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WO1999046266A1 - Benzoxadiazocinyl arthropodicides - Google Patents

Benzoxadiazocinyl arthropodicides Download PDF

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Publication number
WO1999046266A1
WO1999046266A1 PCT/US1999/000882 US9900882W WO9946266A1 WO 1999046266 A1 WO1999046266 A1 WO 1999046266A1 US 9900882 W US9900882 W US 9900882W WO 9946266 A1 WO9946266 A1 WO 9946266A1
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Prior art keywords
come
alkyl
pyridinyl
haloalkyl
column
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PCT/US1999/000882
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French (fr)
Inventor
Stephen Frederick Mccann
Bruce Lawrence Finkelstein
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E.I. Du Pont De Nemours And Company
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Priority to AU23213/99A priority Critical patent/AU2321399A/en
Publication of WO1999046266A1 publication Critical patent/WO1999046266A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/40—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems

Definitions

  • This invention relates to certain benzoxadiazocinyl arthropodicides, their N-oxides, agriculturally suitable salts and compositions, and methods of their use as arthropodicides in both agronomic and nonagronomic environments.
  • arthropod pests The control of arthropod pests is extremely important in achieving high crop efficiency. Arthropod damage to growing and stored agronomic crops can cause significant reduction in productivity and thereby result in increased costs to the consumer. The control of arthropod pests in forestry, greenhouse crops, ornamentals, nursery crops, stored food and fiber products, livestock, household, and public and animal health is also important. Many products are commercially available for these purposes, but the need continues for new compounds which are more effective, less costly, less toxic, environmentally safer or have different modes of action. Jan Svetlik in J. Chem. Soc, Perkin I (1988) pp.2053-8 discloses
  • This invention is directed to a compound of Formula I including all geometric and stereoisomers, N-oxides, agriculturally suitable salts thereof, agricultural compositions containing them and their use as arthropodicides,
  • A is CR 7 R 8 ;
  • E is O, S, CR 16 R 17 or NR 17 ;
  • G is a fused 5- or 6-membered ring which may be aromatic or non-aromatic, optionally containing one or two heteroatoms selected from the group nitrogen, oxygen and sulfur: each R 1 is independently selected from the group halogen, cyano, nitro, formyl, Cj-Cg alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C r C 6 alkoxy, C r C 6 haloalkyl, C2-C haloalkenyl, C 2 -C6 haloalkynyl, C Cg haloalkoxy; C r C 6 alkylthio, C r C 6 haloalkylthio, C r C 6 alkylsulfinyl, C Cg haloalkylsulfinyl, Cj-Cg alkylsulfonyl, C j -Cg haloalky
  • each R 2 is independently selected from the group halogen, nitro, Ci-Cg alkyl, Cj-Cg haloalkyl and C Cg alkoxy; or R 1 and R 2 , when on adjacent atoms, can be taken together along with the atoms to which they are attached to form a 5- or 6- membered ring which may be aromatic or non-aromatic, optionally containing one or two hetero atoms selected from nitrogen, oxygen and sulfur, and optionally substituted with (R 10 ) q ; R 3 and R 4 are each independently selected from the group H; C3-C6 cycloalkyl; Ci-Cg haloalkyl; C2-Cg alkenyl; C2-C6 alky
  • R 5 and R 6 are each independently selected from the group H; C ⁇ -Cg cycloalkyl; C r C 6 haloalkyl; C 2 -C 6 alkenyl; C 2 -C 6 haloalkenyl; C 2 -C 6 alkynyl;
  • R 7 is H, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C r C 6 haloalkyl, C2-Cg alkylcarbonyl, C 2 -C ⁇ alkoxycarbonyl, C -Cg alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl, Q or C j -Cg alkyl optionally substituted with Q; or R 3 and R 7 can be taken together along with the carbon atoms to which they are attached to form a 4-, 5-, 6- or 7-membered ring; or
  • R 4 and R 7 can be taken together along with the carbon atoms to which they are attached to form a 4-, 5-, 6- or 7-membered ring;
  • each R 9 is independently selected from the group H, C Cg alkyl, Cj-Cg haloalkyl, C j -C 6 alkoxy, C Cg haloalkoxy or phenyl optionally substituted with (R 10 ) p ;
  • each R 10 is independently selected from the group halogen, cyano, nitro, formyl, SF 5 , C j -Cg alkyl, C 3 -C 6 cycloalkyl, C -C 6 alkenyl, C -C 6 alkynyl, C ⁇ -C 6 alkoxy, Cj-C 6 haloalkyl, C2-Cg haloalkenyl, C
  • R 13 , R 14 and R 15 are each independently Cj-Cg alkyl or phenyl;
  • R 16 is H or C C 6 alkyl;
  • R 17 is H; C 3 -C 6 cycloalkyl; C r C 6 haloalkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C2-Cg alkylcarbonyl; C2-Cg alkoxycarbonyl; C2-Cg alkylaminocarbonyl; C3-Cg dialkylaminocarbonyl; Q; and Cj-Cg alkyl optionally substituted with cyano, Cj-Cg alkoxy, C r C 6 haloalkoxy or Q; R 18 is H or C ! -C 6 alkyl;
  • R 19 is H, C r C 6 alkyl, C r C 6 haloalkyl, C r C 6 alkoxy, C r C 6 haloalkoxy or phenyl optionally substituted with (R 10 ) p ; m and n are each independently 0, 1 or 2; each p is 0, 1, 2, 3, 4 or 5; and q is O, 1, 2, 3 or 4; provided that a compound of Formula I is other than
  • alkyl used either alone or in compound words such as “alkylthio” or “haloalkyl” includes straight-chain or branched alkyl, such as, methyl, ethyl, M-propyl, /-propyl, or the different butyl, pentyl or hexyl isomers.
