH3 Br 0 CH(CH2N02) 0 CH2CF3
F922 H H F CH3 CI 0 CH(CH2N02) 0 CH2CF3
F923 H H F CH3 CF3 0 CH(CH2N02) 0 CH2CF3
F924 H H F CH3 CH3 0 CH(CH2N02) 0 CH2CF3
F925 H H F CH3 Br 0 CH(CF3) 0 CH2CF3
F926 H H F CH3 CI 0 CH(CF3) 0 CH2CF3
F927
H H F CH3 CF3 0 CH(CF3) 0 CH2CF3
F928 H H F CH3 CH3 0 CH(CF3) 0 CH2CF3
F929 H H F CH3 Br 0 CH(CH2CH=CH2) 0 CH2CF3
F930 H H F CH3 CI 0 CH(CH2CH=CH2) 0 CH2CF3
F931 H H F CH3 CF3 0 CH(CH2CH=CH2) 0 CH2CF3
F932 H H F CH3 CH3 0 CH(CH2CH=CH2) 0 CH2CF3
F933 H H F CH3 Br 0 CH(CH2CH≡CH) 0 CH2CF3
F934 H H F CH3 CI 0 CH(CH2CH≡CH) 0 CH2CF3
F935 H H F CH3 CF3 0 CH(CH2CH≡CH) 0 CH2CF3
F936 H H F CH3 CH3 0 CH(CH2CH≡CH) 0 CH2CF3
F937 H H F CH3 Br 0 CH(CN) 0 CH2CF3
F938 H H F CH3 CI 0 CH(CN) 0 CH2CF3
F939 H H F CH3 CF3 0 CH(CN) 0 CH2CF3
F940 H H F CH3 CH3 0 CH(CN) 0 CH2CF3
F941 H H F CI Br 0 CH(CH2OCH3) 0 CH2CF3
F942 H H F CI CI 0 CH(CH2OCH3) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F943 H H F CI CF3 0 CH(CH2OCH3) 0 CH2CF3
F944 H H F CI CH3 0 CH(CH2OCH3) 0 CH2CF3
F945 H H F CI Br 0 CH(CH2OCH3) s CH2CF3
F946 H H F CI CI 0 CH(CH2OCH3) s CH2CF3
F947 H H F CI CF3 0 CH(CH2OCH3) s CH2CF3
F948 H H F CI CH3 0 CH(CH2OCH3) s CH2CF3
F949 H H F CI Br s CH(CH2OCH3) 0 CH2CF3
F950 H H F CI CI s CH(CH2OCH3) 0 CH2CF3
F951 H H F CI CF3 s CH(CH2OCH3) 0 CH2CF3
F952 H H F CI CH3 s CH(CH2OCH3) 0 CH2CF3
F953 H H F CI Br 0 CH(CH2OCH3) 0 CH2CHF2
F954 H H F CI CI 0 CH(CH2OCH3) 0 CH2CHF2
F955 H H F CI CF3 0 CH(CH2OCH3) 0 CH2CHF2
F956 H H F CI CH3 0 CH(CH2OCH3) 0 CH2CHF2
F957 H H F CI Br 0 CH(CH2OCH3) 0 CH2CH2F
F958 H H F CI CI 0 CH(CH2OCH3) 0 CH2CH2F
F959 H H F CI CF3 0 CH(CH2OCH3) 0 CH2CH2F
F960 H H F CI CH3 0 CH(CH2OCH3) 0 CH2CH2F
F961 H H F CI Br 0 CH(CH2OCH3) 0 CH2CH3
F962 H H F CI CI 0 CH(CH2OCH3) 0 CH2CH3
F963 H H F CI CF3 0 CH(CH2OCH3) 0 CH2CH3
F964 H H F CI CH3 0 CH(CH2OCH3) 0 CH2CH3
F965 H H F CI Br 0 CH(CH2OH) 0 CH2CF3
F966 H H F CI CI 0 CH(CH2OH) 0 CH2CF3
F967 H H F CI CF3 0 CH(CH2OH) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F968 H H F CI CH3 0 CH(CH2OH) 0 CH2CF3
F969 H H F CI Br 0 CH(CH2SH) 0 CH2CF3
F970 H H F CI CI 0 CH(CH2SH) 0 CH2CF3
F971 H H F CI CF3 0 CH(CH2SH) 0 CH2CF3
F972 H H F CI CH3 0 CH(CH2SH) 0 CH2CF3
F973 H H F CI Br 0 CH(CH2SCH3) 0 CH2CF3
F974 H H F CI CI 0 CH(CH2SCH3) 0 CH2CF3
F975 H H F CI CF3 0 CH(CH2SCH3) 0 CH2CF3
F976 H H F CI CH3 0 CH(CH2SCH3) 0 CH2CF3
F977 H H F CI Br 0 CH(CH2N(CH3)2) 0 CH2CF3
F978 H H F CI CI 0 CH(CH2N(CH3)2) 0 CH2CF3
F979 H H F CI CF3 0 CH(CH2N(CH3)2) 0 CH2CF3
F980 H H F CI CH3 0 CH(CH2N(CH3)2) 0 CH2CF3
F981 H H F CI Br 0 CH(CH2N02) 0 CH2CF3
F982
H H F CI CI 0 CH(CH2N02) 0 CH2CF3
F983 H H F CI CF3 0 CH(CH2N02) 0 CH2CF3
F984 H H F CI CH3 0 CH(CH2N02) 0 CH2CF3
F985 H H F CI Br 0 CH(CF3) 0 CH2CF3
F986 H H F CI CI 0 CH(CF3) 0 CH2CF3
F987
H H F CI CF3 0 CH(CF3) 0 CH2CF3
F988 H H F CI CH3 0 CH(CF3) 0 CH2CF3
F989 H H F CI Br 0 CH(CH2CH=CH2) 0 CH2CF3
F990 H H F CI CI 0 CH(CH2CH=CH2) 0 CH2CF3
F991 H H F CI CF3 0 CH(CH2CH=CH2) 0 CH2CF3
F992 H H F CI CH3 0 CH(CH2CH=CH2) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F993 H H F CI Br 0 CH(CH2CH≡CH) 0 CH2CF3
F994 H H F CI CI 0 CH(CH2CH≡CH) 0 CH2CF3
F995 H H F CI CF3 0 CH(CH2CH≡CH) 0 CH2CF3
F996 H H F CI CH3 0 CH(CH2CH≡CH) 0 CH2CF3
F997 H H F CI Br 0 CH(CN) 0 CH2CF3
F998 H H F CI CI 0 CH(CN) 0 CH2CF3
F999 H H F CI CF3 0 CH(CN) 0 CH2CF3
F1000 H H F CI CH3 0 CH(CN) 0 CH2CF3
F1001 H F F F Br 0 CH(CH2OCH3) 0 CH2CF3
F1002 H F F F CI 0 CH(CH2OCH3) 0 CH2CF3
F1003 H F F F CF3 0 CH(CH2OCH3) 0 CH2CF3
F1004 H F F F CH3 0 CH(CH2OCH3) 0 CH2CF3
F1005 H F F F Br 0 CH(CH2OCH3) s CH2CF3
F1006 H F F F CI 0 CH(CH2OCH3) s CH2CF3
F1007 H F F F CF3 0 CH(CH2OCH3) s CH2CF3
F1008 H F F F CH3 0 CH(CH2OCH3) s CH2CF3
F1009 H F F F Br s CH(CH2OCH3) 0 CH2CF3
F1010 H F F F CI s CH(CH2OCH3) 0 CH2CF3
F1011 H F F F CF3 s CH(CH2OCH3) 0 CH2CF3
F1012 H F F F CH3 s CH(CH2OCH3) 0 CH2CF3
F1013 H F F F Br 0 CH(CH2OCH3) 0 CH2CHF2
F1014 H F F F CI 0 CH(CH2OCH3) 0 CH2CHF2
F1015 H F F F CF3 0 CH(CH2OCH3) 0 CH2CHF2
F1016 H F F F CH3 0 CH(CH2OCH3) 0 CH2CHF2 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F1017 H F F F Br 0 CH(CH2OCH3) 0 CH2CH2F
F1018 H F F F CI 0 CH(CH2OCH3) 0 CH2CH2F
F1019 H F F F CF3 0 CH(CH2OCH3) 0 CH2CH2F
F1020 H F F F CH3 0 CH(CH2OCH3) 0 CH2CH2F
F1021 H F F F Br 0 CH(CH2OCH3) 0 CH2CH3
F1022 H F F F CI 0 CH(CH2OCH3) 0 CH2CH3
F1023 H F F F CF3 0 CH(CH2OCH3) 0 CH2CH3
F1024 H F F F CH3 0 CH(CH2OCH3) 0 CH2CH3
F1025 H F F F Br 0 CH(CH2OH) 0 CH2CF3
F1026 H F F F CI 0 CH(CH2OH) 0 CH2CF3
F1027 H F F F CF3 0 CH(CH2OH) 0 CH2CF3
F1028 H F F F CH3 0 CH(CH2OH) 0 CH2CF3
F1029 H F F F Br 0 CH(CH2SH) 0 CH2CF3
F1030 H F F F CI 0 CH(CH2SH) 0 CH2CF3
F1031 H F F F CF3 0 CH(CH2SH) 0 CH2CF3
F1032 H F F F CH3 0 CH(CH2SH) 0 CH2CF3
F1033 H F F F Br 0 CH(CH2SCH3) 0 CH2CF3
F1034 H F F F CI 0 CH(CH2SCH3) 0 CH2CF3
F1035 H F F F CF3 0 CH(CH2SCH3) 0 CH2CF3
F1036 H F F F CH3 0 CH(CH2SCH3) 0 CH2CF3
F1037 H F F F Br 0 CH(CH2N(CH3)2) 0 CH2CF3
F1038 H F F F CI 0 CH(CH2N(CH3)2) 0 CH2CF3
F1039 H F F F CF3 0 CH(CH2N(CH3)2) 0 CH2CF3
F1040 H F F F CH3 0 CH(CH2N(CH3)2) 0 CH2CF3
F1041 H F F F Br 0 CH(CH2N02) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F1042 H F F F CI 0 CH(CH2N02) 0 CH2CF3
F1043 H F F F CF3 0 CH(CH2N02) 0 CH2CF3
F1044 H F F F CH3 0 CH(CH2N02) 0 CH2CF3
F1045 H F F F Br 0 CH(CF3) 0 CH2CF3
F1046 H F F F CI 0 CH(CF3) 0 CH2CF3
F1047 H F F F CF3 0 CH(CF3) 0 CH2CF3
F1048 H F F F CH3 0 CH(CF3) 0 CH2CF3
F1049 H F F F Br 0 CH(CH2CH=CH2) 0 CH2CF3
F1050 H F F F CI 0 CH(CH2CH=CH2) 0 CH2CF3
F1051 H F F F CF3 0 CH(CH2CH=CH2) 0 CH2CF3
F1052 H F F F CH3 0 CH(CH2CH=CH2) 0 CH2CF3
F1053 H F F F Br 0 CH(CH2CH≡CH) 0 CH2CF3
F1054 H F F F CI 0 CH(CH2CH≡CH) 0 CH2CF3
F1055 H F F F CF3 0 CH(CH2CH≡CH) 0 CH2CF3
F1056 H F F F CH3 0 CH(CH2CH≡CH) 0 CH2CF3
F1057 H F F F Br 0 CH(CN) 0 CH2CF3
F1058 H F F F CI 0 CH(CN) 0 CH2CF3
F1059 H F F F CF3 0 CH(CN) 0 CH2CF3
F1060 H F F F CH3 0 CH(CN) 0 CH2CF3
F1061 H CF3 H CF3 Br 0 CH(CH2OCH3) 0 CH2CF3
F1062 H CF3 H CF3 CI 0 CH(CH2OCH3) 0 CH2CF3
F1063 H CF3 H CF3 CF3 0 CH(CH2OCH3) 0 CH2CF3
F1064 H CF3 H CF3 CH3 0 CH(CH2OCH3) 0 CH2CF3
F1065 H CF3 H CF3 Br 0 CH(CH2OCH3) s CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F1066 H CF3 H CF3 CI 0 CH(CH2OCH3) S CH2CF3
F1067 H CF3 H CF3 CF3 0 CH(CH2OCH3) s CH2CF3
F1068 H CF3 H CF3 CH3 0 CH(CH2OCH3) s CH2CF3
F1069 H CF3 H CF3 Br s CH(CH2OCH3) 0 CH2CF3
F1070 H CF3 H CF3 CI s CH(CH2OCH3) 0 CH2CF3
F1071 H CF3 H CF3 CF3 s CH(CH2OCH3) 0 CH2CF3
F1072 H CF3 H CF3 CH3 s CH(CH2OCH3) 0 CH2CF3
F1073 H CF3 H CF3 Br 0 CH(CH2OCH3) 0 CH2CHF2
F1074 H CF3 H CF3 CI 0 CH(CH2OCH3) 0 CH2CHF2
F1075 H CF3 H CF3 CF3 0 CH(CH2OCH3) 0 CH2CHF2
F1076 H CF3 H CF3 CH3 0 CH(CH2OCH3) 0 CH2CHF2
F1077 H CF3 H CF3 Br 0 CH(CH2OCH3) 0 CH2CH2F
F1078 H CF3 H CF3 CI 0 CH(CH2OCH3) 0 CH2CH2F
F1079 H CF3 H CF3 CF3 0 CH(CH2OCH3) 0 CH2CH2F
F1080 H CF3 H CF3 CH3 0 CH(CH2OCH3) 0 CH2CH2F
F1081 H CF3 H CF3 Br 0 CH(CH2OCH3) 0 CH2CH3
F1082 H CF3 H CF3 CI 0 CH(CH2OCH3) 0 CH2CH3
F1083 H CF3 H CF3 CF3 0 CH(CH2OCH3) 0 CH2CH3
F1084 H CF3 H CF3 CH3 0 CH(CH2OCH3) 0 CH2CH3
F1085 H CF3 H CF3 Br 0 CH(CH2OH) 0 CH2CF3
F1086 H CF3 H CF3 CI 0 CH(CH2OH) 0 CH2CF3
F1087 H CF3 H CF3 CF3 0 CH(CH2OH) 0 CH2CF3
F1088 H CF3 H CF3 CH3 0 CH(CH2OH) 0 CH2CF3
F1089 H CF3 H CF3 Br 0 CH(CH2SH) 0 CH2CF3
F1090 H CF3 H CF3 CI 0 CH(CH2SH) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F1091 H CF3 H CF3 CF3 0 CH(CH2SH) 0 CH2CF3
F1092
H CF3 H CF3 CH3 0 CH(CH2SH) 0 CH2CF3
F1093 H CF3 H CF3 Br 0 CH(CH2SCH3) 0 CH2CF3
F1094 H CF3 H CF3 CI 0 CH(CH2SCH3) 0 CH2CF3
F1095 H CF3 H CF3 CF3 0 CH(CH2SCH3) 0 CH2CF3
F1096 H CF3 H CF3 CH3 0 CH(CH2SCH3) 0 CH2CF3
F1097 H CF3 H CF3 Br 0 CH(CH2N(CH3)2) 0 CH2CF3
F1098 H CF3 H CF3 CI 0 CH(CH2N(CH3)2) 0 CH2CF3
F1099 H CF3 H CF3 CF3 0 CH(CH2N(CH3)2) 0 CH2CF3
F1100 H CF3 H CF3 CH3 0 CH(CH2N(CH3)2) 0 CH2CF3
F1101 H CF3 H CF3 Br 0 CH(CH2N02) 0 CH2CF3
F1102 H CF3 H CF3 CI 0 CH(CH2N02) 0 CH2CF3
F1103 H CF3 H CF3 CF3 0 CH(CH2N02) 0 CH2CF3
F1104 H CF3 H CF3 CH3 0 CH(CH2N02) 0 CH2CF3
F1105
H CF3 H CF3 Br 0 CH(CF3) 0 CH2CF3
F1106 H CF3 H CF3 CI 0 CH(CF3) 0 CH2CF3
F1107 H CF3 H CF3 CF3 0 CH(CF3) 0 CH2CF3
F1108 H CF3 H CF3 CH3 0 CH(CF3) 0 CH2CF3
F1109 H CF3 H CF3 Br 0 CH(CH2CH=CH2) 0 CH2CF3
F1110 H CF3 H CF3 CI 0 CH(CH2CH=CH2) 0 CH2CF3
Fllll H CF3 H CF3 CF3 0 CH(CH2CH=CH2) 0 CH2CF3
F1112 H CF3 H CF3 CH3 0 CH(CH2CH=CH2) 0 CH2CF3
F1113 H CF3 H CF3 Br 0 CH(CH2CH≡CH) 0 CH2CF3
F1114 H CF3 H CF3 CI 0 CH(CH2CH≡CH) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F1115 H CF3 H CF3 CF3 0 CH(CH2CH≡CH) 0 CH2CF3
F1116 H CF3 H CF3 CH3 0 CH(CH2CH≡CH) 0 CH2CF3
F1117 H CF3 H CF3 Br 0 CH(CN) 0 CH2CF3
F1118 H CF3 H CF3 CI 0 CH(CN) 0 CH2CF3
F1119 H CF3 H CF3 CF3 0 CH(CN) 0 CH2CF3
F1120 H CF3 H CF3 CH3 0 CH(CN) 0 CH2CF3
F1121 H F H CF3 Br 0 CH(CH2OCH3) 0 CH2CF3
F1122 H F H CF3 CI 0 CH(CH2OCH3) 0 CH2CF3
F1123 H F H CF3 CF3 0 CH(CH2OCH3) 0 CH2CF3
F1124 H F H CF3 CH3 0 CH(CH2OCH3) 0 CH2CF3
F1125 H F H CF3 Br 0 CH(CH2OCH3) s CH2CF3
F1126 H F H CF3 CI 0 CH(CH2OCH3) s CH2CF3
F1127 H F H CF3 CF3 0 CH(CH2OCH3) s CH2CF3
F1128 H F H CF3 CH3 0 CH(CH2OCH3) s CH2CF3
F1129 H F H CF3 Br s CH(CH2OCH3) 0 CH2CF3
F1130 H F H CF3 CI s CH(CH2OCH3) 0 CH2CF3
F1131 H F H CF3 CF3 s CH(CH2OCH3) 0 CH2CF3
F1132 H F H CF3 CH3 s CH(CH2OCH3) 0 CH2CF3
F1133 H F H CF3 Br 0 CH(CH2OCH3) 0 CH2CHF2
F1134 H F H CF3 CI 0 CH(CH2OCH3) 0 CH2CHF2
F1135 H F H CF3 CF3 0 CH(CH2OCH3) 0 CH2CHF2
F1136 H F H CF3 CH3 0 CH(CH2OCH3) 0 CH2CHF2
F1137 H F H CF3 Br 0 CH(CH2OCH3) 0 CH2CH2F
F1138 H F H CF3 CI 0 CH(CH2OCH3) 0 CH2CH2F Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F1139 H F H CF3 CF3 0 CH(CH2OCH3) 0 CH2CH2F
F1140 H F H CF3 CH3 0 CH(CH2OCH3) 0 CH2CH2F
F1141 H F H CF3 Br 0 CH(CH2OCH3) 0 CH2CH3
F1142 H F H CF3 CI 0 CH(CH2OCH3) 0 CH2CH3
F1143 H F H CF3 CF3 0 CH(CH2OCH3) 0 CH2CH3
F1144 H F H CF3 CH3 0 CH(CH2OCH3) 0 CH2CH3
F1145 H F H CF3 Br 0 CH(CH2OH) 0 CH2CF3
F1146 H F H CF3 CI 0 CH(CH2OH) 0 CH2CF3
F1147
H F H CF3 CF3 0 CH(CH2OH) 0 CH2CF3
F1148 H F H CF3 CH3 0 CH(CH2OH) 0 CH2CF3
F1149 H F H CF3 Br 0 CH(CH2SH) 0 CH2CF3
F1150 H F H CF3 CI 0 CH(CH2SH) 0 CH2CF3
F1151
H F H CF3 CF3 0 CH(CH2SH) 0 CH2CF3
F1152 H F H CF3 CH3 0 CH(CH2SH) 0 CH2CF3
F1153 H F H CF3 Br 0 CH(CH2SCH3) 0 CH2CF3
F1154 H F H CF3 CI 0 CH(CH2SCH3) 0 CH2CF3
F1155 H F H CF3 CF3 0 CH(CH2SCH3) 0 CH2CF3
F1156 H F H CF3 CH3 0 CH(CH2SCH3) 0 CH2CF3
F1157
H F H CF3 Br 0 CH(CH2N(CH3)2) 0 CH2CF3
F1158 H F H CF3 CI 0 CH(CH2N(CH3)2) 0 CH2CF3
F1159 H F H CF3 CF3 0 CH(CH2N(CH3)2) 0 CH2CF3
F1160 H F H CF3 CH3 0 CH(CH2N(CH3)2) 0 CH2CF3
F1161 H F H CF3 Br 0 CH(CH2N02) 0 CH2CF3
F1162
H F H CF3 CI 0 CH(CH2N02) 0 CH2CF3
F1163 H F H CF3 CF3 0 CH(CH2N02) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F1164 H F H CF3 CH3 0 CH(CH2N02) 0 CH2CF3
F1165 H F H CF3 Br 0 CH(CF3) 0 CH2CF3
F1166 H F H CF3 CI 0 CH(CF3) 0 CH2CF3
F1167 H F H CF3 CF3 0 CH(CF3) 0 CH2CF3
F1168 H F H CF3 CH3 0 CH(CF3) 0 CH2CF3
F1169 H F H CF3 Br 0 CH(CH2CH=CH2) 0 CH2CF3
F1170 H F H CF3 CI 0 CH(CH2CH=CH2) 0 CH2CF3
F1171 H F H CF3 CF3 0 CH(CH2CH=CH2) 0 CH2CF3
F1172 H F H CF3 CH3 0 CH(CH2CH=CH2) 0 CH2CF3
F1173 H F H CF3 Br 0 CH(CH2CH≡CH) 0 CH2CF3
F1174 H F H CF3 CI 0 CH(CH2CH≡CH) 0 CH2CF3
F1175 H F H CF3 CF3 0 CH(CH2CH≡CH) 0 CH2CF3
F1176 H F H CF3 CH3 0 CH(CH2CH≡CH) 0 CH2CF3
F1177 H F H CF3 Br 0 CH(CN) 0 CH2CF3
F1178 H F H CF3 CI 0 CH(CN) 0 CH2CF3
F1179 H F H CF3 CF3 0 CH(CN) 0 CH2CF3
F1180 H F H CF3 CH3 0 CH(CN) 0 CH2CF3
F1181 H CI H CF3 Br 0 CH(CH2OCH3) 0 CH2CF3
F1182 H CI H CF3 CI 0 CH(CH2OCH3) 0 CH2CF3
F1183 H CI H CF3 CF3 0 CH(CH2OCH3) 0 CH2CF3
F1184 H CI H CF3 CH3 0 CH(CH2OCH3) 0 CH2CF3
F1185 H CI H CF3 Br 0 CH(CH2OCH3) s CH2CF3
F1186 H CI H CF3 CI 0 CH(CH2OCH3) s CH2CF3
F1187 H CI H CF3 CF3 0 CH(CH2OCH3) s CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F1188 H CI H CF3 CH3 0 CH(CH2OCH3) S CH2CF3
F1189 H CI H CF3 Br s CH(CH2OCH3) 0 CH2CF3
F1190 H CI H CF3 CI s CH(CH2OCH3) 0 CH2CF3
F1191 H CI H CF3 CF3 s CH(CH2OCH3) 0 CH2CF3
F1192 H CI H CF3 CH3 s CH(CH2OCH3) 0 CH2CF3
F1193 H CI H CF3 Br 0 CH(CH2OCH3) 0 CH2CHF2
F1194 H CI H CF3 CI 0 CH(CH2OCH3) 0 CH2CHF2
F1195 H CI H CF3 CF3 0 CH(CH2OCH3) 0 CH2CHF2
F1196 H CI H CF3 CH3 0 CH(CH2OCH3) 0 CH2CHF2
F1197 H CI H CF3 Br 0 CH(CH2OCH3) 0 CH2CH2F
F1198 H CI H CF3 CI 0 CH(CH2OCH3) 0 CH2CH2F
F1199 H CI H CF3 CF3 0 CH(CH2OCH3) 0 CH2CH2F
F1200 H CI H CF3 CH3 0 CH(CH2OCH3) 0 CH2CH2F
F1201 H CI H CF3 Br 0 CH(CH2OCH3) 0 CH2CH3
F1202 H CI H CF3 CI 0 CH(CH2OCH3) 0 CH2CH3
F1203 H CI H CF3 CF3 0 CH(CH2OCH3) 0 CH2CH3
F1204 H CI H CF3 CH3 0 CH(CH2OCH3) 0 CH2CH3
F1205 H CI H CF3 Br 0 CH(CH2OH) 0 CH2CF3
F1206 H CI H CF3 CI 0 CH(CH2OH) 0 CH2CF3
F1207 H CI H CF3 CF3 0 CH(CH2OH) 0 CH2CF3
F1208 H CI H CF3 CH3 0 CH(CH2OH) 0 CH2CF3
F1209 H CI H CF3 Br 0 CH(CH2SH) 0 CH2CF3
F1210 H CI H CF3 CI 0 CH(CH2SH) 0 CH2CF3
F1211 H CI H CF3 CF3 0 CH(CH2SH) 0 CH2CF3
F1212 H CI H CF3 CH3 0 CH(CH2SH) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F1213 H CI H CF3 Br 0 CH(CH2SCH3) 0 CH2CF3
F1214
H CI H CF3 CI 0 CH(CH2SCH3) 0 CH2CF3
F1215 H CI H CF3 CF3 0 CH(CH2SCH3) 0 CH2CF3
F1216 H CI H CF3 CH3 0 CH(CH2SCH3) 0 CH2CF3
F1217 H CI H CF3 Br 0 CH(CH2N(CH3)2) 0 CH2CF3
F1218 H CI H CF3 CI 0 CH(CH2N(CH3)2) 0 CH2CF3
F1219 H CI H CF3 CF3 0 CH(CH2N(CH3)2) 0 CH2CF3
F1220 H CI H CF3 CH3 0 CH(CH2N(CH3)2) 0 CH2CF3
F1221
H CI H CF3 Br 0 CH(CH2N02) 0 CH2CF3
F1222 H CI H CF3 CI 0 CH(CH2N02) 0 CH2CF3
F1223 H CI H CF3 CF3 0 CH(CH2N02) 0 CH2CF3
F1224 H CI H CF3 CH3 0 CH(CH2N02) 0 CH2CF3
F1225
H CI H CF3 Br 0 CH(CF3) 0 CH2CF3
F1226 H CI H CF3 CI 0 CH(CF3) 0 CH2CF3
F1227
H CI H CF3 CF3 0 CH(CF3) 0 CH2CF3
F1228 H CI H CF3 CH3 0 CH(CF3) 0 CH2CF3
F1229 H CI H CF3 Br 0 CH(CH2CH=CH2) 0 CH2CF3
F1230 H CI H CF3 CI 0 CH(CH2CH=CH2) 0 CH2CF3
F1231 H CI H CF3 CF3 0 CH(CH2CH=CH2) 0 CH2CF3
F1232
H CI H CF3 CH3 0 CH(CH2CH=CH2) 0 CH2CF3
F1233 H CI H CF3 Br 0 CH(CH2CH≡CH) 0 CH2CF3
F1234 H CI H CF3 CI 0 CH(CH2CH≡CH) 0 CH2CF3
F1235 H CI H CF3 CF3 0 CH(CH2CH≡CH) 0 CH2CF3
F1236 H CI H CF3 CH3 0 CH(CH2CH≡CH) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F1237 H CI H CF3 Br 0 CH(CN) 0 CH2CF3
F1238 H CI H CF3 CI 0 CH(CN) 0 CH2CF3
F1239 H CI H CF3 CF3 0 CH(CN) 0 CH2CF3
F1240 H CI H CF3 CH3 0 CH(CN) 0 CH2CF3
F1241 H H F CF3 Br 0 CH(CH2OCH3) 0 CH2CF3
F1242 H H F CF3 CI 0 CH(CH2OCH3) 0 CH2CF3
F1243 H H F CF3 CF3 0 CH(CH2OCH3) 0 CH2CF3
F1244 H H F CF3 CH3 0 CH(CH2OCH3) 0 CH2CF3
F1245 H H F CF3 Br 0 CH(CH2OCH3) s CH2CF3
F1246 H H F CF3 CI 0 CH(CH2OCH3) s CH2CF3
F1247 H H F CF3 CF3 0 CH(CH2OCH3) s CH2CF3
F1248 H H F CF3 CH3 0 CH(CH2OCH3) s CH2CF3
F1249 H H F CF3 Br s CH(CH2OCH3) 0 CH2CF3
F1250 H H F CF3 CI s CH(CH2OCH3) 0 CH2CF3
F1251 H H F CF3 CF3 s CH(CH2OCH3) 0 CH2CF3
F1252 H H F CF3 CH3 s CH(CH2OCH3) 0 CH2CF3
F1253 H H F CF3 Br 0 CH(CH2OCH3) 0 CH2CHF2
F1254 H H F CF3 CI 0 CH(CH2OCH3) 0 CH2CHF2
F1255 H H F CF3 CF3 0 CH(CH2OCH3) 0 CH2CHF2
F1256 H H F CF3 CH3 0 CH(CH2OCH3) 0 CH2CHF2
F1257 H H F CF3 Br 0 CH(CH2OCH3) 0 CH2CH2F
F1258 H H F CF3 CI 0 CH(CH2OCH3) 0 CH2CH2F
F1259 H H F CF3 CF3 0 CH(CH2OCH3) 0 CH2CH2F
F1260 H H F CF3 CH3 0 CH(CH2OCH3) 0 CH2CH2F
F1261 H H F CF3 Br 0 CH(CH2OCH3) 0 CH2CH3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F1262 H H F CF3 CI 0 CH(CH2OCH3) 0 CH2CH3
F1263 H H F CF3 CF3 0 CH(CH2OCH3) 0 CH2CH3
F1264 H H F CF3 CH3 0 CH(CH2OCH3) 0 CH2CH3
F1265 H H F CF3 Br 0 CH(CH2OH) 0 CH2CF3
F1266 H H F CF3 CI 0 CH(CH2OH) 0 CH2CF3
F1267 H H F CF3 CF3 0 CH(CH2OH) 0 CH2CF3
F1268 H H F CF3 CH3 0 CH(CH2OH) 0 CH2CF3
F1269 H H F CF3 Br 0 CH(CH2SH) 0 CH2CF3
F1270 H H F CF3 CI 0 CH(CH2SH) 0 CH2CF3
F1271 H H F CF3 CF3 0 CH(CH2SH) 0 CH2CF3
F1272 H H F CF3 CH3 0 CH(CH2SH) 0 CH2CF3
F1273 H H F CF3 Br 0 CH(CH2SCH3) 0 CH2CF3
F1274
H H F CF3 CI 0 CH(CH2SCH3) 0 CH2CF3
F1275 H H F CF3 CF3 0 CH(CH2SCH3) 0 CH2CF3
F1276 H H F CF3 CH3 0 CH(CH2SCH3) 0 CH2CF3
F1277 H H F CF3 Br 0 CH(CH2N(CH3)2) 0 CH2CF3
F1278 H H F CF3 CI 0 CH(CH2N(CH3)2) 0 CH2CF3
F1279 H H F CF3 CF3 0 CH(CH2N(CH3)2) 0 CH2CF3
F1280 H H F CF3 CH3 0 CH(CH2N(CH3)2) 0 CH2CF3
F1281 H H F CF3 Br 0 CH(CH2N02) 0 CH2CF3
F1282 H H F CF3 CI 0 CH(CH2N02) 0 CH2CF3
F1283 H H F CF3 CF3 0 CH(CH2N02) 0 CH2CF3
F1284 H H F CF3 CH3 0 CH(CH2N02) 0 CH2CF3
F1285
H H F CF3 Br 0 CH(CF3) 0 CH2CF3
F1286 H H F CF3 CI 0 CH(CF3) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F1287 H H F CF3 CF3 0 CH(CF3) 0 CH2CF3
F1288 H H F CF3 CH3 0 CH(CF3) 0 CH2CF3
F1289 H H F CF3 Br 0 CH(CH2CH=CH2) 0 CH2CF3
F1290 H H F CF3 CI 0 CH(CH2CH=CH2) 0 CH2CF3
F1291 H H F CF3 CF3 0 CH(CH2CH=CH2) 0 CH2CF3
F1292 H H F CF3 CH3 0 CH(CH2CH=CH2) 0 CH2CF3
F1293 H H F CF3 Br 0 CH(CH2CH≡CH) 0 CH2CF3
F1294 H H F CF3 CI 0 CH(CH2CH≡CH) 0 CH2CF3
F1295 H H F CF3 CF3 0 CH(CH2CH≡CH) 0 CH2CF3
F1296 H H F CF3 CH3 0 CH(CH2CH≡CH) 0 CH2CF3
F1297 H H F CF3 Br 0 CH(CN) 0 CH2CF3
F1298 H H F CF3 CI 0 CH(CN) 0 CH2CF3
F1299 H H F CF3 CF3 0 CH(CN) 0 CH2CF3
F1300 H H F CF3 CH3 0 CH(CN) 0 CH2CF3
F1301 H CI CI CI CI 0 CH(CH2OCH3) s CH2CF3
F1302 H CI CI CI CF3 0 CH(CH2OCH3) s CH2CF3
F1303 H CI CI CI CH3 0 CH(CH2OCH3) s CH2CF3
F1304 H CI CI CI CI s CH(CH2OCH3) 0 CH2CF3
F1305 H CI CI CI CF3 s CH(CH2OCH3) 0 CH2CF3
F1306 H CI CI CI CH3 s CH(CH2OCH3) 0 CH2CF3
F1307 H CI CI CI CI 0 CH(CH2OCH3) 0 CH2CHF2
F1308 H CI CI CI CF3 0 CH(CH2OCH3) 0 CH2CHF2
F1309 H CI CI CI CH3 0 CH(CH2OCH3) 0 CH2CHF2
F1310 H CI CI CI Br 0 CH(CH2OCH3) 0 CH2CH2F Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F1311 H CI CI CI CI 0 CH(CH2OCH3) 0 CH2CH2F
F1312
H CI CI CI CF3 0 CH(CH2OCH3) 0 CH2CH2F
F1313 H CI CI CI CH3 0 CH(CH2OCH3) 0 CH2CH2F
F1314 H CI CI CI Br 0 CH(CH2OCH3) 0 CH2CH3
F1315 H CI CI CI CI 0 CH(CH2OCH3) 0 CH2CH3
F1316 H CI CI CI CF3 0 CH(CH2OCH3) 0 CH2CH3
F1317 H CI CI CI CH3 0 CH(CH2OCH3) 0 CH2CH3
F1318 H CI CI CI CI 0 CH(CH2OH) 0 CH2CF3
F1319 H CI CI CI CF3 0 CH(CH2OH) 0 CH2CF3
F1320 H CI CI CI CH3 0 CH(CH2OH) 0 CH2CF3
F1321 H CI CI CI Br 0 CH(CH2SH) 0 CH2CF3
F1322 H CI CI CI CI 0 CH(CH2SH) 0 CH2CF3
F1323 H CI CI CI CF3 0 CH(CH2SH) 0 CH2CF3
F1324 H CI CI CI CH3 0 CH(CH2SH) 0 CH2CF3
F1325
H CI CI CI CI 0 CH(CH2SCH3) 0 CH2CF3
F1326 H CI CI CI CF3 0 CH(CH2SCH3) 0 CH2CF3
F1327 H CI CI CI CH3 0 CH(CH2SCH3) 0 CH2CF3
F1328 H CI CI CI CI 0 CH(CH2N(CH3)2) 0 CH2CF3
F1329 H CI CI CI CF3 0 CH(CH2N(CH3)2) 0 CH2CF3
F1330 H CI CI CI CH3 0 CH(CH2N(CH3)2) 0 CH2CF3
F1331 H CI CI CI CI 0 CH(CH2N02) 0 CH2CF3
F1332 H CI CI CI CF3 0 CH(CH2N02) 0 CH2CF3
F1333 H CI CI CI CH3 0 CH(CH2N02) 0 CH2CF3
F1334
H CI CI CI CI 0 CH(CF3) 0 CH2CF3
F1335 H CI CI CI CF3 0 CH(CF3) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F1336 H CI CI CI CH3 0 CH(CF3) 0 CH2CF3
F1337 H CI CI CI CI 0 CH(CH2CH=CH2) 0 CH2CF3
F1338 H CI CI CI CF3 0 CH(CH2CH=CH2) 0 CH2CF3
F1339 H CI CI CI CH3 0 CH(CH2CH=CH2) 0 CH2CF3
F1340 H CI CI CI CI 0 CH(CH2CH≡CH) 0 CH2CF3
F1341 H CI CI CI CF3 0 CH(CH2CH≡CH) 0 CH2CF3
F1342 H CI CI CI CH3 0 CH(CH2CH≡CH) 0 CH2CF3
F1343 H CI CI CI CI 0 CH(CN) 0 CH2CF3
F1344 H CI CI CI CF3 0 CH(CN) 0 CH2CF3
F1345 H CI CI CI CH3 0 CH(CN) 0 CH2CF3
F1346 H CI H CI Br 0 CH(CH2OCH3) 0 CH2CF3
F1347 H CI H CI CI 0 CH(CH2OCH3) 0 CH2CF3
F1348 H CI H CI CF3 0 CH(CH2OCH3) 0 CH2CF3
F1349 H CI H CI CH3 0 CH(CH2OCH3) 0 CH2CF3
F1350 H CI H CI Br 0 CH(CH2OCH3) s CH2CF3
F1351 H CI H CI CI 0 CH(CH2OCH3) s CH2CF3
F1352 H CI H CI CF3 0 CH(CH2OCH3) s CH2CF3
F1353 H CI H CI CH3 0 CH(CH2OCH3) s CH2CF3
F1354 H CI H CI Br s CH(CH2OCH3) 0 CH2CF3
F1355 H CI H CI CI s CH(CH2OCH3) 0 CH2CF3
F1356 H CI H CI CF3 s CH(CH2OCH3) 0 CH2CF3
F1357 H CI H CI CH3 s CH(CH2OCH3) 0 CH2CF3
F1358 H CI H CI Br 0 CH(CH2OCH3) 0 CH2CHF2
F1359 H CI H CI CI 0 CH(CH2OCH3) 0 CH2CHF2 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F1360 H CI H CI CF3 0 CH(CH2OCH3) 0 CH2CHF2
F1361 H CI H CI CH3 0 CH(CH2OCH3) 0 CH2CHF2
F1362 H CI H CI Br 0 CH(CH2OCH3) 0 CH2CH2F
F1363 H CI H CI CI 0 CH(CH2OCH3) 0 CH2CH2F
F1364 H CI H CI CF3 0 CH(CH2OCH3) 0 CH2CH2F
F1365 H CI H CI CH3 0 CH(CH2OCH3) 0 CH2CH2F
F1366 H CI H CI Br 0 CH(CH2OCH3) 0 CH2CH3
F1367 H CI H CI CI 0 CH(CH2OCH3) 0 CH2CH3
F1368 H CI H CI CF3 0 CH(CH2OCH3) 0 CH2CH3
F1369 H CI H CI CH3 0 CH(CH2OCH3) 0 CH2CH3
F1370 H CI H CI Br 0 CH(CH2OH) 0 CH2CF3
F1371 H CI H CI CI 0 CH(CH2OH) 0 CH2CF3
F1372
H CI H CI CF3 0 CH(CH2OH) 0 CH2CF3
F1373 H CI H CI CH3 0 CH(CH2OH) 0 CH2CF3
F1374
H CI H CI Br 0 CH(CH2SH) 0 CH2CF3
F1375 H CI H CI CI 0 CH(CH2SH) 0 CH2CF3
F1376 H CI H CI CF3 0 CH(CH2SH) 0 CH2CF3
F1377 H CI H CI CH3 0 CH(CH2SH) 0 CH2CF3
F1378 H CI H CI Br 0 CH(CH2SCH3) 0 CH2CF3
F1379 H CI H CI CI 0 CH(CH2SCH3) 0 CH2CF3
F1380 H CI H CI CF3 0 CH(CH2SCH3) 0 CH2CF3
F1381 H CI H CI CH3 0 CH(CH2SCH3) 0 CH2CF3
F1382 H CI H CI Br 0 CH(CH2N(CH3)2) 0 CH2CF3
F1383 H CI H CI CI 0 CH(CH2N(CH3)2) 0 CH2CF3
F1384 H CI H CI CF3 0 CH(CH2N(CH3)2) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F1385 H CI H CI CH3 0 CH(CH2N(CH3)2) 0 CH2CF3
F1386 H CI H CI Br 0 CH(CH2N02) 0 CH2CF3
F1387 H CI H CI CI 0 CH(CH2N02) 0 CH2CF3
F1388 H CI H CI CF3 0 CH(CH2N02) 0 CH2CF3
F1389 H CI H CI CH3 0 CH(CH2N02) 0 CH2CF3
F1390 H CI H CI Br 0 CH(CF3) 0 CH2CF3
F1391 H CI H CI CI 0 CH(CF3) 0 CH2CF3
F1392 H CI H CI CF3 0 CH(CF3) 0 CH2CF3
F1393 H CI H CI CH3 0 CH(CF3) 0 CH2CF3
F1394 H CI H CI Br 0 CH(CH2CH=CH2) 0 CH2CF3
F1395 H CI H CI CI 0 CH(CH2CH=CH2) 0 CH2CF3
F1396 H CI H CI CF3 0 CH(CH2CH=CH2) 0 CH2CF3
F1397
H CI H CI CH3 0 CH(CH2CH=CH2) 0 CH2CF3
F1398 H CI H CI Br 0 CH(CH2CH≡CH) 0 CH2CF3
F1399 H CI H CI CI 0 CH(CH2CH≡CH) 0 CH2CF3
F1400 H CI H CI CF3 0 CH(CH2CH≡CH) 0 CH2CF3
F1401 H CI H CI CH3 0 CH(CH2CH≡CH) 0 CH2CF3
F1402 H CI H CI Br 0 CH(CN) 0 CH2CF3
F1403 H CI H CI CI 0 CH(CN) 0 CH2CF3
F1404 H CI H CI CF3 0 CH(CN) 0 CH2CF3
F1405
H CI H CI CH3 0 CH(CN) 0 CH2CF3
F1406 H H CI CI Br 0 CH(CH2OCH3) 0 CH2CF3
F1407 H H CI CI CI 0 CH(CH2OCH3) 0 CH2CF3
F1408 H H CI CI CF3 0 CH(CH2OCH3) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F1409 H H CI CI CH3 0 CH(CH2OCH3) 0 CH2CF3
F1410 H H CI CI Br 0 CH(CH2OCH3) s CH2CF3
F1411 H H CI CI CI 0 CH(CH2OCH3) s CH2CF3
F1412 H H CI CI CF3 0 CH(CH2OCH3) s CH2CF3
F1413 H H CI CI CH3 0 CH(CH2OCH3) s CH2CF3
F1414 H H CI CI Br s CH(CH2OCH3) 0 CH2CF3
F1415 H H CI CI CI s CH(CH2OCH3) 0 CH2CF3
F1416 H H CI CI CF3 s CH(CH2OCH3) 0 CH2CF3
F1417 H H CI CI CH3 s CH(CH2OCH3) 0 CH2CF3
F1418 H H CI CI Br 0 CH(CH2OCH3) 0 CH2CHF2
F1419 H H CI CI CI 0 CH(CH2OCH3) 0 CH2CHF2
F1420 H H CI CI CF3 0 CH(CH2OCH3) 0 CH2CHF2
F1421 H H CI CI CH3 0 CH(CH2OCH3) 0 CH2CHF2
F1422 H H CI CI Br 0 CH(CH2OCH3) 0 CH2CH2F
F1423 H H CI CI CI 0 CH(CH2OCH3) 0 CH2CH2F
F1424 H H CI CI CF3 0 CH(CH2OCH3) 0 CH2CH2F
F1425 H H CI CI CH3 0 CH(CH2OCH3) 0 CH2CH2F
F1426 H H CI CI Br 0 CH(CH2OCH3) 0 CH2CH3
F1427 H H CI CI CI 0 CH(CH2OCH3) 0 CH2CH3
F1428 H H CI CI CF3 0 CH(CH2OCH3) 0 CH2CH3
F1429 H H CI CI CH3 0 CH(CH2OCH3) 0 CH2CH3
F1430 H H CI CI Br 0 CH(CH2OH) 0 CH2CF3
F1431 H H CI CI CI 0 CH(CH2OH) 0 CH2CF3
F1432 H H CI CI CF3 0 CH(CH2OH) 0 CH2CF3
F1433 H H CI CI CH3 0 CH(CH2OH) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F1434 H H CI CI Br 0 CH(CH2SH) 0 CH2CF3
F1435
H H CI CI CI 0 CH(CH2SH) 0 CH2CF3
F1436 H H CI CI CF3 0 CH(CH2SH) 0 CH2CF3
F1437 H H CI CI CH3 0 CH(CH2SH) 0 CH2CF3
F1438 H H CI CI Br 0 CH(CH2SCH3) 0 CH2CF3
F1439 H H CI CI CI 0 CH(CH2SCH3) 0 CH2CF3
F1440 H H CI CI CF3 0 CH(CH2SCH3) 0 CH2CF3
F1441 H H CI CI CH3 0 CH(CH2SCH3) 0 CH2CF3
F1442
H H CI CI Br 0 CH(CH2N(CH3)2) 0 CH2CF3
F1443 H H CI CI CI 0 CH(CH2N(CH3)2) 0 CH2CF3
F1444 H H CI CI CF3 0 CH(CH2N(CH3)2) 0 CH2CF3