  • alkenyl includes straight-chain or branched alkenes such as ethenyl, 1 -propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers.
  • Alkenyl also includes polyenes such as
  • Alkynyl includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers. "Alkynyl” can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl.
  • Alkoxy includes, for example, methoxy, ethoxy, «-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers.
  • Alkylthio includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers.
  • Alkylsulfinyl includes both enantiomers of an alkylsulfinyl group.
  • alkylsulfinyl examples include CH 3 S(O), CH 3 CH 2 S(O), CH 3 CH 2 CH 2 S(O), (CH 3 ) 2 CHS(O) and the different butylsulfinyl, pentylsulfinyl and hexylsulfinyl isomers.
  • alkylsulfonyl examples include CH 3 S(O) 2 , CH 3 CH 2 S(O) 2 , CH 3 CH 2 CH 2 S(O) 2 , (CH 3 ) 2 CHS(O) 2 and the different butylsulfonyl, pentylsulfonyl and hexylsulfonyl isomers.
  • Alkylamino and dialkylamino are defined analogously to the above examples.
  • Cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • G is "a fused 5- or 6-membered ring which may be aromatic or non-aromatic, optionally containing one or two heteroatoms selected from the group nitrogen, oxygen and sulfur" includes, for example, cyclohexyl, cyclopentyl, phenyl, thienyl and pyridinyl.
  • R 1 and R 2 are taken together to "form a 5- or 6- membered ring which may be aromatic or non-aromatic, optionally containing one or two hetero atoms selected from nitrogen, oxygen and sulfur, and optionally substituted with (R 10 ) q " include, for example, naphthalenyl and quinolinyl.
  • aromatic ring denotes a fully unsaturated ring in which the ring system is aromatic (where aromatic indicates that the H ⁇ ckel rule is satisfied for the ring).
  • non-aromatic ring denotes a fully saturated ring as well as partially or fully unsaturated ring (where non-aromatic indicates that the H ⁇ ckel rule is not satisfied for the ring).
  • the heterocydic rings can be attached through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.
  • aromatic and non-aromatic ring systems containing 1 to 4 heteroatoms selected from the group nitrogen, oxygen and sulfur, containing no more than 2 oxygens and no more than 2 sulfurs include, pyrrolidinyl; piperidinyl; tetrahydrofuranyl; tetrahydro-2H-pyranyl; 1,3-dioxanyl; 1,3-dithianyl; 4,5-dihydrooxazolyl; 4,5-dihydrothiazolyl; lH-pyrrolyl; furanyl; thienyl; lH-pyrazolyl; lH-imidazolyl; isoxazolyl; oxazolyl; isothiazolyl; thiazolyl; 1H- 1,2, 3 -triazolyl; 2H-l,2,3-triazolyl; lH-l,2,4-triazolyl; 4H-l,2,4-triazolyl; 1,2,3-oxadiazol
  • halogen either alone or in compound words such as “haloalkyl” includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as “haloalkyl”, said alkyl may be partially or fully substituted with halogen atoms which may be the same or different.
  • haloalkyl include F 3 C, C1CH 2 , CF 3 CH 2 and CF 3 CC1 2 .
  • haloalkynyl include HC ⁇ CCHCl, CF 3 C ⁇ C, CC1 3 C ⁇ C and FCH 2 C ⁇ CCH 2 .
  • haloalkoxy include CF 3 O, CCl 3 CH 2 O, HCF 2 CH 2 CH 2 O and CF 3 CH 2 O.
  • haloalkylthio include CC1 3 S, CF 3 S, CC1 3 CH 2 S and C1CH 2 CH 2 CH 2 S.
  • haloalkylsulfmyl include CF 3 S(O), CCl 3 S(O), CF 3 CH 2 S(O) and CF 3 CF 2 S(O).
  • haloalkylsulfonyl examples include CF 3 S(O) 2 , CCl 3 S(O) 2 , CF 3 CH 2 S(O) 2 and CF 3 CF 2 S(O) 2 .
  • haloalkoxyalkoxy examples include CF 3 OCH 2 O, CICH2CH2OCH2CH2O, CI3CCH2OCH2O as well as branched alkyl derivatives.
  • C j -C3 alkylsulfonyl designates methylsulfonyl through propylsulfonyl.
  • nitrogen containing heterocycles can form N-oxides since the nitrogen requires an available lone pair for oxidation to the oxide; one skilled in the art will recognize those nitrogen containing heterocycles which can form N-oxides.
  • nitrogen containing heterocycles which can form N-oxides.
  • tertiary amines can form N-oxides.
  • N-oxides of heterocycles and tertiary amines are very well known by one skilled in the art including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethydioxirane.
  • MCPBA peroxy acids
  • alkyl hydroperoxides such as t-butyl hydroperoxide
  • sodium perborate sodium perborate
  • dioxiranes such as dimethydioxirane
  • the salts of the compounds of the invention include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids.
  • inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids.
  • the salts of the compounds of the invention also include those formed with organic bases (e.g., pyridine, ammonia, or triethylamine) or inorganic bases (e.g., hydrides, hydroxides, or carbonates of sodium, potassium, lithium, calcium, magnesium or barium) when the compound contains an acidic group such as a carboxylic acid or phenol.
  • organic bases e.g., pyridine, ammonia, or triethylamine
  • inorganic bases e.g., hydrides, hydroxides, or carbonates of sodium, potassium, lithium, calcium, magnesium or barium
  • Preferred compounds for reasons of better activity and/or ease of synthesis are:
  • R 3 is H or Cj-Cg alkyl optionally substituted with 1-3 halogen or R 3 is phenyl optionally substituted with (R 10 ) p ;
  • R 7 is H or C r C 6 alkyl
  • R 8 is H
  • R 17 is H or C r C 3 alkyl;
  • R 18 is H, C r C 3 alkyl;
  • R 19 is H, C r C 3 alkyl.
  • G is a fused cyclohexyl, cyclopentyl, phenyl, naphthalenyl, thienyl, pyridinyl or quinolinyl ring;
  • R 3 is H or C r C 6 alkyl;
  • R 4 is H or CH 3 .
  • Preferred 3 Compounds of Preferred 2 wherein: G is a fused phenyl ring; each R 1 is independently selected from the group consisting of halogen, C j -C3 alkyl, C1-C3 haloalkyl and C1-C3 haloalkoxy;
  • R 5 and R 6 are each independently H, C j -Cg alkyl, C alkylcarbonyl, C2-C6 alkoxycarbonyl, C1-C3 alkylsulfonyl, 3-pyridinylmethyl 7 optionally substituted with 1-2 halogens or 5-thiazolylmethyl optionally substituted with halogen; and p and q are each independently 0, 1 or 2.
  • This invention also relates to arthropodicidal compositions comprising arthropodicidally effective amounts of the compounds of the invention and at least one of a surfactant, a solid diluent or a liquid diluent.
  • the preferred compositions of the present invention are those which comprise the above preferred compounds.
  • This invention also relates to arthropodicidal compositions comprising arthropodicidally effective amounts of (2 ⁇ ,6 ⁇ )-(3,6-dihydro-2-methyl-2,6-methano-2H-l,3,5-benzoxadiazocin-4-yl)cyanamide and at least one of a surfactant, a solid diluent or a liquid diluent.
  • This invention also relates to a method for controlling arthropods comprising contacting the arthropods or their environment with an arthropodicidally effective amount of the compounds of the invention (e.g., as a composition described herein).
  • the preferred methods of use are those involving the above preferred compounds.
  • This invention also relates to a method for controlling arthropods comprising contacting the arthropods or their environment with an arthropodicidally effective amount (2 ⁇ ,6 ⁇ )-(3,6-dihydro-2-methyl-2,6-methano-2H-l,3,5-benzoxadiazocin-4-yl)cyanamide (e.g., as a composition described herein).
  • Compounds of this invention can exist as one or more stereoisomers.
  • the various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers.
  • a compound of Formula I may exist as geometric isomer I or la, or both I and la.
  • the present invention comprises compounds selected from Formula I, N-oxides and agriculturally suitable salts thereof.
  • the compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form.
  • a compound of Formula I wherein R 5 is H may exist as tautomer lb or Ic, or both lb and Ic; and a compound of Formula I wherein R 6 is H may exist as tautomer Id or Ie, or both Id and Ie.
  • the present invention comprises all tautomeric forms of compounds of Formula I.
  • compounds of Formula I can exist as syn or anti isomers.
  • a compound of Formula I may exist as isomers I or If, or both I and If.
  • the present invention comprises all syn and anti isomeric forms of compounds of Formula I.
  • the compounds of Formula I can be prepared by one or more of the following methods and variations as described in Schemes 1-14.
  • the definitions of R ! -R 19 , G, E, X and X 1 in the compounds of Formulae 1-25 are as defined above in the Summary of the Invention or as defined below in the Schemes.
  • Compounds of Formulae Ia-If are various subsets of the compounds of Formula I, and all substituents for Formulae Ia-If are as defined above for Formula I.
  • X is halogen, alkylsulfonate, arylsulfonate, or R -X is an anhydride of a carboxylic acid or sulfonic acid or R -X is an alkyl or aryl isocyanate.
  • Compounds of Formula 1 can be highly varied and include alkylating agents such as alkyl halides, alkyl sulfonates and the like; acylating agents such as acyl halides and acyl anhydrides and pyrocarbonates; sulfonylating agents such as sulfonyl halides and sulfonic anhydrides; and carbamoylating reagents such as alkyl and aryl isocyanates.
  • Typical Scheme 1 reactions involve mixing a compound of Formula I (R 6 is H) with one to ten molar equivalents of a compound of Formula 1 in the presence of one molar equivalent of a proton acceptor.
  • Typical proton acceptors include sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, alkyl lithiums, lithium amides (such as lithium diisopropylamide) amines (such as pyridine, triethylamine and 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU)) and hydroxide bases (such as sodium hydroxide and potassium hydroxide).
  • lithium amides such as lithium diisopropylamide
  • amines such as pyridine, triethylamine and 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
  • hydroxide bases such as sodium hydroxide and potassium hydroxide.
  • Scheme 1 reactions are usually carried out in a solvent, including polar aprotic solvents (such as tetrahydrofuran, NN-dimethylformamide, NN-dimethylacetamide and 1 -methyl-2-pyrrolidinone), alcohols such as methanol, ethanol and 2-propanol, or water. In some cases, a solvent is not used.
  • Scheme 1 reactions are typically run at temperatures ranging from 0 °C to the reflux temperature of the solvent and the reactions are usually complete within 2 to 48 hours.
  • the products of Formula I (R 6 is other than H) can be isolated by chromatography, crystallization or, in some cases, by the addition of water to the reaction followed by filtration of the product.
  • Compounds of Formula I where R 5 is other than H can be prepared by the reaction of a compound of Formula I (where R 5 is H) with a compound of Formula 2 in the presence of a proton acceptor as depicted in Scheme 2. 10 Scheme 2
  • Step i of Scheme 3 is an example of a Scheme 1 reaction using di-tert-butyl pyrocarbonate (3) as the compound of Formula 1.
  • the product of Step i reacts with a compound of Formula 2 as described in Scheme 2.