F1445 H H CI CI CH3 0 CH(CH2N(CH3)2) 0 CH2CF3
F1446 H H CI CI Br 0 CH(CH2N02) 0 CH2CF3
F1447 H H CI CI CI 0 CH(CH2N02) 0 CH2CF3
F1448 H H CI CI CF3 0 CH(CH2N02) 0 CH2CF3
F1449 H H CI CI CH3 0 CH(CH2N02) 0 CH2CF3
F1450 H H CI CI Br 0 CH(CF3) 0 CH2CF3
F1451 H H CI CI CI 0 CH(CF3) 0 CH2CF3
F1452
H H CI CI CF3 0 CH(CF3) 0 CH2CF3
F1453 H H CI CI CH3 0 CH(CF3) 0 CH2CF3
F1454 H H CI CI Br 0 CH(CH2CH=CH2) 0 CH2CF3
F1455 H H CI CI CI 0 CH(CH2CH=CH2) 0 CH2CF3
F1456 H H CI CI CF3 0 CH(CH2CH=CH2) 0 CH2CF3
F1457
H H CI CI CH3 0 CH(CH2CH=CH2) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F1458 H H CI CI Br 0 CH(CH2CH≡CH) 0 CH2CF3
F1459 H H CI CI CI 0 CH(CH2CH≡CH) 0 CH2CF3
F1460 H H CI CI CF3 0 CH(CH2CH≡CH) 0 CH2CF3
F1461 H H CI CI CH3 0 CH(CH2CH≡CH) 0 CH2CF3
F1462 H H CI CI Br 0 CH(CN) 0 CH2CF3
F1463 H H CI CI CI 0 CH(CN) 0 CH2CF3
F1464 H H CI CI CF3 0 CH(CN) 0 CH2CF3
F1465 H H CI CI CH3 0 CH(CN) 0 CH2CF3
F1466 H CI F CI CI 0 CH(CH2OCH3) 0 CH2CF3
F1467 H CI F CI CF3 0 CH(CH2OCH3) 0 CH2CF3
F1468 H CI F CI CH3 0 CH(CH2OCH3) 0 CH2CF3
F1469 H CI F CI Br 0 CH(CH2OCH3) s CH2CF3
F1470 H CI F CI CI 0 CH(CH2OCH3) s CH2CF3
F1471 H CI F CI CF3 0 CH(CH2OCH3) s CH2CF3
F1472 H CI F CI CH3 0 CH(CH2OCH3) s CH2CF3
F1473 H CI F CI Br s CH(CH2OCH3) 0 CH2CF3
F1474 H CI F CI CI s CH(CH2OCH3) 0 CH2CF3
F1475 H CI F CI CF3 s CH(CH2OCH3) 0 CH2CF3
F1476 H CI F CI CH3 s CH(CH2OCH3) 0 CH2CF3
F1477 H CI F CI Br 0 CH(CH2OCH3) 0 CH2CHF2
F1478 H CI F CI CI 0 CH(CH2OCH3) 0 CH2CHF2
F1479 H CI F CI CF3 0 CH(CH2OCH3) 0 CH2CHF2
F1480 H CI F CI CH3 0 CH(CH2OCH3) 0 CH2CHF2
F1481 H CI F CI Br 0 CH(CH2OCH3) 0 CH2CH2F Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F1482 H CI F CI CI 0 CH(CH2OCH3) 0 CH2CH2F
F1483 H CI F CI CF3 0 CH(CH2OCH3) 0 CH2CH2F
F1484 H CI F CI CH3 0 CH(CH2OCH3) 0 CH2CH2F
F1485 H CI F CI Br 0 CH(CH2OCH3) 0 CH2CH3
F1486 H CI F CI CI 0 CH(CH2OCH3) 0 CH2CH3
F1487 H CI F CI CF3 0 CH(CH2OCH3) 0 CH2CH3
F1488 H CI F CI CH3 0 CH(CH2OCH3) 0 CH2CH3
F1489 H CI F CI Br 0 CH(CH2OH) 0 CH2CF3
F1490 H CI F CI CI 0 CH(CH2OH) 0 CH2CF3
F1491 H CI F CI CF3 0 CH(CH2OH) 0 CH2CF3
F1492 H CI F CI CH3 0 CH(CH2OH) 0 CH2CF3
F1493 H CI F CI Br 0 CH(CH2SH) 0 CH2CF3
F1494
H CI F CI CI 0 CH(CH2SH) 0 CH2CF3
F1495 H CI F CI CF3 0 CH(CH2SH) 0 CH2CF3
F1496 H CI F CI CH3 0 CH(CH2SH) 0 CH2CF3
F1497 H CI F CI Br 0 CH(CH2SCH3) 0 CH2CF3
F1498 H CI F CI CI 0 CH(CH2SCH3) 0 CH2CF3
F1499 H CI F CI CF3 0 CH(CH2SCH3) 0 CH2CF3
F1500 H CI F CI CH3 0 CH(CH2SCH3) 0 CH2CF3
F1501 H CI F CI Br 0 CH(CH2N(CH3)2) 0 CH2CF3
F1502 H CI F CI CI 0 CH(CH2N(CH3)2) 0 CH2CF3
F1503 H CI F CI CF3 0 CH(CH2N(CH3)2) 0 CH2CF3
F1504 H CI F CI CH3 0 CH(CH2N(CH3)2) 0 CH2CF3
F1505
H CI F CI Br 0 CH(CH2N02) 0 CH2CF3
F1506 H CI F CI CI 0 CH(CH2N02) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F1507 H CI F CI CF3 0 CH(CH2N02) 0 CH2CF3
F1508 H CI F CI CH3 0 CH(CH2N02) 0 CH2CF3
F1509 H CI F CI Br 0 CH(CF3) 0 CH2CF3
F1510 H CI F CI CI 0 CH(CF3) 0 CH2CF3
F1511 H CI F CI CF3 0 CH(CF3) 0 CH2CF3
F1512 H CI F CI CH3 0 CH(CF3) 0 CH2CF3
F1513 H CI F CI Br 0 CH(CH2CH=CH2) 0 CH2CF3
F1514 H CI F CI CI 0 CH(CH2CH=CH2) 0 CH2CF3
F1515 H CI F CI CF3 0 CH(CH2CH=CH2) 0 CH2CF3
F1516 H CI F CI CH3 0 CH(CH2CH=CH2) 0 CH2CF3
F1517 H CI F CI Br 0 CH(CH2CH≡CH) 0 CH2CF3
F1518 H CI F CI CI 0 CH(CH2CH≡CH) 0 CH2CF3
F1519 H CI F CI CF3 0 CH(CH2CH≡CH) 0 CH2CF3
F1520 H CI F CI CH3 0 CH(CH2CH≡CH) 0 CH2CF3
F1521 H CI F CI Br 0 CH(CN) 0 CH2CF3
F1522 H CI F CI CI 0 CH(CN) 0 CH2CF3
F1523 H CI F CI CF3 0 CH(CN) 0 CH2CF3
F1524 H CI F CI CH3 0 CH(CN) 0 CH2CF3
F1525 H Br H Br CI 0 CH(CH2OCH3) 0 CH2CF3
F1526 H Br H Br CF3 0 CH(CH2OCH3) 0 CH2CF3
F1527 H Br H Br CH3 0 CH(CH2OCH3) 0 CH2CF3
F1528 H Br H Br Br 0 CH(CH2OCH3) s CH2CF3
F1529 H Br H Br CI 0 CH(CH2OCH3) s CH2CF3
F1530 H Br H Br CF3 0 CH(CH2OCH3) s CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F1531 H Br H Br CH3 0 CH(CH2OCH3) S CH2CF3
F1532 H Br H Br Br s CH(CH2OCH3) 0 CH2CF3
F1533 H Br H Br CI s CH(CH2OCH3) 0 CH2CF3
F1534 H Br H Br CF3 s CH(CH2OCH3) 0 CH2CF3
F1535 H Br H Br CH3 s CH(CH2OCH3) 0 CH2CF3
F1536 H Br H Br Br 0 CH(CH2OCH3) 0 CH2CHF2
F1537 H Br H Br CI 0 CH(CH2OCH3) 0 CH2CHF2
F1538 H Br H Br CF3 0 CH(CH2OCH3) 0 CH2CHF2
F1539 H Br H Br CH3 0 CH(CH2OCH3) 0 CH2CHF2
F1540 H Br H Br Br 0 CH(CH2OCH3) 0 CH2CH2F
F1541 H Br H Br CI 0 CH(CH2OCH3) 0 CH2CH2F
F1542 H Br H Br CF3 0 CH(CH2OCH3) 0 CH2CH2F
F1543 H Br H Br CH3 0 CH(CH2OCH3) 0 CH2CH2F
F1544 H Br H Br Br 0 CH(CH2OCH3) 0 CH2CH3
F1545 H Br H Br CI 0 CH(CH2OCH3) 0 CH2CH3
F1546 H Br H Br CF3 0 CH(CH2OCH3) 0 CH2CH3
F1547 H Br H Br CH3 0 CH(CH2OCH3) 0 CH2CH3
F1548 H Br H Br Br 0 CH(CH2OH) 0 CH2CF3
F1549 H Br H Br CI 0 CH(CH2OH) 0 CH2CF3
F1550 H Br H Br CF3 0 CH(CH2OH) 0 CH2CF3
F1551 H Br H Br CH3 0 CH(CH2OH) 0 CH2CF3
F1552 H Br H Br Br 0 CH(CH2SH) 0 CH2CF3
F1553 H Br H Br CI 0 CH(CH2SH) 0 CH2CF3
F1554 H Br H Br CF3 0 CH(CH2SH) 0 CH2CF3
F1555 H Br H Br CH3 0 CH(CH2SH) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F1556 H Br H Br Br 0 CH(CH2SCH3) 0 CH2CF3
F1557
H Br H Br CI 0 CH(CH2SCH3) 0 CH2CF3
F1558 H Br H Br CF3 0 CH(CH2SCH3) 0 CH2CF3
F1559 H Br H Br CH3 0 CH(CH2SCH3) 0 CH2CF3
F1560 H Br H Br Br 0 CH(CH2N(CH3)2) 0 CH2CF3
F1561 H Br H Br CI 0 CH(CH2N(CH3)2) 0 CH2CF3
F1562 H Br H Br CF3 0 CH(CH2N(CH3)2) 0 CH2CF3
F1563 H Br H Br CH3 0 CH(CH2N(CH3)2) 0 CH2CF3
F1564
H Br H Br Br 0 CH(CH2N02) 0 CH2CF3
F1565 H Br H Br CI 0 CH(CH2N02) 0 CH2CF3
F1566 H Br H Br CF3 0 CH(CH2N02) 0 CH2CF3
F1567 H Br H Br CH3 0 CH(CH2N02) 0 CH2CF3
F1568 H Br H Br Br 0 CH(CF3) 0 CH2CF3
F1569 H Br H Br CI 0 CH(CF3) 0 CH2CF3
F1570 H Br H Br CF3 0 CH(CF3) 0 CH2CF3
F1571 H Br H Br CH3 0 CH(CF3) 0 CH2CF3
F1572 H Br H Br Br 0 CH(CH2CH=CH2) 0 CH2CF3
F1573 H Br H Br CI 0 CH(CH2CH=CH2) 0 CH2CF3
F1574
H Br H Br CF3 0 CH(CH2CH=CH2) 0 CH2CF3
F1575
H Br H Br CH3 0 CH(CH2CH=CH2) 0 CH2CF3
F1576 H Br H Br Br 0 CH(CH2CH≡CH) 0 CH2CF3
F1577 H Br H Br CI 0 CH(CH2CH≡CH) 0 CH2CF3
F1578 H Br H Br CF3 0 CH(CH2CH≡CH) 0 CH2CF3
F1579 H Br H Br CH3 0 CH(CH2CH≡CH) 0 CH2CF3 Compound Substituted (Cl-
Rl R2 R3 R4 RIO Wl W2 Rl la Number C8) alkyl
F1580 H Br H Br Br 0 CH(CN) 0 CH2CF3
F1581 H Br H Br CI 0 CH(CN) 0 CH2CF3
F1582 H Br H Br CF3 0 CH(CN) 0 CH2CF3
F1583 H Br H Br CH3 0 CH(CN) 0 CH2CF3
Subsequently Exemplified Prophetic Example CI: Preparation of (R)-tert-butyl (3- methoxy-l-oxo-l-((2,2,2-trifluoroethyl)amino)propan-2-yl)carbamate (CI)
Figure imgf000223_0001
To a stirred solution of /?-((ieri-butoxycarbonyl)amino)-3-methoxypropanoic acid (2.53 g, 11.5 mmol) and EDC»HC1 (2.52 g, 13.1 mmol) in methylene chloride (20 mL), was added 2,2,2-trifluoroethanamine (2.10 g, 21.2 mmol) followed DMAP (1.59 g, 13.0 mmol). After stirring 24 h under N2 at ambient temperature the organic phase was washed with a 10 % HC1 solution (3X), a sat. NaHCC>3 solution (3X) and once with brine. The organic phase was then dried over MgS04, concentrated under reduced pressure and purified by medium pressure chromatography (Si02; eluting with 20 to 50% gradient of EtOAc in hexanes) to afford the title compound as a white solid (1.37 g, 40%).
Compound C5 in Table IB were made in accordance with the procedures disclosed in Subsequently Exemplified Prophetic Example CI.
Subsequently Exemplified Prophetic Example C7: Preparation of (/f)-benzyl (3- hydroxy-l-oxo-l-((2,2,2-trifluoroethyl)amino)propan-2-yl)carbamate (C7)
Figure imgf000223_0002
To a stirred solution of (/?)-2-(((benzyloxy)carbonyl)amino)-3-hydroxy-propanoic acid (4.88 g, 20.4 mmol) in methylene chloride (20 mL) cooled in an ice/sat. NH4C1 water bath, was added isobutyl chloroformate (2.64 mL, 20.4 mmol). The reaction mixture under a CaS04 drying tube was stirred for 10 min, then was treated with N-methylmorpholine (2.30 mL, 20.91 mmol ) in 5 mL of methylene chloride dropwise over the course of 15 min. After 45 min. 2,2,2-trifluoroethanamine (5.83 g, 58.8 mmol) in 15 mL of methylene chloride was added dropwise over the course of 15 min. The resulting viscous white mixture was diluted with 75 mL of methylene chloride. After stirring 48 h at ambient temperature the mixture was diluted ethyl acetate and washed with a 10 % HC1 solution (3X), a 10 % K2C03 solution (2X) and once with brine. The solution was then dried over MgS04 and concentrated under reduced pressure to afford the title compound as a white solid (6.4 g, 98%)
Subsequently Exemplified Prophetic Example C8: Preparation of 2-{tert- butoxycarbonylamino)-3-oxo-3-(2,2,2-trifluoroethylamino)propyl methanesulfonate (C8)
Figure imgf000224_0001
Methanesulfonyl chloride (0.22 g, 1.9 mmol) was added to a stirred solution of tert- butyl N-[(l/?)-l-(hydroxymethyl)-2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]carbamate (0.50 g, 1.8 mmol) and triethylamine (TEA )(0.10, 1.9 mmol) in methylene chloride (DCM) at 0 °C. The reaction mixture was stirred at RT for 2 h. The reaction mixture was then poured into ice water and extracted with EtOAc. The organic layer was washed with water, dried (Na2SC>4) filtered and concentrated in vacuo. The residue was purified by column chromatography (Si02 100-200 mesh; eluting with 20% EtOAc in Pet ether) to afford the title compound as an off white solid (0.50 g, 79%).
Subsequently Exemplified Prophetic Example C9: Preparation of fert-Butyl 3- (dimethylamino)-l-oxo-l-(2,2,2-trifluoroethylamino)propan-2-ylcarbamate (C9)
Figure imgf000224_0002
TEA (0.74 mL, 5.5 mmol) was added to a stirred solution of 2-(tert- butoxycarbonylamino)-3-oxo-3-(2,2,2-trifluoroethylamino)propyl methanesulfonate (0.50 g, 1.4 mmol) at RT. After stirring for 2 h, dimethylamine (2M in THF, 10 mL) and methanol (10 mL) were added and stirred for 12 h. The volatiles were evaporated and the residue was diluted with DCM and washed with brine followed by water. The organic layer was dried (Na2S04), filtered and concentrated in vacuo. The residue was purified by column chromatography (Si02 100-200 mesh; eluting with 40% EtOAc in Pet ether) to afford the title compound as a brown gum (0.40 g, 47% pure by LCMS).
Subsequently Exemplified Prophetic Example CIO: Preparation of 2-amino-3- (dimethylamino)-jV-(2,2,2-trifluoroethyl)propanamide hydrochloride (CIO)
Figure imgf000225_0001
Dioxane in HCI was added to a stirred solution of ieri-butyl 3-(dimethylamino)-l- oxo- l-(2,2,2-trifluoroethylamino)propan-2-ylcarbamate (0.4 g, 1.27 mmol) in 1,4 dioxane (10 mL) at 0 °C and the reaction mixture was stirred at RT for 6 h. The volatiles were evaporated and the residue was triturated with ether to afford the title compound as an off white solid (160 mg).
Compound C4 in Table IB was made in accordance with the procedures disclosed in Subsequently Exemplified Prophetic Example CIO from C3, prepared in the following manner
Figure imgf000225_0002
To a stirred solution of L-serine (2.0 g, 9.75 mmol) in anhydrous 1 ,2-dichloroethene (DCE) (30.0 mL) was added EDC HCI (2.80 g, 14.62 mmol), 2,2,2-trifluoroethanamine (1.06 g, 10.72 mmol) and DMAP (0.598 g, 4.87 mmol) in that order. The resulting reaction mixture was stirred at RT for 18 h. Reaction mixture was concentrated in vacuo and residue was taken up in ether, washed with 0.1N HCI then washed with aq. NaHC03, dried over MgS04, filtered and concentrated to give (5)-tert-butyl (3-hydroxy-l-oxo-l-((2,2,2- trifluoroethyl)amino)propan-2-yl)carbamate as a white solid. This material was used without further purification.
Compounds C2 and C6 in Table IB were made in accordance with the procedures disclosed in Subsequently Exemplified Prophetic Example CIO.
Subsequently Exemplified Prophetic Example F19: Preparation of (£')-2-bromo- V-(3- (dimethylamino)-l-oxo-l-(2,2,2-trifluoroethylamino)propan-2-yl)-4-(4,4,4-trifluoro-3- (3,4,5-trichlorophenyl)but-l-enyl)benzamide (F19)
Figure imgf000226_0001
To a stirred solution of ((£')-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but- l-enyl)benzoic acid (0.2 g , 0.41 mmol) in DCM (5.0 mL) was added 2-amino-3- (dimethylamino)-N-(2,2,2-trifluoroethyl)propanamide hydrochloride (0.15 g, 0.61 mmol)) followed by benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (213.4 mg, 0.412 mmol) and DIPEA (0.17 mL, 1.02 mmol), and the resultant reaction mixture was stirred at RT for 12 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, 100-200 mesh; eluting with 40% ethyl acetate/ petroleum ether) afforded the title compound as a brown solid (95 mg, 32%).
Compound F1329 in Table 1A were made in accordance with the procedures disclosed in Subsequently Exemplified Prophetic Example F19.
Subsequently Exemplified Prophetic Example F13B: Preparation of 2-bromo-/V-((/f)-3- hydroxy-l-oxo-l-(2,2,2-trifluoroethylamino)propan-2-yl)-4-((^)-4,4,4-trifluoro-3-(3,4,5- trichlorophenyl)but-l-enyl)benzamide (F13B)
Figure imgf000226_0002
To a stirred solution of (£)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l- enyl)benzoic acid (150 mg, 0.307 mmol) in THF was added (/?)-2-amino-3-hydroxy-N- (2,2,2-trifluoroethyl)propanamide hydrochloride (62 mg, 0.368 mmol), 1- hydroxybenzotriazole hydrate (HOBt»H20) (62 mg, 0.460 mmol), N-(3- dimethylaminopropyl)-N' -ethylcarbodiimide hydrochloride (EDC»HC1) (88 mg, 0.460 mmol) and N,N-diisopropylethylamine (DIEA) (0.15 mL, 0.921 mmol) and the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers was washed with brine, dried over Na2S04 and concentrated under reduced pressure. Purification by flash column chromatography (Si02, 100-200 mesh; eluting with 30 % hexane:EtOAc ) afforded the title compound as a pale brown-solid (95 mg, 47%).
Compounds Fl, F4, F6, F19, F1319, F1320, and F1329 in Table 1A were made in accordance with the procedures disclosed in Subsequently Exemplified Prophetic Example F13B.
Example A: BIOASSAYS ON BEET ARMYWORM ("BAW") AND CORN EARWORM ("CEW") AND CABBAGE LOOPER ("CL")
BAW has few effective parasites, diseases, or predators to lower its population. BAW infests many weeds, trees, grasses, legumes, and field crops. In various places, it is of economic concern upon asparagus, cotton, corn, soybeans, tobacco, alfalfa, sugar beets, peppers, tomatoes, potatoes, onions, peas, sunflowers, and citrus, among other plants. CEW is known to attack corn and tomatoes, but it also attacks artichoke, asparagus, cabbage, cantaloupe, collards, cowpeas, cucumbers, eggplant, lettuce, lima beans, melon, okra, peas, peppers, potatoes, pumpkin, snap beans, spinach, squash, sweet potatoes, and watermelon, among other plants. CEW is also known to be resistant to certain insecticides. CL feeds on a wide variety of cultivated plants and weeds. It feeds readily on crucifers, and has been reported damaging broccoli, cabbage, cauliflower, Chinese cabbage, collards, kale, mustard, radish, rutabaga, turnip, and watercress. Other vegetable crops injured include beet, cantaloupe, celery, cucumber, lima bean, lettuce, parsnip, pea, pepper, potato, snap bean, spinach, squash, sweet potato, tomato, and watermelon. CL is also known to be resistant to certain insecticides. Consequently, because of the above factors control of these pests is important. Furthermore, molecules that control these pests are useful in controlling other pests.
Certain molecules disclosed in this document were tested against BAW and CEW and CL using procedures described in the following examples. In the reporting of the results, the "BAW & CEW & CL Rating Table" was used (See Table Section).
BIOASSAYS ON BAW (Spodoptera exigua)
Bioassays on BAW were conducted using a 128-well diet tray assay, one to five second instar BAW larvae were placed in each well (3 mL) of the diet tray that had been previously filled with 1 mL of artificial diet to which 50 μg/cm2 of the test compound
(dissolved in 50 μL· of 90: 10 acetone- water mixture) had been applied (to each of eight wells) and then allowed to dry. Trays were covered with a clear self-adhesive cover, and held at 25 °C, 14: 10 light-dark for five to seven days. Percent mortality was recorded for the larvae in each well; activity in the eight wells was then averaged. The results are indicated in the table entitled "Table 3: Assay Results" (See Table Section).
BIOASSAYS ON CEW (Helicoverpa zed)
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 μg /cm2 of the test compound (dissolved in 50 μΕ of 90: 10 acetone-water mixture) had been applied (to each of eight wells) and then allowed to dry. Trays were covered with a clear self-adhesive cover, and held at 25 °C, 14: 10 light-dark for five to seven days. Percent mortality was recorded for the larvae in each well; activity in the eight wells was then averaged. The results are indicated in the table entitled "Table 3: Assay Results" (See Table Section).
Bioassays on CL (Trichoplusia ni)
Bioassays on CL were conducted using a 128-well diet tray assay. One to five second instar CL larvae were placed in each well (3 mL) of the diet tray that had been previously filled with 1 mL of artificial diet to which 50 μg /cm2 of the test compound (dissolved in 50 μL· of 90: 10 acetone-water mixture) had been applied (to each of eight wells) and then allowed to dry. Trays were covered with a clear self-adhesive cover, and held at 25 °C, 14: 10 light-dark for five to seven days. Percent mortality was recorded for the larvae in each well; activity in the eight wells was then averaged. The results are indicated in the table entitled "Table 3A: Assay Results" (See Table Section).
Example B: BIOASSAYS ON GREEN PEACH APHID ("GPA") {Myzus persicae).
GPA is the most significant aphid pest of peach trees, causing decreased growth, shriveling of the leaves, and the death of various tissues. It is also hazardous because it acts as a vector for the transport of plant viruses, such as potato virus Y and potato leafroll virus to members of the nightshade/potato family Solanaceae, and various mosaic viruses to many other food crops. GPA attacks such plants as broccoli, burdock, cabbage, carrot, cauliflower, daikon, eggplant, green beans, lettuce, macadamia, papaya, peppers, sweet potatoes, tomatoes, watercress, and zucchini, among other plants. GPA also attacks many ornamental crops such as carnation, chrysanthemum, flowering white cabbage, poinsettia, and roses. GPA has developed resistance to many pesticides.
Certain molecules disclosed in this document were tested against GPA using procedures described in the following example. In the reporting of the results, the "GPA Rating Table" was used (See Table Section). Cabbage seedlings grown in 3-inch pots, with 2-3 small (3-5 cm) true leaves, were used as test substrate. The seedlings were infested with 20-50 GPA (wingless adult and nymph stages) one day prior to chemical application. Four pots with individual seedlings were used for each treatment. Test compounds (2 mg) were dissolved in 2 mL of acetone/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 hand-held aspirator-type sprayer was used for spraying a solution to both sides of cabbage leaves until runoff. Reference plants (solvent check) were sprayed with the diluent only containing 20% by volume of acetone/methanol (1:1) solvent. Treated plants were held in a holding room for three days at approximately 25 °C and ambient relative humidity (RH) prior to grading. Evaluation was conducted by counting the number of live aphids per plant under a microscope. Percent Control was measured by using Abbott's correction formula (W.S. Abbott, "A Method of Computing the Effectiveness of an
Insecticide" J. Econ. Entomol. 18 (1925), pp.265-267) as follows.
Corrected % Control = 100 * (X - Y) / X
where
X = No. of live aphids on solvent check plants and
Y = No. of live aphids on treated plants
The results are indicated in the table entitled "Table 3: Assay Results" (See Table Section).
PESTICIDALLY ACCEPTABLE ACID ADDITION SALTS, SALT DERIVATIVES, SOLVATES, ESTER DERIVATIVES, POLYMORPHS, ISOTOPES AND
RADIONUCLIDES
Molecules of Formula One may be formulated into pesticidally acceptable acid addition salts. By way of a non-limiting example, an amine function can form salts with hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, benzoic, citric, malonic, salicylic, malic, fumaric, oxalic, succinic, tartaric, lactic, gluconic, ascorbic, maleic, aspartic, benzenesulfonic, methanesulfonic, ethanesulfonic, hydroxymethanesulfonic, and hydroxyethanesulfonic acids. Additionally, by way of a non-limiting example, an acid function can form salts including those derived from alkali or alkaline earth metals and those derived from ammonia and amines. Examples of preferred cations include sodium, potassium, and magnesium.
Molecules of Formula One may be formulated into salt derivatives. By way of a non- limiting example, a salt derivative can be prepared by contacting a free base with a sufficient amount of the desired acid to produce a salt. A free base may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide (NaOH), potassium carbonate, ammonia, and sodium bicarbonate. As an example, in many cases, a pesticide, such as 2,4-D, is made more water-soluble by converting it to its dimethylamine salt..
Molecules of Formula One may be formulated into stable complexes with a solvent, such that the complex remains intact after the non-complexed solvent is removed. These complexes are often referred to as "solvates." However, it is particularly desirable to form stable hydrates with water as the solvent.
Molecules of Formula One may be made into ester derivatives. These ester derivatives can then be applied in the same manner as the invention disclosed in this document is applied.
Molecules of Formula One may be made as various crystal polymorphs.
Polymorphism is important in the development of agrochemicals since different crystal polymorphs or structures of the same molecule can have vastly different physical properties and biological performances.
Molecules of Formula One may be made with different isotopes. Of particular importance are molecules having 2H (also known as deuterium) in place of ]Η.
Molecules of Formula One may be made with different radionuclides. Of particular importance are molecules having 14C.
STEREOISOMERS
Molecules of Formula One may exist as one or more stereoisomers. Thus, certain molecules can be produced as racemic mixtures. It will be appreciated by those skilled in the art that one stereoisomer may be more active than the other stereoisomers. Individual stereoisomers may be obtained by known selective synthetic procedures, by conventional synthetic procedures using resolved starting materials, or by conventional resolution procedures. Certain molecules disclosed in this document can exist as two or more isomers. The various isomers include geometric isomers, diastereomers, and enantiomers. Thus, the molecules disclosed in this document include geometric isomers, racemic mixtures, individual stereoisomers, and optically active mixtures. It will be appreciated by those skilled in the art that one isomer may be more active than the others. The structures disclosed in the present disclosure are drawn in only one geometric form for clarity, but are intended to represent all geometric forms of the molecule.