  • the product of Step ii reacts with an acid, which results in the removal of the 11 t-butoxy carbonyl group and the formation of compounds of Formula I (R 5 is other than H, R 6 is H).
  • Acids used in Step iii reactions include trifluoroacetic and hydrochloric acids.
  • Reaction temperatures can range from 20 °C to the reflux temperature of the solvent and the reactions are usually complete in 2 to 48 hours.
  • a great number of the compounds of Formula 5 can be obtained from commercial sources (for example, when G forms a phenyl ring, then compounds of Formula 5 [where E is O] are comprised of the well-known salicylaldehydes [R 3 is H], o-hydroxyacetophenones [R 3 is Me] and o-hydroxybenzophenones [R 3 is optionally substituted phenyl].
  • Salicylaldehydes of Formula 5 (E is O, R 3 is H), can be prepared by the 13
  • ⁇ -Hydroxy phenyl alkyl ketones of Formula 5 (E is O, R 3 is optionally substituted alkyl) and o-hydroxy phenyl aryl ketones of Formula 5 (E is O, R 3 is optionally substituted aryl) can be prepared by a number of methods, including the Friedel-Crafts acylation (see Chem. Revs., (1955), vol. 55, p. 229) depicted in Scheme 7. Phenols of Formula 7 may be obtained from commercial suppliers.
  • Step i of Scheme 8 the methoxy thiophenes of Formula 9 are acylated using either the Nilsmeier reagent (POC ⁇ /NN-dimethylformamide ) to give compounds of Formula 10 (R 3 is H) or by a Friedel-Crafts acylation procedure (R 3 COCl/AlCl3) to give compounds of Formula 10 (R 3 is other than H).
  • Procedures for conducting Step i of Scheme 8 are well-known to those skilled in the art (see, e.g., Chem. Rev., (1955), vol. 55, p. 229 and J. Chem. Soc, Section C (1967), p. 779).
  • Step ii of Scheme 8 the methyl ether is removed using boron tribromide in a solvent such as dichloromethane (for an example, see Org. Synth., Collect, vol. V, (1973), p. 412).
  • a solvent such as dichloromethane
  • Formula 5b (R 3 is H) using an oxidant such as activated manganese dioxide in a solvent such as methylene chloride or toluene at temperatures ranging from ambient to the refluxing temperature of the solvent.
  • an oxidant such as activated manganese dioxide in a solvent such as methylene chloride or toluene at temperatures ranging from ambient to the refluxing temperature of the solvent.
  • aldehydes of Formula 5b (R 3 is H) react with a compound of Formula 14 to form secondary alcohols of Formula 13.
  • keto-esters of Formula 15 are reduced to alcohols of Formula 16 using sodium borohydride in a polar solvent such as ethanol at temperatures 17 ranging from 0 °C to 78 °C for times ranging from 1 hour to 3 days.
  • a polar solvent such as ethanol
  • alternative reduction procedures are available for the conversion of a compound of Formula 15 to a compound of Formula 16 (using, e.g., aluminum triisopropoxide, Baker's yeast or hydrogen with a platinum or nickel catalyst, see Helv. Chim. Acta, (1952), vol. 35, p. 2406).
  • the esters of Formula 17 are reduced to primary alcohols of Formula 18 using preferably lithium aluminum hydride in an ethereal solvent, or diisobutylaluminum hydride in dichloromethane, tetrahydrofuran or toluene as depicted in Step iii of Scheme 10.
  • Numerous procedures for analogous ester reductions are available in the chemical literature (see, e.g., Tetrahedron Lett. (1995), p. 2097 and Synlett, (1993), p. 27).
  • Step iv of Scheme 10 the primary alcohols of Formula 18 are oxidized to aldehydes of Formula 19 using oxidants such as the Swera reagent (dimethyl sulfoxide, oxalyl chloride), pyridinium chlorochromate (PCC) or (rc-Pr ⁇ NRuO ⁇ These are standard procedures for organic synthesis and are well-known to those skilled in the art (for two examples, see J. Org. Chem., (1992), vol. 57, p. 4512 and Tetrahedron-Asymmetry, (1995), p. 2131).
  • silyl ethers of Formula 19 are converted to alcohols of
  • Formula 5c using a fluoride-ion source such as tetrabutylammonium fluoride, potassium fluoride, aqueous hydrofluoric acid or pyridine- hydrofluoric acid.
  • a fluoride-ion source such as tetrabutylammonium fluoride, potassium fluoride, aqueous hydrofluoric acid or pyridine- hydrofluoric acid.
  • non-fluoride-ion de-silylation procedures are available as well (see, e.g., J. Am. Chem. Soc, (1985), vol. 107, p. 4577).
  • the preparation of compounds of Formula 5d (compounds of Formula 5 where E is O and R 3 is other than H) can be achieved using procedures depicted in Scheme 11.
  • Step iii of Scheme 11 removal of the silyl protecting group from compounds of Formula 21 to form alcohols of Formula 5 is realized via procedures which are completely analogous to those already described for Scheme 10, Step v reactions.
  • X is a leaving group such as halogen, alkoxy or dialkylamino, or the compound of Formula 23 is an acid anhydride 19
  • Scheme 12 reactions involve the reaction of mercaptans of Formula 22 with typically 2 molar equivalents of n-butyllithium and 2 molar equivalents of N,N,N,N-tetramethylenediamine (TMEDA) in a solvent such as tetrahydrofuran or cyclohexane at temperatures ranging from -78 °C to the refluxing temperature of the solvent for 0.25 to 12 hours, followed by treatment with compounds of Formula 23 (1-2 molar equivalents) at 0 °C to ambient temperature.
  • the products of Formula 5e are typically isolated by acidification of the reaction medium followed by extractive work-up.
  • compounds of Formula 23 are typically N,N-dimethylformamide or N-formylpiperidine.