COMBINATIONS Molecules of Formula One may also be used in combination (such as, in a compositional mixture, or a simultaneous or sequential application) with one or more compounds having acaricidal, algicidal, avicidal, bactericidal, fungicidal, herbicidal, insecticidal, molluscicidal, nematicidal, rodenticidal, or virucidal properties. Additionally, the molecules of Formula One may also be used in combination (such as, in a compositional mixture, or a simultaneous or sequential application) with compounds that are antifeedants, bird repellents, chemosterilants, herbicide safeners, insect attractants, insect repellents, mammal repellents, mating disrupters, plant activators, plant growth regulators, or synergists. Examples of such compounds in the above groups that may be used with the Molecules of Formula One are - (3-ethoxypropyl)mercury bromide, 1 ,2-dichloropropane, 1,3- dichloropropene, 1-methylcyclopropene, 1-naphthol, 2-(octylthio)ethanol, 2,3,5-tri- iodobenzoic acid, 2,3,6-TBA, 2,3,6-TBA-dimethylammonium, 2,3,6-TBA-lithium, 2,3,6- TBA-potassium, 2,3,6-TBA-sodium, 2,4,5-T, 2,4,5-T-2-butoxypropyl, 2,4,5-T-2-ethylhexyl, 2,4,5-T-3-butoxypropyl, 2,4,5-TB, 2,4,5-T-butometyl, 2,4,5-T-butotyl, 2,4,5-T-butyl, 2,4,5- T-isobutyl, 2,4,5-T-isoctyl, 2,4,5-T-isopropyl, 2,4,5-T-methyl, 2,4,5-T-pentyl, 2,4,5-T- sodium, 2,4,5-T-triethylammonium, 2,4,5-T-trolamine, 2,4-D, 2,4-D-2-butoxypropyl, 2,4-D- 2-ethylhexyl, 2,4-D-3-butoxypropyl, 2,4-D-ammonium, 2,4-DB, 2,4-DB-butyl, 2,4-DB- dimethylammonium, 2,4-DB-isoctyl, 2,4-DB -potassium, 2,4-DB-sodium, 2,4-D-butotyl, 2,4- D-butyl, 2,4-D-diethylammonium, 2,4-D-dimethylammonium, 2,4-D-diolamine, 2,4-D- dodecylammonium, 2,4-DEB, 2,4-DEP, 2,4-D-ethyl, 2,4-D-heptylammonium, 2,4-D- isobutyl, 2,4-D-isoctyl, 2,4-D-isopropyl, 2,4-D-isopropylammonium, 2,4-D-lithium, 2,4-D- meptyl, 2,4-D-methyl, 2,4-D-octyl, 2,4-D-pentyl, 2,4-D-potassium, 2,4-D-propyl, 2,4-D- sodium, 2,4-D-tefuryl, 2,4-D-tetradecylammonium, 2,4-D-triethylammonium, 2,4-D-tris(2- hydroxypropyl)ammonium, 2,4-D-trolamine, 2iP, 2-methoxyethylmercury chloride, 2- phenylphenol, 3,4-DA, 3,4-DB, 3,4-DP, 4-aminopyridine, 4-CPA, 4-CPA-potassium, 4-CPA- sodium, 4-CPB, 4-CPP, 4-hydroxyphenethyl alcohol, 8 -hydroxy quinoline sulfate, 8- phenylmercurioxyquinoline, abamectin, abscisic acid, ACC, acephate, acequinocyl, acetamiprid, acethion, acetochlor, acetophos, acetoprole, acibenzolar, acibenzolar-S-methyl, acifluorfen, acifluorfen-methyl, acifluorf en- sodium, aclonifen, acrep, acrinathrin, acrolein, acrylonitrile, acypetacs, acypetacs-copper, acypetacs-zinc, alachlor, alanycarb, albendazole, aldicarb, aldimorph, aldoxycarb, aldrin, allethrin, allicin, allidochlor, allosamidin, alloxydim, alloxydim-sodium, allyl alcohol, allyxycarb, alorac, α/ρΛα-cypermethrin, α/ρ ζα-endosulfan, ametoctradin, ametridione, ametryn, amibuzin, amicarbazone, amicarthiazol, amidithion, amidoflumet, amidosulfuron, aminocarb, aminocyclopyrachlor, aminocyclopyrachlor-methyl, aminocyclopyrachlor-potassium, aminopyralid, aminopyralid-potassium, aminopyralid-tris(2- hydroxypropyl)ammonium, amiprofos-methyl, amiprophos, amisulbrom, amiton, amiton oxalate, amitraz, amitrole, ammonium sulfamate, ammonium a-naphthaleneacetate, amobam, ampropylfos, anabasine, ancymidol, anilazine, anilofos, anisuron, anthraquinone, antu, apholate, aramite, arsenous oxide, asomate, aspirin, asulam, asulam-potassium, asulam- sodium, athidathion, atraton, atrazine, aureofungin, aviglycine, aviglycine hydrochloride, azaconazole, azadirachtin, azafenidin, azamethiphos, azimsulfuron, azinphos-ethyl, azinphos- methyl, aziprotryne, azithiram, azobenzene, azocyclotin, azothoate, azoxystrobin, bachmedesh, barban, barium hexafluorosilicate, barium polysulfide, barthrin, BCPC, beflubutamid, benalaxyl, benalaxyl-M, benazolin, benazolin-dimethylammonium, benazolin- ethyl, benazolin-potassium, bencarbazone, benclothiaz, bendiocarb, benfluralin, benfuracarb, benfuresate, benodanil, benomyl, benoxacor, benoxafos, benquinox, bensulfuron, bensulfuron-methyl, bensulide, bensultap, bentaluron, bentazone, bentazone- sodium, benthiavalicarb, benthiavalicarb-isopropyl, benthiazole, bentranil, benzadox, benzadox- ammonium, benzalkonium chloride, benzamacril, benzamacril-isobutyl, benzamorf, benzfendizone, benzipram, benzobicyclon, benzofenap, benzofluor, benzohydroxamic acid, benzoximate, benzoylprop, benzoylprop-ethyl, benzthiazuron, benzyl benzoate,
benzyladenine, berberine, berberine chloride, ^eta-cyfluthrin, ^eto-cypermethrin, bethoxazin, bicyclopyrone, bifenazate, bifenox, bifenthrin, bifujunzhi, bilanafos, bilanafos-sodium, binapacryl, bingqingxiao, bioallethrin, bioethanomethrin, biopermethrin, bioresmethrin, biphenyl, bisazir, bismerthiazol, bispyribac, bispyribac-sodium, bistrifluron, bitertanol, bithionol, bixafen, blasticidin-S, borax, Bordeaux mixture, boric acid, boscalid, brassinolide, brassinolide-ethyl, brevicomin, brodifacoum, brofenvalerate, brofluthrinate, bromacil, bromacil-lithium, bromacil-sodium, bromadiolone, bromethalin, bromethrin, bromfenvinfos, bromoacetamide, bromobonil, bromobutide, bromocyclen, bromo-DDT, bromofenoxim, bromophos, bromophos-ethyl, bromopropylate, bromothalonil, bromoxynil, bromoxynil butyrate, bromoxynil heptanoate, bromoxynil octanoate, bromoxynil-potassium,
brompyrazon, bromuconazole, bronopol, bucarpolate, bufencarb, buminafos, bupirimate, buprofezin, Burgundy mixture, busulfan, butacarb, butachlor, butafenacil, butamifos, butathiofos, butenachlor, butethrin, buthidazole, buthiobate, buthiuron, butocarboxim, butonate, butopyronoxyl, butoxycarboxim, butralin, butroxydim, buturon, butylamine, butylate, cacodylic acid, cadusafos, cafenstrole, calcium arsenate, calcium chlorate, calcium cyanamide, calcium polysulfide, calvinphos, cambendichlor, camphechlor, camphor, captafol, captan, carbamorph, carbanolate, carbaryl, carbasulam, carbendazim, carbendazim benzenesulfonate, carbendazim sulfite, carbetamide, carbofuran, carbon disulfide, carbon tetrachloride, carbophenothion, carbosulfan, carboxazole, carboxide, carboxin, carfentrazone, carfentrazone-ethyl, carpropamid, cartap, cartap hydrochloride, carvacrol, carvone, CDEA, cellocidin, CEPC, ceralure, Cheshunt mixture, chinomethionat, chitosan, chlobenthiazone, chlomethoxyfen, chloralose, chloramben, chloramben-ammonium, chloramben-diolamine, chloramben-methyl, chloramben-methylammonium, chloramben-sodium, chloramine phosphorus, chloramphenicol, chloraniformethan, chloranil, chloranocryl, chlorantraniliprole, chlorazifop, chlorazifop-propargyl, chlorazine, chlorbenside, chlorbenzuron, chlorbicyclen, chlorbromuron, chlorbufam, chlordane, chlordecone, chlordimeform, chlordimeform hydrochloride, chlorempenthrin, chlorethoxyfos, chloreturon, chlorfenac, chlorfenac- ammonium, chlorfenac-sodium, chlorfenapyr, chlorfenazole, chlorfenethol, chlorfenprop, chlorfenson, chlorfensulphide, chlorfenvinphos, chlorfluazuron, chlorflurazole, chlorfluren, chlorfluren-methyl, chlorflurenol, chlorflurenol-methyl, chloridazon, chlorimuron, chlorimuron-ethyl, chlormephos, chlormequat, chlormequat chloride, chlornidine, chlornitrofen, chlorobenzilate, chlorodinitronaphthalenes, chloroform, chloromebuform, chloromethiuron, chloroneb, chlorophacinone, chlorophacinone-sodium, chloropicrin, chloropon, chloropropylate, chlorothalonil, chlorotoluron, chloroxuron, chloroxynil, chlorphonium, chlorphonium chloride, chlorphoxim, chlorprazophos, chlorprocarb, chlorpropham, chlorpyrifos, chlorpyrifos-methyl, chlorquinox, chlorsulfuron, chlorthal, chlorthal-dimethyl, chlorthal-monomethyl, chlorthiamid, chlorthiophos, chlozolinate, choline chloride, chromafenozide, cinerin I, cinerin II, cinerins, cinidon-ethyl, cinmethylin, cinosulfuron, ciobutide, cisanilide, cismethrin, clethodim, climbazole, cliodinate, clodinafop, clodinafop-propargyl, cloethocarb, clofencet, clofencet-potassium, clofentezine, clofibric acid, clofop, clofop-isobutyl, clomazone, clomeprop, cloprop, cloproxydim, clopyralid, clopyralid-methyl, clopyralid-olamine, clopyralid-potassium, clopyralid-tris(2- hydroxypropyl)ammonium, cloquintocet, cloquintocet-mexyl, cloransulam, cloransulam- methyl, closantel, clothianidin, clotrimazole, cloxyfonac, cloxyfonac-sodium, CMA, codlelure, colophonate, copper acetate, copper acetoarsenite, copper arsenate, copper carbonate, basic, copper hydroxide, copper naphthenate, copper oleate, copper oxychloride, copper silicate, copper sulfate, copper zinc chromate, coumachlor, coumafuryl, coumaphos, coumatetralyl, coumithoate, coumoxystrobin, CPMC, CPMF, CPPC, credazine, cresol, crimidine, crotamiton, crotoxyphos, crufomate, cryolite, cue-lure, cufraneb, cumyluron, cuprobam, cuprous oxide, curcumenol, cyanamide, cyanatryn, cyanazine, cyanofenphos, cyanophos, cyanthoate, cyantraniliprole, cyazofamid, cybutryne, cyclafuramid, cyclanilide, cyclethrin, cycloate, cycloheximide, cycloprate, cycloprothrin, cyclosulfamuron, cycloxaprid, cycloxydim, cycluron, cyenopyrafen, cyflufenamid, cyflumetofen, cyfluthrin, cyhalofop, cyhalofop-butyl, cyhalothrin, cyhexatin, cymiazole, cymiazole hydrochloride, cymoxanil, cyometrinil, cypendazole, cypermethrin, cyperquat, cyperquat chloride, cyphenothrin, cyprazine, cyprazole, cyproconazole, cyprodinil, cyprofuram, cypromid, cyprosulfamide, cyromazine, cythioate, daimuron, dalapon, dalapon-calcium, dalapon-magnesium, dalapon- sodium, daminozide, dayoutong, dazomet, dazomet-sodium, DBCP, J-camphor, DCIP, DCPTA, DDT, debacarb, decafentin, decarbofuran, dehydroacetic acid, delachlor, deltamethrin, demephion, demephion-O, demephion-S, demeton, demeton-methyl, demeton- O, demeton-O-methyl, demeton-S, demeton-S-methyl, demeton- S-methylsulphon, desmedipham, desmetryn, J-fanshiluquebingjuzhi, diafenthiuron, dialifos, di-allate, diamidafos, diatomaceous earth, diazinon, dibutyl phthalate, dibutyl succinate, dicamba, dicamba-diglycolamine, dicamba-dimethylammonium, dicamba-diolamine, dicamba- isopropylammonium, dicamba-methyl, dicamba-olamine, dicamba-potassium, dicamba- sodium, dicamba-trolamine, dicapthon, dichlobenil, dichlofenthion, dichlofluanid, dichlone, dichloralurea, dichlorbenzuron, dichlorflurenol, dichlorflurenol-methyl, dichlormate, dichlormid, dichlorophen, dichlorprop, dichlorprop-2-ethylhexyl, dichlorprop-butotyl, dichlorprop-dimethylammonium, dichlorprop-ethylammonium, dichlorprop-isoctyl, dichlorprop-methyl, dichlorprop-P, dichlorprop-P-2-ethylhexyl, dichlorprop-P- dimethylammonium, dichlorprop-potassium, dichlorprop-sodium, dichlorvos, dichlozoline, diclobutrazol, diclocymet, diclofop, diclofop-methyl, diclomezine, diclomezine-sodium, dicloran, diclosulam, dicofol, dicoumarol, dicresyl, dicrotophos, dicyclanil, dicyclonon, dieldrin, dienochlor, diethamquat, diethamquat dichloride, diethatyl, diethatyl-ethyl, diethofencarb, dietholate, diethyl pyrocarbonate, diethyltoluamide, difenacoum,
difenoconazole, difenopenten, difenopenten-ethyl, difenoxuron, difenzoquat, difenzoquat metilsulfate, difethialone, diflovidazin, diflubenzuron, diflufenican, diflufenzopyr, diflufenzopyr-sodium, diflumetorim, dikegulac, dikegulac-sodium, dilor, dimatif, dimefluthrin, dimefox, dimefuron, dimepiperate, dimetachlone, dimetan, dimethacarb, dimethachlor, dimethametryn, dimethenamid, dimethenamid-P, dimethipin, dimethirimol, dimethoate, dimethomorph, dimethrin, dimethyl carbate, dimethyl phthalate,
dimethylvinphos, dimetilan, dimexano, dimidazon, dimoxystrobin, dinex, dinex-diclexine, dingjunezuo, diniconazole, diniconazole-M, dinitramine, dinobuton, dinocap, dinocap-4, dinocap-6, dinocton, dinofenate, dinopenton, dinoprop, dinosam, dinoseb, dinoseb acetate, dinoseb-ammonium, dinoseb-diolamine, dinoseb-sodium, dinoseb-trolamine, dinosulfon, dinotefuran, dinoterb, dinoterb acetate, dinoterbon, diofenolan, dioxabenzofos, dioxacarb, dioxathion, diphacinone, diphacinone-sodium, diphenamid, diphenyl sulfone, diphenylamine, dipropalin, dipropetryn, dipyrithione, diquat, diquat dibromide, disparlure, disul, disulfiram, disulfoton, disul-sodium, ditalimfos, dithianon, dithicrofos, dithioether, dithiopyr, diuron, d- limonene, DMPA, DNOC, DNOC-ammonium, DNOC-potassium, DNOC-sodium, dodemorph, dodemorph acetate, dodemorph benzoate, dodicin, dodicin hydrochloride, dodicin-sodium, dodine, dofenapyn, dominicalure, doramectin, drazoxolon, DSMA, dufulin, EBEP, EBP, ecdysterone, edifenphos, eglinazine, eglinazine-ethyl, emamectin, emamectin benzoate, EMPC, empenthrin, endosulfan, endothal, endothal-diammonium, endothal- dipotassium, endothal-disodium, endothion, endrin, enestroburin, EPN, epocholeone, epofenonane, epoxiconazole, eprinomectin, epronaz, EPTC, erbon, ergocalciferol, erlujixiancaoan, esdepallethrine, esfenvalerate, esprocarb, etacelasil, etaconazole, etaphos, etem, ethaboxam, ethachlor, ethalfluralin, ethametsulfuron, ethametsulfuron-methyl, ethaprochlor, ethephon, ethidimuron, ethiofencarb, ethiolate, ethion, ethiozin, ethiprole, ethirimol, ethoate-methyl, ethofumesate, ethohexadiol, ethoprophos, ethoxyfen, ethoxyfen- ethyl, ethoxyquin, ethoxysulfuron, ethychlozate, ethyl formate, ethyl 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, etofenprox, etoxazole, etridiazole, etrimfos, eugenol, EXD, famoxadone, famphur, fenamidone, fenaminosulf, fenamiphos, fenapanil, fenarimol, fenasulam, fenazaflor, fenazaquin, fenbuconazole, fenbutatin oxide, fenchlorazole, fenchlorazole-ethyl,
fenchlorphos, fenclorim, fenethacarb, fenfluthrin, fenfuram, fenhexamid, fenitropan, fenitrothion, fenjuntong, fenobucarb, fenoprop, fenoprop-3-butoxypropyl, fenoprop- butometyl, fenoprop-butotyl, fenoprop-butyl, fenoprop-isoctyl, fenoprop-methyl, fenoprop- potassium, fenothiocarb, fenoxacrim, fenoxanil, fenoxaprop, fenoxaprop-ethyl, fenoxaprop-P, fenoxaprop-P-ethyl, fenoxasulfone, fenoxycarb, fenpiclonil, fenpirithrin, fenpropathrin, fenpropidin, fenpropimorph, fenpyrazamine, fenpyroximate, fenridazon, fenridazon- potassium, fenridazon-propyl, fenson, fensulfothion, fenteracol, fenthiaprop, fenthiaprop- ethyl, fenthion, fenthion-ethyl, fentin, fentin acetate, fentin chloride, fentin hydroxide, fentrazamide, fentrifanil, fenuron, fenuron TCA, fenvalerate, ferbam, ferimzone, ferrous sulfate, fipronil, flamprop, flamprop-isopropyl, flamprop-M, flamprop-methyl, flamprop-M- isopropyl, flamprop-M-methyl, flazasulfuron, flocoumafen, flometoquin, flonicamid, florasulam, fluacrypyrim, fluazifop, fluazifop-butyl, fluazifop-methyl, fluazifop-P, fluazifop- P-butyl, fluazinam, fluazolate, fluazuron, flubendiamide, flubenzimine, flucarbazone, flucarbazone-sodium, flucetosulfuron, fluchloralin, flucofuron, flucycloxuron, flucythrinate, fludioxonil, fluenetil, fluensulfone, flufenacet, flufenerim, flufenican, flufenoxuron, flufenprox, flufenpyr, flufenpyr-ethyl, flufiprole, flumethrin, flumetover, flumetralin, flumetsulam, flumezin, flumiclorac, flumiclorac-pentyl, flumioxazin, flumipropyn, flumorph, fluometuron, fluopicolide, fluopyram, fluorbenside, fluoridamid, fluoroacetamide, fluorodifen, fluoroglycofen, fluoroglycofen-ethyl, fluoroimide, fluoromidine, fluoronitrofen, fluothiuron, fluotrimazole, fluoxastrobin, flupoxam, flupropacil, flupropadine, flupropanate, flupropanate-sodium, flupyradifurone, flupyrsulfuron, flupyrsulfuron-methyl, flupyrsulfuron- methyl-sodium, fluquinconazole, flurazole, flurenol, flurenol-butyl, flurenol-methyl, fluridone, flurochloridone, fluroxypyr, fluroxypyr-butometyl, fluroxypyr-meptyl,
flurprimidol, flursulamid, flurtamone, flusilazole, flusulfamide, fluthiacet, fluthiacet-methyl, flutianil, flutolanil, flutriafol, fluvalinate, fluxapyroxad, fluxofenim, folpet, fomesafen, fomesafen-sodium, fonofos, foramsulfuron, forchlorfenuron, formaldehyde, formetanate, formetanate hydrochloride, formothion, formparanate, formparanate hydrochloride, fosamine, fosamine-ammonium, fosetyl, fosetyl-aluminium, fosmethilan, fospirate, fosthiazate, fosthietan, frontalin, fuberidazole, fucaojing, fucaomi, funaihecaoling, fuphenthiourea, furalane, furalaxyl, furamethrin, furametpyr, furathiocarb, furcarbanil, furconazole, furconazole-cis, furethrin, furfural, furilazole, furmecyclox, furophanate, furyloxyfen, gamma-cyhalothrin, gamma-HCR, genit, gibberellic acid, gibberellins, gliftor, glufosinate, glufosinate-ammonium, glufosinate-P, glufosinate-P-ammonium, glufosinate-P-sodium, glyodin, glyoxime, glyphosate, glyphosate-diammonium, glyphosate-dimethylammonium, glyphosate-isopropylammonium, glyphosate-monoammonium, glyphosate-potassium, glyphosate-sesquisodium, glyphosate-trimesium, glyphosine, gossyplure, grandlure, griseofulvin, guazatine, guazatine acetates, halacrinate, halfenprox, halofenozide, halosafen, halosulfuron, halosulfuron-methyl, haloxydine, haloxyfop, haloxyfop-etotyl, haloxyfop- methyl, haloxyfop-P, haloxyfop-P-etotyl, haloxyfop-P-methyl, haloxyfop-sodium, HCH, hemel, hempa, HEOD, heptachlor, heptenophos, heptopargil, heterophos, hexachloroacetone, hexachlorobenzene, hexachlorobutadiene, hexachlorophene, hexaconazole, hexaflumuron, hexaflurate, hexalure, hexamide, hexazinone, hexylthiofos, hexythiazox, HHDN, holosulf, huancaiwo, huangcaoling, huanjunzuo, hydramethylnon, hydrargaphen, hydrated lime, hydrogen cyanide, hydroprene, hymexazol, hyquincarb, IAA, IBA, icaridin, imazalil, imazalil nitrate, imazalil sulfate, imazamethabenz, imazamethabenz-methyl, imazamox, imazamox- ammonium, imazapic, imazapic-ammonium, imazapyr, imazapyr-isopropylammonium, imazaquin, imazaquin-ammonium, imazaquin-methyl, imazaquin- sodium, imazethapyr, imazethapyr-ammonium, imazosulfuron, imibenconazole, imicyafos, imidacloprid, imidaclothiz, iminoctadine, iminoctadine triacetate, iminoctadine trialbesilate, imiprothrin, inabenfide, indanofan, indaziflam, indoxacarb, inezin, iodobonil, iodocarb, iodomethane, iodosulfuron, iodosulfuron-methyl, iodosulfuron-methyl-sodium, iofensulfuron,
iofensulfuron-sodium, ioxynil, ioxynil octanoate, ioxynil-lithium, ioxynil-sodium, ipazine, ipconazole, ipfencarbazone, iprobenfos, iprodione, iprovalicarb, iprymidam, ipsdienol, ipsenol, IPSP, isamidofos, isazofos, isobenzan, isocarbamid, isocarbophos, isocil, isodrin, isofenphos, isofenphos-methyl, isolan, isomethiozin, isonoruron, isopolinate, isoprocarb, isopropalin, isoprothiolane, isoproturon, isopyrazam, isopyrimol, isothioate, isotianil, isouron, isovaledione, isoxaben, isoxachlortole, isoxadifen, isoxadifen-ethyl, isoxaflutole, isoxapyrifop, isoxathion, ivermectin, izopamfos, japonilure, japothrins, jasmolin I, jasmolin II, jasmonic acid, jiahuangchongzong, jiajizengxiaolin, jiaxiangjunzhi, jiecaowan, jiecaoxi, jodfenphos, juvenile hormone I, juvenile hormone II, juvenile hormone III, kadethrin, karbutilate, karetazan, karetazan-potassium, kasugamycin, kasugamycin hydrochloride, kejunlin, kelevan, ketospiradox, ketospiradox-potassium, kinetin, kinoprene, kresoxim- methyl, kuicaoxi, lactofen, lambda-cyhalothrin, latilure, lead arsenate, lenacil, lepimectin, leptophos, lindane, lineatin, linuron, lirimfos, litlure, looplure, lufenuron, lvdingjunzhi, lvxiancaolin, lythidathion, MAA, malathion, maleic hydrazide, malonoben, maltodextrin, MAMA, mancopper, mancozeb, mandipropamid, maneb, matrine, mazidox, MCPA, MCPA- 2-ethylhexyl, MCPA-butotyl, MCPA-butyl, MCPA-dimethylammonium, MCPA-diolamine, MCPA-ethyl, MCPA-isobutyl, MCPA-isoctyl, MCPA-isopropyl, MCPA-methyl, MCPA- olamine, MCPA-potassium, MCPA-sodium, MCPA-thioethyl, MCPA-trolamine, MCPB, MCPB-ethyl, MCPB-methyl, MCPB-sodium, mebenil, mecarbam, mecarbinzid, mecarphon, mecoprop, mecoprop-2-ethylhexyl, mecoprop-dimethylammonium, mecoprop-diolamine, mecoprop-ethadyl, mecoprop-isoctyl, mecoprop-methyl, mecoprop-P, mecoprop-P-2- ethylhexyl, mecoprop-P-dimethylammonium, mecoprop-P-isobutyl, mecoprop-potassium, mecoprop-P-potassium, mecoprop-sodium, mecoprop-trolamine, medimeform, medinoterb, medinoterb acetate, medlure, mefenacet, mefenpyr, mefenpyr-diethyl, mefluidide, mefluidide-diolamine, mefluidide-potassium, megatomoic acid, menazon, mepanipyrim, meperfluthrin, mephenate, mephosfolan, mepiquat, mepiquat chloride, mepiquat pentaborate, mepronil, meptyldinocap, mercuric chloride, mercuric oxide, mercurous chloride, merphos, mesoprazine, mesosulfuron, mesosulfuron-methyl, mesotrione, mesulfen, mesulfenfos, metaflumizone, metalaxyl, metalaxyl-M, metaldehyde, metam, metam-ammonium, metamifop, metamitron, metam-potassium, metam-sodium, metazachlor, metazosulfuron, metazoxolon, metconazole, metepa, metflurazon, methabenzthiazuron, methacrifos, methalpropalin, methamidophos, methasulfocarb, methazole, methfuroxam, methidathion, methiobencarb, methiocarb, methiopyrisulfuron, methiotepa, methiozolin, methiuron, methocrotophos, methometon, methomyl, methoprene, methoprotryne, methoquin-butyl, methothrin, methoxychlor, methoxyfenozide, methoxyphenone, methyl apholate, methyl bromide, methyl eugenol, methyl iodide, methyl isothiocyanate, methylacetophos, methylchloroform, methyldymron, methylene chloride, methylmercury benzoate, methylmercury dicyandiamide, methylmercury pentachlorophenoxide,
methylneodecanamide, metiram, metobenzuron, metobromuron, metofluthrin, metolachlor, metolcarb, metominostrobin, metosulam, metoxadiazone, metoxuron, metrafenone, metribuzin, metsulfovax, metsulfuron, metsulfuron-methyl, mevinphos, mexacarbate, mieshuan, milbemectin, milbemycin oxime, milneb, mipafox, mirex, MNAF, moguchun, molinate, molosultap, monalide, monisouron, monochloroacetic acid, monocrotophos, monolinuron, monosulfuron, monosulfuron-ester, monuron, monuron TCA, morfamquat, morfamquat dichloride, moroxydine, moroxydine hydrochloride, morphothion, morzid, moxidectin, MSMA, muscalure, myclobutanil, myclozolin, N-(ethylmercury)-p- toluenesulphonanilide, nabam, naftalofos, naled, naphthalene, naphthaleneacetamide, naphthalic anhydride, naphthoxyacetic acids, naproanilide, napropamide, naptalam, naptalam-sodium, natamycin, neburon, niclosamide, niclosamide-olamine, nicosulfuron, nicotine, nifluridide, nipyraclofen, nitenpyram, nithiazine, nitralin, nitrapyrin, nitrilacarb, nitrofen, nitrofluorfen, nitrostyrene, nitrothal-isopropyl, norbormide, norflurazon, nomicotine, noruron, novaluron, noviflumuron, nuarimol, OCH, octachlorodipropyl ether, octhilinone, ofurace, omethoate, orbencarb, orfralure, ortho-dichlorobenzene,
orthosulfamuron, oryctalure, orysastrobin, oryzalin, osthol, ostramone, oxabetrinil, oxadiargyl, oxadiazon, oxadixyl, oxamate, oxamyl, oxapyrazon, oxapyrazon-dimolamine, oxapyrazon-sodium, oxasulfuron, oxaziclomefone, oxine-copper, oxolinic acid,
oxpoconazole, oxpoconazole fumarate, oxycarboxin, oxydemeton-methyl, oxydeprofos, oxydisulfoton, oxyfluorfen, oxymatrine, oxytetracycline, oxytetracycline hydrochloride, paclobutrazol, paichongding, para-dichlorobenzene, parafluron, paraquat, paraquat dichloride, paraquat dimetilsulfate, parathion, parathion-methyl, parinol, pebulate, pefurazoate, pelargonic acid, penconazole, pencycuron, pendimethalin, penflufen, penfluron, penoxsulam, pentachlorophenol, pentanochlor, penthiopyrad, pentmethrin, pentoxazone, perfluidone, permethrin, pethoxamid, phenamacril, phenazine oxide, phenisopham, phenkapton, phenmedipham, phenmedipham-ethyl, phenobenzuron, phenothrin, phenproxide, phenthoate, phenylmercuriurea, phenylmercury acetate, phenylmercury chloride,
phenylmercury derivative of pyrocatechol, phenylmercury nitrate, phenylmercury salicylate, phorate, phosacetim, phosalone, phosdiphen, phosfolan, phosfolan-methyl, phosglycin, phosmet, phosnichlor, phosphamidon, phosphine, phosphocarb, phosphorus, phostin, phoxim, phoxim-methyl, phthalide, picloram, picloram-2-ethylhexyl, picloram-isoctyl, picloram- methyl, picloram-olamine, picloram-potassium, picloram-triethylammonium, picloram-tris(2- hydroxypropyl)ammonium, picolinafen, picoxystrobin, pindone, pindone- sodium, pinoxaden, piperalin, piperonyl butoxide, piperonyl cyclonene, piperophos, piproctanyl, piproctanyl bromide, piprotal, pirimetaphos, pirimicarb, pirimioxyphos, pirimiphos-ethyl, pirimiphos- methyl, plifenate, polycarbamate, polyoxins, polyoxorim, polyoxorim-zinc, polythialan, potassium arsenite, potassium azide, potassium cyanate, potassium gibberellate, potassium naphthenate, potassium polysulfide, potassium thiocyanate, potassium a-naphthaleneacetate, ρρ'-ΌΌΎ, prallethrin, precocene I, precocene II, precocene III, pretilachlor, primidophos, primisulfuron, primisulfuron- methyl, probenazole, prochloraz, prochloraz-manganese, proclonol, procyazine, procymidone, prodiamine, profenofos, profluazol, profluralin, profluthrin, profoxydim, proglinazine, proglinazine-ethyl, prohexadione, prohexadione- calcium, prohydrojasmon, promacyl, promecarb, prometon, prometryn, promurit, propachlor, propamidine, propamidine dihydrochloride, propamocarb, propamocarb hydrochloride, propanil, propaphos, propaquizafop, propargite, proparthrin, propazine, propetamphos, propham, propiconazole, propineb, propisochlor, propoxur, propoxycarbazone,
propoxycarbazone-sodium, propyl isome, propyrisulfuron, propyzamide, proquinazid, prosuler, prosulfalin, prosulfocarb, prosulfuron, prothidathion, prothiocarb, prothiocarb hydrochloride, prothioconazole, prothiofos, prothoate, protrifenbute, proxan, proxan-sodium, prynachlor, pydanon, pymetrozine, pyracarbolid, pyraclofos, pyraclonil, pyraclostrobin, pyraflufen, pyraflufen-ethyl, pyrafluprole, pyramat, pyrametostrobin, pyraoxystrobin, pyrasulfotole, pyrazolynate, pyrazophos, pyrazosulfuron, pyrazosulfuron-ethyl, pyrazothion, pyrazoxyfen, pyresmethrin, pyrethrin I, pyrethrin II, pyrethrins, pyribambenz-isopropyl, pyribambenz-propyl, pyribencarb, pyribenzoxim, pyributicarb, pyriclor, pyridaben, pyridafol, pyridalyl, pyridaphenthion, pyridate, pyridinitril, pyrifenox, pyrifluquinazon, pyriftalid, pyrimethanil, pyrimidifen, pyriminobac, pyriminobac-methyl, pyrimisulfan, pyrimitate, pyrinuron, pyriofenone, pyriprole, pyripropanol, pyriproxyfen, pyrithiobac, pyrithiobac- sodium, pyrolan, pyroquilon, pyroxasulfone, pyroxsulam, pyroxychlor, pyroxyfur, quassia, quinacetol, quinacetol sulfate, quinalphos, quinalphos-methyl, quinazamid, quinclorac, quinconazole, quinmerac, quinoclamine, quinonamid, quinothion, quinoxyfen, quintiofos, quintozene, quizalofop, quizalofop-ethyl, quizalofop-P, quizalofop-P-ethyl, quizalofop-P- tefuryl, quwenzhi, quyingding, rabenzazole, rafoxanide, rebemide, resmethrin, rhodethanil, rhodojaponin-III, ribavirin, rimsulfuron, rotenone, ryania, saflufenacil, saijunmao, saisentong, salicylanilide, sanguinarine, santonin, schradan, scilliroside, sebuthylazine, secbumeton, sedaxane, selamectin, semiamitraz, semiamitraz chloride, sesamex, sesamolin, sethoxydim, shuangjiaancaolin, siduron, siglure, silafluofen, silatrane, silica gel, silthiofam, simazine, simeconazole, simeton, simetryn, sintofen, SMA, S-metolachlor, sodium arsenite, sodium azide, sodium chlorate, sodium fluoride, sodium fluoroacetate, sodium hexafluorosilicate, sodium naphthenate, sodium orthophenylphenoxide, sodium pentachlorophenoxide, sodium polysulfide, sodium thiocyanate, sodium a-naphthaleneacetate, sophamide, spinetoram, spinosad, spirodiclofen, spiromesifen, spirotetramat, spiroxamine, streptomycin, streptomycin sesquisulfate, strychnine, sulcatol, sulcofuron, sulcofuron-sodium, sulcotrione, sulfallate, sulfentrazone, sulfiram, sulfluramid, sulfometuron, sulfometuron-methyl, sulfosulfuron, sulfotep, sulfoxaflor, sulfoxide, sulfoxime, sulfur, sulfuric acid, sulfuryl fluoride, sulglycapin, sulprofos, sultropen, swep, toi/-fluvalinate, tavron, tazimcarb, TCA, TCA-ammonium, TCA- calcium, TCA-ethadyl, TCA-magnesium, TCA-sodium, TDE, tebuconazole, tebufenozide, tebufenpyrad, tebufloquin, tebupirimfos, tebutam, tebuthiuron, tecloftalam, tecnazene, tecoram, teflubenzuron, tefluthrin, tefuryltrione, tembotrione, temephos, tepa, TEPP, tepraloxydim, terallethrin, terbacil, terbucarb, terbuchlor, terbufos, terbumeton,
terbuthylazine, terbutryn, tetcyclacis, tetrachloroethane, tetrachlorvinphos, tetraconazole, tetradifon, tetrafluron, tetramethrin, tetramethylfluthrin, tetramine, tetranactin, tetrasul, thallium sulfate, thenylchlor, theta-cypermethrin, thiabendazole, thiacloprid, thiadifluor, thiamethoxam, thiapronil, thiazafluron, thiazopyr, thicrofos, thicyofen, thidiazimin, thidiazuron, thiencarbazone, thiencarbazone-methyl, thifensulfuron, thifensulfuron-methyl, thifluzamide, thiobencarb, thiocarboxime, thiochlorfenphim, thiocyclam, thiocyclam hydrochloride, thiocyclam oxalate, thiodiazole-copper, thiodicarb, thiofanox, thiofluoximate, thiohempa, thiomersal, thiometon, thionazin, thiophanate, thiophanate-methyl, thioquinox, thiosemicarbazide, thiosultap, thiosultap-diammonium, thiosultap-disodium, thiosultap- monosodium, thiotepa, thiram, thuringiensin, tiadinil, tiaojiean, tiocarbazil, tioclorim, tioxymid, tirpate, tolclofos-methyl, tolfenpyrad, tolylfluanid, tolylmercury acetate, topramezone, tralkoxydim, tralocythrin, tralomethrin, tralopyril, transfluthrin,
transpermethrin, tretamine, triacontanol, triadimefon, triadimenol, triafamone, tri-allate, triamiphos, triapenthenol, triarathene, triarimol, triasulfuron, triazamate, triazbutil, triaziflam, triazophos, triazoxide, tribenuron, tribenuron-methyl, tribufos, tributyltin oxide, tricamba, trichlamide, trichlorfon, trichlormetaphos-3, trichloronat, triclopyr, triclopyr-butotyl, triclopyr-ethyl, triclopyr-triethylammonium, tricyclazole, tridemorph, tridiphane, trietazine, trifenmorph, trifenofos, trifloxystrobin, trifloxysulfuron, trifloxysulfuron-sodium, triflumizole, triflumuron, trifluralin, triflusulfuron, triflusulfuron-methyl, trifop, trifop- methyl, trifopsime, triforine, trihydroxytriazine, trimedlure, trimethacarb, trimeturon, trinexapac, trinexapac-ethyl, triprene, tripropindan, triptolide, tritac, triticonazole, tritosulfuron, trunc-call, uniconazole, uniconazole-P, urbacide, uredepa, valerate, validamycin, valifenalate, valone, vamidothion, vangard, vaniliprole, vernolate, vinclozolin, warfarin, warfarin-potassium, warfarin-sodium, xiaochongliulin, xinjunan, xiwojunan, XMC, xylachlor, xylenols, xylylcarb, yishijing, zarilamid, zeatin, zengxiaoan, zeta-cypermethrin, zinc naphthenate, zinc phosphide, zinc thiazole, zineb, ziram, zolaprofos, zoxamide, zuomihuanglong, a-chlorohydrin, a-ecdysone, a-multistriatin, and a-naphthaleneacetic acid. For more information consult the "COMPENDIUM OF PESTICIDE COMMON NAMES" located at http://www.alanwood.i et/pesticides/index.html. Also consult "THE PESTICIDE MANUAL" 14th Edition, edited by C D S Tomlin, copyright 2006 by British Crop Production Council, or its prior or more recent editions.