  • compounds of Formula 5e may be prepared via nitriles of Formula 24 as shown in Scheme 13.
  • Scheme 14 reactions are usually performed in a solvent such as an alcohol (e.g., -propanol or ethanol), tetrahydrofuran or aromatic hydrocarbon (e.g., benzene or toluene).
  • a solvent such as an alcohol (e.g., -propanol or ethanol), tetrahydrofuran or aromatic hydrocarbon (e.g., benzene or toluene).
  • Reactions are typically carried out at temperatures ranging from O °C to 150 °C, with the reflux temperature of the solvent being preferred. Reactions are typically complete in 1 to 72 hours.
  • Diamines of Formula 25 can be prepared by known methods (e.g., Chem. Pharm. Bull, (1966), vol. 14, p. 324) or by methods known to one skilled in the art.
  • Step B Preparation of re/-r(2R,6R)-3.6-dihvdro-2-methyl-2.6-methano-2H-l.3.5- benzoxadiazocin-4-vncyanamide
  • cyanamide 0.25 g (1.5 mmol) of the product of the previous step, cyanamide (0.3 g, 3.1 mmol), 1 ,2-dimethoxyethane (2 mL) and piperidine (two drops) was heated at reflux for 5 h, cooled to ambient temperature, diluted with 1, 2 -dimethoxy ethane (5 mL) and filtered.
  • aqueous layer was extracted with ethyl acetate (3 X 100 mL) and the combined organic layers were washed with water (4 X 100 mL), dried over anhydrous magnesium sulfate and concentrated to give 0.21 g of a crude product that was chromatographed on silica gel using 1:1 hexane-ethyl acetate to give 60 mg of the title compound as a solid, mp 216 °C (dec).
  • Aqueous sodium hydroxide (10.5 mL, 1.0 N) was added to a solution of 5-chlorosalicylaldehyde (1.5 g, 9.6 mmol) and acetone (7 mL) at ambient temperature. After 18 h, the reaction was cooled to 5 °C and then 12.5 mL of 1 N aqueous hydrochloric acid was added dropwise. The resulting solid product was removed by filtration and washed with 1 N aqueous hydrochloric acid. After drying, 1.7 g of the title compound was isolated as a tan solid, mp 157 °C (dec). !
  • Step B Preparation of re/-r(2R.6R)-8-chloro-3,6-dihydro-2-methyl-2.6-methano-2H- 1 ,3 ,5-benzoxadiazocin-4-yl]cyanamide
  • 1,3-naphthalenediamine prepared according to Chem. Pharm. Bull, (1966), vol. 14, p. 324) in 70 mL of 2-propanol was added 1.87 g (7.93 mmol) of diphenyl cyanocarbonimidate. The mixture was refluxed for 4 h. After cooling 0.93 g of the title compound was filtered off, mp > 250 °C. !H ⁇ MR (300 MHz, Me 2 SO- ⁇ / 6 ) ⁇ 8.16 (br s,lH), 7.83 (br s,lH), 7.20 (m,4H), 4.40 (br s,lH), 3.94 (br s,lH), 2.84 (m,2H), 2.02 (m,2H).

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Abstract

Compounds of formula (I), and their N-oxydes and agriculturally suitable salts, are disclosed which are useful as arthropodicides, wherein A is CR7R8; E is O, S, CR?16R17 or NR17¿; G is a fused 5- or 6-membered ring which may be aromatic or non-aromatic, optionally containing one or two heteroatoms selected from the group nitrogen, oxygen and sulfur; and R?1-R8, R16 and R17¿ are as defined in the disclosure. Also disclosed are compositions containing the compounds of formula (I) and a method for controlling arthropods which involves contacting the arthropods or their environment with an effective amount of a compound of formula (I).

Description

TITLE BENZOXADIAZOCINYL ARTHROPODICIDES BACKGROUND OF THE INVENTION This invention relates to certain benzoxadiazocinyl arthropodicides, their N-oxides, agriculturally suitable salts and compositions, and methods of their use as arthropodicides in both agronomic and nonagronomic environments.
The control of arthropod pests is extremely important in achieving high crop efficiency. Arthropod damage to growing and stored agronomic crops can cause significant reduction in productivity and thereby result in increased costs to the consumer. The control of arthropod pests in forestry, greenhouse crops, ornamentals, nursery crops, stored food and fiber products, livestock, household, and public and animal health is also important. Many products are commercially available for these purposes, but the need continues for new compounds which are more effective, less costly, less toxic, environmentally safer or have different modes of action. Jan Svetlik in J. Chem. Soc, Perkin I (1988) pp.2053-8 discloses
(2α,6α)-(3,6-dihydro-2-methyl-2,6-methano-2H-l,3,5-benzoxadiazocin-4-yl)-cyanamide, however, no agricultural utility is disclosed.
The benzoxadiazocinyl arthropodicides of the present invention are not disclosed in this publication. SUMMARY OF THE INVENTION
This invention is directed to a compound of Formula I including all geometric and stereoisomers, N-oxides, agriculturally suitable salts thereof, agricultural compositions containing them and their use as arthropodicides,
R"
R
• Ν. CΝ
Figure imgf000003_0001
R5
I wherein: A is CR7R8;
E is O, S, CR16R17 or NR17;
G is a fused 5- or 6-membered ring which may be aromatic or non-aromatic, optionally containing one or two heteroatoms selected from the group nitrogen, oxygen and sulfur: each R1 is independently selected from the group halogen, cyano, nitro, formyl, Cj-Cg alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, CrC6 alkoxy, CrC6 haloalkyl, C2-C haloalkenyl, C2-C6 haloalkynyl, C Cg haloalkoxy; CrC6 alkylthio, CrC6 haloalkylthio, CrC6 alkylsulfinyl, C Cg haloalkylsulfinyl, Cj-Cg alkylsulfonyl, Cj-Cg haloalkylsulfonyl,
C2-Cg alkylcarbonyl, C^-Cg alkoxycarbonyl, C2-Cg alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl, Cj-Cg alkylamino, and C^-Cg dialkylamino; each R2 is independently selected from the group halogen, nitro, Ci-Cg alkyl, Cj-Cg haloalkyl and C Cg alkoxy; or R1 and R2, when on adjacent atoms, can be taken together along with the atoms to which they are attached to form a 5- or 6- membered ring which may be aromatic or non-aromatic, optionally containing one or two hetero atoms selected from nitrogen, oxygen and sulfur, and optionally substituted with (R10)q; R3 and R4 are each independently selected from the group H; C3-C6 cycloalkyl; Ci-Cg haloalkyl; C2-Cg alkenyl; C2-C6 alkynyl; C2-C6 alkylcarbonyl;
C2-C6 alkoxycarbonyl; C2-Cg alkylaminocarbonyl; C3-C8 dialkylaminocarbonyl; Q; and Cj-Cg alkyl optionally substituted with cyano, Cj-Cg alkoxy, Cj-Cg haloalkoxy or Q; R5 and R6 are each independently selected from the group H; Cβ-Cg cycloalkyl; CrC6 haloalkyl; C2-C6 alkenyl; C2-C6 haloalkenyl; C2-C6 alkynyl;
C2-C6 haloalkynyl; RHC(=Y); Rl SO2; (R9)2NSO2; Q; and CrC6 alkyl optionally substituted with cyano, C3-C6 cycloalkyl, Cj-Cg alkoxy, Cj-Cg haloalkoxy, R1 O, R12S, R12SO2, (R9)2NSO2, RπC(=Y), (R13)(R14)(R15)Si or Q; Y is O, S or NR9;
R7 is H, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, CrC6 haloalkyl, C2-Cg alkylcarbonyl, C2-Cβ alkoxycarbonyl, C -Cg alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl, Q or Cj-Cg alkyl optionally substituted with Q; or R3 and R7 can be taken together along with the carbon atoms to which they are attached to form a 4-, 5-, 6- or 7-membered ring; or
R4 and R7 can be taken together along with the carbon atoms to which they are attached to form a 4-, 5-, 6- or 7-membered ring; R8 is H or CrC6 alkyl; or R7 and R8 can be taken together as =CR18R19; each R9 is independently selected from the group H, C Cg alkyl, Cj-Cg haloalkyl, Cj-C6 alkoxy, C Cg haloalkoxy or phenyl optionally substituted with (R10)p; each R10 is independently selected from the group halogen, cyano, nitro, formyl, SF5, Cj-Cg alkyl, C3-C6 cycloalkyl, C -C6 alkenyl, C -C6 alkynyl, Cι-C6 alkoxy, Cj-C6 haloalkyl, C2-Cg haloalkenyl, C^-Cg haloalkynyl, Cj-Cg haloalkoxy; Cj-Cg alkylthio, Cj-Cg haloalkylthio, Cj-Cg alkylsulfinyl, Cj-Cg haloalkylsulfinyl, Cj-Cg alkylsulfonyl, Ci-Cg haloalkylsulfonyl, C2-Cg alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-Cg alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl, Ci-Cg alkylamino and C2~Cg dialkylamino; each R1 1 is independently selected from the group H, hydroxy, amino, Cj-C6 alkyl, Cι-C6 haloalkyl, Cj-Cg alkoxy, C Cg haloalkoxy, Ci-Cg alkylthio, Cj-Cg haloalkylthio, Cι-C6 alkylamino, C2-Cg dialkylamino, QNH and Q; each Q is a phenyl or a 5- or 6-membered heterocydic ring which may be aromatic or non-aromatic, containing 1 to 4 heteroatoms selected from the group nitrogen, oxygen and sulfur, provided that each heterocydic ring contains no more than 2 oxygens and no more than 2 sulfurs, each phenyl or heterocydic ring optionally substituted with (R10)p; each R12 is independently selected from the group Cj-Cg alkyl, Cj-Cg haloalkyl, Cj-Cg alkoxy, Cj-Cg haloalkoxy and phenyl optionally substituted with (R10)p;
R13, R14 and R15 are each independently Cj-Cg alkyl or phenyl; R16 is H or C C6 alkyl;
R17 is H; C3-C6 cycloalkyl; CrC6 haloalkyl; C2-C6 alkenyl; C2-C6 alkynyl; C2-Cg alkylcarbonyl; C2-Cg alkoxycarbonyl; C2-Cg alkylaminocarbonyl; C3-Cg dialkylaminocarbonyl; Q; and Cj-Cg alkyl optionally substituted with cyano, Cj-Cg alkoxy, CrC6 haloalkoxy or Q; R18 is H or C!-C6 alkyl;
R19 is H, CrC6 alkyl, CrC6 haloalkyl, CrC6 alkoxy, CrC6 haloalkoxy or phenyl optionally substituted with (R10)p; m and n are each independently 0, 1 or 2; each p is 0, 1, 2, 3, 4 or 5; and q is O, 1, 2, 3 or 4; provided that a compound of Formula I is other than
(2α,6α)-(3,6-dihydro-2-methyl-2,6-methano-2H-l,3,5-benzoxadiazocin-4-yl)- cyanamide.
In the above recitations, the term "alkyl", used either alone or in compound words such as "alkylthio" or "haloalkyl" includes straight-chain or branched alkyl, such as, methyl, ethyl, M-propyl, /-propyl, or the different butyl, pentyl or hexyl isomers. "Alkenyl" includes straight-chain or branched alkenes such as ethenyl, 1 -propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers. "Alkenyl" also includes polyenes such as
1 ,2-propadienyl and 2,4-hexadienyl. "Alkynyl" includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers. "Alkynyl" can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl.