BIOPESTICIDES
Molecules of Formula One may also be used in combination (such as in a
compositional mixture, or a simultaneous or sequential application) with one or more biopesticides. The term "biopesticide" is used for microbial biological pest control agents that are applied in a similar manner to chemical pesticides. Commonly these are bacterial, but there are also examples of fungal control agents, including Trichoderma spp. and
Ampelomyces quisqualis (a control agent for grape powdery mildew). Bacillus subtilis are used to control plant pathogens. Weeds and rodents have also been controlled with microbial agents. One well-known insecticide example is Bacillus thuringiensis, a bacterial disease of Lepidoptera, Coleoptera, and Diptera. Because it has little effect on other organisms, it is considered more environmentally friendly than synthetic pesticides. Biological insecticides include products based on:
1. entomopathogenic fungi {e.g. Metarhizium anisopliae);
2. entomopathogenic nematodes (e.g. Steinernema feltiae); and
3. entomopathogenic viruses (e.g. Cydia pomonella granulo virus).
Other examples of entomopathogenic organisms include, but are not limited to, baculoviruses, bacteria and other prokaryotic organisms, fungi, protozoa and Microsproridia. Biologically derived insecticides include, but not limited to, rotenone, veratridine, as well as microbial toxins; insect tolerant or resistant plant varieties; and organisms modified by recombinant DNA technology to either produce insecticides or to convey an insect resistant property to the genetically modified organism. In one embodiment, the molecules of Formula One may be used with one or more biopesticides in the area of seed treatments and soil amendments. The Manual of Biocontrol Agents gives a review of the available biological insecticide (and other biology -based control) products. Copping L.G. (ed.) (2004). The Manual of Biocontrol Agents (formerly the Biopesticide Manual) 3rd Edition. British Crop Production Council (BCPC), Farnham, Surrey UK.
OTHER ACTIVE COMPOUNDS
Molecules of Formula One may also be used in combination (such as in a
compositional mixture, or a simultaneous or sequential application) with one or more of the following:
I. 3-(4-chloro-2,6-dimethylphenyl)-4-hydroxy-8-oxa-l-azaspiro[4,5]dec-3-en-2-one; 2. 3-(4'-chloro-2,4-dimethyl[l,l '-biphenyl]-3-yl)-4-hydroxy-8-oxa-l-azaspiro[4,5]dec-
3-en-2-one;
3. 4-[[(6-chloro-3-pyridinyl)methyl]methylamino]-2(5H)-furanone;
4. 4-[[(6-chloro-3-pyridinyl)methyl]cyclopropylamino]-2(5H)-furanone;
5. 3-chloro-N2-[(15')-l-methyl-2-(methylsulfonyl)ethyl]-Nl-[2-methyl-4-[l,2,2,2- tetrafluoro- 1 -(trifluoromethyl)ethyl]phenyl]- 1 ,2-benzenedicarboxamide;
6. 2-cyano-N-ethyl-4-fluoro-3-methoxy-benenesulfonamide;
7. 2-cy ano-N-ethyl- 3 -methoxy-benzenesulf onamide ;
8. 2-cyano-3-difluoromethoxy-N-ethyl-4-fluoro-benzenesulfonamide;
9. 2-cyano-3-fluoromethoxy-N-ethyl-benzenesulfonamide;
10. 2-cyano-6-fluoro-3-methoxy-N,N-dimethyl-benzenesulfonamide;
I I . 2-cyano-N-ethyl-6-fluoro-3-methoxy-N-methyl-benzenesulfonamide;
12. 2-cyano-3-difluoromethoxy-N,N-dimethylbenzenesulfon-amide;
13. 3 -(difluoromethyl)-N- [2-(3 ,3-dimethylbutyl)phenyl] - 1 -methyl- lH-pyrazole-4- carboxamide;
14. N-ethyl-2,2-dimethylpropionamide-2-(2,6-dichloro-a,a,a-trifluoro-/?-tolyl) hydrazone;
15. N-ethyl-2,2-dichloro-l-methylcyclopropane-carboxamide-2-(2,6-dichloro-a,a,a- trifluoro-/?-tolyl) hydrazone nicotine;
16. 0-{(E-)-[2-(4-chloro-phenyl)-2-cyano-l-(2-trifluoromethylphenyl)-vinyl] } S-methyl thiocarbonate; 17. (E)-Nl-[(2-chloro-l,3-thiazol-5-ylmethyl)]-N2-cyano-Nl-methylacetamidine;
18. l-(6-chloropyridin-3-ylmethyl)-7-methyl-8-nitro- 1,2,3, 5,6 ,7-hexahydro-imidazo[l,2- a]pyridin-5-ol;
19. 4-[4-chlorophenyl-(2-butylidine-hydrazono)methyl)]phenyl mesylate; and
20. N-Ethyl-2,2-dichloro-l-methylcyclopropanecarboxamide-2-(2,6-dichloro- alpha, alpha, a//? za-trifluoro-p-tolyl)hydrazone.
SYNERGISTIC MIXTURES
Molecules of Formula One may be used with certain active compounds to form synergistic mixtures where the mode of action of such compounds compared to the mode of action of the molecules of Formula One are the same, similar, or different. Examples of modes of action include, but are not limited to: acetylcholinesterase inhibitor; sodium channel modulator; chitin biosynthesis inhibitor; GABA and glutamate-gated chloride channel antagonist; GABA and glutamate-gated chloride channel agonist; acetylcholine receptor agonist; acetylcholine receptor antagonist; MET I inhibitor; Mg-stimulated ATPase inhibitor; nicotinic acetylcholine receptor; Midgut membrane disrupter; oxidative phosphorylation disrupter, and ryanodine receptor (RyRs). Generally, weight ratios of the molecules of Formula One in a synergistic mixture with another compound are from about 10: 1 to about 1: 10, in another embodiment from about 5: 1 to about 1 :5, and in another embodiment from about 3: 1, and in another embodiment about 1: 1.
FORMULATIONS
A pesticide is rarely suitable for application in its pure form. It is usually necessary to add other substances so that the pesticide can be used at the required concentration and in an appropriate form, permitting ease of application, handling, transportation, storage, and maximum pesticide activity. Thus, pesticides are formulated into, for example, baits, concentrated emulsions, dusts, emulsifiable concentrates, fumigants, gels, granules, microencapsulations, seed treatments, suspension concentrates, suspoemulsions, tablets, water soluble liquids, water dispersible granules or dry flowables, wettable powders, and ultra-low volume solutions. For further information on formulation types see "Catalogue of Pesticide Formulation Types and International Coding System" Technical Monograph n°2, 5th Edition by CropLife International (2002).
Pesticides are applied most often as aqueous suspensions or emulsions prepared from concentrated formulations of such pesticides. Such water-soluble, water- suspendable, or emulsifiable formulations are either solids, usually known as wettable powders, or water dispersible granules, or liquids usually known as emulsifiable concentrates, or aqueous suspensions. Wettable powders, which may be compacted to form water dispersible granules, comprise an intimate mixture of the pesticide, a carrier, and surfactants. The concentration of the pesticide is usually from about 10% to about 90% by weight. The carrier is usually selected from among the attapulgite clays, the montmorillonite clays, the diatomaceous earths, or the purified silicates. Effective surfactants, comprising from about 0.5% to about 10% of the wettable powder, are found among sulfonated lignins, condensed
naphthalenesulfonates, naphthalenesulfonates, alkylbenzenesulfonates, alkyl sulfates, and non-ionic surfactants such as ethylene oxide adducts of alkyl phenols.
Emulsifiable concentrates of pesticides comprise a convenient concentration of a pesticide, such as from about 50 to about 500 grams per liter of liquid dissolved in a carrier that is either a water miscible solvent or a mixture of water-immiscible organic solvent and emulsifiers. Useful organic solvents include aromatics, especially xylenes and petroleum fractions, especially the high-boiling naphthalenic and olefinic portions of petroleum such as heavy aromatic naphtha. Other organic solvents may also be used, such as the terpenic solvents including rosin derivatives, aliphatic ketones such as cyclohexanone, and complex alcohols such as 2-ethoxyethanol. Suitable emulsifiers for emulsifiable concentrates are selected from conventional anionic and non-ionic surfactants.
Aqueous suspensions comprise suspensions of water-insoluble pesticides dispersed in an aqueous carrier at a concentration in the range from about 5% to about 50% by weight. Suspensions are prepared by finely grinding the pesticide and vigorously mixing it into a carrier comprised of water and surfactants. Ingredients, such as inorganic salts and synthetic or natural gums may also be added, to increase the density and viscosity of the aqueous carrier. It is often most effective to grind and mix the pesticide at the same time by preparing the aqueous mixture and homogenizing it in an implement such as a sand mill, ball mill, or piston-type homogenizer.
Pesticides may also be applied as granular compositions that are particularly useful for applications to the soil. Granular compositions usually contain from about 0.5% to about 10% by weight of the pesticide, dispersed in a carrier that comprises clay or a similar substance. Such compositions are usually prepared by dissolving the pesticide in a suitable solvent and applying it to a granular carrier which has been pre-formed to the appropriate particle size, in the range of from about 0.5 to about 3 mm. Such compositions may also be formulated by making a dough or paste of the carrier and compound and crushing and drying to obtain the desired granular particle size. Dusts containing a pesticide are prepared by intimately mixing the pesticide in powdered form with a suitable dusty agricultural carrier, such as kaolin clay, ground volcanic rock, and the like. Dusts can suitably contain from about 1% to about 10% of the pesticide. They can be applied as a seed dressing or as a foliage application with a dust blower machine.
It is equally practical to apply a pesticide in the form of a solution in an appropriate organic solvent, usually petroleum oil, such as the spray oils, which are widely used in agricultural chemistry.
Pesticides can also be applied in the form of an aerosol composition. In such compositions the pesticide is dissolved or dispersed in a carrier, which is a pressure- generating propellant mixture. The aerosol composition is packaged in a container from which the mixture is dispensed through an atomizing valve.
Pesticide baits are formed when the pesticide is mixed with food or an attractant or both. When the pests eat the bait they also consume the pesticide. Baits may take the form of granules, gels, flowable powders, liquids, or solids. They can be used in pest harborages.
Fumigants are pesticides that have a relatively high vapor pressure and hence can exist as a gas in sufficient concentrations to kill pests in soil or enclosed spaces. The toxicity of the fumigant is proportional to its concentration and the exposure time. They are characterized by a good capacity for diffusion and act by penetrating the pest' s respiratory system or being absorbed through the pest' s cuticle. Fumigants are applied to control stored product pests under gas proof sheets, in gas sealed rooms or buildings or in special chambers.
Pesticides can be microencapsulated by suspending the pesticide particles or droplets in plastic polymers of various types. By altering the chemistry of the polymer or by changing factors in the processing, microcapsules can be formed of various sizes, solubility, wall thicknesses, and degrees of penetrability. These factors govern the speed with which the active ingredient within is released, which in turn, affects the residual performance, speed of action, and odor of the product.
Oil solution concentrates are made by dissolving pesticide in a solvent that will hold the pesticide in solution. Oil solutions of a pesticide usually provide faster knockdown and kill of pests than other formulations due to the solvents themselves having pesticidal action and the dissolution of the waxy covering of the integument increasing the speed of uptake of the pesticide. Other advantages of oil solutions include better storage stability, better penetration of crevices, and better adhesion to greasy surfaces.
Another embodiment is an oil-in-water emulsion, wherein the emulsion comprises oily globules which are each provided with a lamellar liquid crystal coating and are dispersed in an aqueous phase, wherein each oily globule comprises at least one compound which is agriculturally active, and is individually coated with a monolamellar or oligolamellar layer comprising: (1) at least one non-ionic lipophilic surface-active agent, (2) at least one non- ionic hydrophilic surface-active agent and (3) at least one ionic surface- active agent, wherein the globules having a mean particle diameter of less than 800 nanometers. Further information on the embodiment is disclosed in U.S. patent publication 20070027034 published February 1, 2007, having Patent Application serial number 11/495,228. For ease of use, this embodiment will be referred to as "OrWE".
For further information consult "Insect Pest Management" 2nd Edition by D. Dent, copyright CAB International (2000). Additionally, for more detailed information consult "Handbook of Pest Control - The Behavior, Life History, and Control of Household Pests" by Arnold Mallis, 9th Edition, copyright 2004 by GIE Media Inc.
OTHER FORMULATION COMPONENTS
Generally, when the molecules disclosed in Formula One are used in a formulation, such formulation can also contain other components. These components include, but are not limited to, (this is a non-exhaustive and non-mutually exclusive list) wetters, spreaders, stickers, penetrants, buffers, sequestering agents, drift reduction agents, compatibility agents, anti-foam agents, cleaning agents, and emulsifiers. A few components are described forthwith.
A wetting agent is a substance that when added to a liquid increases the spreading or penetration power of the liquid by reducing the interfacial tension between the liquid and the surface on which it is spreading. Wetting agents are used for two main functions in agrochemical formulations: during processing and manufacture to increase the rate of wetting of powders in water to make concentrates for soluble liquids or suspension concentrates; and during mixing of a product with water in a spray tank to reduce the wetting time of wettable powders and to improve the penetration of water into water-dispersible granules. Examples of wetting agents used in wettable powder, suspension concentrate, and water-dispersible granule formulations are: sodium lauryl sulfate; sodium dioctyl sulfosuccinate; alkyl phenol ethoxylates; and aliphatic alcohol ethoxylates.
A dispersing agent is a substance which adsorbs onto the surface of particles and helps to preserve the state of dispersion of the particles and prevents them from
reaggregating. Dispersing agents are added to agrochemical formulations to facilitate dispersion and suspension during manufacture, and to ensure the particles redisperse into water in a spray tank. They are widely used in wettable powders, suspension concentrates and water-dispersible granules. Surfactants that are used as dispersing agents have the ability to adsorb strongly onto a particle surface and provide a charged or steric barrier to reaggregation of particles. The most commonly used surfactants are anionic, non-ionic, or mixtures of the two types. For wettable powder formulations, the most common dispersing agents are sodium lignosulfonates. For suspension concentrates, very good adsorption and stabilization are obtained using polyelectrolytes, such as sodium naphthalene sulfonate formaldehyde condensates. Tristyrylphenol ethoxylate phosphate esters are also used. Non-ionics such as alkylarylethylene oxide condensates and EO-PO block copolymers are sometimes combined with anionics as dispersing agents for suspension concentrates. In recent years, new types of very high molecular weight polymeric surfactants have been developed as dispersing agents. These have very long hydrophobic 'backbones' and a large number of ethylene oxide chains forming the 'teeth' of a 'comb' surfactant. These high molecular weight polymers can give very good long-term stability to suspension concentrates because the hydrophobic backbones have many anchoring points onto the particle surfaces. Examples of dispersing agents used in agrochemical formulations are: sodium lignosulfonates; sodium naphthalene sulfonate formaldehyde condensates; tristyrylphenol ethoxylate phosphate esters; aliphatic alcohol ethoxylates; alkyl ethoxylates; EO-PO block copolymers; and graft copolymers.
An emulsifying agent is a substance which stabilizes a suspension of droplets of one liquid phase in another liquid phase. Without the emulsifying agent the two liquids would separate into two immiscible liquid phases. The most commonly used emulsifier blends contain alkylphenol or aliphatic alcohol with twelve or more ethylene oxide units and the oil- soluble calcium salt of dodecylbenzenesulfonic acid. A range of hydrophile-lipophile balance ("HLB") values from 8 to 18 will normally provide good stable emulsions. Emulsion stability can sometimes be improved by the addition of a small amount of an EO-PO block copolymer surfactant.
A solubilizing agent is a surfactant which will form micelles in water at
concentrations above the critical micelle concentration. The micelles are then able to dissolve or solubilize water-insoluble materials inside the hydrophobic part of the micelle. The types of surfactants usually used for solubilization are non- ionics, sorbitan monooleates, sorbitan monooleate ethoxylates, and methyl oleate esters.
Surfactants are sometimes used, either alone or with other additives such as mineral or vegetable oils as adjuvants to spray-tank mixes to improve the biological performance of the pesticide on the target. The types of surfactants used for bioenhancement depend generally on the nature and mode of action of the pesticide. However, they are often non-ionics such as: alkyl ethoxylates; linear aliphatic alcohol ethoxylates; aliphatic amine ethoxylates.
A carrier or diluent in an agricultural formulation is a material added to the pesticide to give a product of the required strength. Carriers are usually materials with high absorptive capacities, while diluents are usually materials with low absorptive capacities. Carriers and diluents are used in the formulation of dusts, wettable powders, granules and water- dispersible granules.
Organic solvents are used mainly in the formulation of emulsifiable concentrates, oil- in-water emulsions, suspoemulsions, and ultra-low volume formulations, and to a lesser extent, granular formulations. Sometimes mixtures of solvents are used. The first main groups of solvents are aliphatic paraffinic oils such as kerosene or refined paraffins. The second main group (and the most common) comprises the aromatic solvents such as xylene and higher molecular weight fractions of C9 and CIO aromatic solvents. Chlorinated hydrocarbons are useful as cosolvents to prevent crystallization of pesticides when the formulation is emulsified into water. Alcohols are sometimes used as cosolvents to increase solvent power. Other solvents may include vegetable oils, seed oils, and esters of vegetable and seed oils.
Thickeners or gelling agents are used mainly in the formulation of suspension concentrates, emulsions and suspoemulsions to modify the rheology or flow properties of the liquid and to prevent separation and settling of the dispersed particles or droplets.
Thickening, gelling, and anti-settling agents generally fall into two categories, namely water- insoluble particulates and water-soluble polymers. It is possible to produce suspension concentrate formulations using clays and silicas. Examples of these types of materials, include, but are not limited to, montmorillonite, bentonite, magnesium aluminum silicate, and attapulgite. Water-soluble polysaccharides have been used as thickening-gelling agents for many years. The types of polysaccharides most commonly used are natural extracts of seeds and seaweeds or are synthetic derivatives of cellulose. Examples of these types of materials include, but are not limited to, guar gum; locust bean gum; carrageenam; alginates; methyl cellulose; sodium carboxymethyl cellulose (SCMC); hydroxyethyl cellulose (HEC). Other types of anti-settling agents are based on modified starches, polyacrylates, polyvinyl alcohol and polyethylene oxide. Another good anti-settling agent is xanthan gum.
Microorganisms can cause spoilage of formulated products. Therefore preservation agents are used to eliminate or reduce their effect. Examples of such agents include, but are not limited to: propionic acid and its sodium salt; sorbic acid and its sodium or potassium salts; benzoic acid and its sodium salt; p-hydroxybenzoic acid sodium salt; methyl p- hydroxybenzoate; and l,2-benzisothiazolin-3-one (BIT).
The presence of surfactants often causes water-based formulations to foam during mixing operations in production and in application through a spray tank. In order to reduce the tendency to foam, anti-foam agents are often added either during the production stage or before filling into bottles. Generally, there are two types of anti-foam agents, namely silicones and non- silicones. Silicones are usually aqueous emulsions of dimethyl
polysiloxane, while the non-silicone anti-foam agents are water-insoluble oils, such as octanol and nonanol, or silica. In both cases, the function of the anti-foam agent is to displace the surfactant from the air-water interface.
"Green" agents {e.g., adjuvants, surfactants, solvents) can reduce the overall environmental footprint of crop protection formulations. Green agents are biodegradable and generally derived from natural and/or sustainable sources, e.g. plant and animal sources.
Specific examples are: vegetable oils, seed oils, and esters thereof, also alkoxylated alkyl polyglucosides.
For further information, see "Chemistry and Technology of Agrochemical
Formulations" edited by D.A. Knowles, copyright 1998 by Kluwer Academic Publishers.
Also see "Insecticides in Agriculture and Environment - Retrospects and Prospects" by A.S.
Perry, I. Yamamoto, I. Ishaaya, and R. Perry, copyright 1998 by Springer- Verlag.
PESTS
In general, the molecules of Formula One may be used to control pests e.g. beetles, earwigs, cockroaches, flies, aphids, scales, whiteflies, leafhoppers, ants, wasps, termites, moths, butterflies, lice, grasshoppers, locusts, crickets, fleas, thrips, bristletails, mites, ticks, nematodes, and symphylans.
In another embodiment, the molecules of Formula One may be used to control pests in the Phyla Nematoda and/or Arthropoda.
In another embodiment, the molecules of Formula One may be used to control pests in the Subphyla Chelicerata, Myriapoda, and/or Hexapoda.
In another embodiment, the molecules of Formula One may be used to control pests in the Classes of Arachnida, Symphyla, and/or Insecta.
In another embodiment, the molecules of Formula One may be used to control pests of the Order Anoplura. A non-exhaustive list of particular genera includes, but is not limited to, Haematopinus spp., Hoplopleura spp., Linognathus spp., Pediculus spp., and Polyplax spp. A non-exhaustive list of particular species includes, but is not limited to, Haematopinus asini, Haematopinus suis, Linognathus setosus, Linognathus ovillus, Pediculus humanus capitis, Pediculus humanus humanus, and Pthirus pubis.
In another embodiment, the molecules of Formula One may be used to control pests in the Order Coleoptera. A non-exhaustive list of particular genera includes, but is not limited to, Acanthoscelides spp., Agriotes spp., Anthonomus spp., Apion spp., Apogonia spp., Aulacophora spp., Bruchus spp., Cerosterna spp., Cerotoma spp., Ceutorhynchus spp., Chaetocnema spp., Colaspis spp., Ctenicera spp., Curculio spp., Cyclocephala spp.,
Diabrotica spp., Hypera spp., Ips spp., Lyctus spp., Megascelis spp., Meligethes spp., Otiorhynchus spp., Pantomorus spp., Phyllophaga spp., Phyllotreta spp., Rhizotrogus spp., Rhynchites spp., Rhynchophorus spp., Scolytus spp., Sphenophorus spp., Sitophilus spp., and Tribolium spp. A non-exhaustive list of particular species includes, but is not limited to, Acanthoscelides obtectus, Agrilus planipennis, Anoplophora glabripennis, Anthonomus grandis, Ataenius spretulus, Atomaria linearis, Bothynoderes punctiventris, Bruchus pisorum, Callosobruchus maculatus, Carpophilus hemipterus, Cassida vittata, Cerotoma trifurcata, Ceutorhynchus assimilis, Ceutorhynchus napi, Conoderus scalaris, Conoderus stigmosus, Conotrachelus nenuphar, Cotinis nitida, Crioceris asparagi, Cryptolestes ferrugineus, Cryptolestes pusillus, Cryptolestes turcicus, Cylindrocopturus adspersus, Deporaus marginatus, Dermestes lardarius, Dermestes maculatus, Epilachna varivestis, Faustinus cubae, Hylobius pales, Hypera postica, Hypothenemus hampei, Lasioderma serricorne, Leptinotarsa decemlineata, Liogenys fuscus, Liogenys suturalis, Lissorhoptrus oryzophilus, Maecolaspis joliveti, Melanotus communis, Meligethes aeneus, Melolontha melolontha, Oberea brevis, Oberea linearis, Oryctes rhinoceros, Oryzaephilus mercator, Oryzaephilus surinamensis, Oulema melanopus, Oulema oryzae, Phyllophaga cuyabana, Popillia japonica, Prostephanus truncatus, Rhyzopertha dominica,, Sitona lineatus,
Sitophilus granarius, Sitophilus oryzae, Sitophilus zeamais, Stegobium paniceum, Tribolium castaneum, Tribolium confusum, Trogoderma variabile, and Zabrus tenebrioides.
In another embodiment, the molecules of Formula One may be used to control pests of the Order Dermaptera.
In another embodiment, the molecules of Formula One may be used to control pests of the Order Blattaria. A non-exhaustive list of particular species includes, but is not limited to, Blattella germanica, Blatta orientalis, Parcoblatta pennsylvanica, Periplaneta americana, Periplaneta australasiae, Periplaneta brunnea, Periplaneta fuliginosa, Pycnoscelus surinamensis, and Supella longipalpa. In another embodiment, the molecules of Formula One may be used to control pests of the Order Diptera. A non-exhaustive list of particular genera includes, but is not limited to, Aedes spp., Agromyza spp., Anastrepha spp., Anopheles spp., Bactrocera spp., Ceratitis spp., Chrysops spp., Cochliomyia spp., Contarinia spp., Culex spp., Dasineura spp., Delia spp., Drosophila spp., Fannia spp., Hylemyia spp., Liriomyza spp., Musca spp., Phorbia spp., Tabanus spp., and Tipula spp. A non-exhaustive list of particular species includes, but is not limited to, Agromyza frontella, Anastrepha suspensa, Anastrepha ludens, Anastrepha obliqa, Bactrocera cucurbitae, Bactrocera dorsalis, Bactrocera invadens, Bactrocera zonata, Ceratitis capitata, Dasineura brassicae, Delia platura, Fannia canicularis, Fannia scalaris, Gasterophilus intestinalis, Gracillia perseae, Haematobia irritans, Hypoderma lineatum,
Liriomyza brassicae, Melophagus ovinus, Musca autumnalis, Musca domestica, Oestrus ovis, Oscinellafrit, Pegomya betae, Psila rosae, Rhagoletis cerasi, Rhagoletis pomonella, Rhagoletis mendax, Sitodiplosis mosellana, and Stomoxys calcitrans.
In another embodiment, the molecules of Formula One may be used to control pests of the Order Hemiptera. A non-exhaustive list of particular genera includes, but is not limited to, Adelges spp., Aulacaspis spp., Aphrophora spp., Aphis spp., Bemisia spp., Ceroplastes spp., Chionaspis spp., Chrysomphalus spp., Coccus spp., Empoasca spp., Lepidosaphes spp., Lagynotomus spp., Lygus spp., Macrosiphum spp., Nephotettix spp., Nezara spp., Philaenus spp., Phytocoris spp., Piezodorus spp., Planococcus spp.,
Pseudococcus spp., Rhopalosiphum spp., Saissetia spp., Therioaphis spp., Toumeyella spp., Toxoptera spp., Trialeurodes spp., Triatoma spp. and Unaspis spp. A non-exhaustive list of particular species includes, but is not limited to, Acrosternum hilare, Acyrthosiphon pisum, Aleyrodes proletella, Aleurodicus dispersus, Aleurothrixus floccosus, Amrasca biguttula biguttula, Aonidiella aurantii, Aphis gossypii, Aphis glycines, Aphis pomi, Aulacorthum solani, Bemisia argentifolii, Bemisia tabaci, Blissus leucopterus, Brachycorynella asparagi, Brevennia rehi, Brevicoryne brassicae, Calocoris norvegicus, Ceroplastes rubens, Cimex hemipterus, Cimex lectularius, Dagbertus fasciatus, Dichelops furcatus, Diuraphis noxia, Diaphorina citri, Dysaphis plantaginea, Dysdercus suturellus, Edessa meditabunda, Eriosoma lanigerum, Eurygaster maura, Euschistus heros, Euschistus servus, Helopeltis antonii, Helopeltis theivora, Icerya purchasi, Idioscopus nitidulus, Laodelphax striatellus, Leptocorisa oratorius, Leptocorisa varicornis, Lygus hesperus, Maconellicoccus hirsutus, Macrosiphum euphorbiae, Macrosiphum granarium, Macrosiphum rosae, Macrosteles quadrilineatus, Mahanarva jrimbiolata, Metopolophium dirhodum, Mictis longicornis, Myzus persicae, Nephotettix cinctipes, Neurocolpus longirostris, Nezara viridula, Nilaparvata lugens, Parlatoria pergandii, Parlatoria ziziphi, Peregrinus maidis, Phylloxera vitifoliae, Physokermes piceae,, Phytocoris californicus, Phytocoris relativus, Piezodorus guildinii, Poecilocapsus lineatus, Psallus vaccinicola, Pseudacysta perseae, Pseudococcus brevipes, Quadraspidiotus perniciosus, Rhopalosiphum maidis, Rhopalosiphum padi, Saissetia oleae, Scaptocoris castanea, Schizaphis graminum, Sitobion avenae, Sogatella furcifera,
Trialeurodes vaporariorum, Trialeurodes abutiloneus, Unaspis yanonensis, and Zulia entrerriana.
In another embodiment, the molecules of Formula One may be used to control pests of the Order Hymenoptera. A non-exhaustive list of particular genera includes, but is not limited to, Acromyrmex spp., Atta spp., Camponotus spp., Diprion spp., Formica spp., Monomorium spp., Neodiprion spp., Pogonomyrmex spp., Polistes spp., Solenopsis spp., Vespula spp., and Xylocopa spp. A non-exhaustive list of particular species includes, but is not limited to, Athalia rosae, Atta texana, Iridomyrmex humilis, Monomorium minimum, Monomorium pharaonis, Solenopsis invicta, Solenopsis geminata, Solenopsis molesta, Solenopsis richtery, Solenopsis xyloni, and Tapinoma sessile.
In another embodiment, the molecules of Formula One may be used to control pests of the Order Isoptera. A non-exhaustive list of particular genera includes, but is not limited to, Coptotermes spp., Cornitermes spp., Cryptotermes spp., Heterotermes spp., Kalotermes spp., Incisitermes spp., Macrotermes spp., Marginitermes spp., Microcerotermes spp., Procornitermes spp., Reticulitermes spp., Schedorhinotermes spp., and Zootermopsis spp. A non-exhaustive list of particular species includes, but is not limited to, Coptotermes curvignathus, Coptotermes frenchi, Coptotermes formosanus, Heterotermes aureus, Microtermes obesi, Reticulitermes banyulensis, Reticulitermes grassei, Reticulitermes flavipes, Reticulitermes hageni, Reticulitermes hesperus, Reticulitermes santonensis, Reticulitermes speratus, Reticulitermes tibialis, and Reticulitermes virginicus.
In another embodiment, the molecules of Formula One may be used to control pests of the Order Lepidoptera. A non-exhaustive list of particular genera includes, but is not limited to, Adoxophyes spp., Agrotis spp., Argyrotaenia spp., Cacoecia spp., Caloptilia spp., Chilo spp., Chrysodeixis spp., Colias spp., Crambus spp., Diaphania spp., Diatraea spp., Earias spp., Ephestia spp., Epimecis spp., Feltia spp., Gortyna spp., Helicoverpa spp., Heliothis spp., Indarbela spp., Lithocolletis spp., Loxagrotis spp., Malacosoma spp., Peridroma spp., Phyllonorycter spp., Pseudaletia spp., Sesamia spp., Spodoptera spp., Synanthedon spp., and Yponomeuta spp. A non-exhaustive list of particular species includes, but is not limited to, Achaea janata, Adoxophyes orana, Agrotis ipsilon, Alabama argillacea, Amorbia cuneana, Amyelois transitella, Anacamptodes defectaria, Anarsia lineatella, Anomis sabulifera, Anticarsia gemmatalis, Archips argyrospila, Archips rosana, Argyrotaenia citrana, Autographa gamma, Bonagota cranaodes, Borbo cinnara, Bucculatrix thurberiella, Capua reticulana, Carposina niponensis, Chlumetia transversa, Choristoneura rosaceana, Cnaphalocrocis medinalis, Conopomorpha cramerella, Cossus cossus, Cydia caryana, Cydia funebrana, Cydia molesta, Cydia nigricana, Cydia pomonella, Darna diducta, Diatraea saccharalis, Diatraea grandiosella, Earias insulana, Earias vittella, Ecdytolopha aurantianum, Elasmopalpus lignosellus, Ephestia cautella, Ephestia elutella, Ephestia kuehniella, Epinotia aporema, Epiphyas postvittana, Erionota thrax, Eupoecilia ambiguella, Euxoa auxiliaris, Grapholita molesta, Hedylepta indicata, Helicoverpa armigera,
Helicoverpa zea, Heliothis virescens, Hellula undalis, Keiferia lycopersicella, Leucinodes orbonalis, Leucoptera coffeella, Leucoptera malifoliella, Lobesia botrana, Loxagrotis albicosta, Lymantria dispar, Lyonetia clerkella, Mahasena corbetti, Mamestra brassicae, Maruca testulalis, Metisa plana, Mythimna unipuncta, Neoleucinodes elegantalis, Nymphula depunctalis, Operophtera brumata, Ostrinia nubilalis, Oxydia vesulia, Pandemis cerasana, Pandemis heparana, Papilio demodocus, Pectinophora gossypiella, Peridroma saucia, Perileucoptera coffeella, Phthorimaea operculella, Phyllocnistis citrella, Pieris rapae, Plathypena scabra, Plodia interpunctella, Plutella xylostella, Polychrosis viteana, Prays endocarpa, Prays oleae, Pseudaletia unipuncta, Pseudoplusia includens, Rachiplusia nu, Scirpophaga incertulas, Sesamia inferens, Sesamia nonagrioides, Setora nitens, Sitotroga cerealella, Sparganothis pilleriana, Spodoptera exigua, Spodoptera frugiperda, Spodoptera eridania, Thecla basilides, Tineola bisselliella, Trichoplusia ni, Tuta absoluta, Zeuzera coffeae, and Zeuzera pyrina.
In another embodiment, the molecules of Formula One may be used to control pests of the Order Mallophaga. A non-exhaustive list of particular genera includes, but is not limited to, Anaticola spp., Bovicola spp., Chelopistes spp., Goniodes spp., Menacanthus spp., and Trichodectes spp. A non-exhaustive list of particular species includes, but is not limited to, Bovicola bovis, Bovicola caprae, Bovicola ovis, Chelopistes meleagridis, Goniodes dissimilis, Goniodes gigas, Menacanthus stramineus, Menopon gallinae, and Trichodectes canis.
In another embodiment, the molecules of Formula One may be used to control pests of the Order Orthoptera. A non-exhaustive list of particular genera includes, but is not limited to, Melanoplus spp., and Pterophylla spp. A non-exhaustive list of particular species includes, but is not limited to, Anabrus simplex, Gryllotalpa africana, Gryllotalpa australis, Gryllotalpa brachyptera, Gryllotalpa hexadactyla, Locusta migratoria, Microcentrum retinerve, Schistocerca gregaria, and Scudderia furcata.
In another embodiment, the molecules of Formula One may be used to control pests of the Order Siphonaptera. A non-exhaustive list of particular species includes, but is not limited to, Ceratophyllus gallinae, Ceratophyllus niger, Ctenocephalides canis,
Ctenocephalides felis, and Pulex irritans.
In another embodiment, the molecules of Formula One may be used to control pests of the Order Thysanoptera. A non-exhaustive list of particular genera includes, but is not limited to, Caliothrips spp., Frankliniella spp., Scirtothrips spp., and Thrips spp. A non- exhaustive list of particular sp. includes, but is not limited to, Frankliniella fusca,
Frankliniella occidentalis, Frankliniella schultzei, Frankliniella williamsi, Heliothrips haemorrhoidalis, Rhipiphorothrips cruentatus, Scirtothrips citri, Scirtothrips dorsalis, and Taeniothrips rhopalantennalis, Thrips hawaiiensis, Thrips nigropilosus, Thrips orientalis, Thrips t abaci.
In another embodiment, the molecules of Formula One may be used to control pests of the Order Thysanura. A non-exhaustive list of particular genera includes, but is not limited to, Lepisma spp. and Thermobia spp.
In another embodiment, the molecules of Formula One may be used to control pests of the Order Acarina. A non-exhaustive list of particular genera includes, but is not limited to, Acarus spp., Aculops spp., Boophilus spp., Demodex spp., Dermacentor spp., Epitrimerus spp., Eriophyes spp., Ixodes spp., Oligonychus spp., Panonychus spp., Rhizoglyphus spp., and Tetranychus spp. A non-exhaustive list of particular species includes, but is not limited to, Acarapis woodi, Acarus siro, Aceria mangiferae, Aculops lycopersici, Aculus pelekassi, Aculus schlechtendali, Amblyomma americanum, Brevipalpus obovatus, Brevipalpus phoenicis, Dermacentor variabilis, Dermatophagoides pteronyssinus, Eotetranychus carpini, Notoedres cati, Oligonychus coffeae, Oligonychus ilicis, Panonychus citri, Panonychus ulmi, Phyllocoptruta oleivora, Polyphagotarsonemus lotus, Rhipicephalus sanguineus, Sarcoptes scabiei, Tegolophus perseaflorae, Tetranychus urticae, and Varroa destructor.
In another embodiment, the molecules of Formula One may be used to control pest of the Order Symphyla. A non-exhaustive list of particular sp. includes, but is not limited to, Scutigerella immaculata.
In another embodiment, the molecules of Formula One may be used to control pests of the Phylum Nematoda. A non-exhaustive list of particular genera includes, but is not limited to, Aphelenchoides spp., Belonolaimus spp., Criconemella spp., Ditylenchus spp., Heterodera spp., Hirschmanniella spp., Hoplolaimus spp., Meloidogyne spp., Pratylenchus spp., and Radopholus spp. A non-exhaustive list of particular sp. includes, but is not limited to, Dirofilaria immitis, Heterodera zeae, Meloidogyne incognita, Meloidogyne javanica, Onchocerca volvulus, Radopholus similis, and Rotylenchulus reniformis.
For additional information consult "HANDBOOK OF PEST CONTROL - THE
BEHAVIOR, LIFE HISTORY, AND CONTROL OF HOUSEHOLD PESTS" by Arnold Mallis, 9th
Edition, copyright 2004 by GIE Media Inc.
APPLICATIONS
Molecules of Formula One are generally used in amounts from about 0.01 grams per hectare to about 5000 grams per hectare to provide control. Amounts from about 0.1 grams per hectare to about 500 grams per hectare are generally preferred, and amounts from about 1 gram per hectare to about 50 grams per hectare are generally more preferred.
The area to which a molecule of Formula One is applied can be any area inhabited (or maybe inhabited, or traversed by) a pest, for example: where crops, trees, fruits, cereals, fodder species, vines, turf and ornamental plants, are growing; where domesticated animals are residing; the interior or exterior surfaces of buildings (such as places where grains are stored), the materials of construction used in building (such as impregnated wood), and the soil around buildings. Particular crop areas to use a molecule of Formula One include areas where apples, corn, sunflowers, cotton, soybeans, canola, wheat, rice, sorghum, barley, oats, potatoes, oranges, alfalfa, lettuce, strawberries, tomatoes, peppers, crucifers, pears, tobacco, almonds, sugar beets, beans and other valuable crops are growing or the seeds thereof are going to be planted. It is also advantageous to use ammonium sulfate with a molecule of Formula One when growing various plants.
Controlling pests generally means that pest populations, pest activity, or both, are reduced in an area. This can come about when: pest populations are repulsed from an area; when pests are incapacitated in or around an area; or pests are exterminated, in whole, or in part, in or around an area. Of course, a combination of these results can occur. Generally, pest populations, activity, or both are desirably reduced more than fifty percent, preferably more than 90 percent. Generally, the area is not in or on a human; consequently, the locus is generally a non-human area.
The molecules of Formula One may be used in mixtures, applied simultaneously or sequentially, alone or with other compounds to enhance plant vigor (e.g. to grow a better root system, to better withstand stressful growing conditions). Such other compounds are, for example, compounds that modulate plant ethylene receptors, most notably 1- methylcyclopropene (also known as 1-MCP). Furthermore, such molecules may be used during times when pest activity is low, such as before the plants that are growing begin to produce valuable agricultural commodities. Such times include the early planting season when pest pressure is usually low.
The molecules of Formula One can be applied to the foliar and fruiting portions of plants to control pests. The molecules will either come in direct contact with the pest, or the pest will consume the pesticide when eating leaf, fruit mass, or extracting sap, that contains the pesticide. The molecules of Formula One can also be applied to the soil, and when applied in this manner, root and stem feeding pests can be controlled. The roots can absorb a molecule taking it up into the foliar portions of the plant to control above ground chewing and sap feeding pests.
Generally, with baits, the baits are placed in the ground where, for example, termites can come into contact with, and/or be attracted to, the bait. Baits can also be applied to a surface of a building, (horizontal, vertical, or slant surface) where, for example, ants, termites, cockroaches, and flies, can come into contact with, and/or be attracted to, the bait. Baits can comprise a molecule of Formula One.
The molecules of Formula One can be encapsulated inside, or placed on the surface of a capsule. The size of the capsules can range from nanometer size (about 100-900 nanometers in diameter) to micrometer size (about 10-900 microns in diameter).
Because of the unique ability of the eggs of some pests to resist certain pesticides, repeated applications of the molecules of Formula One may be desirable to control newly emerged larvae.
Systemic movement of pesticides in plants may be utilized to control pests on one portion of the plant by applying (for example by spraying an area) the molecules of Formula One to a different portion of the plant. For example, control of foliar- feeding insects can be achieved by drip irrigation or furrow application, by treating the soil with for example pre- or post-planting soil drench, or by treating the seeds of a plant before planting.
Seed treatment can be applied to all types of seeds, including those from which plants genetically modified to express specialized traits will germinate. Representative examples include those expressing proteins toxic to invertebrate pests, such as Bacillus thuringiensis or other insecticidal toxins, those expressing herbicide resistance, such as "Roundup Ready" seed, or those with "stacked" foreign genes expressing insecticidal toxins, herbicide resistance, nutrition-enhancement, drought resistance, or any other beneficial traits.
Furthermore, such seed treatments with the molecules of Formula One may further enhance the ability of a plant to better withstand stressful growing conditions. This results in a healthier, more vigorous plant, which can lead to higher yields at harvest time. Generally, about 1 gram of the molecules of Formula One to about 500 grams per 100,000 seeds is expected to provide good benefits, amounts from about 10 grams to about 100 grams per 100,000 seeds is expected to provide better benefits, and amounts from about 25 grams to about 75 grams per 100,000 seeds is expected to provide even better benefits.
It should be readily apparent that the molecules of Formula One may be used on, in, or around plants genetically modified to express specialized traits, such as Bacillus thuringiensis or other insecticidal toxins, or those expressing herbicide resistance, or those with "stacked" foreign genes expressing insecticidal toxins, herbicide resistance, nutrition- enhancement, or any other beneficial traits.
The molecules of Formula One may be used for controlling endoparasites and ectoparasites in the veterinary medicine sector or in the field of non-human animal keeping. The molecules of Formula One are applied, such as by oral administration in the form of, for example, tablets, capsules, drinks, granules, by dermal application in the form of, for example, dipping, spraying, pouring on, spotting on, and dusting, and by parenteral administration in the form of, for example, an injection.
The molecules of Formula One may also be employed advantageously in livestock keeping, for example, cattle, sheep, pigs, chickens, and geese. They may also be employed advantageously in pets such as, horses, dogs, and cats. Particular pests to control would be fleas and ticks that are bothersome to such animals. Suitable formulations are administered orally to the animals with the drinking water or feed. The dosages and formulations that are suitable depend on the species.
The molecules of Formula One may also be used for controlling parasitic worms, especially of the intestine, in the animals listed above.
The molecules of Formula One may also be employed in therapeutic methods for human health care. Such methods include, but are limited to, oral administration in the form of, for example, tablets, capsules, drinks, granules, and by dermal application.
Pests around the world have been migrating to new environments (for such pest) and thereafter becoming a new invasive species in such new environment. The molecules of Formula One may also be used on such new invasive species to control them in such new environment.
The molecules of Formula One may also be used in an area where plants, such as crops, are growing (e.g. pre-planting, planting, pre-harvesting) and where there are low levels (even no actual presence) of pests that can commercially damage such plants. The use of such molecules in such area is to benefit the plants being grown in the area. Such benefits, may include, but are not limited to, improving the health of a plant, improving the yield of a plant (e.g. increased biomass and/or increased content of valuable ingredients), improving the vigor of a plant (e.g. improved plant growth and/or greener leaves), improving the quality of a plant (e.g. improved content or composition of certain ingredients), and improving the tolerance to abiotic and/or biotic stress of the plant.
Before a pesticide can be used or sold commercially, such pesticide undergoes lengthy evaluation processes by various governmental authorities (local, regional, state, national, and international). Voluminous data requirements are specified by regulatory authorities and must be addressed through data generation and submission by the product registrant or by a third party on the product registrant's behalf, often using a computer with a connection to the World Wide Web. These governmental authorities then review such data and if a determination of safety is concluded, provide the potential user or seller with product registration approval. Thereafter, in that locality where the product registration is granted and supported, such user or seller may use or sell such pesticide.
A molecule according to Formula One can be tested to determine its efficacy against pests. Furthermore, mode of action studies can be conducted to determine if said molecule has a different mode of action than other pesticides. Thereafter, such acquired data can be disseminated, such as by the internet, to third parties.
The headings in this document are for convenience only and must not be used to interpret any portion hereof.
TABLE SECTION
Figure imgf000259_0001
Table 1: Structures for Compounds
Figure imgf000259_0002
Figure imgf000260_0001
Figure imgf000261_0001
Figure imgf000262_0001
Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000267_0001
AC54
AC57
AC58
AC59
AC60
AC61
Figure imgf000269_0001
Figure imgf000270_0001
Figure imgf000271_0001
Figure imgf000272_0001
Figure imgf000273_0001
Figure imgf000274_0001
AC105
AC106
AC107
AC108
AC109
Figure imgf000276_0001
Figure imgf000277_0001
Figure imgf000278_0001
BC9
BCIO
BC11
BC12
BC13
BC14
Figure imgf000280_0001
Figure imgf000281_0001
Figure imgf000282_0001
Figure imgf000283_0001
Figure imgf000284_0001
Figure imgf000285_0001
Figure imgf000286_0001
Figure imgf000287_0001
Figure imgf000288_0001
Figure imgf000289_0001
Figure imgf000290_0001
Figure imgf000291_0001
Figure imgf000292_0001
Figure imgf000293_0001
Figure imgf000294_0001
Figure imgf000295_0001
Figure imgf000296_0001
Figure imgf000297_0001
Figure imgf000298_0001
Figure imgf000299_0001
Table 1A: Structures of Subsequently Exemplified Prophetic Compounds
Figure imgf000300_0001
Figure imgf000301_0001
Table IB: Structures for Intermediate Compounds
Figure imgf000301_0002
Figure imgf000302_0001
Table 2: Analytical Data for Compounds in Table 1.
Figure imgf000302_0002
7.67 (s, 3H), 7.64 (d,7 =
8.0 Hz, 2H), 7.42 (d, 7 =
8.0 Hz, 2H), 6.91 (dd, 7
444.12
AC5 = 15.6, 8.0 Hz, IH),
«M+H]+)
6.80 (d,7 = 15.6 Hz,
IH), 4.80 (m, IH), 3.60
(br s, 8H)
7.40 (m, 2H), 7.26 (m,
3H), 6.56 (d,7 = 16.0
468.40 Hz, IH), 6.48 (dd, 7 = 1657, 1113,
AC6
([M-H]-) 16.0, 8.0 Hz, IH), 5.82 804
(br s, IH), 4.08 (m, 3H),
2.52 (s, 3H)
8.39 (s, IH), 7.74 (m,
IH), 7.39 (m, 3H), 7.24
(m, 4H), 6.58 (d, 7 =
511.02 16.0 Hz, IH), 6.38 (dd, 3276, 1645,
AC7
([M-H]) 7 = 16.0, 8.0 Hz, IH), 1111,801
6.16 (brs, IH), 4.63 (m,
2H),4.12 (m, IH), 2.41
(s, 3H)
7.39 (s, IH), 7.22 (m,
2H),7.19(m, 3H), 6.53
(d,7 = 16.0 Hz, IH),
6.39-6.34 (dd,7 = 16.0,
454.11 1748, 1112,
AC8 8.0 Hz, IH), 4.22 (m,
([M-H]") 801
IH), 3.95 (t, 7 = 7.0 Hz,
2H),2.62 (t, 7=8.0 Hz,
2H),2.30 (s, 3H),2.18
(m, 2H)
7.45 (t, 7 = 7.6 Hz, IH),
7.36 (m, 2H), 7.21 (m,
3H),7.15 (m, 4H), 6.56
(d,7= 16.0 Hz, IH),
494.02 3276, 1645,
AC9 6.38 (dd, 7= 16.0, 8.4
([M-H]") 1112, 801
Hz, IH), 6.08 (br s, IH),
4.68 (d, 7 =5.6 Hz, 2H),
4.11 (m, 1H),2.44 (s,
3H) 7.38 (t,/ = 1.6 Hz, 1H),
7.34 (d, 7=7.6 Hz, 1H),
7.27 (m, 2H), 7.24 (m,
2H), 6.57 (d,/ = 16.0
140- 458.00 Hz, 1H), 6.40 (dd, / =
A10
143 ([M-H]-) 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)
7.39-7.29 (m, 9H), 7.24
(m, 2H), 6.56 (d,/ =
16.0 Hz, 1H), 6.38 (dd,
476.17 3287, 1644,
AC11 / = 16.0, 8.0 Hz, 1H),
([M-H]") 1112, 801
5.99 (br s, 1H), 4.63 (d,
7=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+H]+) 6.58 (d,/= 16.0 Hz, 1112, 800
1H), 6.40 (dd,/= 16.0,
8.0 Hz, 1H), 4.75 (d,/ =
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,/= 16.0 Hz,
1H), 6.45 (m 1H), 6.42
490.04
AC13 75-78 (dd,/= 16.0, 8.4 Hz,
([M-H]")
1H), 4.91 (m 1H), 4.64
(m, 2H), 4.14 (m, 1H),
4.04 (m, 2H), 2.46 (s,
3H)
8.63 (s,2H), 7.76 (d,/ =
8.0 Hz, 1H), 7.36 (m,
3H), 7.22 (m, 1H), 7.13
480.99 (m, 2H), 6.57 (d,/ =
3293, 1645,
AC14 ([M+2H]+ 16.0 Hz, 1H), 6.39 (dd,
1113,800
) /= 16.0, 8.0 Hz, 1H),
6.13 (brs, 1H), 4.66 (d,
7=5.6 Hz, 2H), 4.11
(m, 1H), 2.46 (s, 3H) 7.45 (s, IH), 7.37 (m,
IH), 7.34 (m, IH), 7.26
(m, 3H), 7.22 (m, IH),
6.57 (d, 7 = 16.0 Hz,
516.86 3246, 1635,
AC15 59-61 IH), 6.40 (dd, 7 = 16.0,
([M-H]-) 1112, 801
8.0 Hz, IH), 6.18 (m,
IH), 4.71 (d, 7 = 6.4 Hz,
2H), 4.11 (m, IH), 2.46
(s, 3H)
8.47 (m, IH), 8.19 (s,
IH), 7.76 (m, IH), 7.47
(m, 2H), 7.37 (m, IH),
7.28 (m, 2H), 7.24 (m,
506.93 IH), 7.21 (m, IH), 6.59 1657, 1113,
AC16
([M+H]+) (d, 7 = 16.0 Hz, IH), 801
6.39 (dd, 7 = 16.0, 8.4
Hz, IH), 4.12 (m, IH),
2.48 (s, 3H), 1.88 (s,
6H)
7.49 (m, 2H), 7.38 (m,
IH), 7.29 (m, 4H), 7.08
(m, 3H), 6.91 (m, IH),
494.98 6.61 (d, 7 = 16.0 Hz,
AC17 70-73
([M-H]") IH), 6.48 (m, IH), 6.43
(dd, 7 = 16.0, 8.0 Hz,
lH), 4.13 (m, IH), 2.49
(s, 3H)
8.73 (d, 7 = 4.8 Hz, 2H),
7.53 (d, 7 = 8.4 Hz, IH),
7.37 (m, IH), 7.27 (m,
4H), 7.23 (m, IH), 7.11
155- 480.44 (m, IH), 6.60 (d, 7 =
AC18
158 «M+H]+) 16.0 Hz, IH), 6.41 (dd,
7 = 16.0, 8.0 Hz, IH),
4.90 (d, 7 = 4.8 Hz, 2H),
4.13 (m, 1H), 2.52 (s,
3H) 7.37 (m, IH), 7.33 (d, J
= 7.6 Hz, IH), 7.27 (m,
2H), 7.22 (m, 2H), 6.57
(d,/ = 16.0 Hz, IH),
6.39 (dd, 7=16.0, 8.0
471.66
AC19 55-57 Hz, IH), 6.10 (brs, IH),
([Μ+ΗΓ)
4.13 (m, 2H), 3.94 (m,
IH), 3.79 (m, 2H), 3.35
(m, IH), 2.45 (s, 3H),
2.14 (m, IH), 1.71 (m,
2H), 1.65 (m, IH).
7.37 (m, 2H), 7.27 (m,
2H), 7.23 (m, 2H), 6.57
(d,/ = 16.0 Hz, IH), 3437, 1664,
467.68
AC20 6.38 (m, 3H), 6.01 (m, 1265, 1114,
«M+H]+)
1H),4.63 (d, 7=5.6 Hz, 746 2H),4.13(m, IH), 2.45
(s, 3H)
8.44 (s, IH), 8.18 (s,
IH), 7.83 (br s, IH),
7.38 (m, 2H), 7.27 (m,
2H), 7.25 (m, 2H), 7.21
528.78
AC21 61-64 (m, IH), 6.57 (d,/ =
«M+H]+)
16.0 Hz, IH), 6.40 (dd,
/= 16.0, 8.0 Hz, IH),
5.01 (s,2H), 4.11 (m,
IH), 2.43 (s, 3H)
8.39 (s, IH), 7.73 (m,
IH), 7.40 (s, IH), 7.35
(m, 2H), 7.22 (m, 3H),
6.57 (d,/ = 16.0 Hz,
545.08 3270, 1642,
AC22 IH), 6.38 (dd,/= 16.0,
([M-H]-) 1111,809
7.6 Hz, IH), 6.14 (brs,
1H),4.62 (d, 7=6.0 Hz,
2H),4.13(m, IH), 2.45
(s, 3H)
7.42 (s, 2H), 7.36 (m,
IH), 7.24 (m, 2H), 6.59
(d,/= 16.0 Hz, IH),
3273, 1641,
492.35 6.40 (dd,/= 16.0, 8.0
AC23 1250, 1113,
([M-H]) Hz, IH), 6.20 (br s, IH),
807 5.46 (m, 1H),4.15 (m,
IH), 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, IH),
129- 526.98 6.48(dd,7 = 16.0,8.0 3298, 1664,
AC24
132 ([Μ+ΗΓ) Hz, 1H),4.19 (d,7 = 1113,803
5.2, 2H), 4.08 (m, IH),
3.99 (m, 2H), 2.46 (s,
3H)
7.41 (m, 3H), 7.27 (m,
2H), 6.58 (d,7 = 15.6
3257, 1652,
542.24 Hz, IH), 6.42 (m, 2H),
AC25 1316, 1109,
([M-H]) 4.92 (m, IH), 4.65 (m,
807 2H),4.14 (m, IH), 4.09
(m, 2H), 2.46 (s, 3H)
7.45 (s, IH), 7.40 (s,
2H),7.34 (d, 7=8.0 Hz,
IH), 7.22 (m, 2H), 6.54
550.69 (d,7 = 16.0 Hz, IH), 3255, 1638,
AC26
([M-H]") 6.38 (dd, 7=16.0, 8.0 1113,809
Hz, IH), 4.71 (d, 7 = 6.0
Hz, 2H), 4.11 (m, IH),
2.46 (s, 3H)
8.46 (d, 7 = 4.0 Hz, IH),
8.20 (s, IH), 7.76 (m,
IH), 7.47 (m, 2H), 7.41
(s, 2H), 7.23 (m, 2H),
541.00 1653, 1113,
AC27 7.21 (m, IH), 6.59 (d, 7
([M-H]") 809
= 16.0 Hz, IH), 6.37
(dd,7= 16.0, 8.4 Hz,
1H),4.11 (m, IH), 2.48
(s, 3H), 1.88 (s, 6H)
8.40 (s, IH), 7.74 (m,
2H), 7.42 (m, 3H), 7.36
(m, 2H), 6.72 (br s, IH),
564.84 6.52 (d,7= 16.0 Hz, 3267,1650,
AC28 65-67
([M-H]) IH), 6.43 (dd,7=16.0, 1112, 809
8.0 Hz, IH), 4.66 (d,7 =
6.4 Hz, 2H), 4.12 (m,
IH) 7.71 (d,/ = 8.4 Hz, IH),
7.42 (m, 3H), 7.35 (m, IH), 6.75 (br s, IH),
511.78 6.56 (d,/ = 16.0 Hz,
AC29 75-78
([M-H]-) IH), 6.43 (dd,/ = 16.0,
8.0 Hz, IH), 5.49 (m, 1H),4.14 (m, IH), 3.50 (m, 4H)
7.42 (d, 7=8.4 Hz, IH), 7.44 (s, IH), 7.40 (s, IH), 7.38 (m, IH), 7.06
110- 543.72 (brs, IH), 6.58 (d,/ =
AC30
113 ([M-H]) 15.6 Hz, IH), 6.45 (dd,
/ = 15.6, 8.0 Hz, IH), 4.93 (m, IH), 4.65 (m, 2H),4.13(m, 3H)
8.42 (s, IH), 7.76 (m, IH), 7.61 (m, 2H), 7.39
610.73
AC31 68-70 (m, 4H), 6.54 -6.39 (m,
([M+H]+)
3H),4.66 (d, 7=6.0 Hz, 2H),4.12 (m, IH)
7.61 (m, 2H), 7.40 (m, 3H), 6.54 (m, 2H), 6.40
555.89
AC32 78-80 (dd,/= 16.0, 8.0 Hz,
([M-H]")
IH), 5.46 (m, IH), 4.14 (m, IH), 3.50 (m, 4H)
7.62 (s, IH), 7.58 (d,/ = 8.0 Hz, IH), 7.40 (m, 3H), 6.84 (br s, IH),
182- 587.68 6.55 (d,/= 15.6 Hz,
AC33
184 ([M-H]") IH), 6.45 (dd, 7=15.6,
7.6 Hz, IH), 4.93 (m 1H),4.65 (m, 2H), 4.13 (m, 4H)
7.67 (s, IH), 7.61 (d,/ = 6.0 Hz, IH), 7.53 (m, IH), 7.41 (s, 2H), 6.64 (d,/= 16.0 Hz, IH),
151- 545.83
AC34 6.40 (dd,/= 16.0, 8.0
153 ([M-H])
Hz, IH), 6.18 (brs, IH), 5.44 (m, lH),4.14(m, IH), 3.50 (m, 2H), 3.40 (m, 2H) 7.70 (s, IH), 7.63 (m,
1H),7.53 (d, 7 = 7.6 Hz,
IH), 7.41 (s, 2H), 6.53
100- 577.71 3257, 1655,
AC35 (d,7 = 16.0 Hz, IH),
102 ([M-H]) 1113,808
6.49 (m, 2H), 4.93 (m,
1H),4.64 (m, 2H), 4.13
(m, IH), 4.03 (m, 2H)
8.40 (s, IH), 7.73 (m,
2H), 7.61 (d, 7=8.4 Hz,
1H),7.52 (d, 7=8.0 Hz,
IH), 7.40 (s, 2H), 7.35
600.83 (d, 7 = 8.0 Hz, IH), 6.63
AC36 81-83
([M+H]+) (d,7= 16.0 Hz, IH),
6.46 (dd,7= 16.0,7.6
Hz, IH), 6.14 (m, IH),
4.63 (d, 7 =6.0 Hz, 2H),
4.14 (m, IH)
8.39 (s, IH), 7.73 (m,
IH), 7.48 (m, 2H), 7.34
(d, 7 = 7.6 Hz, IH), 7.24
(m, 3H), 6.55 (d, 7 =
512.68 3268, 1644,
AC37 16.0 Hz, IH), 6.41 (dd,
([M+H]+) 1109,820
7= 16.0, 7.6 Hz, IH),
6.12 (m, 1H),4.62 (d, 7
= 6.0 Hz, 2H), 4.13 (m,
IH), 2.45 (s, 3H)
8.46 (m, IH), 7.73 (m,
IH), 7.35 (m, 4H), 7.22
(m, 2H), 6.56 (d, 7 =
528.85 16.0 Hz, IH), 6.38 (dd,
AC38 79-80
([M-H]") 7= 16.0, 8.0 Hz, IH),
4.62 (d, 7 =6.0 Hz, 2H),
4.10 (m, 1H),2.45 (s,
3H)
9.19 (s, IH), 8.79 (s,
2H), 7.37 (m, 2H), 7.23
(m, 2H), 7.21 (m, IH),
6.57 (d,7= 16.0 Hz,
141- 477.83
AC39 IH), 6.40 (dd,7= 16.0,
144 ([M-H]") 7.6 Hz IH), 6.21 (m,
1H),4.65 (s, 2H),4.11
(m, IH), 2.46 (s, 3H) 8.33 (t, 7 = 5.6 Hz, 1H),
8.61 (m, 1H), 7.68 (m,
3H), 7.48 (m, 2H), 6.86
(dd, 7 = 15.6, 8.2 Hz
484.67 1H), 6.74 (d, 7 = 15.6
AC40 69-72
«M+H]+) Hz, 1H), 4.44 (m, 1H),
3.76 (d, 7 = 6.0 Hz, 2H),
2.54 (m, 1H), 2.67 (s,
3H), 0.59 (m, 2H), 0.54
(m, 2H)
8.66 (d, 7 = 7.6 Hz, 1H),
8.39 (t, 7 = 5.6 Hz, 1H),
7.65 (s, 3H), 7.45 (m,
3H), 6.86 (dd, 7 = 15.6,
196- 515.00 8.8 Hz, 1H), 6.74 (d, 7 =
AC41
199 ([M-H] ) 15.6 Hz, 1H), 5.01 (m,
1H), 4.99 (m, 1H), 3.78
(d, 7 = 6.0 Hz, 2H), 3.40
(m, 2H), 3.22 (m, 2H),
2.37 (m, 3H)
7.99 (d, 7 = 8.0 Hz,
1H), 7.89 (d, 7 = 8.0 Hz,
1H), 7.51 (m, 2H), 7.44
(m, 2H), 7.27 (m, 4H),
534.72 6.71 (t, 7 = 5.2 Hz, 1H),
AC42 79-82
«M+H]+) 6.59 (d, 7 = 16.0 Hz,
1H), 6.41 (dd, 7 = 16.0,
8.0 Hz, 1H), 5.05 (d, 7 =
1.6 Hz, 2H), 4.12 (m,
1H), 2.52 (m, 3H)
8.69 (s, 1H), 8.52 (s,
2H), 7.45 (d, 7 = 7.6 Hz,
1H), 7.37 (d, 7 = 2.0 Hz,
1H), 7.26 (m, 2H), 7.21
481.75 1663,
(m, 1H), 6.83 (s, 1H),
AC43 1608,1168,
([M+H]+) 6.58 (d, 7 = 16.0 Hz,
1114, 801 1H), 6.40 (dd, 7 = 16.0,
8.4 Hz, 1H), 4.81 (d, 7 =
5.6 Hz, 2H), 4.12 (t, 7 =
8.4 Hz 1H), 2.45 (s, 3H) 8.44 (d, J =2.4 Hz, IH),
7.69 (d, J =2.4 Hz, IH),
7.37 (m, IH), 7.33 (s,
1H),7.31 (s, 1H),7.26
(m, IH), 7.24 (m, 3H),
528.01 6.57 (d,7 = 16.0 Hz,
1640, 1166,
AC44 IH), 6.39 (dd,7 = 16.0,
([Μ+ΗΓ) 1112, 800
8.0 Hz, IH), 5.96 (d,7 =
7.2 Hz, IH), 5.32 (t,7 =
7.2 Hz, IH), 4.11 (t, 7 =
8.4 Hz, IH), 2.41 (s,
3H), 1.61 (d, 7 = 7.2 Hz,
3H)
7.66 (s, IH), 7.37 (d,7 =
6.8 Hz, 2H), 7.26 (m,
3H), 7.18(m, IH), 7.11
512.88 (m, 2H), 6.99 (m, IH),
1657, 1167,
AC45 6.57 (d,7 = 15.6 Hz,
«M+H]+) 1106, 800
IH), 6.39 (dd,7 = 15.6,
8.0 Hz, IH), 4.11 (t, 7 =
8.4 Hz, IH), 3.36 (s,
3H), 2.43 (s, 3H)
8.42 (d, J = 2.0 Hz, IH),
7.76 (d, J = 2.4 Hz, IH),
7.61 (m, 2H), 7.39 (m,
575.93 3H), 7.26 (s, 2H), 6.54
AC46 61-64
«M+H]+) (d,7 = 16.0 Hz, IH),
6.42 (dd,7 = 16.0,7.6
Hz, 1H),4.65 (d, 7 = 6.0
Hz, 2H), 4.14 (m, IH)
10.02 (s, IH), 9.87 (s,
IH), 8.47 (t, 7=6.0 Hz,
IH), 7.66 (s, 3H), 7.44
(s, IH), 7.40 (d,7=3.6
525.89 Hz, 2H), 6.86 (dd,7 =
AC47 15.6, 9.2 Hz, IH), 6.74 3280, 1640
([M-H]-) (d,7= 15.6 Hz, IH),
4.82 (t,7 = 9.6 Hz, 2H),
3.88 (d, 7 =6.0 Hz, 2H),
2.36 (s, 3H), 1.63 (m,
IH), 0.76 (m, 4H) 7.37 (m, 7H), 7.34 (m,
3H), , 6.57 (d, J = 16.0
509.96 Hz, 1H), 6.39 (dd, / =
AC48 16.0, 8.0 Hz, 1H), 6.01 3275, 1642
([M-H]-) (m, 1H), 4.60 (d, 7 = 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
«M+H]+) (d, / = 16.0 Hz, 1H), 1025, 2219
6.47 (dd, / = 16.0, 8.0
Hz, 1H), 4.66 (d, 7 = 5.6
Hz, 2H), 4.14 (m, 1H)
8.72 (m, 1H), 7.67 (s,
3H), 7.46 (s, 1H), 7.40
481.88 (m, 2H), 7.08 (s, 1H),
1654, 1112,
AC50 6.82 (m, 2H), 6.55 (d, J
([M+H]+) 800, 3069
= 7.6 Hz, 1H), 4.82 (m,
1H), 4.48 (s, 2H), 3.65
(s, 3H), 2.38 (s, 3H)
7.45 (d, 7 = 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, / = 1652, 1571,
AC51 16.0 Hz, 1H), 6.40 (dd, 802, 1114,
«M+H]+) / = 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, / = 15.6
Hz, 1H), 6.37 (dd, / =
15.6, 8.0 Hz, 1H), 5.61
488.29 (d, 7 = 8.0 Hz, 1H), 4.21 1635, 11134,
AC52
([M-H] ) (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) 8.49 (d, J =2.0 Hz, IH),
7.69 (d, J =2.4 Hz, IH),
7.43 (d, 7=8.0 Hz, IH),
7.34 (m, 3H), 7.26 (m,
532.92 2H), 6.95 (m, IH), 6.58 1651, 3027,
AC53
([Μ+ΗΓ) (d,7 = 16.0 Hz, IH), 815, 1113
6.38 (dd, 7=16.0, 8.0
Hz, IH), 4.72 (d, 7=5.2
Hz, 2H), 4.09 (m, IH),
2.47 (s, 3H)
8.37 (d, 7 =5.2 Hz, IH),
7.41 (d, 7 =8.0 Hz, IH),
7.36 (m, 3H),7.31 (m,
IH), 7.26 (m, 2H), 6.58
529.06 (d,7= 16.0 Hz, IH), 1654, 3434,
AC54
([M-H]) 6.40 (dd,7= 16.0,7.6 814, 1112
Hz, IH), 5.20 (t,7=5.6
Hz, 1H),4.63 (d,7 = 6.0
Hz, 2H), 4.13 (m, IH),
2.18 (s,3H)
8.69 (t,7 = 6.0 Hz, IH),
8.58 (t, 7 = 6.0 Hz, IH),
7.92 (s, IH), 7.87 (d,7 =
6.4 Hz, 2H), 7.62 (d, 7 =
8.4 Hz, IH), 7.45 (d, 7 =
464.96 8.4 Hz, IH), 7.0 (m, 3417, 1658,
AC57
([M+H]+) IH), 6.76 (d,7= 15.6 1165,817
Hz, IH), 6.76 (dd, 7 =