"Alkoxy" includes, for example, methoxy, ethoxy, «-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers. "Alkylthio" includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers. "Alkylsulfinyl" includes both enantiomers of an alkylsulfinyl group. Examples of "alkylsulfinyl" include CH3S(O), CH3CH2S(O), CH3CH2CH2S(O), (CH3)2CHS(O) and the different butylsulfinyl, pentylsulfinyl and hexylsulfinyl isomers. Examples of "alkylsulfonyl" include CH3S(O)2, CH3CH2S(O)2, CH3CH2CH2S(O)2, (CH3)2CHS(O)2 and the different butylsulfonyl, pentylsulfonyl and hexylsulfonyl isomers. "Alkylamino" and "dialkylamino" and the like, are defined analogously to the above examples. "Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
Examples where G is "a fused 5- or 6-membered ring which may be aromatic or non-aromatic, optionally containing one or two heteroatoms selected from the group nitrogen, oxygen and sulfur" includes, for example, cyclohexyl, cyclopentyl, phenyl, thienyl and pyridinyl. Examples of G where R1 and R2 are taken together to "form a 5- or 6- membered ring which may be aromatic or non-aromatic, optionally containing one or two hetero atoms selected from nitrogen, oxygen and sulfur, and optionally substituted with (R10)q" include, for example, naphthalenyl and quinolinyl.
The term "aromatic" ring denotes a fully unsaturated ring in which the ring system is aromatic (where aromatic indicates that the Hϋckel rule is satisfied for the ring). The term "non-aromatic" ring denotes a fully saturated ring as well as partially or fully unsaturated ring (where non-aromatic indicates that the Hϋckel rule is not satisfied for the ring). The heterocydic rings can be attached through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen. Examples of aromatic and non-aromatic ring systems containing 1 to 4 heteroatoms selected from the group nitrogen, oxygen and sulfur, containing no more than 2 oxygens and no more than 2 sulfurs, include, pyrrolidinyl; piperidinyl; tetrahydrofuranyl; tetrahydro-2H-pyranyl; 1,3-dioxanyl; 1,3-dithianyl; 4,5-dihydrooxazolyl; 4,5-dihydrothiazolyl; lH-pyrrolyl; furanyl; thienyl; lH-pyrazolyl; lH-imidazolyl; isoxazolyl; oxazolyl; isothiazolyl; thiazolyl; 1H- 1,2, 3 -triazolyl; 2H-l,2,3-triazolyl; lH-l,2,4-triazolyl; 4H-l,2,4-triazolyl; 1,2,3-oxadiazolyl; 1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl; 1,3,4-oxadiazolyl; 1,2,3-thiadiazolyl; 1,2,4-thiadiazolyl; 1,2,5-thiadiazolyl; 1,3,4-thiadiazolyl; lH-tetrazolyl; 2H-tetrazolyl; pyridinyl; pyridazinyl; pyrimidinyl; pyrazinyl; 1,3,5-triazinyl; 1,2,4-triazinyl; and 1,2,4,5-tetrazinyl.
The term "halogen", either alone or in compound words such as "haloalkyl", includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as "haloalkyl", said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of "haloalkyl" include F3C, C1CH2, CF3CH2 and CF3CC12. The terms "haloalkenyl", "haloalkynyl", "haloalkoxy", "haloalkylthio", "haloalkylsulfmyl", "haloalkylsulfonyl" and the like, are defined analogously to the term "haloalkyl". Examples of "haloalkenyl" include (C1)2C=CHCH2 and CF3CH2CH=CHCH2. Examples of
"haloalkynyl" include HC≡CCHCl, CF3C≡C, CC13C≡C and FCH2C≡CCH2. Examples of "haloalkoxy" include CF3O, CCl3CH2O, HCF2CH2CH2O and CF3CH2O. Examples of "haloalkylthio" include CC13S, CF3S, CC13CH2S and C1CH2CH2CH2S. Examples of "haloalkylsulfmyl" include CF3S(O), CCl3S(O), CF3CH2S(O) and CF3CF2S(O). Examples of "haloalkylsulfonyl" include CF3S(O)2, CCl3S(O)2, CF3CH2S(O)2 and CF3CF2S(O)2. Examples of "haloalkoxyalkoxy" include CF3OCH2O, CICH2CH2OCH2CH2O, CI3CCH2OCH2O as well as branched alkyl derivatives.
The total number of carbon atoms in a substituent group is indicated by the "Cj-C;" prefix where i and j are numbers from 1 to 8. For example, Cj-C3 alkylsulfonyl designates methylsulfonyl through propylsulfonyl. Examples of "alkylaminocarbonyl" include CH3NHC(=O), CH3CH2CH2NHC(=O) and (CH3)2CHNH(C=O) and the different butylamino- or pentylaminocarbonyl isomers. Examples of "dialkylaminocarbonyl" include (CH3)2NC(=O), CH3CH2CH2N(CH3)C(=O) and ((CH3)2CH)2NH(C=O).