15.6, 8.0 Hz, IH), 4.01
(m, 7 =8.0 Hz, IH),
3.71 (m, 2H), 3.49 (m,
2H)
7.62 (m, 2H), 7.40 (s,
2H), 7.37 (d, 7= 1.6 Hz,
IH), 6.61 (t, 7 = 4.8 Hz,
124.4- 599.76 IH), 6.55 (d, 7= 16.0
AC58
126.9 «M+H]+) Hz, IH), 6.41 (dd, 7 =
16.0, 7.6 Hz, IH), 4.16
(d, 7 = 6.0 Hz, 2H), 4.01
(m, IH), 1.56 (s, 9H) 8.42 (d, 7 = 2.1 Hz, IH),
8.29 (d, 7 = 7.5 Hz, IH),
7.51 (m, 2H), 7.39 (m,
497.40 IH), 7.36 (m, 4H), 7.28
AC59 80-83 (m, IH), 6.61 (d,7 =
([M-H]-) 15.9 Hz, IH), 6.45 (dd,
7= 15.9, 7.8 Hz IH),
4.14 (t, 7 = 8.4 Hz, IH),
2.51 (s, 3H)
8.52 (s, IH), 8.39 (d, 7 =
1.8 Hz, 2H), 7.70 (d, 7 =
2.1Hz, IH), 7.62 (s,
IH), 7.43 (s, IH), 7.35
515.09 1668, 1589,
(m, 3H), 6.62 (d,7 =
AC60 1167, 1113,
([M+H]-) 16.2 Hz, IH), 6.52 (dd,
802 7= 16.2, 7.5 Hz, IH),
4.62 (d, 7 =6.3 Hz, 2H),
4.19 (m, 1H),2.76 (s,
3H)
8.07 (t, 7 = 8.0 Hz, IH),
7.39 (t, 7 = 2.0 Hz, IH),
7.28 (d, 7= 1.2 Hz, 3H),
7.17 (d, 7= 1.6 Hz, IH),
461.90 7.11 (m, IH), 6.59 (d, 7 1658, 1114,
AC61
([M-H]") = 15.6 Hz, IH), 6.47 801
(dd,7= 15.6, 7.6 Hz,
IH), 5.49 (m, IH), 4.14
(t,7=8.4 Hz, IH), 3.48
(m, 4H)
8.62 (t,7 = 6.4 Hz, IH),
8.46 (m, IH), 7.73 (m,
5H),7.48 (d,7 = 7.6 Hz,
105- 528.88
AC62 1H),7.03 (dd,7= 15.6,
108 ([M-H]) 9.2 Hz, IH), 6.81 (d, J =
15.6 Hz, IH), 4.86 (m,
IH), 3.97 (m, 4H)
8.43 (s, IH), 7.76 (d,7 =
2.4 Hz, IH), 7.60 (m,
2H),7.38 (d,7 = 7.6 Hz,
594.67 1H),7.33 (d,7=6.4 Hz,
AC63 77-80 3H), 6.54 (d,7= 16.0 3257, 1653
([M+H]+) Hz, IH), 6.46 (m, IH),
6.41 (dd,7= 16.08.0
Hz, 1H),4.65 (d,7 = 6.0
Hz, 2H), 4.15 (m, IH) 7.72 (d, 7=8.0 Hz, IH),
7.44 (s, IH), 7.40 (s,
2H),7.36 (d, 7=6.8 Hz,
1H),7.05 (t, 7 =5.2 Hz,
580.72 IH), 6.70 (t, 7 =5.2 Hz,
AC64 83-85
([M-H]-) IH), 6.57 (d,7= 15.6
Hz, IH), 6.44 (dd, 7 =
15.6, 8.0 Hz, IH), 4.23
(d, 7 = 5.6 Hz, 2H), 4.15
(m, IH), 4.01 (m, 2H)
8.39 (d, 7 = 2.0 Hz, IH),
8.12 (t, 7 = 8.4 Hz, IH),
7.71 (d, 7 = 2.4 Hz, IH),
534.72 7.34 (m, 3H), 7.26 (m,
1658, 1113,
AC65 1H),7.11 (m, 2H), 6.59
([M-H]") 817, 2925
(d,7= 16.0 Hz, IH),
6.46 (dd,7= 16.0, 8.0
Hz, 1H),4.66 (d,7 = 5.2
Hz, 2H), 4.13 (m, IH)
7.88 (s, IH), 7.63 (d,7 =
1.6 Hz, IH), 7.57 (d, 7 =
8.0 Hz, IH), 7.40 (m,
2H), 6.80 (t, 7 =5.6 Hz,
624.61 IH), 6.70 (t, 7 =5.6 Hz,
AC66 73-75
([M-H]") IH), 6.56 (d,7= 16.0
Hz, IH), 6.44 (dd, 7 =
16.0, 8.0 Hz, IH), 4.22
(m, 2H), 4.12 (m, IH),
4.01 (m, 2H)
8.07 (t,7 = 8.0 Hz, IH),
7.34 (d, 7 =6.0 Hz, 2H),
7.28 (s, IH), 7.17(s,
479.82 2H), 6.59 (d,7= 15.6
AC67 3272, 1644
([M-H]") Hz, IH), 6.46 (dd, 7 =
15.6, 8.0 Hz, IH), 5.49
(m, IH), ,4.12 (m, IH),
3.49 (m, 4H). 8.6 (t, 7=6.4 Hz, IH),
8.45 (m, IH), 7.86 (d, 7
= 6.4 Hz, 2H), 7.75 (t, 7
= 8.0 Hz, IH), 7.63 (d, 7
546.80 = 12.0 Hz, IH), 7.48 (d,
AC68 90-93 3315, 1684
([M-H]-) 7 =8.0 Hz, 1H),7.03
(dd,7= 15.6, 9.6 Hz,
IH), 6.80 (d,7= 15.6
Hz, IH), 4.88 (m, IH),
3.96 (m, 4H)
7.41 (d, 7 =8.0 Hz, IH),
7.34 (d, 7 =5.6 Hz, 2H),
7.26 (m, IH), 7.23 (m,
IH), 6.81 (s, IH), 6.57
542.82 (d,7= 15.6 Hz, IH),
AC69 3294, 1685
([M-H]") 6.55 (s, IH), 6.39 (dd, 7
= 15.6, 8.0 Hz, IH),
4.18 (m, 2H),4.13(m,
IH), 3.97 (m, 2H), 2.46
(s, 3H)
8.38 (d, 7 = 2.4 Hz, IH),
8.22 (d, 7 =6.8 Hz, 2H),
7.71 (d, 7 = 2.4 Hz, IH),
7.35 (d, 7 =6.0 Hz, 2H),
7.30 (d, 7 = 7.6 Hz, IH),
176- 545.23 7.15 (d, 7= 1.6 Hz, IH),
AC70
178 ([M-H]") 6.93 (d,7= 1.2 Hz, IH),
6.60 (d,7= 15.6 Hz,
IH), 6.43 (dd,7=15.6,
7.6 Hz, IH), 4.66 (d,7 =
6.0 Hz, 2H), 4.13 (m,
IH), 3.98 (s, 3H)
8.24 (d, 7 = 7.6 Hz, IH),
8.15 (d, 7 =8.4 Hz, IH),
7.35 (d, 7 =6.0 Hz, 2H),
7.13 (d, 7= 1.2 Hz, IH),
492.20 6.92 (s, IH), 6.61 (d,7 = 1639, 3079,
AC71
([M-H]) 16.0 Hz, IH), 6.43 (dd, 858
7= 16.0, 7.6 Hz, IH),
5.48 (m, lH),4.13(m,
IH), 4.03 (s, 3H), 3.48
(m, 4H) 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,7 = 16.0
543.05 Hz, 1H), 6.36 (dd,7 = 1642, 3246,
AC72
([M-H]-) 16.0, 8.0 Hz, 1H), 6.12 814, 1113
(t, 7=5.6 Hz, 1H),4.62
(d, 7 = 6.0 Hz, 2H), 4.20
(m, 1H), 2.82 (m, 2H),
1.45 (t, 7 = 5.6 Hz, 3H)
8.72 (s, 1H), 7.97 (d,7 =
7.2 Hz, 1H), 7.70 (d, 7 =
8.4 Hz, 1H), 7.61 (m,
644.78 2H), 7.40 (m, 2H), 6.55 3431, 1652,
AC75
«M+H]+) (m, 2H), 6.42 (dd,7 = 1171,809
16.0, 8.0 Hz, 1H), 4.76
(d, 7 = 6.0 Hz, 2H), 4.12
(m, 1H)
8.87 (t,7 = 6.0 Hz, 1H),
8.34 (d, 7 = 2.1 Hz, 1H),
7.85 (d, 7 =6.3 Hz, 3H),
7.48 (m, 4H), 6.57 (d, 7
531.34 = 15.6 Hz, 1H), 6.45 3120, 1708,
AC76
([M+H]+) (dd,7= 15.6, 9.0 Hz, 1171
1H), 4.84 (m, 1H), 4.49
(d, 7 = 5.7 Hz, 2H), 2.82
(m, 2H), 2.36 (t, 7 =5.6
Hz , 3H)
8.87 (t,7 = 6.0 Hz, 1H),
8.34 (d, 7 = 2.1 Hz, 1H),
7.85 (d, 7 =6.3 Hz, 3H),
531.1 7.48 (m, 4H), 6.57 (d, 7
3444, 1648,
AC77 = 15.6 Hz, 1H), 6.45
«M+H]+) 1114,814
(dd,7= 15.6, 8.0 Hz,
1H), 4.84 (m, 1H), 4.49
(d,7 = 5.7 Hz, 2H), 2.36
(s, 3H)
8.59 (t, 7 = 6.4 Hz, 1H),
8.47 (t,7 = 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+H]+) (d,7= 15.6 Hz, 1H),
4.85 (t,7 = 8.0 Hz 1H),
3.98 (m, 4H), 2.58 (s,
3H) 8.69 (t, 7 = 6.0 Hz, IH),
8.58 (t, 7 = 6.0 Hz, IH),
7.92 (s, IH), 7.87 (d,7 =
610.97 6.4 Hz, 2H), 7.62 (d, 7 =
3303, 1658,
AC79 8.4 Hz, IH), 7.45 (d, 7 =
«M+H]+) 1166,817
8.4 Hz, IH), 7.0 (m,
IH), 6.76 (d,7= 15.6
Hz, IH) 4.83 (t, 7=8.0
Hz, IH), 3.98 (m, 4H)
7.37 (m, 3H), 7.26 (m,
IH), 7.24 (m, IH), 6.59
561.06 (d,7= 15.6 Hz, IH),
3412, 1624,
AC80 6.39 (dd, 7= 15.6, 8.0
«M+H]+) 1157,825
Hz, IH), 4.24 (m, 4H),
3.90 (m, IH), 2.83 (m,
2H), 1.26 (m, 3H)
8.73 (d, 7 =5.6 Hz, IH),
8.45 (t,7 = 6.0 Hz, IH),
7.76 (s, 3H), 7.45 (m,
546.93 3H), 6.86 (dd,7= 16.0,
AC81 9.2 Hz, IH), 4.83 (m,
9-92 ([M-H]-) 1H),4.56 (m, 2H), 4.51
(m, IH), 4.10 (m, 2H),
3.85 (d, 7 =6.0 Hz, 2H),
2.50 (m, 3H)
7.38 (d, 7= 1.8 Hz, 2H),
7.33 (s, IH), 7.27 (s,
3H), 6.58 (d,7= 16.0
477.69 Hz, IH), 6.42 (d, 7 = 8.1 1646, 1353,
AC82 Hz, IH), 6.36 (dd,7 = 1196, 1112,
«M+H]+) 16.0, 7.8 Hz, IH), 4.71 800
(m, IH), 4.23 (m, 3H),
3.26 (m, 2H), 2.45 (s,
3H)
8.07 (t, 7 =8.4 Hz, IH),
7.39 (t, 7= 1.6 Hz, IH),
7.31 (d, 7= 1.2 Hz, IH),
7.26 (m, 2H), 7.23 (m,
493.83 lH),7.19(d,7= 1.6 Hz, 1527, 1113,
AC83 IH), 6.60 (d,7= 16.8 801, 1167,
([M-H]) Hz, IH), 6.49 (dd,7 = 1321
16.8, 7.6 Hz, IH), 4.90
(m, IH), 4.64 (m, 2H),
4.14 (m, 2H),4.10(m,
IH) 8.07 (t, 7 = 8.0 Hz, IH),
7.34 (m, 3H),7.19(d,7
511.75 = 13.2 Hz, IH), 6.60 (d, 1645, 1113,
AC84 7= 16.4 Hz, IH), 6.48 804, 3030,
([M-H]-) (dd,7= 16.4, 8.0 Hz, 1245
IH), 4.88 (m, IH), 4.62
(m, 2H), 4.12 (m, 3H)
8.60 (d, 7 =6.8 Hz, IH),
8.15 (d, 7 =8.4 Hz, IH),
7.35 (d, 7 =6.0 Hz, IH),
523.83 7.15 (d, 7 = 7.2 Hz, IH),
1652, 3039,
AC85 6.94 (s, IH), 6.60 (d,7 =
([M-H]") 802, 1114
15.6 Hz, IH), 6.44 (dd,
7 = 7.6,7.6 Hz, IH),
4.93 (m, IH), 4.62 (m,
2H),4.13(m, 6H)
7.35 (d, 7 =6.3 Hz, 3H),
7.26 (m, 2H), 7.20 (m,
IH), 6.60 (d,7= 15.9
524.36 Hz, IH), 6.47 (dd, 7 =
3333, 1651,
AC86 15.9, 6.6 Hz, IH), 4.86
«M+H]+) 815
(m, IH), 4.65 (m, 2H),
4.13 (m, 3H),2.84 (q,
2.8 Hz, 2H), 1.26 (m,
3H)
8.07 (t,7 = 8.0 Hz, IH),
7.52 (m, 3H),7.19(d,7
495.82 = 13.2 Hz, IH), 6.59 (d,
1623, 1114,
AC87 7= 16.4 Hz, IH), 6.47
([M-H]") 816
(dd,7= 16.4, 8.0 Hz,
IH), 4.69 (m, IH), 4.23
(m, 3H), 3.29 (m, 2H)
7.43 (m, 2H), 7.27 (m,
2H), 7.23 (m, 2H), 6.58
(d,7= 16.0 Hz, IH),
509.89 6.41 (dd,7= 16.0,7.6 1666, 1166,
AC89
«M+H]+) Hz, 1H),4.79 (d,7 = 5.6 1112, 800
Hz, 2H), 4.14 (m, IH),
2.48 (s, 3H), 2.18 (m,
IH), 1.16 (m, 4H) 8.34 (m, IH), 8.27 (m,
1H),7.60 (d,7 = 1.6 Hz, 1H),7.49 (d, 7=8.0 Hz, 2H), 7.40 (s, 2H), 7.36
656.9 (dd, 7=8.2, 1.7 Hz,
AC90 IH), 6.53 (d, 7= 16.0
([M-H]-) Hz, IH), 6.38 (dd,7 =
15.9, 7.9 Hz, IH), 4.89 (d, 7 = 8.4 Hz, 2H), 4.48 (d, 7 = 9.0 Hz, 2H), 4.11 (m, IH)
8.18 (t, 7 = 5.0 Hz, IH), 7.58 (d, 7= 1.6 Hz, IH), 7.47 (d, 7 =8.0 Hz, IH), 7.40 (s, 2H), 7.34 (dd, 7
640.9 = 8.1, 1.6 Hz, IH), 6.52
AC91
([M-H]") (m, 2H), 6.37 (dd,7 =
15.9, 7.9 Hz, IH), 4.54 (d, 7 = 4.9 Hz, 2H), 4.12 (m, IH), 3.99 (qd,7 = 8.9, 6.5 Hz, 2H)
9.16 (d, 7= 6.1 Hz, IH), 7.65 (d,7= 1.6 Hz, IH), 7.57 (d, 7 =8.0 Hz, IH), 7.41 (m, 3H), 7.21 (t, 7
640.9 = 5.6 Hz, IH), 6.55 (d, 7
AC92 = 15.9 Hz, IH), 6.41
([M-H]") (dd,7= 15.9, 7.8 Hz,
1H),4.59 (d,7=5.6 Hz, 2H),4.45 (qd,7=9.0, 6.0 Hz, 2H), 4.12 (q, 7 = 7.2 Hz, IH)
13 C NMR (δ)3
169.91,
169.84,
7.52-7.41 (d, 7 = 8.2 Hz, 138.23, IH), 7.39-7.34 (m, IH), 137.41, 7.24-7.17 (d, 7 = 1.8 Hz, 136.84, 2H), 7.02-6.92 (m, 2H), 134.79, 6.90-6.83 (d, 7 = 11.4 134.69, Hz, IH), 6.71 (br s, IH), 131.07,
485.5 6.17 (br s, IH), 6.12- 128.69,
AC93 6.01 (dd, 7 = 11.4, 10.3 127.49,
([Μ+ΗΓ) Hz, IH), 4.44-4.38 (d, 7 127.43,
= 4.2 Hz, IH), 4.35-4.27 126.72, (m, IH), 4.10-3.99 (d, 7 126.61 (q, 7 = = 5.1 Hz, 2H), 2.78-2.67 212.10 Hz), (m, IH), 2.44 (s, 3H), 125.61, 0.88-0.78 (m, 2H), 0.60- 123.76, 47.89 0.45 (m, 2H) (q, 7 = 28.28
Hz), 43.46,
22.65, 19.97,
8.21
8.36 - 8.24 (d, .7 = 2.4
Hz, IH), 7.75 - 7.64 (m,
IH), 7.38 - 7.24 (m,
3H), 7.24 - 7.09 (d, 7 =
1.8 Hz, 2H), 6.99 - 6.90
511.6 3262, 1607,
(m, 2H), 6.89 - 6.74 (d,
AC94 1247, 1164,
([Ml") 7 = 11.4 Hz, IH), 6.63 - 1111 6.43 (m, IH), 6.14 - 5.98 (m, IH), 4.69 - 4.51 (d, .7 = 6.1 Hz, 2H),
4.37 - 4.20 (m, IH),
2.46 - 2.31 (s, 3H)
7.58 (d, 7 = 7.9 Hz, IH),
7.44 - 7.29 (m, 3H),
7.14 (dd, 7 = 7.9, 1.6
Hz, IH), 6.86 (d, 7 =
626.9 11.4 Hz, IH), 6.76 (t, 7
AC95 48-61
([Μ+Η]+) = 5.9 Hz, IH), 6.59 (br
s, IH), 6.21 - 6.04 (m,
1H), 4.23 (d, 7 = 5.5 Hz,
IH), 3.98 (qd, 7 = 9.0,
6.5 Hz, 2H) 8.83 (s, IH), 8.06 (br,
IH), 7.90 (s, 2H), 7.63
(d, J = 8.1 Hz, 2H), 7.53
61 (m, IH), 6.94 (m, IH),
AC96 9.6 6.77 (d, 7 = 15.3 Hz, 1616, 1114
«M+H]+) IH), 6.63 (d, 7 = 9.3 Hz,
IH), 4.84 (m, IH), 4.30
(d, 7 = 5.6 Hz, 2H), 2.99
(s, 6H)
8.20 (d, 7 = 2.1 Hz, IH),
7.73 (d, 7 = 2.7 Hz, IH),
7.60 (m, 2H), 7.39 (s,
2H), 7.29 (m, IH), 6.79
606.6
AC97 (d, 7 = 8.4 Hz, IH), 6.55 1644, 1113
«M+H]+)
(d, 7 = 15.9 Hz, IH),
6.40 (m, 2H), 4.60 (d, 7
= 2.7 Hz, 2H), 4.13 (m,
IH), 3.95 (s, 3H)
9.04 (t, 7 = 6.0 Hz, IH),
8.60 (t, 7 = 6.6 Hz, IH),
8.25 (s, IH), 7.97 (d, 7 =
8.1 Hz, IH), 7.87 (d, 7 =
577.87 6.3 Hz, 2H), 7.69 (d, 7 =
AC98 1663, 1168
«M+H]+) 7.5 Hz, IH), 7.15 (dd, 7
= 15.9, 9.3 Hz, IH),
6.89 (d, 7 = 15.9 Hz,
IH), 4.86 (m, IH), 3.98
(m, 4H).
8.69 (t, 7 = 6.0 Hz, IH),
8.58 (t, 7 = 6.6 Hz, IH),
7.91 (s, IH), 7.85 (m,
IH), 7.61 (m, 2H), 7.52
574.81
AC99 (m, 2H), 6.98 (dd, 7 = 1650, 1164
«M+H]+)
15.3, 9.0 Hz, IH), 6.76
(d, 7 = 15.3 Hz, IH),
4.81 (m, 1H), 4.01 (m,
4H) 8.29 (s, IH), 8.22 (d, 7
= 8.1 Hz, IH), 7.93 (d, J
= 7.8 Hz, IH), 7.72 (m,
IH), 7.65 (m, 2H), 7.40
673.80 (s,2H), 7.18(br, IH),
ACIOO 3403, 1659
«M+H]+) 6.59 (d, 7 = 16.0 Hz,
IH), 6.43 (dd, 7=16.0,
7.6 Hz, IH), 5.02 (d,7 =
1.2 Hz, 2H), 4.12 (m,
IH)
7.56 (d, 7=9.0 Hz, IH),
7.39 (d, 7=6.0 Hz, 2H),
7.26 (m, 2H), 6.54 (d, 7
= 15.9 Hz, IH), 6.37
636.83
AC101 (dd,7=8.0, 15.9 Hz, 1637, 1113
«M+H]+)
IH), 4.01 (m, IH), 3.84
(m, 2H), 3.33 (m, 2H),
3.04 (m, 2H), 2.84 (m,
3H), 2.62 (m, IH)
7.60 (m, 2H), 7.32 (m,
IH), 7.03 (d, 7 = 7.2 Hz,
2H), 6.74 (br, IH), 6.62
592.84 (br, IH), 6.56 (d,7 =
AC102 16.2 Hz, IH), 6.41 (dd, 1668, 1167
([M+H]+) 7= 16.2, 7.8 Hz, IH),
4.22 (d, 7 =5.4 Hz, 2H),
4.14 (m, 1H),4.01 (m,
2H)
8.40 (d, 7 = 8.0 Hz, IH),
7.92 (d, 7 = 5.2 Hz, IH),
7.59 (d, 7 = 8.0 Hz, IH),
7.35 (d, 7 = 8.0 Hz, IH),
6.99 (dd,7= 16.0,7.6
Hz, IH), 6.76 (d,7 =
612.7 16.0 Hz, IH), 4.84 (m,
99.2- 1634, 1113,
AC103 «M+H]+) 1H),4.23 (d,7= 13.2
105.0 809
Hz, IH), 3.97 (m, IH),
3.79 (d,7= 13.6 Hz,
IH), 3.16 (t, 7= 11.2
Hz, IH), 2.77 (t, 7 =
11.2 Hz, IH), 1.99 (s,
3H), 1.88 (m, 2H), 1.45
(m, 2H) 7.60 (m, 2H), 7.40 (m
3H), 6.55 (d, 7 = 15.6 3437, Hz, IH), 6.41 (dd, 7 = 1644,
680.97 15.6, 7.8 Hz, IH), 4.24
AC104 1113,
«M+H]+) (m, IH), 3.34 (m, 2H),
2.90 (m, IH), 2.24 (m, 807, 2H), 1.52(m, 2H), 1.34 511
(m, 4H)
7.59 (s, IH), 7.55 (m,
IH), 7.50 (m, 1H),7.40
(m, 2H), 6.54(d, 7 =
3303, 1649,
609.9 16.0 Hz, IH), 6.50 (7 =
AC105 1115, 2242,
«M+H]+) 16.0, 8.0 Hz, IH), 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, IH), 7.51 (d, 7 =
8.4 Hz, IH), 7.40 (s,
2H), 7.36 (d, 7 = 6.8 Hz,
IH), 6.54 (d, 7 = 16.0 3417,
584.95 Hz, IH), 6 .40 (dd, 7 = 1648,
AC106 16.0, 8.0 Hz, IH), 6.03
«M+H]+) (d, 7 = 8.0 Hz, IH), 4.11 1112,
(m, 2H), 3.10 (m, 2H), 805, 555 2.50 (m, 2H ), 2.50 (s,
3H) (m, 2H ), 1.94 (m,
2H)
8.41 (d, 7 = 7.8 Hz, IH),
7.90 (s, 2H), 7.62 (m,
2H), 7.51(m, IH), 6.92 3303, (dd, 7 = 15.9, 9.0 Hz, 1645, IH), 6.77 (d, 7 = 15.9
609.9 Hz, IH), 4.81 (m, IH), 1115,
AC107
([M+H]+) 3.73 (s, 2H), 3.31 (m, 2243,
IH), 3.28 (m, IH), 2.82
(t, 7 = 11.4 Hz, 2H), 810, 2.82 (m, 2H), 2.30 (m, 507 2H), 1.88 (m, 2H), 1.57
(m, 2H) 7.60 (m, 2H) 7.39 (s,
2H), 7.28 (m, IH), 6.56 3420, (d,7 = 15.6 Hz, IH), 1649, 6.40 (dd,7 = 15.6,7.8
626.9 Hz, IH), 5.91 (m, IH), 1113,
AC108
([M+H]+) 4.65 (m, 2H),4.10(m, 809,
IH), 4.07 (m, 2H), 3.59
(m, IH), 2.74 (m, 2H), 554 2.13 (m, 4H), 2.07 (m,
IH)
7.56 (m, 2H), 7.39 (s,
2H), 7.29 (s, IH), 6.50
(d, 7=15.9 Hz, IH),
6.41 (dd,7 = 15.9, 8.0
614.6
AC109 Hz IH), 4.09 (m, IH), 1647, 1113
«M+H]+)
3.88 (m, 2H), 3.49 (m,
2H),2.92 (m, 2H), 2.81
(m, IH), 2.74 (m, 2H),
2.25 (m, 4H)
11.20 (s, IH), 8.66 (br,
IH), 7.92 (m, 3H), 7.62
(d, 7 = 8.0 Hz, IH), 7.45
572.6 (d, 7 = 8.0 Hz, IH), 6.77 3412, 1690,
AC110 (dd,7= 15.6, 9.2 Hz, 1114, 846,
([M+H]+) IH), 6.77 (d,7= 15.6 559
Hz, IH), 4.85 (m, IH),
3.74 (d, 7 =5.2 Hz, 2H),
3.61 (s, 3H)
8.63 (t,7 = 6.0 Hz, IH),
8.04 (t,7 = 6.0 Hz, IH),
7.92 (m, 3H), 7.62 (d, 7
= 1.2 Hz, IH), 7.47 (d, 7
= 7.6 Hz, IH), 7.00 (dd,
582.79 7= 15.6, 8.8 Hz, IH), 3419, 1659,
AC111
([M+H]+) 6.77 (d, 7= 15.6 Hz, 843, 557
IH), 5.19 (d, 7= 1.6 Hz,
IH), 5.01 (d, 7= 1.2 Hz,
IH), 4.85 (m, IH), 3.86
(d, 7 = 5.6 Hz, 2H), 3.75
(t,7=5.6 Hz, 2H) 8.84 (br, IH), 8.58 (m,
IH), 8.30 (m, IH), 7.91
(s,2H), 7.61 (d, 7=8.1
Hz, IH), 7.42 (d, 7 = 7.8
582.79 Hz, IH), 7.00 (dd, 7 = 3399, 1662,
AC112 15.6, 9.3 Hz, IH), 6.77 1114, 807,
«M+H]+) (d,7= 15.6 Hz, IH), 582
4.85 (m, 1H),4.11 (d, 7
= 5.6 Hz, IH), 3.73 (d, 7
= 5.6 Hz, IH), 3.04 (s,
6H)
8.48 (t, 7 = 5.2 Hz, IH),
8.3 (s, IH), 7.90 (s, 2H),
7.79 (dd, 7 = 2.0, 2.0 Hz
2H),7.58(d,7=8.4 Hz,
626.88
1H)7.46 (d, 7 = 7.6 Hz, 3431, 1651,
AC113 ([M+H]+) 1H)7.26 (d, 7 = 7.6 Hz, 1113,808,
IH), 6.98 (m, IH), 6.75 554
(d,7= 15.6 Hz, IH),
4.85 (m, IH), 3.49 (d, 7
= 6.4 Hz, 2H) 2.87 (t, 7
= 6.4 Hz, 2H)
8.77 (s, IH), 8.58 (d, 7 =
7.2 Hz, 2H), 7.93 (d,7 =
7.2 Hz, 2H), 7.60 (dd, 7
= 1.2, 0.8 Hz, IH), 7.37
113.7- 570.7 (d, 7 = 7.6 Hz, IH), 6.99
AC114
117.5 ([M+H]+) (m, IH), 6.77 (d,7=16
Hz, IH), 4.85 (m, IH),
4.10 (m, 1H)3.29 (m,
2H), 3.05 (m, 2H), 2.0
(m, 2H), 1.76 (m, 2H)
8.43 (s, IH), 7.79 (d,7 =
8.0 Hz, IH), 7.51 (m,
1H),7.36 (d,7=8.4 Hz,
529.00 3H), 7.21 (m, 3H), 6.55
1589, 3459,
AC115 (d,7= 15.6 Hz, IH),
«M+H]+) 801, 1110
6.36 (dd, 7= 15.6, 8.0
Hz, IH), 5.04 (d,7 = 5.6
Hz, 2H), 4.10 (m, IH),
2.35 (s, 3H) 7.99 (d, 7=8.4 Hz, IH),
7.46 (d, 7 = 1.6 Hz, IH),
7.34 (d, J =6.4 Hz, 2H),
614.87 7.28 (m, 2H), 6.62 (m, 3424, 1657,
AC116
([M+H]+) 2H), 6.47 (dd,7 = 16.0, 1165
7.2 Hz, IH), 4.23 (m,
2H),4.12 (m, IH), 4.00
(m, 2H)
8.39 (br, IH), 7.85 (br,
IH), 7.62 (m, 3H), 7.53
(d, 7 = 8.0 Hz, IH), 7.46
(s, IH), 7.40 (d, 7=8.0
525.42 Hz, IH), 7.17 (m, IH), 3401, 1636,
AC117
([M-H]-) 6.78 (dd, 7= 16.0, 8.8 1113,750
Hz, IH), 6.70 (m, IH),
4.77 (m, IH), 4.66 (s,
IH), 4.32 (s, IH), 2.97
(s, 3H), 2.16 (s,3H)
7.36 (d, 7 =8.0 Hz, 2H),
7.27 (m, 2H), 7.22 (m,
2H), 6.57 (d,7= 16.0
Hz, IH), 6.38 (dd,7 =
471.79 16.0, 8.0 Hz, IH), 6.10 3437, 1655,
AC118 (br, 1H),4.15 (m, 2H), 1262, 1105,
([M+H]+) 3.89 (m, IH), 3.80 (m, 802
2H), 3.35 (m, IH), 2.46
(s, 3H), 2.06 (s,lH),
1.96 (m, 2H), 1.65 (m,
IH)
7.39 (s,2H), 7.25-7.18
(m, 3H), 6.58 (d, 7 =
16.0 Hz, IH), 6.30 (dd,
492.17 7= 16.0, 8.4 Hz, IH), 3211, 1569,
BCl
([M+H]+) 5.91-5.70 (br, 2H), 1113,806
4.05 (m, IH), 3.05 - 2.80 (m, 6H), 2.70 (m,
IH), 1.81 (m, IH) 8.80 (s, IH), 8.20 (s,
IH), 7.82 (m, 3H), 7.4
(s,2H), 6.62 (d, 7=16.0
Hz, IH), 6.52 (dd, / =
506.4 2923, 1542,
BC2 16.0, 8.0 Hz, IH),
«M+H]+) 1033, 805
4.18(m, IH), 3.38 (m,
2H),2.98 (m, 2H), 2.71
(m, IH), 2.04 (m, 2H),
1.54 (s, 3H).
7.40 (s, 2H), 7.33-7.22
(m, 3H), 6.61 (d,/ =
16.0 Hz, IH), 6.34 - 6.28 (dd,/= 16.0, 8.0
518.04 3120, 1592,
BC3 Hz, IH), 5.96-5.80 (m,
([M-H]-) 1146, 895
3H), 5.22 (m, 4H), 4.01
(m, 2H), 2.84 - 2.99 (m,
2H), 2.71 (m, IH), 1.86
(m, IH)
7.39 (s, 2H), 7.25-7.20
(m, 3H), 6.34 (d,/ =
16.0 Hz, IH), 6.30 (dd, J
= 16.0, 8.0 Hz, IH),
529.02 5.81 (br, IH), 5.48 (m, 3283, 1652,
BC4
([M+H]+) 1H),4.10 (m, IH), 3.10 1241,811
(m, 2H), 2.86-3.07 (m,
2H),2.86 (m, IH), 1.81
(m, IH);
7.40 (s, 2H), 7.21 (s,
1H),7.12 (m, IH), 6.56
(d,/= 16.0 Hz, IH),
6.32 (dd,/ = 16.0, 8.4
Hz, IH), 5.85 (brs, IH), 3489, 3291,
544.25
BC5 5.23 (brs, IH), 4.12 (m, 1655, 1112,
([M-H])
IH), 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) 7.40 (s,2H), 7.31-7.18
(m, 3H), 6.58 (d,/ =
16.0 Hz, IH), 6.24 - 6.28 (dd,/= 16.0, 8.0
485.96 Hz, IH), 5.40 (br, IH), 3429, 1114,
BC6
([M-H]-) 4.01 (m, 2H), 2.78 - 804
3.01 (m, 2H),2.51 (s,
IH), 1.86 (m, IH), 1.20
(m, 2H), 1.01 (m, 2H),
0.78 (m, 2H)
7.40 (s,2H), 7.31 (s,
IH), 7.18 (m, IH), 7.18
(s, IH), 6.58 (d,/= 16.0
Hz, IH), 6.32 (dd, / =
16.0, 8.0 Hz, IH), 5.78
500.01 3296, 1115,
BC7 (brs, IH), 5.21 (br s,
([M-H]") 806
IH), 4.01 (m, IH), 2.78
(m, 2H), 2.01 (m, IH),
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,/= 16.0 Hz, IH),
6.34 (dd,/= 16.0, 8.0
511.88 Hz, IH), 5.83 (br, IH), 1657, 1113,
BC8
([M-H]") 5.52 (m, lH),4.12(m, 855
IH), 3.12 (m, 2H), 3.06- 2.82 (m, 2H), 2.75 (m,
IH), 1.85 (m, IH)
8.30 (s, IH), 7.68 (d,/ =
6.4 Hz, IH), 7.38-7.20
(m, 5H), 6.60 (d,/ =
16.0 Hz, IH), 6.34 (dd,
179- 556.83 /= 16.0, 8.0 Hz, IH),
BC9
181 ([M-H]) 5.63 (br, IH), 5.52 (m,
1H),4.12 (m, IH), 3.56
(s, 2H), 3.06-2.82 (m,
2H), 2.70 (m, IH), 1.82
(m, IH) 7.38-7.20 (m, 5H), 6.62
(d,7 = 16.0 Hz, IH),
6.34 (dd,7 = 16.0, 8.0
497.98 Hz, IH), 5.83 (br, IH),
3027, 1654,
BC10 5.52 (m, lH),4.12(m,
([M-H]-) 815
IH), 3.02 (m, 3H), 2.82
(m, IH), 2.50 (m, 3H),
1.82 (m, IH), 1.42 (m,
IH)
7.80 (m, IH), 7.48 (m,
2H),7.326.65 (d,7 =
530.09 16.0 Hz, IH), 6.54 (dd,
7 = 16.0, 8.0 Hz, IH), 1715, 1113,
BC11 ([M-H]")
5.38 (m, lH),4.18(m, 816 IH), 3.62 (m, IH), 3.32
(m, IH), 2.86 (m, IH),
1.81 (m, IH)
7.32, (d, 7 = 6.0 Hz, 2H)
7.28 (m, IH), 7.20 (d, 7
= 8.0, IH), 7.14 (d, 7 =
8.8, IH), 6.70 (d,7 =
514.86 8.0 Hz, IH), 6.60 (m, 3428, 1112,
BC12
«M+H]+) 2H),4.15 (m, IH), 3.85 857
(m, IH), 3.65 (m, IH),
3.46 (m, 2H), 3.19 (m,
2H);
8.33 (br, IH), 7.59 (s,
553.06 IH), 7.45 (m, 3H), 6.72
121-
BC13 ([M-H]) (d, 7 = 3.6, IH) ,6.39
126
(m, IH), 4.71 (t, 7 = 7.2
Hz, 2H), 4.15 (m, 2H)
8.83 (t,7 = 6.6 Hz, IH),
8.42 (t, 7= 14.7 Hz,
IH), 8.22 (d, 7=8.1 Hz,
554.0 IH), 8.13 (t, 7= 6.3 Hz,
172-
BC14 IH), 7.98-7.86 (m, 2H),
175 ([M-H]") 7.16-7.07 (m, IH),
7.01 - 6.93 (m, IH),
4.96-4.81 (m, 3H),
4.00 - 3.88 (m, 2H) 7.37 (m, 3H), 7.28 (m,
4H), 6.60 (d,7 = 16.0 Hz, IH), 6.36 (dd,7 =
107- 402.00
CCl 16.0, 8.0 Hz, IH), 5.75
109 ([M+H]+)
(brs, 1H),4.46 (d,7=6 Hz, 2H), 4.01 (m, IH), 2.11 (s, 3H)
7.37 (m, 3H), 7.28 (m, 4H), 6.60 (d,7 = 16.0 Hz, IH), 6.35 (dd,7 =
118- 428.11 16.0, 8.0 Hz, IH), 5.83
CC2
120 ([M+H]+) (brs, 1H),4.46 (d,7 =
6.0 Hz, 2H), 4.11 (m, IH), 1.40 (m, IH), 1.02 (m, 2H), 0.77 (m, 2H)
7.38 (m, 3H), 7.27 (m, 3H), 6.60 (d,7 = 16.0 Hz, IH), 6.36 (dd,7 =
119- 468.20 16.0, 8.4 Hz, IH), 5.00
CC3
122 ([M-H]) (brs, 1H),4.48 (d,7 =
5.6 Hz, 2H), 4.11 (m, IH), 3.15 (q, 7=10.4 Hz, 2H)
7.37 (m, 3H), 7.28 (m, 3H), 6.60 (d,7 = 16.0 Hz, IH), 6.35 (dd,7 = 16.0, 8.0 Hz, IH), 5.69
414.16
CC4 (brs, 1H),4.46 (d,7 =
([M-H]")
6.0 Hz, 2H), 4.21 (m, 1H),2.29 (q, 7=5.8 Hz, 2H), 1.30 (t, 7 = 7.2 Hz, 3H)
7.40 (m, 3H), 7.28 (m, 2H), 6.60 (d,7= 15.6 Hz, IH), 6.33 (dd,7 =
460.28 15.6, 8.0 Hz, IH), 5.84
CC5
([M-H]") (brs, 1H),4.46 (d,7 =
5.6 Hz, 2H), 4.10 (m, IH), 1.36 (m, IH), 1.02 (m, 2H), 0.77 (m, 2H) 7.40 (m, 3H), 7.26 (m,
IH), 6.60 (d,7 = 16.0
Hz, IH), 6.34 (dd, 7 =
106- 504.08 16.0, 8.0 Hz, IH), 5.96
CC6
108 ([M-H]-) (brs, 1H),4.49 (d,7 =
5.6 Hz, 2H), 4.10 (m,
IH), 3.15 (q, 7=10.8
Hz, 2H)
7.42 (m, 4H), 7.24 (m,
2H), 6.53 (d, 7=16.0
Hz, IH), 6.36 (dd,7 =
127- 436.03
CC7 16.0, 8.0 Hz, IH) , 5.86
128 ([M+H]+)
(brs, 1H),4.51 (d,7 =
6.0 Hz, 2H), 4.05 (m,
IH), 2.02 (s, 3H)
8.58 (t, 7 = 5.6 Hz, IH),
7.72 (m, IH), 7.66 (m,
3H),7.49 (d,7=8.0 Hz,
1H),7.30 (d,7=8.0 Hz,
129- 462.15 IH), 6.90 (dd,7= 16.0,
CC8
131 ([M+H]+) 8.0 Hz, IH), 6.73 (d,7 =
16 Hz, IH), 4.81 (m,
1H),4.33 (d,7=6.0 Hz,
IH), 1.64 (m, IH), 0.68
(m, 4H)
7.41 (m, 3H), 7.26 (m,
3H), 6.54 (d,7= 16.0
Hz, IH), 6.37 (dd, 7 =
132- 504.25
CC9 16.0, 8.0 Hz, IH), 6.13
134 ([M+H]+)
(brs, 1H),4.56 (d,7 =
6.0 Hz, 2H), 4.11 (m,
IH), 3.13(m, 2H)
7.38 (m, 4H), 6.56 (d, 7
= 16.0 Hz, IH), 6.38
538.03
(dd,7= 16.0, 8.0 Hz, 1651, 1112,
CC10 ([M+2H]+
IH), 6.18 (m, IH), 4.58 807
) (m, 2H), 4.08 (m, IH),
3.08 (m, 2H) 7.42 (m, 3H), 7.24 (m,
IH), 6.54 (d,/ = 15.6
Hz, IH), 6.34 (dd, / =
111— 494.12 16.0, 8.0 Hz, IH), 6.03 ecu 112 ([M-H]-) (m, IH), 4.53 (d, 7=6.0
Hz, IH), 4.10 (m, IH),
1.39 (m, IH), 1.00 (m,
2H), 0.77 (m, 2H)
7.39 (s,4H), 7.34 (d,/ =
8.0 Hz, IH), 7.26 (m,
IH), 6.57 (d,/ = 16.0
510.07 Hz, IH), 6.35 (dd,/ =
CC12 76-78
([M-H]) 16.0, 8.0 Hz, IH), 6.10
(brs, 1H),4.49 (d,/ =
6.0 Hz, 2H), 4.10 (m,
IH), 1.20 (s, 9H)
8.51 (d, 7=5.2 Hz, IH),
7.63 (s, IH), 7.51 (m,
IH), 7.45 (m, 2H), 7.39
563.37 (s, 2H), 7.28 (m, IH),
CC13 73-76
([M-H]) 6.58 (m, 2H), 6.37 (dd, J
= 16.0, 8.0 Hz, IH),
4.71 (d, 7=6.0 Hz, IH),
4.11 (m, IH)
8.51 (m, IH), 8.30 (d, /
= 2.4 Hz, IH), 7.73 (m,
1H),7.61 (s, 2H),7.51
581.45 (s, IH), 7.32 (m, 3H),
3430, 1656,
CC14 ([M+1H]+ 6.66 (d,/= 16.0 Hz,
1109,806
) IH), 6.56 (dd,/= 16.0,
8.4 Hz, IH), 4.50 (m,
1H),4.45 (d, 7=5.6 Hz,
IH), 3.56 (s, 2H)
7.40 (m, 3H), 7.33 (m,
IH), 7.22 (m, 2H), 6.54
(d,/= 15.6 Hz, IH),
6.34 (dd,/= 16.0, 8.0 3293, 1651,
480.24
CC15 Hz, IH), 6.03 (br s, IH), 1543, 1114,
«M+H]+)
4.53 (d, 7=6.0 Hz, 2H), 812 4.13 (m, IH), 1.41 (m,
IH), 1.00 (m, 2H), 0.77
(m, 2H) 7.42 (s, IH), 7.37 (m,
3H), 7.22 (m, IH), 6.54
(d,7 = 16.0 Hz, IH),
520.33 6.36 (dd, 7 = 16.0, 8.0 3307, 1665,
CC16
([M-H]) Hz, IH), 6.19 (brs, IH), 1114,813
4.51 (d, 7=6.0 Hz, 2H),
4.21 (m, IH), 3.33 (m,
2H)
7.51 (m, 2H),7.39(m,
2H), 7.24 (m, 2H), 6.52
(d,7 = 15.6 Hz, IH),
6.38 (dd, 7 = 15.6,7.6
117- 459.83 3293, 1633,
CC17 Hz, IH), 6.02 (br s, IH),
119 ([M-H]") 1110, 820
4.53 (d, 7=6.0 Hz, 2H),
4.14 (m, IH), 1.38 (m,
IH) ), 1.00 (m, 2H),
0.77 (m, 2H)
7.48 (m, 2H), 7.41 (s,
1H),7.36 (d, 7=8.0 Hz,
IH), 7.23 (m, 2H), 6.52
(d,7= 16.0 Hz, IH),
119- 501.88 3435, 1644,
CC18 6.39 (dd, 7= 16.0, 8.0
123 ([M-H]") 1111,817
Hz, IH), 6.13 (brs, IH),
4.56 (d, 7 =6.0 Hz, 2H),
4.15 (m, IH), 3.13(m,
2H)
7.41 (m, 2H), 7.24 (m,
IH), 6.53 (d, 7= 16.0
Hz, IH), 6.35 (dd,7 =
530 3435, 1644,
CC19 16.0, 8.0 Hz, IH), 4.53
«M+H]+) 1111,817
(m, 2H), 4.10 (m, IH),
3.42 (m, 2H), 2.97 (s,
3H), 2.78 (m, 2H)
7.42 (m, 3H), 7.24 (m,
IH), 6.54 (d,7= 15.6
Hz, IH), 6.34 (dd, 7 =
512 15.6, 8.0 Hz, IH), 6.03 3293, 1633,
CC20
«M+H]+) (m 1H),4.53 (d, 7=6.0 1110, 820
Hz, IH), 4.10 (m, IH),
1.19 (m, IH), 1.00 (m,
2H), 0.77 (m, 2H) (DMSO- ) 8.62 (m,
IH), 7.95 (s, IH), 7.85
(m, IH), 7.66 (m, 3H),
7.47 (d, 7= 8.0 Hz, IH),
493.99
CC21 55-58 6.98 (dd, 7=16.0, 8.0
([M-H]-)
Hz, IH), 6.84 (d,7 =
16.0 Hz, IH), 4.83 (m,
1H),4.44 (s, 2H), 1.68
(m, IH), 0.71 (m, 4H)
8.62 (m, IH), 7.90 (s,
3H), 7.82 (m, IH), 7.45
(m, IH), 6.98 (m, IH),
530.01
CC22 67-69 6.84 (d,7 = 16.0 Hz,
«M+H]+)
IH), 4.82 (m, IH), 4.4
(s, 2H), 1.66 (m, IH),
0.72 (m, 4H)
9.02 (br s, IH), 8.54 (br
s, IH), 8.26 (br s, IH),
7.48-7.54 (m, 3H),
564.99 7.22-7.42 (m, 3H),
CC23 69-71
([M-H]) 6.59 - 6.62 (m, 2H),
6.38-6.42 (m, IH),
4.82 (m, 2H),4.19(s,
IH)
7.64 (s, IH), 7.54 (s,
2H), 7.46 (s, 2H), 6.62
(d,7 = 16.0 Hz, IH),
125- 570.26 6.41 (dd,7 = 16.0, 8.4
CC24
127 ([M-H]") Hz, IH), 6.03 (m, IH),
4.65 (d, 7=6.4 Hz, 2H),
4.14 (m, IH,), 3.13 (q, 7
= 10.6 Hz, 2H)
7.60 (s, IH), 7.40 (s,
2H),7.37 (d, 7=8.0 Hz,
1H),7.31 (d, 7=8.0 Hz,
IH), 6.53 (d, 1H,7 =
579.86 16.0 Hz), 6.35 (dd,7 = 3297, 1663,
CC25
([M-H]") 16.0, 8.0 Hz, IH), 6.17 1114, 809
(brs, 1H),4.56 (d,7 =
6.4 Hz, 2H), 4.12 (m,
IH), 3.15 (q, 7= 10.6
Hz, 2H) 7.59 (s, IH), 7.39 (m,
2H), 7.30 (s, IH), 6.53
(d,/ = 16.0 Hz, IH),
6.35 (dd,/ = 16.0, 8.0
129- 539.89
CC26 Hz, IH), 6.06 (br s, IH),
131 ([Μ+ΗΓ)
4.42 (d, 7=4.4 Hz, 2H),
4.12 (m, IH), 1.35 (brs,
IH), 0.95 (br s, 2H),
0.75 (m, 2H)
7.39 (s,2H), 7.33 (t,/ =
7.6 Hz, IH), 7.14 (m,
2H), 6.56 (d,/ = 16.0
519.95 Hz, IH), 6.35 (dd,/ =
CC27 16.0, 7.6 Hz, IH), 6.06 3306, 1786
([M-H]) (brs, 1H),4.52 (d,/ =
16.0 Hz, 2H), 4.08 (m,
IH), 3.90 (s, 2H), 3.13
(m, 2H)
7.39 (s, 2H), 7.35 (m,
1H),7.14 (m, 2H), 6.55
(d,/ = 15.6 Hz, IH),
477.93 6.33 (dd,/ = 15.6, 8.0 3625, 1747
CC28 Hz, IH), 5.93 (brs, IH),
([M-H]") 4.49 (d,/ = 16.0 Hz,
2H),4.10 (m, IH), 1.36
(m, IH), 1.00 (m, 2H),
0.77 (m, 2H)
8.58 (d, 7 = 4.6 Hz, IH),
7.74 (m, IH), 7.62 (m,
2H), 7.52 (m, IH), 7.4
(s, 2H), 7.3 (m, IH), 7.2
(m, 2H), 6.60 (d,/ =
620.86 16.0 Hz, IH), 6.38 (dd, 1645, 1115,
CC29
([M-H]") /= 16.0, 8.0 Hz, IH), 808
5.02 (s, IH), 4.8 (s, IH),
4.8(d,/= 10 Hz, 2H),
4.10 (m, IH), 1.8 (m,
IH), 1.2 (m, 2H),0.6
(m, 2H) 7.41 (m, 4H), 7.24 (m,
IH), 6.53 (d, 7 = 16.0
Hz, IH), 6.35 (dd, 7 =
16.0, 8.0 Hz, IH), 6.12
101- 559.75
CC30 (br s, IH), 4.53 (m, 2H),
104 ([M-H]-) 4.10 (m, IH), 3.42 (m,
2H), 2.91 (s, 3H), 2.78
(m, 2H)
7.58 (m, 2H), 7.41 (m,
3H), 7.24 (m, IH), 6.53
(d, 7 = 16.0 Hz, IH),
6.35 (dd, 7 = 16.0, 8.0
177- 463 ([M-
CC31 Hz, IH), 4.70 (br s, IH),
178 H]-) 4.43 (s, 2H), 4.08 (m,
IH), 3.21 (m, 2H), 1.25
(m, 3H);
7.66 (m, 2H), 7.54 (m,
IH), 7.41 (s, 2H), 6.62
(d, 7 = 16.0 Hz, IH),
141- 532.99
CC32 6.40 (dd, 7 = 16.0, 8.0
142 ([M+H]+)
Hz, IH), 4.59 (s, 3H),
4.19 (m, IH), 3.25 (m,
2H), 1.15 (m, 2H)
7.57 (s, IH), 7.40 (m,
2H), 7.30 (s, IH), 7.20
(br s, IH), 6.53 (d, 7 =
16.0 Hz, IH), 6.33 (dd,
3338, 1631,
540.88 7 = 16.0, 8.0 Hz, IH),
CC33 1578, 1114,
([M-H]") 6.06 (br s, IH), 4.75 (br
809 s, IH), 4.42 (s, 2H), 4.20
(br s, IH), 4.15 (m, 2H),
3.20 (m, 2H), 1.15 (m,
3H)
7.42 (m, 3H), 7.28 (m,
2H), 6.54 (d, 7 = 16.0
Hz, IH), 6.36 (dd, 7 =
118- 541.40 16.0, 8.0 Hz, IH), 4.96
CC34
120 «M+H]+) (m, IH), 4.51 (d, 7 = 5.6
Hz, 2H), 4.12 (m, IH),
3.69 (t, 7 = 4.8 Hz, 4H),
3.35 (t, 7 = 4.8 Hz, IH) 9.95 (brs, IH), 8.17 (d,
7 = 4.8 Hz, IH), 7.61 (d,
J =6.4 Hz), 7.43 (m,
3H), 7.24 (m, 2H), 6.90
547.82 (t, 7=5.6 Hz, IH), 6.66
CC35 78-79
([Μ+ΗΓ) (d, 7 =8.4 Hz, IH), 6.54
(d,7= 16.0 Hz, IH),
6.33 (dd,7= 16.0, 8.0
Hz, 1H),4.65 (d,7=6.0
Hz, IH), 4.09 (m, IH)
7.39 (m, 4H), 7.28 (m,
IH), 6.54 (d,7= 16.0
Hz, IH), 6.34 (dd, 7 =
497 ([M- 16.0, 8.0 Hz, IH), 4.97 3350, 1705,
CC36
H]-) (brs, 1H),4.38 (d,7 = 1114, 808
6.0 Hz, 2H), 4.10 (m,
IH), 2.9 (s, 3H), 2.7 (s,
3H)
7.49 (d,7=8Hz, IH),
7.41 (d, 7 = 7.2 Hz, 2H),
7.26 (m, 2H), 6.50 (d, 7
= 16 Hz, IH), 6.35 (dd,
515.01
CC37 88-91 7= 16.0, 8.0 Hz, IH),
«M+H]+)
6.0 (brs, IH), 5.73 (brs,
IH), 4.80 (br s, 2H),
4.09 (m, IH), 1.23 (m,
3H)
7.48 (d,7=8Hz, IH),
7.39 (m, 3H), 7.27 (m,
IH), 6.54 (d,7= 16 Hz,
IH), 6.33 (dd,7=6.0,
526.97 8.0Hz, IH), 6.17 (brs,
CC38 63-66
([M+H]+) IH), 5.92 (br s, IH),
5.83 (m, 2H), 5.29 (t, 7
= 15.4 Hz, 2H), 4.80 (br
s, 2H), 4.12 (m, IH),
4.02 (br s, 2H)
7.39 (m, 4H), 7.28 (m,
IH), 6.54 (d,7= 16.0
Hz, IH), 6.34 (dd, 7 =
526.09 3350, 1705,
CC39 16.0, 8.0 Hz, IH), 4.97
([M-H]-) 1114, 808
(brs, 1H),4.38 (d,7 =
6.0 Hz, 2H), 4.10 (m,
IH), 1.53 (s, 9H) 7.46 (m, 5H), 7.29 (m,
IH), 7.20 (m, 3H), 6.55
(d, 7 = 16.0 Hz, IH),
159- 580.25
CC40 6.37 (dd, 7 = 16.0, 8.0
160 ([M-H] )
Hz, IH), 5.62 (br s, IH),
4.55 (d, J = 6.4 Hz, 2H),
4.11 (m, IH)
7.48 (m, IH), 7.43 (m,
3H), 7.38 (m, IH), 7.23
(s, IH), 6.55 (d, 7 = 16.0
512.22 1740, 1701,
CC41 Hz, IH), 6.36 (d, 7 =
([M-H] ) 1114, 808
16.0 Hz, IH), 4.60 (d,
2H), 4.18 (m, IH), 3.85
(s, 3H)
(DMSO- ) 9.45 (br s,
2H), 7.90 (s, 2H), 7.75
(s, IH), 7.46 (br s, IH),
161- 578.96
CC42 7.28 (br s, IH), 6.93 (m,
163 ([M-H]")
IH), 6.75 (br s, IH),
4.80 (m, IH), 4.40 (br s,
2H), 3.90 (br s, 2H)
8.11 (d, 7 = 4.0 Hz, IH),
7.40 (m, 5H), 7.22 (m,
140- 505.39 IH), 6.61 (m, 2H), 6.35
CC43
142 «M+H]+) (m, 2H), 4.94 (br s, IH)
4.61 (d, 7 = 6.4 Hz, 2H),
4.11 (m, IH)
8.41 (s, IH), 7.77 (s,
IH), 7.47 (br s, IH),
7.40 (s, 2H), 6.58 (d, 7 =
536.88 16.0 Hz, IH), 6.45 (dd, 3320, 1674,
CC44
([M-H] ) 7 = 16.0, 8.0 Hz, IH), 1114, 808
4.68 (d, 7 = 4.0 Hz, 2H),
4.14 (m, IH), 3.24 (q, 7
= 10.8 Hz, 2H)
8.41 (s, IH), 7.76 (s,
1H), 7.40 (s, 2H), 7.15
(br s, IH), 6.58 (d, 7 =
494.88 16.0 Hz, IH), 6.44 (dd,
3309, 1659,
CC45 7 = 16.0, 8.0 Hz, IH),
([M-H]") 1115, 808
4.67 (d, 7 = 4.4 Hz, 2H),
4.16 (m, IH), 1.57 (m,
IH), 1.04 (m, 2H), 0.87
(m, 2H) 8.06 (m, IH), 7.61 (m,
4H), 7.48 (s, 2H), 7.44
(d, 7 = 8.0 Hz, IH), 7.38
151- 554.04 (m, IH), 6.42 (m, IH),
CC46
153 5.92 (br s, IH), 4.92 (m,
([M-H]-)
2H), 4.24 (m, IH), 3.12
(m, 2H)
8.06 (m, 2H), 7.61 (m,
4H), 7.48 (s, 2H), 7.44
(d, 7 = 8.0 Hz, IH), 7.38
478.09 3309, 1659,
CC47 (m, 2H), 6.42 (m, IH),
([M+H]+) 1115, 808
4.92 (s, 2H), 1.36 (m,
IH), 1.00 (m, 2H), 0.77
(m, 2H)
8.06 (m, 2H), 7.61 (m,
3H), 7.48 (s, 2H), 7.44
(d, 7 = 8.0 Hz, IH), 7.38
511.05 3309, 1659,
CC48 (m, 2H), 6.42 (m, IH),
([M+H]+) 1115, 808
4.92 (s, 2H), 1.36 (m,
IH), 1.00 (m, 2H), 0.77
(m, 2H)
8.06 (m, IH), 7.98 (m,
IH), 7.61 (m, 3H), 7.48
(s, 2H), 7.44 (d, 7 = 8.0
Hz, IH), 7.38 (m, 2H),
515.33
CC49 84-87 6.42 (m, IH), 4.92 (s,
([M+H]+). 2H), 4.6 (br s, IH), 4.24
(m, IH), 3.21 (m, 2H),
1.2 (t, 7 = 4.6 Hz, 3H)
9.81 (s, IH), 7.90 (s,
IH), 7.84 (s, 2H), 7.34
(d, 7 = 8.4 Hz, 2H), 6.65
(d, 7 = 15.6 Hz, IH),
138- 461.32 6.61 (m, IH), 6.57 (s,
CC50
140 IH), 6.48 (dd, 7 = 15.6, ([M-1H]-)
8.8 Hz, IH), 4.74 (m,
IH), 1.64 (m, IH), 0.75
(m, 4H); 7.56 (brs, IH), 7.4 (s,
3H), 7.3 (m, 3H), 7.05
(brs, IH), 6.8 (d, 7=6
149- 505.31
CC51 Hz, 2H), 6.57 (m, 2H),
150 ([M-H]-) 6.20 (m, 2H), 4.05 (m,
IH), 3.2 (q,7 = 10.4 Hz,
2H)
7.40 (s,2H), 7.18 (s,
IH), 7.08 (s, IH), 6.85
(m, IH), 6.45 (m, IH),
464.87 3309, 1659,
CC52 6.20 (m, IH), 5.55
([M-H]) 1115,808
(s,lH), 4.08 (m, IH),
1.30- 1.10 (m, 4H),
1.90 (m,lH)
7.40 (s,2H), 7.18 (s,
IH), 7.08 (s, IH), 6.85
506 (m, IH), 6.45 (m, IH), 3309, 1659,
CC53
([M+H]+) 6.20 (m, IH), 5.55 1115,808
(s,lH), 4.08 (m, IH),
3.21 (m, 2H)
7.28 (s, 2H), 7.25 (m,
2H),7.10 (d, 7=8.0 Hz,
2H), 6.89 (d,7 = 11.4
504 Hz, IH), 6.07 (br s, IH),
CC54
([M+H]+) 6.01 (m, 1H),4.51 (d, 7
= 5.8 Hz, 2H), 4.34 (m,
IH), 3.12 (q, 7 = 7.5 Hz,
2H)
8.56 (s, IH), 8.11 (s,
1H),7.68 (d, 7=8.4 Hz,
2H), 7.54 (d, 7=8.4 Hz,
398.05 2H),7.38 (t,7= 1.8 Hz,
DCl 93-97
«M+H]+) IH), 7.29 (s, 2H), 6.62
(d,7= 15.6 Hz, IH),
6.42 (dd,7= 15.6, 8.2
Hz, IH), 4.15 (m, IH)
8.59 (s, IH), 8.13 (s,
1H),7.69 (d,7=8.5 Hz,
2H),7.55 (d,7=8.5 Hz,
3121, 1524,
363.0746 2H), 7.41 - 7.29 (m,
DC2 1251, 1165,
(363.075) 4H), 6.64 (d,7= 15.7
1119 Hz, IH), 6.47 (dd, 7 =
15.9, 8.0 Hz, IH), 4.17
(m, IH) 8.56 (s, IH), 8.11 (s,
1H),7.65 (d, 7=8.4 Hz,
2H),7.52 (d, 7=8.3 Hz, 1521, 1246,
329.1144
DC3 2H), 7.40 (m, 5H), 6.61 1219, 1162,
(329.114)
(d,7= 15.8 Hz, IH), 1152, 1107 6.51 (dd,7= 15.9,7.7
Hz, IH), 4.18 (m, IH)
8.56 (s, IH), 8.10 (s,
1H),7.66 (d,7 = 2.0 Hz,
2H),7.52 (d,7=8.8 Hz,
2H), 7.38 (d, 7 = 2.4 Hz, 3147, 1528,
364.11
DC4 2H), 7.34 (d, 7=8.4 Hz, 1494, 1246,
«M+H]+)
2H), 6.61 (d,7= 16.0 1165, 1108 Hz, IH), 6.40 (dd, 7 =
16.0, 7.6 Hz, IH), 4.15
(m, IH)
8.54 (s, IH), 8.10 (s,
1H),7.62 (d,7=8.3 Hz,
2H),7.50 (d,7=8.4 Hz,
2H),7.25 (d,7=8.3 Hz, 3122, 3047,
344.25
DC5 2H),7.20 (d,7=8.0 Hz, 1523, 1252,
«M+H]+)
2H), 6.60 (d,7= 16.0 1160, 1107 Hz, IH), 6.51 (dd, 7 =
16.0, 8.0 Hz, IH), 4.15
(m, IH), 2.37 (s, 3H)
8.55 (s, IH), 8.10 (s,
1H),7.65 (d,7=8.8 Hz,
2H),7.52 (d,7=8.8 Hz,
2H),7.32 (d,7=8.8 Hz, 3124, 2936,
360.28
DC6 2H), 6.95 (d,7=8.8 Hz, 1522, 1249,
«M+H]+)
2H), 6.60 (d,7= 16.0 1160 Hz, IH), 6.56 (dd,7 =
16.0, 7.4 Hz, IH), 4.15
(m, IH), 3.82 (s, 3H)
8.55 (s, IH), 8.10 (s,
1H),7.62 (d,7=8.8 Hz,
2H),7.5 (d, 7 =8.4 Hz,
348 2H), 7.38 (m, 2H), 7.12 3141, 1512,
DC7
«M+H]+) (m, 2H), 6.61 (d,7 = 1246, 1118
16.0 Hz, IH), 6.40 (dd,
7= 16.0, 7.6 Hz, IH),
4.15 (m, IH) 8.57 (s, IH), 8.11 (s,
IH), 7.65 (d, J = 1.2 Hz,
2H),7.52 (d, 7=8.0 Hz,
3116, 1628,
366.13 2H), 6.95 (m, 2H), 6.82
DC8 1524, 1252,
([M+H]+) (m, IH), 6.65 (d,7 =
1168, 1118 16.0 Hz, IH), 6.50 (dd,
7 = 16.0, 8.0 Hz, IH),
4.15 (m, IH)
8.71 (s, IH), 8.20 (s,
1H),7.70 (d, 7=8.0 Hz,
2H),7.57 (d, 7=8.0 Hz,
348.11 2H),7.40 (m, IH), 7.19 3115, 1525,
DC9
«M+H]+) (m, 3H), 6.60 (d,7 = 1248, 1174
16.0 Hz, IH), 6.40 (dd,
7= 16.0, 8.4 Hz, IH),
4.15 (m, IH)
8.75 (s, IH), 8.20 (s,
IH), 7.72 (d, 7=8.4 Hz,
2H), 7.6 (d, 7 =8.4 Hz,
3114, 1526,
348.11 2H), 7.20 - 7.40 (m,
DC10 1259, 1238,
«M+H]+) 4H), 6.60 (d,7= 16.0
1193, 1114 Hz, IH), 6.40 (dd, 7 =
16.0, 8.0 Hz, IH,), 4.60
(m, IH)
8.55 (s, IH), 8.10 (s,
1H),7.65 (d,7=8.8 Hz,
2H), 7.52 (d, 7=8.4 Hz,
75.5- 358.14 2H), 7.01 (s, 3H), 6.60
DC11
78.5 ([M+H]+) (d,7= 16.0 Hz, IH),
6.51 (dd,7= 16.0,7.8
Hz, IH), 4.15 (m, IH),
2.34 (s, 6H)
8.58 (s, IH), 8.10 (s,
1H),7.68 (d,7=8.4 Hz,
2H), 7.53 (m, 4H), 7.2 3055, 2930,
398.05
DC12 (s, IH) 6.62 (d,7= 15.6 1523, 1250,
([M+H]+)
Hz, IH), 6.44 (dd, 7 = 1165 15.6, 8.0 Hz, IH), 4.15
(m, IH) 8.58 (s, IH), 8.10 (s,
IH), 7.62 (d, 7=8.4 Hz,
2H), 7.55 (m, 4H), 7.25 3108, 1523,
396.16
DC13 (m, IH), 6.64 (d,7 = 1249, 1166,
([Μ+ΗΓ)
16.0 Hz, IH), 6.40 (dd, 1127
7 = 16.0, 8.0 Hz, IH),
4.90 (m, IH)
8.58 (s, IH), 8.10 (s,
IH), 7.62 (d, 7=8.4 Hz,
2H), 7.55 (m, 4H), 7.25 3117,2925,
398.05
DC14 (m, IH), 6.67 (d,7 = 1526, 1246,
«M+H]+)
16.0 Hz, IH), 6.40 (dd, 1172, 1117 7 = 16.0, 8.0 Hz, IH),
5.00 (m, IH)
8.58 (s, IH), 8.10 (s,
1H),7.66 (d, 7=8.0 Hz,
2H), 7.52 (m, 3H), 7.40
(d, 7 = 8.0 Hz, IH), 7.30 3120, 1524,
397.95
DC15 (dd,7=8.4, 2.9 Hz, 1267, 1176,
«M+H]+)
IH), 6.64 (d,7= 16.0 1112 Hz, IH), 6.40 (dd, 7 =
16.0, 8.0 Hz, IH), 4.90
(m, IH)
8.61 (s, IH), 8.13 (s,
IH), 7.92 (s, IH), 7.86
(s,2H), 7.70 (d,7 = 7.0
466 Hz, 2H), 7.54 (d, 7 = 7.0
DC16
«M+H]+) Hz, 2H), 6.67 (d,7 =
16.0 Hz, IH), 6.46 (dd,
7= 16.0, 8.0 Hz, IH),
4.35 (m, IH)
8.58 (s, IH), 8.1 (s, IH),
7.68 (d, 7 =8.4 Hz, 2H),
7.54 (d, 7 =8.4 Hz, 2H), 3122, 3076,
430.06 7.51 (s, IH), 7.42 (s, 2929, 1523,
DC17
([M+H]+) IH), 6.68 (d,7= 16.0 1250, 1168,
Hz, IH), 6.35 (dd,7 = 1114 16.0, 8.0, Hz, IH), 4.98
(m, IH) 8.57 (s, IH), 8.11 (s,
1H),7.69 (d, 7=8.8 Hz,
2H), 7.54 (d, 7=8.4 Hz,
429.91
DC18 92-95 2H), 7.42 (s, 2H), 6.65
([Μ+ΗΓ)
(d,7= 16.0 Hz, IH),
6.40 (dd,7= 16.0, 8.0
Hz, IH), 4.10 (m, IH)
8.58 (s, IH), 8.12 (s,
1H),7.68 (d,7=8.0 Hz,
2H), 7.64 (s, IH), 7.59
430.321 (s, IH), 7.55 (m, 3H),
DC19 97-99
«M+H]+) 6.60 (d,7= 16.0 Hz,
IH), 6.40 (dd,7= 16.0,
8.0 Hz, IH), 4.22 (m,
IH)
8.58 (s, IH), 8.15 (s,
IH), 7.70 (d, 7=8.4 Hz,
2H),7.58 (d,7=8.4 Hz, 2937, 1524,
427.0463
2H), 7.36 (s, 2H), 6.62 1482, 1278,
DC20 (427.0466
(d,7= 16.0 Hz, IH), 1249, 1166,
) 6.43 (dd,7= 16.0, 8.0 1112
Hz, IH), 4.12 (m, IH),
3.88 (s, 3H)
8.42 (s, IH), 7.60 (d,7 =
8.0 Hz, 2H), 7.50 (d,7 =
8.0 Hz, 2H), 7.40 (s,
3108, 1572,
412.04 IH), 7.22 (s, 2H), 6.60
DC21 1531, 1242,
«M+H]+) (d,7= 16.0 Hz, IH),
1172, 1104 6.42 (dd,7= 16.0, 8.0
Hz, IH), 4.15 (m, IH),
2.5 (s, 3H)
8.62 (s, IH), 7.78 (d,7 =
8.0 Hz, 2H), 7.60 (d,7 =
8.0 Hz, 2H), 7.40 (s,
147- 441.01
DC22 IH), 7.30 (s, 2H), 6.67
149 ([M-H]-)
(d,7= 16.0 Hz, IH),
6.48 (dd, 7= 16.0, 8.0
Hz, IH), 4.15 (m, IH) 7.95 (s, IH), 7.35 (d,/ =
8.0 Hz, 2H), 7.46 (d,/ =
8.0 Hz, 2H), 7.39 (s,
412.05 IH), 7.29 (s, 2H), 6.67
DC23 1112, 799
([Μ+ΗΓ) (d,/ = 16.0 Hz, IH),
6.45 (dd,/ = 16.0, 8.0
Hz, IH), 4.12 (m, IH),
2.51 (s, 3H)
8.10 (s, IH), 7.52 (d,/ =
8.0 Hz, 2H), 7.42-7.38
(m, 3H), 7.28 (s, 2H),
133- 440.03
DC24 6.67 (d,/ = 16.0 Hz,
134 ([M+H]+)
IH), 6.45 (dd, 7=16.0,
8.0 Hz, IH), 4.16 (m,
IH), 2.79 (s, 3H)
7.97 (s, IH), 7.59 (d,/ =
8.0 Hz, 2H), 7.53 (d,/ =
8.0 Hz, 2H), 7.38 (m,
442.02 IH), 7.29 (s, 2H), 6.65 1167, 1114,
DC25
([M-H]-) (d,/ = 16.0 Hz, IH), 800
6.42 (dd,/ = 16.0, 8.0
Hz, IH), 4.17 (m, IH),
2.74 (s, 3H)
8.12 (s, IH), 7.49 (d,/ =
8.0 Hz, 2H), 7.40-7.37
(m 3H), 7.28 (s, 2H),
1689, 1253,
464.03 6.66 (d,/ = 16.0 Hz,
DC26 1166, 1114,
([M-H]) IH), 6.44 (dd,/ = 16.0,
979, 964 8.0 Hz, IH), 4.14 (m,
IH), 3.22 (m, IH), 1.09
-1.16(m, 4H)
8.19 (s, IH), 7.64 (d,/ =
7.2 Hz, 2H), 7.55 (d, 7.2
Hz, 2H), 7.39 (s, IH),
1571, 1331,
473.94 7.30 (s,2H), 6.62 (d,/ =
DC27 1170, 1113,
([M-H]) 16.0 Hz, IH), 6.42 (dd,
764 7=8.0, 16.0 Hz, IH),
4.18 (m, IH), 3.58 (s,
3H) 8.79 (s, IH), 8.18 (s,
IH), 7.80 (m, 3H), 7.52
(m, 2H), 7.24 (m, IH), 3126, 2233,
421.22
DC28 6.63 (d, / = 16.0 Hz, 1516, 1250,
([Μ+ΗΓ)
IH), 6.54 (d, / = 16.0, 1165, 1109 7.6 Hz, IH), 4.19 ( m,
IH)
8.80 (s, IH), 8.2 (s, IH),
7.75 - 7.82 (m, 3H),
7.41 (t, J = 2 Hz, IH),
421.22 3005, 1716,
DC29 7.26 (m, 2H), 6.65 (d, J
«M+H]+) 1363, 1223
= 16.0 Hz, IH), 6.52
(dd, / = 16.0, 7.6 Hz,
lH), 4.16 (m, IH)
8.81 (s, IH), 8.20 (s,
IH), 7.94 (s, IH), 7.85
(m, 3H), 7.79 (m, 2H), 2964, 2234,
489.17
DC30 6.70 (d, / = 16.0 Hz, 1289, 1166,
«M+H]+)
IH), 6.58 (dd, / = 16.0, 1136 8.0 Hz, IH), 4.35 (m,
IH)
8.80 (s, IH), 8.20 (s,
IH), 7.82 (m, 3H), 7.4
117- 455.27 (s, 2H), 6.62 (d, 7 = 16.0
DC31
118 «M+H]+) Hz, IH), 6.52 (dd, / =
16.0, 8.0 Hz, IH), 4.18
(m, IH)
8.82 (s, IH), 8.22 (s,
IH), 7.82-7.78 (m, 3H),
388.0705 3126, 2234,
7.38-7.30 (m, 3H), 6.62
DC32 (388.0703 1520, 1280,
(d, / = 16.1 Hz, IH),
) 1164, 1112
6.56 (dd, / = 16.1, 6.8
Hz, IH), 4.18 (m, IH)
8.80 (s, IH), 8.20 (s,
IH), 7.82-7.80 (m, 3H), 3122, 3086,
455.22 7.70-7.50 (m, 3H), 6.65 2234, 1517,
DC33
([M-H]-) (d, 7 = 16.9 Hz, IH), 1327, 1168,
6.54 (dd, / = 16.9, 6.8 1113 Hz, IH), 4.25 (m, IH) 8.85 (s, IH), 8.23 (brs,
IH), 7.83-7.78 (m, 3H), 3122, 2934,
452.0412 7.33 (s,2H), 6.69 (d,/ = 2231, 1516,
DC34 (452.0419 14.9 Hz, IH), 6.50 (dd, 1480, 1248,
) /= 14.9, 7.2 Hz, IH), 1211, 1165,
4.15 (m, IH), 3.90 (s, 1111 3H)
8.60 (s, IH), 8.20 (s,
IH), 7.82 (m, 3H), 7.28
2233, 1518,
439.01 (m, 2H), 6.65 (d,/ =
DC35 1250, 1169,
([M-H]-) 16.0 Hz, IH), 6.48 (dd,
1035,817 /= 16.0, 8.0 Hz, IH),
4.20 (m, IH)
8.70 (s, IH), 7.80 (m,
3H), 7.40 (s, IH), 7.28 2927, 2233,
437.25 (s,2H), 6.63 (d,/= 16.0 1572, 1531,
DC36
([M+H]+) Hz, IH), 6.50 (dd,/ = 1248, 1166,
16.0, 8.0 Hz, IH), 4.18 1112 (m, IH), 2.50 (s, IH)
8.86 (s, IH), 7.89 (m,
3H), 7.40 (s, IH), 7.30
109- 466.10 (s,2H), 6.68 (d,/= 16.0
DC37
111 ([M-H]") Hz, IH), 6.57 (dd, / =
16.0, 8.0 Hz, IH), 4.18
(m, IH)
8.58 (s, IH), 7.75 (m,
3H), 7.40 (s, IH), 7.28
436.11 (s,2H), 6.61 (d,/= 16.0
DC38 96-98
([M-H]") Hz, IH), 6.42 (dd, / =
16.0, 8.2 Hz, IH), 4.40
(brs, 2H), 4.15 (m, IH)
8.65 (s, IH), 8.18 (brs,
IH), 7.80-7.70 (m, 3H),
7.40 (s, IH), 7.27 (s,
3352, 2237,
224- 480.30 2H), 7.36 (m, IH), 7.28
DC39 1707, 1163,
226 «M+H]+) (m, 2H), 6.60 (d,/ =
841 16.8 Hz, IH), 6.47 (m,
lH),4.16(m, IH), 2.40
(br s, 3H)
8.86 (s, IH), 7.88 (m,
3H), 7.44 (s, 2H), 6.67
436.11
DC40 70-73 (d,/= 16.0 Hz, IH),
([M-2H])
6.56(dd,/= 16.07.6
Hz, IH), 4.19 (m, IH) (DMSO- ) 8.72 (s,
IH), 8.26 (s, IH), 8.01
(d, 7=8.4 Hz, IH), 7.91
(s,2H), 7.77 (d, 7=8.4
469.95
DC41 72-75 Hz, IH), 6.42 (dd, 7 =
([M-H]-)
15.6, 9.2 Hz, IH), 6.83
(d,7= 15.6 Hz, IH),
5.87 (s, 2H), 4.89 (m,
IH)
8.78 (s, 2H), 7.83 (s,
IH), 7.80 (m, 2H), 7.42
(s,2H), 6.65 (d,7= 16.4
104- 609.98 Hz, IH), 6.51 (dd, 7 = 2234, 1714,
DC42
107 ([M+H]+) 16.4, 7.8 Hz, IH), 4.17 1114, 807
(m, IH), 42.16 (m, 2H),
1.25 (m, 4H), 1.00 (m,
4H),
(DMSO- ) 10.94 (br s,
IH), 8.36 (s, IH), 8.08
(m, 7 =8.4 Hz, IH),
7.91 (s,2H), 7.84 (d,7 = 3233, 2233,
109- 540.04
DC43 8.4 Hz, IH), 7.13 (dd, 7 1699, 1114,
112 ([M+H]+)
= 15.6, 9.2 Hz, IH), 807 6.87 (d,7= 15.6 Hz,
IH), 4.92 (m, IH), 1.99
(br s, IH), 0.82 (s, 4H)
8.33 (s, IH), 8.23 (s,
IH), 7.66 (s, IH), 7.60
(s, IH), 7.41 (m, IH),
435.26 7.28 (m, 2H), 6.62 (d, 7 2236,1510,
DC44
[M-H]" = 16.0 Hz, IH), 6.51 1114, 801
(dd,7= 16.0, 7.8 Hz,
lH),4.16(m, IH), 2.20
(s, 3H)
8.36 (s, IH), 8.23 (s,
IH), 7.66 (s, IH), 7.60
468.87 (s, IH), 7.41 (s, 2H),
DC45 75-78 6.62 (d, 7= 16.4 Hz,
[M-H]" IH), 6.51 (dd,7= 16.4,
7.6 Hz, IH), 4.16 (m,
IH), 2.20 (s, 3H) 13C NMR (δ)3
155.63, 153.27,
8.83 (s, IH), 8.21 (s, 153.12, IH), 7.83 (d, J = 8.5 Hz, 143.01, 1H), 7.61 (d, 7 = 1.9 Hz, 137.89, IH), 7.52 (dd, J = 8.4, 136.25,
411.4
DC46 I.9 Hz, IH), 7.28 (d, 7 = 134.03,
([M]+) 3.8 Hz, 2H), 6.93 (d, / = 133.88,
II.5 Hz, IH), 6.26 - 132.23, 6.20 (m, IH), 4.22 (m, 131.23, IH) 131.18,
129.20, 126.17, 125.04, 124.99
8.51 (s, IH), 8.14 (s,
IH), 7.75 (s, IH), 7.5
(m, 2H), 7.4 (s, IH),
139- 474.16
DC47 7.30 (m, 2H), 6.60 (d, /
141 ([M-H] )
= 16.0 Hz, IH), 6.50
(dd, / = 16.0, 8.0 Hz,
IH), 4.15 (m, IH)
8.69 (s, IH), 8.14 (s,
1H), 7.96 (d, 7 = 4.8 Hz,
IH), 7.39-7.27 (m, 5H),
124- 414.05
DC48 6.95 (d, / = 16.0 Hz,
126 [M-H]" IH), 6.51 (dd, 7 = 16.0,
7.6 Hz, IH), 4.13 (m,
IH)
8.57 (s, IH), 8.14 (s,
IH), 7.60 (m, 2H), 7.44
463.96 (m, 3H), 6.95 (d, / =
DC49 81-83
[M-H]" 16.0 Hz, IH), 6.51 (dd,
J = 16.0, 7.6 Hz, IH),
4.13 (m, IH)
8.56 (s, IH), 8.13 (s,
1H), 7.59 (d, 7 = 1.2 Hz,
2H), 7.44 (m, 2H), 7.28
140- 430.07
DC50 (m, 2H), 6.61 (d, 7 = 1110, 803
143 [M-H]") 16.0 Hz, IH), 6.47 (dd,
J = 16.0, 8.0 Hz, IH),
4.15 (m, IH) 8.32 (s, IH), 8.15 (s,
IH), 7.82 (s, IH), 7.73
(d, 7=8.4 Hz, IH), 7.53
(d, 7=8.4 Hz, IH), 7.41
118- 464.22
DC51 (s, IH), 7.29 (s, 2H),
121 ([M-H]-)
6.70 (d,7= 15.6 Hz,
IH), 6.50 (dd,7= 15.6,
8.0 Hz, IH), 4.20 (m,
IH)
9.99 (s, IH), 8.42 (s,
IH), 8.12 (s, IH), 8.01
3123, 3079, (s, IH), 7.68 (m, IH),
2925, 1692,
7.44 (m, IH), 7.33 (m,
DC52 1571, 1512,
IH), 7.22 (s, 2H), 6.62
1253, 1164, (d, 7 =16.7 Hz, IH),
1111
6.45 (dd,7= 16.7, 9.3
Hz, IH), 4.10 (m, IH)
8.30 (m, IH), 8.00 (br s,
IH), 7.75 (m, 1H),7.68
(m, IH), 7.55 (m, IH),
7.36 (m, IH), 7.28 (m, 3250, 3043,
DC53
2H), 6.70 (m, IH), 6.58 1683, 1116 (br s, IH), 6.33 (m, IH),
5.88 (m, 2H),4.10(m,
IH)
8.40 (s, IH), 8.13 (s,
IH), 8.02 (s, IH), 7.76
(d, 7 = 8.4 Hz, IH), 7.59
(d, 7 = 8.0 Hz, IH), 7.4
441.07
DC54 56-58 (s, IH), 7.29 (m, 2H),
([M-H])
6.69 (d,7= 15.6 Hz,
IH), 6.57 (dd,7= 15.6,
7.8 Hz, IH), 4.15 (m,
IH)
8.37 (s, IH), 8.18 (s,
IH), 7.39 (s, IH), 7.30
(m, 2H), 7.19 (d, 7= 8.0
412.97 Hz, IH), 6.90 (m, 2H),
DC55
([M+H]+) 6.55 (d,7= 15.6 Hz,
IH), 6.38 (dd,7= 15.6,
8.2 Hz, IH), 4.20 (m,
IH), 2.50 (br s, 2H) 9.59 (brs, IH), 8.55 (s,
IH), 8.47 (s, 2H), 8.23
(s, IH), 7.30 (m, 4H),
175- 453 ([M-
DC56 6.62 (d,7 = 16.0 Hz,
177 H]-)
IH), 6.40 (dd,7 = 16.0,
8.0 Hz, IH), 4.15 (m,
IH), 2.20 (s, 3H)
8.33 (s, IH), 8.16 (s,
IH), 7.38 (s, IH), 7.29
(s,2H), 7.15 (d, 7 = 7.6
Hz, IH), 6.80 (d, 7 = 7.6 3342,3112,
426.0627
Hz, IH), 6.74 (m, IH), 2931, 1606,
DC57 (426.0626
6.60 (d,7= 15.6 Hz, 1583, 1574,
) IH), 6.35 (dd,7=15.6, 1528, 1153
8.4 Hz, IH), 5.40 (brs,
lH),4.15(m, IH), 2.90
(s, 3H)
(DMSO- ) 8.76 (s,
IH), 8.16 (s, 1H),7.90
(br s, IH), 7.83 (s, IH),
7.70 (d, 7 = 7.9 Hz, IH), 3403, 3304,
440.0424
7.71-7.67 (m, 3H), 7.58 3178, 1674,
DC58 94-97 (440.0419
(d, 7 = 7.9 Hz, IH), 7.52 1571, 1169,
) (brs, IH), 7.00 (dd, 7 = 1108
15.8, 8.7 Hz, IH), 6.85
(d, 7= 15.8 Hz, IH),
4.85 (m, IH)
(DMSO- ) 9.00 (s,
IH), 8.63 (s, IH), 8.17
(s, IH), 7.70-7.59 (m,
DC59 87-90 5H),7.00 (dd,7= 16.2,
9.7 Hz, IH), 6.85 (d,7 =
16.2 Hz, IH), 5.90 (br s
2H), 4.83 (m, IH)
8.32 (s, IH), 8.10 (s,
IH), 7.97 (s, IH), 7.65
(d, 7 = 8.1 Hz, IH), 7.47
(d, 7 = 8.1 Hz, IH), 7.40
469.0577 2987, 1725,
(m, IH), 7.28 (s, 2H),
DC60 (469.0572 1518, 1275,
6.62 (d,7= 16.5 Hz,
) 1166, 1113
IH), 6.49 (dd,7= 16.5,
7.7 Hz, IH), 4.23-4.04
(m, 3H), 1.15 (t, 7= 8.0
Hz, 3H) (DMSO- ) 9.90 (s,
IH), 8.17 (s, IH), 8.15
(m, IH), 7.90 (m, IH),
7.71 (m, 2H), 7.67 (m,
442.15
130- IH), 7.62 (d, 7 = 7.3 Hz,
DC61 ([Μ+ΗΓ)
132 1H),7.03 (dd,7 = 16.5,
8.3 Hz, IH), 6.62 (d,7 =
16.5 Hz, IH), 4.87 (m,
IH)
8.27 (s, IH), 8.23 (s,
IH), 7.40 (m, 3H), 7.30
(m, 3H), 6.64 (d,7 = 1513, 1252,
412.10
DC62 16.0 Hz, IH), 6.45 (dd, 1166, 1112,
«M+H]+)
7 = 16.0, 8.0 Hz, IH), 801 4.19 (m, 1H),2.21 (s,
3H)
8.26 (s, IH), 8.12 (s,
1H),7.42 (s, 2H),7.18-
2928,
446.01 7.28 (m, 3H), 6.62 (d, 7
2525,1249,
DC63 = 15.6 Hz, IH), 6.39
«M+H]+) 1169, 1114,
(dd,7 = 15.6, 9.4 Hz,
809 1H),4.10 (m, IH), 2.25
(s, 3H)
8.84 (d, 7=5.8 Hz, 2H),
8.33 (s, IH), 8.20 (s,
IH), 7.75 (m, IH), 7.60
(d, 7 = 28.6 Hz, IH),
475.03 7.58-7.48 (m, 3H), 7.42 1683, 1167,
DC64
([M+H]+) (m, IH), 7.28 (s, 2H), 650, 479
6.71 (d,7= 16.9 Hz,
IH), 6.39 (dd,7= 16.9,
8.2 Hz, IH), 4.15 (m,
IH)
8.55 (s, IH), 8.12 (s,
IH), 7.55 (m, 3H), 7.39
(m, IH), 7.30 (d,7= 1.6
412.05 Hz, IH), 6.85 (d,7 =
DC65 722, 111
([M+H]+) 16.0 Hz, IH), 6.41 (dd,
7= 16.0, 8.0 Hz, IH),
4.17 (m, 1H),2.40 (s,
3H) 8.59 (s, 1H), 8.14 (s,
1H), 7.94 (s, 1H), 7.70
(d, 7=8.0 Hz, 1H), 7.61
468.26 (d, 7 =8.0 Hz, 1H), 7.43
DC66 60-61
([M+H]+) (s,2H), 7.23 (d,7 = 16.0
Hz, 1H), 6.41 (dd, 7 =
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+H]+) (s,2H), 7.03 (d,7 = 16.0
Hz, 1H), 6.43 (dd, 7 =
16.0, 8.0 Hz, 1H), 0.21
(m, 1H)
8.71 (s, 1H), 8.18 (s,
1H), 7.71 (d, 7=8.0 Hz,
2H),7.55 (d, 7=8.0 Hz,
412.03
DC68 2H), 7.37 (s, 1H), 7.28
«M+H]+)
(m, 2H), 6.08 (d,7 =
16.0 Hz, 1H), 4.26 (m,
1H), 2.05 (s, 3H)
8.56 (s, 1H), 8.11 (s,
1H),7.70 (d, .7=8.5 Hz,
2H),7.56 (d, 7=8.5 Hz,
162- 414.03
DC69 2H), 7.54 (m, 2H), 7.40
168 ([M+H]+)
(m, 1H), 6.91 (d,7 =
16.5 Hz, 1H), 6.66 (d, 7
= 16.5 Hz, 1H)
8.58 (s, 1H), 8.13 (s,
1H), 7.73 (d, 7=8.7 Hz,
2H),7.60 (d,7=8.7 Hz,
99- 428.05 2H), 7.46 (m, 2H), 7.42
DC70
103 ([M+H]+) (m, 1H), 6.85 (d,7 =
16.2 Hz, 1H), 6.40 (d, 7
= 16.2 Hz, 1H), 3.42 (s,
3H)
¾ NMR spectral data were acquired using a 400 MHz instrument in CDC13 except where noted. HRMS data are noted observed value (theoretical value).
Table 2A: Analytical Data for Compounds in Table 1A. R
Compound 19F
ESIMS ]H NMR (5)a
Number NMR (thin film) cm"1
(300 MHz, DMSO-i¾
8.70 (t, 7 = 6.9 Hz, IH),
8.65 (s, IH), 7.93 (s,
IH), 7.92-7.91 (m, 2H),
7.60 (d, 7 = 7.8 Hz,
3305, IH), 7.40 (d, J = 8.1
1653,
669.0 Hz, IH), 7.01 (dd, 7 =
Fl 1163,
UM+H]+) 15.9, 9.3 Hz, IH), 6.77
750, (d, 7 = 15.9 Hz, IH),
555 4.86 (t, 7 = 9.6 Hz, IH),
4.73-4.66 (m, IH),
4.04-3.80 (m, 2H), 3.59
(d , 7 = 6.3 Hz, 2H),
3.27 (s, 3H).
(300 MHz, DMSO-d6)
8.69 (t, 7 = 6.0 Hz, IH),
8.41 (s, IH), 7.89 (s,
IH), 7.48 (d, 7 = 8.4
Hz, IH), 7.39-7.29 (m,
3419, 3H), 6.88 (dd, 7 = 16.2,
603.0 1645,
F4 8.4 Hz, IH), 6.75 (d, 7
([M-H]-) 1163,
= 15.6 Hz, IH), 4.85 (t,
748 7 = 8.4 Hz, IH), 4.71- 4.69 (m, IH), 3.97-3.86
(m, 2H), 3.59 (d , 7 =
6.3 Hz, 2H). 3.27 (s,
3H), 2.33 (s, 3H).
(300 MHz, DMSO-i¾
8.79 (bs, IH), 8.65 (s, 7
= 6.0 Hz, IH), 7.98 (s,
IH), 7.92-7.87 (m, 3H),
7.53 (d, 7 = 7.8 Hz,
3300, IH), 7.09 (dd, 7 = 15.9,
658.8 1660,
F6 9.3 Hz, IH), 6.89 (d, 7
UM+H]+) 1165,
= 15.9 Hz, IH) 4.89 (t,
747 7 = 9.0 Hz, IH), 4.74- 4.67 (m, IH), 3.98-3.87
(m, 2H), 3.57 (d , 7 =
6.3 Hz, 2H). 3.26 (s,
3H). 7.64 (d, 7=1.6 Hz,
IH), 7.55 (d, 7=8.0
Hz, IH), 7.41 (s, 3H),
7.39 (d, 7= 1.5 Hz,
IH), 7.20 (d,7 = 7.3
(376
Hz, IH), 6.54 (d,7 =
MHz,
16.3 Hz, IH), 6.41 (dd,
CDC13)
655 ([M- 7= 15.9, 7.8 Hz, IH),
F13A H]-) δ , - 4.67 (ddd,7 = 7.1,4.5,
68.55, 2.4 Hz, IH), 4.35 (ddd,
-72.34.
7= 11.6, 4.0, 2.4 Hz,
IH), 4.10 (d, 7 = 7.9
Hz, IH), 3.95 (m, 2H),
3.75 (ddd, 7= 11.7, 9.6,
4.6 Hz, IH), 2.94 (dd, 7
= 9.7, 4.0 Hz, IH).
(300 MHz, DMSO-d6)
8.58 (t,7=6.3 Hz, IH),
8.46 (s, IH), 7.93 (s,
IH), 7.92-7.91 (m, 2H),
7.61 (d, 7 = 8.1 Hz,
IH), 7.46 (d,7 = 7.8 3296,
655.0 Hz, IH), 7.01 (dd, 7 = 1653,
F13B
UM+H]+) 15.3, 8.7 Hz, IH), 6.77 1164,
(d,7= 15.6 Hz, IH), 749 4.97 (t, 7= 5.4 Hz, IH),
4.86-4.80 (m, IH),
4.54-4.50 (m, IH),
3.97-3.89 (m, 2H), 3.66
(d, 7= 5.1 Hz, 2H).
(DMSO-i¾ 8.80 (t,7 =
6.4 Hz, IH), 8.66 (s,
IH), 7.94 (s, IH), 7.92- 7.88 (m, 3H) 7.50 (d, 7
3419, = 7.2 Hz, IH), 7.08 (dd,
1652,
681.97 7= 16.0, 8.8 Hz, IH),
F19 1165,
([M+H]+) 6.88 (d,7= 15.6 Hz,
750, IH), 4.88-4.83 (m, IH),
559 4.63 (bs, IH), 3.96-3.92
(m, 2H), 3.08 (d , 7 =
4.8 Hz, 2H), 2.20 (s,
6H). (300 MHz, OMSO-d6)
8.60 (t, 7 = 6.3 Hz, 1H),
8.54 (s, 1H), 7.98 (s,
1H), 7.92-7.91 (m, 3H),
7.59 (d, 7 = 7.8 Hz,
3410, 1H), 7.09 (dd, 7 = 15.6,
645.1 1654,
F1319 8.7 Hz, 1H), 6.89 (d, 7
UM+H]+) 1165,
= 15.9 Hz, 1H), 4.99 (t,
808 7 = 5.4 Hz, 1H), 4.89- 4.83 (m, 1H), 4.53-4.50
(m, 1H), 3.93-3.90 (m,
2H), 3.66 (d , 7 = 5.7
Hz, 2H).
(300 MHz, DMSO-i¾
8.58 (t, 7 = 6.0 Hz, 1H),
8.18 (s, 1H), 7.89 (s,
1H), 7.48 (d, 7 = 8.4
Hz, 1H), 7.44-7.35 (m,
3H), 7.59 (d, 7 = 7.8 3305, Hz, 1H), 6.89 (dd, 7 = 2927,
591.1
F1320 15.6, 8.4 Hz, 1H), 6.75 1644,
([M+H]+)
(d, 7 = 15.6 Hz, 1H), 1164, 4.96 (t, 7 = 6.0 Hz, 1H), 748 4.86-4.80 (m, 1H),
4.51-4.47 (m, 1H),
3.97-3.88 (m, 2H), 3.65
(d , 7 = 6.0 Hz, 2H).
2.35 (s ,3H).
(DMSO-i¾ 8.80 (t, 7 =
6.4 Hz, 1H), 8.66 (s,
1H), 7.94 (s, 1H), 7.92- 7.88 (m, 3H), 7.50 (d, 7
= 7.2 Hz, 1H), 7.08 (dd, 3414,
672.01 7 = 16.0, 8.8 Hz, 1H), 1668,
F1329
UM+H]+) 6.88 (d, 7 = 15.6 Hz, 1165,
1H), 4.88-4.83 (m, 1H), 750. 4.63 (bs, 1H), 3.96-3.92
(m, 2H), 3.08 (d , 7 =
4.8 Hz, 2H), 2.20 (s,
6H).
¾ NMR spectral data were acquired using a 400 MHz instrument in CDC13 except where noted. HRMS data are noted observed value (theoretical value).
Table 2B: Analytical Data for Compounds in Table IB.
Figure imgf000358_0001
(101
MHz, CD3OD) δ
169.08, δ 125.68
(q,/ = 277.9 Hz),
(CD3OD) 4.09- 61.54,
131- 3.88 (m, 4H), 3.83 56.34,
C6
138 (dd,/ = 11.5,6.4 41.47
Hz, 1H). (q,/ =
34.9
Hz); 19F NMR
(376 MHz, DMSO- d6)5- 70.64. DMSO-d6) 8.56
(t, 7 = 6.3 Hz,
1H), 7.37-7.21 (m,
5H), 5.04 (d,/ =
(376 3.8 Hz, 2H), 4.89
MHz,
161- (t, 7 = 5.7 Hz,
C7 DMSO- 163 1H),4.11 (dt,/ =
d6)5- 7.9, 5.7 Hz, 1H),
70.65.
3.89 (ddd,/ =
15.9, 8.0, 5.0 Hz,
2H), 3.70 - 3.46
(m, 2H).
(300 MHz,
DMSO-i¾ δ 8.73
(s, 1H), 7.30 (d, J
= 8.1 Hz, 1H),
103- 362.75
C8 4.38-4.37 (m, 1H),
106 ([M-H]-)
4.31-4.22 (m, 2H),
3.95-3.89 (m, 2H),
3.17 (s, 3H), 1.39
(s, 9H). (300 MHz,
DMSO-i¾ 8.61 (t,
7 = 6.3 Hz, IH),
6.77 (d, 7 = 7.8
Hz, IH), 4.09-
C9
4.04 (m, IH),
3.95-3.83 (m, 2H),
2.40 (d , 7 = 7.2
Hz, 2H), 2.13 (s,
6H), 1.37 (s, 9H).
(DMSO-d6) 9.5
(bs, IH), 8.65 (s,
CIO 2H), 4.51-4.49 (m,
IH), 4.06-4.02 (m,
2H), 3.56 (bs,
2H), 2.80 (s, 6H).
¾ NMR spectral data were acquired using a 400 MHz instrument in CDC13 except where noted. HRMS data are noted observed value (theoretical value).
Table 3: Assays Results
Figure imgf000361_0001
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 Compound BAW CEW GPA
Number Rating Rating Rating
AC48 A A B
AC49 A A B
AC50 A D B
AC51 A A B
AC52 A A B
AC53 A A B
AC54 A A B
AC57 A A B
AC58 A A B
AC59 A A B
AC60 A A B
AC61 A A B
AC62 A A D
AC63 A A B
AC64 A A B
AC65 A A B
AC66 A A B
AC67 A A B
AC68 A A D
AC69 A A A
AC70 D D B
AC71 A A B
AC72 A A B
AC75 A A B 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
ACIOO C C C Compound BAW CEW GPA
Number Rating Rating Rating
AC101 D D C
AC102 D A C
AC103 A A D
AC104 A A B
AC105 A A D
AC106 A A B
AC107 B A D
AC108 B D D
AC109 D D C
AC110 A A C
AC111 A A C
AC112 A A C
AC113 B A D
AC114 A B D
AC115 A A D
AC116 C C C
AC117 A D B
AC118 A D D
BC1 A A D
BC2 A A D
BC3 A A D
BC4 A A B
BC5 A A B
BC6 A A D Compound BAW CEW GPA
Number Rating Rating Rating
BC7 A A D
BC8 A A B
BC9 A A D
BC10 A A B
BC11 C C C
BC12 C C C
BC13 A A D
BC14 A D D
CC1 D D D
CC2 A A B
CC3 A A D
CC4 A B B
CC5 A A B
CC6 A A B
CC7 A A B
CC8 A A D
CC9 A A B
CC10 A A B ecu A A B
CC12 D D B
CC13 A A B
CC14 A D D
CC15 A A B
CC16 A A B 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 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
CC50 A A D
CC51 A A D
CC52 A D D
CC53 D D B
CC54 A A C
DC1 A A D
DC2 D D C
DC3 B D C
DC4 A D C
DC5 D D C
DC6 D D C
DC7 A D C
DC8 A D C
DC9 D D C
DC10 D D C Compound BAW CEW GPA
Number Rating Rating Rating
DC11 A D C
DC12 A A B
DC13 A A C
DC14 D D C
DC15 D D C
DC16 A A C
DC17 A A C
DC18 A A C
DC19 A A C
DC20 A D C
DC21 D D C
DC22 D D C
DC23 D A C
DC24 D D C
DC25 D D C
DC26 D D C
DC27 D D C
DC28 A A B
DC29 A A C
DC30 A A C
DC31 A A B
DC32 D D C
DC33 A A C
DC34 A A B 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
DC50 A A c
DC51 A A c
DC52 D D c
DC53 D A c
DC54 D D c
DC55 D D c
DC56 D D c
DC57 A A c
DC58 D D c Compound BAW CEW GPA
Number Rating Rating Rating
DC59 D D C
DC60 A A C
DC61 D D C
DC62 A A C
DC63 A A C
DC64 D D C
DC65 D A C
DC66 A A C
DC67 A A C
DC68 A A C
DC69 D D C
DC70 A A C
Table 3A: Assays Results for Subsequently Exemplified Prophetic Compounds
Figure imgf000371_0001

Claims

WE CLAIM
Figure imgf000372_0001
Formula One
wherein:
(a) Rl is selected from
(1) H, F, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, S(C C8)alkyl, S(halo(C C8)alkyl), S(0)(C C8)alkyl, S(0)(halo(Ci-C8)alkyl), S(0)2(C C8)alkyl, S(0)2(halo(C C8)alkyl), N(R14)(R15),
(2) substituted (Ci-C8)alkyl, wherein said substituted (Ci-C8)alkyl has one or more substituents selected from CN and N02,
(3) substituted halo(Ci-C8)alkyl, wherein said substituted halo(d- C8)alkyl, has one or more substituents selected from CN and N02,
(4) substituted (Ci-C8)alkoxy, wherein said substituted (Ci-C8)alkoxy has one or more substituents selected from CN and N02, and
(5) substituted halo(Ci-C8)alkoxy, wherein said substituted halo(C
C8)alkoxy has one or more substituents selected from CN and N02;
(b) R2 is selected from
(1) H, F, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, S(C C8)alkyl, S(halo(C C8)alkyl), S(0)(C C8)alkyl, S(0)(halo(Ci-C8)alkyl), S(0)2(C C8)alkyl, S(0)2(halo(C C8)alkyl), N(R14)(R15),
(2) substituted (Ci-C8)alkyl, wherein said substituted (Ci-C8)alkyl has one or more substituents selected from CN and N02,
(3) substituted halo(Ci-C8)alkyl, wherein said substituted halo(d- C8)alkyl, has one or more substituents selected from CN and N02,
(4) substituted (Ci-C8)alkoxy, wherein said substituted (Ci-C8)alkoxy has one or more substituents selected from CN and N02, and (5) substituted halo(Ci-C8)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, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, S(C C8)alkyl, S(halo(C C8)alkyl), S(0)(C C8)alkyl,
S(0)(halo(Ci-C8)alkyl), S(0)2(C C8)alkyl, S(0)2(halo(C C8)alkyl), N(R14)(R15),
(2) substituted (Ci-C8)alkyl, wherein said substituted (C C8)alkyl has one or more substituents selected from CN and N02,
(3) substituted halo(Ci-C8)alkyl, wherein said substituted halo(d- C8)alkyl, has one or more substituents selected from CN and N02,
(4) substituted (Ci-C8)alkoxy, wherein said substituted (Ci-C8)alkoxy has one or more substituents selected from CN and N02, and
(5) substituted halo(Ci-C8)alkoxy, wherein said substituted halo(Ci- C8)alkoxy has one or more substituents selected from CN and N02;
(d) R4 is selected from
(1) H, F, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, S(C C8)alkyl, S(halo(C C8)alkyl), S(0)(C C8)alkyl, S(0)(halo(Ci-C8)alkyl), S(0)2(C C8)alkyl, S(0)2(halo(C C8)alkyl), N(R14)(R15),
(2) substituted (Ci-C8)alkyl, wherein said substituted (Ci-C8)alkyl has one or more substituents selected from CN and N02,
(3) substituted halo(Ci-C8)alkyl, wherein said substituted halo(d- C8)alkyl, has one or more substituents selected from CN and N02,
(4) substituted (Ci-C8)alkoxy, wherein said substituted (Ci-C8)alkoxy has one or more substituents selected from CN and N02, and
(5) substituted halo(Ci-C8)alkoxy, wherein said substituted halo(C
C8)alkoxy has one or more substituents selected from CN and N02;
(e) R5 is selected from
(1) H, F, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, S(C C8)alkyl, S(halo(C C8)alkyl), S(0)(C C8)alkyl, S(0)(halo(Ci-C8)alkyl), S(0)2(C C8)alkyl, S(0)2(halo(C C8)alkyl), N(R14)(R15),
(2) substituted (Ci-C8)alkyl, wherein said substituted (Ci-C8)alkyl has one or more substituents selected from CN and N02,
(3) substituted halo(Ci-C8)alkyl, wherein said substituted halo(d- C8)alkyl, has one or more substituents selected from CN and N02, (4) substituted (Ci-Cs)alkoxy, wherein said substituted (Ci-C8)alkoxy has one or more substituents selected from CN and N02, and
(5) substituted halo(Ci-Cs)alkoxy, wherein said substituted halo(d- C8)alkoxy has one or more substituents selected from CN and N02;
(f) R6 is a (C C8)haloalkyl;
(g) R7 is selected from H, F, CI, Br, I, OH, (C C8)alkoxy, and halo(C
C8)alkoxy;
(h) R8 is selected from H, (C C8)alkyl, halo(C C8)alkyl, OR14, and
N(R14)(R15);
(i) R9 is selected from H, F, CI, Br, I, (C C8)alkyl, halo(C C8)alkyl, (C
C8)alkoxy, halo(C C8)alkoxy, OR14, and N(R14)(R15);
(j) R10 is selected from
(1) H, F, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C
C8)alkoxy, halo(C C8)alkoxy, cyclo(C3-C6)alkyl, S(C C8)alkyl, S(halo(C C8)alkyl), S(0)(Ci-C8)alkyl, S(0)(halo(C C8)alkyl), S(0)2(C C8)alkyl, S(0)2(halo(C C8)alkyl), NR14R15, C(=0)H, C(=0)N(R14)(R15), CN(R14)(R15)(=NOH), (C=0)0(C C8)alkyl, (C=0)OH, heterocyclyl, (C2-C8)alkenyl, halo(C2-C8)alkenyl, (C2-C8)alkynyl,
(2) substituted (Ci-C8)alkyl, wherein said substituted (Ci-C8)alkyl has one or more substituents selected from OH, (Ci-C8)alkoxy, S(Ci-C8)alkyl, S(0)(Ci-C8)alkyl, S(0)2(Ci-C8)alkyl, NR14R15, and
(3) substituted halo(Ci-C8)alkyl, wherein said substituted halo(d- C8)alkyl, has one or more substituents selected from (C]-C8)alkoxy, S(C]-C8)alkyl, S(0)(Cr C8)alkyl, S(0)2(C C8)alkyl, and N(R14)(R15);
(k) Rll is C(=X5)N(H)((substituted(Ci-C8)alkyl)C(=X5)N(Rl la)(Rl la))
wherein each X5 is independently selected from O or S, and
wherein each Rlla is independently selected from H, (Ci-C8)alkyl, substituted (Ci-C8)alkyl, halo(Ci-C8)alkyl, substituted halo(Ci-C8)alkyl, cyclo(C3-C8)alkyl, substituted cyclo(C3-C8)alkyl, halocyclo(C3-C8)alkyl,
wherein each said substituted (Ci-C8)alkyl has one or more substituents selected from F, CI, Br, I, CN, N02, OC(=0)H, OH, (C C8)alkoxy, halo(C C8)alkyl, substituted halo(Ci-C8)alkyl, (C2-C8)alkenyl, substituted (C2-C8)alkenyl, substituted halo(C2- C8)alkenyl, (C2-C8)alkynyl, substituted (C2-C8)alkynyl, substituted halo(C2-C8)alkynyl, cyclo(C3-C8)alkyl, substituted cyclo(C3-C8)alkyl, halocyclo(C3-C8)alkyl,
C(X5)N(Rlla)(Rlla), S(C C8)alkyl, S(0)(C C8)alkyl, S(0)2(C C8)alkyl, OS(0)2aryl, N((Ci-C8)alkyl)2 (wherein each (Ci-C8)alkyl is independently selected), aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,
wherein each said substituted aryl has one or more substituents selected from F, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, S(Ci-C8)alkyl, S(halo(C C8)alkyl), N((C C8)alkyl)2 (wherein each (C C8)alkyl is independently selected), and oxo,
wherein each said substituted heterocyclyl has one or more substituents selected from F, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, S(C C8)alkyl, S(halo(C C8)alkyl), N((C C8)alkyl)2 (wherein each (C C8)alkyl is independently selected), C(=0)(C C8)alkyl, C(=0)(C3-C6)cycloalkyl, S(=0)2(C C8)alkyl, NR14R15, and oxo, wherein each said substituted- aryl has one or more substituents selected from F, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C
C8)alkoxy, S(C C8)alkyl, S(halo(C C8)alkyl), N((C C8)alkyl)2 (wherein each (C C8)alkyl is independently selected), and oxo,
wherein said substituted halo(Ci-C8)alkyl, has one or more substituents selected from CN and N02,
wherein said substituted (C2-C8)alkenyl, has one or more substituents selected from CN and N02,
wherein said substituted halo(C2-C8)alkenyl, has one or more substituents selected from CN and N02,
wherein said substituted (C2-C8)alkynyl, has one or more substituents selected from CN and N02,
wherein said substituted halo(C2-C8)alkynyl, has one or more substituents selected from CN and N02,
wherein said substituted cyclo(C3-C8)alkenyl, has one or more substituents selected from CN and N02,
wherein said substituted halocyclo(C3-C8)alkenyl, has one or more substituents selected from CN and N02;
(1) R12 is selected from (v), H, F, CI, Br, I, CN, (C C8)alkyl, halo(C C8)alkyl, (Ci-C8)alkoxy, halo(Ci-C8)alkoxy, and cyclo(C3-C6)alkyl;
(m) R13 is selected from (v), H, F, CI, Br, I, CN, (C C8)alkyl, halo(C C8)alkyl, (Ci-C8)alkoxy, and halo(Ci-C8)alkoxy;
(n) each R14 is independently selected from H, (Ci-C8)alkyl, (C2-C8)alkenyl, substituted (Ci-C8)alkyl, halo(Ci-C8)alkyl, substituted halo(Ci-C8)alkyl), (Ci-C8)alkoxy, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (Ci-C8)alkyl-aryl, (Ci-C8)alkyl-(substituted-aryl), O- (Ci-C8)alkyl-aryl, 0-(Ci-C8)alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C C8)alkyl-heterocyclyl, (C C8)alkyl-(substituted-heterocyclyl), 0-(C C8)alkyl- heterocyclyl, 0-(C C8)alkyl-(substituted-heterocyclyl), N(R16)(R17), (C C8)alkyl- C(=0)N(R16)(R17), C(=0)(C C8)alkyl, C(=0)(halo(Ci-C8)alkyl),C(=0)(C3-C6)cycloalkyl, (Ci-C8)alkyl-C(=0)0(Ci-C8)alkyl, C(=0)H
wherein each said substituted (C]-C8)alkyl has one or more substituents selected from CN, and N02,
wherein each said substituted halo(Ci-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, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, S(Ci-C8)alkyl, S(halo(C C8)alkyl), N((C C8)alkyl)2 (wherein each (C C8)alkyl is independently selected), and oxo, and
wherein each said substituted-heterocyclyl has one or more substituents selected from F, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, (C3-C6)cycloalkyl S(C C8)alkyl, S(halo(C C8)alkyl), N((C C8)alkyl)2 (wherein each (Ci-C8)alkyl is independently selected), heterocyclyl, C(=0)(C C8)alkyl, C(=0)0(C C8)alkyl, and oxo, (wherein said alkyl, alkoxy, and heterocyclyl, may be further substituted with one or more of F, CI, Br, I, CN, and N02);
(o) each R15 is independently selected from H, (Ci-C8)alkyl, (C2-C8)alkenyl, substituted (C C8)alkyl, halo(C C8)alkyl, substituted halo(C C8)alkyl), (C C8)alkoxy, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (Ci-C8)alkyl-aryl, (Ci-C8)alkyl-(substituted-aryl), O- (Ci-C8)alkyl-aryl, 0-(Ci-C8)alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C C8)alkyl-heterocyclyl, (C C8)alkyl-(substituted-heterocyclyl), 0-(C C8)alkyl- heterocyclyl, 0-(C C8)alkyl-(substituted-heterocyclyl), N(R16)(R17), (C C8)alkyl- C(=0)N(R16)(R17), C(=0)(C C8)alkyl, C(=0)(halo(C C8)alkyl), C(=0)(C3-C6)cycloalkyl, (Ci-C8)alkyl-C(=0)0(Ci-C8)alkyl, C(=0)H
wherein each said substituted (Ci-C8)alkyl has one or more substituents selected from CN, and N02,
wherein each said substituted halo(Ci-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, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, S(Ci-C8)alkyl, S(halo(C C8)alkyl), N((Ci-C8)alkyl)2 (wherein each (C C8)alkyl is independently selected), and oxo, and
wherein each said substituted-heterocyclyl has one or more substituents selected from F, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, (C3-C6)cycloalkyl S(C C8)alkyl, S(halo(C C8)alkyl), N((C C8)alkyl)2 (wherein each (Ci-C8)alkyl is independently selected), heterocyclyl, C(=0)(C C8)alkyl, C(=0)0(C C8)alkyl, and oxo, (wherein said alkyl, alkoxy, and heterocyclyl, may be further substituted with one or more of F, CI, Br, I, CN, and N02);
(p) each R16 is independently selected from H, (Ci-C8)alkyl, substituted-(d- C8)alkyl, halo(Ci-C8)alkyl, substituted-halo(Ci-C8)alkyl, cyclo(C3-C6)alkyl, aryl, substituted- aryl, (C C8)alkyl-aryl, (C C8)alkyl-(substituted-aryl), 0-(C C8)alkyl-aryl, 0-(C C8)alkyl- (substituted-aryl), heterocyclyl, substituted-heterocyclyl, (Ci-C8)alkyl-heterocyclyl, (Cr C8)alkyl-(substituted-heterocyclyl), 0-(C C8)alkyl-heterocyclyl, 0-(C C8)alkyl- (substituted-heterocyclyl), 0-(Ci-C8)alkyl
wherein each said substituted (Ci-C8)alkyl has one or more substituents selected from CN, and N02,
wherein each said substituted halo(Ci-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, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, S(Ci-C8)alkyl, S(halo(C C8)alkyl), N((C C8)alkyl)2 (wherein each (C C8)alkyl is independently selected), and oxo, and
wherein each said substituted-heterocyclyl has one or more substituents selected from F, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, S(C C8)alkyl, S(halo(C C8)alkyl), N((C C8)alkyl)2 (wherein each (C C8)alkyl is independently selected), and oxo;
(q) each R17 is independently selected from H, (Ci-C8)alkyl, substituted-(d- C8)alkyl, halo(Ci-C8)alkyl, substituted-halo(Ci-C8)alkyl, cyclo(C3-C6)alkyl, aryl, substituted- aryl, (C C8)alkyl-aryl, (C C8)alkyl-(substituted-aryl), 0-(C C8)alkyl-aryl, 0-(C C8)alkyl- (substituted-aryl), heterocyclyl, substituted-heterocyclyl, (Ci-C8)alkyl-heterocyclyl, (Cr C8)alkyl-(substituted-heterocyclyl), 0-(C C8)alkyl-heterocyclyl, 0-(C C8)alkyl- (substituted-heterocyclyl), 0-(Ci-C8)alkyl
wherein each said substituted (Ci-C8)alkyl has one or more substituents selected from CN, and N02, wherein each said substituted halo(Ci-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, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, S(Ci-C8)alkyl, S(halo(C C8)alkyl), N((C C8)alkyl)2 (wherein each (C C8)alkyl is independently selected), and oxo, and
wherein each said substituted-heterocyclyl has one or more substituents selected from F, CI, Br, I, CN, N02, (C C8)alkyl, halo(C C8)alkyl, (C C8)alkoxy, halo(C C8)alkoxy, S(C C8)alkyl, S(halo(C C8)alkyl), N((C C8)alkyl)2 (wherein each (C C8)alkyl is independently selected), and oxo;
(r) XI is selected from N and CR12;
(s) X2 is selected from N, CR9, and CR13;
(t) X3 is selected from N and CR9; and
(v) R12 and R13 together form a linkage containing 3 to 4 atoms selected from C, N, O, and S, wherein said linkage connects back to the ring to form a 5 to 6 member saturated or unsaturated cyclic ring, wherein said linkage has at least one substituent X4 wherein X4 is selected from R14, N(R14)(R15), N(R14)(C(=0)R14), N(R14)(C(=S)R14),
N(R14)(C(=0)N(R14)(R14)), N(R14)(C(=S)N(R14)(R14)), N(R14)(C(=0)N(R14)((C2- C8)alkenyl)), N(R14)(C(=S)N(R14)((C2-C8)alkenyl)), wherein each R14 is independently selected.
2. A molecule according to claim 1 where said molecule has one of the following structures
Figure imgf000378_0001
Figure imgf000379_0001
3. A composition comprising a molecule according to claims 1 or 2 further comprising:
(a) one or more compounds having acaricidal, algicidal, avicidal, bactericidal, fungicidal, herbicidal, insecticidal, moUuscicidal, nematicidal, rodenticidal, or virucidal properties; or (b) one or more compounds that are antifeedants, bird repellents, chemosterilants, herbicide safeners, insect attractants, insect repellents, mammal repellents, mating disrupters, plant activators, plant growth regulators, or synergists; or
(c) both (a) and (b).
4. A process comprising applying a molecule according to claims 1 or 2 to an area to control a pest, in an amount sufficient to control such pest.
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