One skilled in the art will appreciate that not all nitrogen containing heterocycles can form N-oxides since the nitrogen requires an available lone pair for oxidation to the oxide; one skilled in the art will recognize those nitrogen containing heterocycles which can form N-oxides. One skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for the preparation of N-oxides of heterocycles and tertiary amines are very well known by one skilled in the art including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethydioxirane. These methods for the preparation of N-oxides have been extensively described and reviewed in the literature, see for example: T. L. Gilchrist in Comprehensive Organic Synthesis, vol. 7, pp 748-750, S. V. Ley, Ed., Pergamon Press; M. Tisler and B. Stanovnik in Comprehensive Heterocydic Chemistry, vol. 3, pp 18-20, A. J. Boulton and A. McKillop, Eds., Pergamon Press; M. R. Grimmett and B. R. T. Keene in Advances in Heterocydic Chemistry, vol. 43, pp 149-161, A. R. Katritzky, Ed., Academic Press; M. Tisler and B. Stanovnik in Advances in Heterocydic Chemistry, vol. 9, pp 285-291, A. R. Katritzky and A. J. Boulton, Eds., Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk in Advances in Heterocydic Chemistry, vol. 22, pp 390-392, A. R. Katritzky and A. J. Boulton, Eds., Academic Press. When a compound is substituted with a substituent bearing a subscript that indicates the number of said substituents can exceed 1, said substituents (when they exceed 1) are independently selected from the group of defined substituents.
When a group contains a substituent which can be hydrogen, for example R7 or R8, then, when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted.
The salts of the compounds of the invention include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids. The salts of the compounds of the invention also include those formed with organic bases (e.g., pyridine, ammonia, or triethylamine) or inorganic bases (e.g., hydrides, hydroxides, or carbonates of sodium, potassium, lithium, calcium, magnesium or barium) when the compound contains an acidic group such as a carboxylic acid or phenol. Preferred compounds for reasons of better activity and/or ease of synthesis are:
Preferred 1. Compounds of Formula I above, and N-oxides and agriculturally suitable salts thereof, wherein: E is O or CR16R17;
R3 is H or Cj-Cg alkyl optionally substituted with 1-3 halogen or R3 is phenyl optionally substituted with (R10)p;
R7 is H or CrC6 alkyl; R8 is H; or
R7 and R8 can be taken together as =CR18R19; R17 is H or CrC3 alkyl; R18 is H, CrC3 alkyl; and
R19 is H, CrC3 alkyl. Preferred 2. Compounds of Preferred 1 wherein:
G is a fused cyclohexyl, cyclopentyl, phenyl, naphthalenyl, thienyl, pyridinyl or quinolinyl ring; R3 is H or CrC6 alkyl; and
R4 is H or CH3. Preferred 3. Compounds of Preferred 2 wherein: G is a fused phenyl ring; each R1 is independently selected from the group consisting of halogen, Cj-C3 alkyl, C1-C3 haloalkyl and C1-C3 haloalkoxy;
R5 and R6 are each independently H, Cj-Cg alkyl, C alkylcarbonyl, C2-C6 alkoxycarbonyl, C1-C3 alkylsulfonyl, 3-pyridinylmethyl 7 optionally substituted with 1-2 halogens or 5-thiazolylmethyl optionally substituted with halogen; and p and q are each independently 0, 1 or 2. This invention also relates to arthropodicidal compositions comprising arthropodicidally effective amounts of the compounds of the invention and at least one of a surfactant, a solid diluent or a liquid diluent. The preferred compositions of the present invention are those which comprise the above preferred compounds.
This invention also relates to arthropodicidal compositions comprising arthropodicidally effective amounts of (2α,6α)-(3,6-dihydro-2-methyl-2,6-methano-2H-l,3,5-benzoxadiazocin-4-yl)cyanamide and at least one of a surfactant, a solid diluent or a liquid diluent.
This invention also relates to a method for controlling arthropods comprising contacting the arthropods or their environment with an arthropodicidally effective amount of the compounds of the invention (e.g., as a composition described herein). The preferred methods of use are those involving the above preferred compounds.
This invention also relates to a method for controlling arthropods comprising contacting the arthropods or their environment with an arthropodicidally effective amount (2α,6α)-(3,6-dihydro-2-methyl-2,6-methano-2H-l,3,5-benzoxadiazocin-4-yl)cyanamide (e.g., as a composition described herein). Compounds of this invention can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. For example, a compound of Formula I may exist as geometric isomer I or la, or both I and la. One skilled in the art will appreciate that one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers. Accordingly, the present invention comprises compounds selected from Formula I, N-oxides and agriculturally suitable salts thereof. The compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form.
R° R° CN R. 1 1
Ν Ν.
•CΝ
Figure imgf000009_0001
G J <iγ
.Ν. ^ Ν \R5.
*RJ
(R2)rn
Figure imgf000009_0002
(R 2 2)mo ^ \
R la 8
One skilled in the art will recognize that some compounds of Formula I can exist in one or more tautomeric forms. For example, a compound of Formula I wherein R5 is H may exist as tautomer lb or Ic, or both lb and Ic; and a compound of Formula I wherein R6 is H may exist as tautomer Id or Ie, or both Id and Ie. The present invention comprises all tautomeric forms of compounds of Formula I.
R .
N . NH CN
Figure imgf000010_0001
Figure imgf000010_0003
.N
H
(R2)m ΕC (R2)ώ R lb Ic
When R5 is H
H
I N. R
^CN N NH
Figure imgf000010_0002
" " "CN
N^
Figure imgf000010_0004
~RJ •R3
(R2Wi R (R2)ώ R
Id Ie
When R° is H
One skilled in the art will also recognize that compounds of Formula I can exist as syn or anti isomers. For example, a compound of Formula I may exist as isomers I or If, or both I and If. The present invention comprises all syn and anti isomeric forms of compounds of Formula I.
R° R° CN
R . I ι R3\ 1 ^ ^CN
Figure imgf000010_0005
.N G Λ ^NA ^N
^TN
•RJ \ R5
^
(R2)m Ε? ^
Figure imgf000010_0006
V
If
When R5 is H DETAILS OF THE INVENTION
The compounds of Formula I can be prepared by one or more of the following methods and variations as described in Schemes 1-14. The definitions of R!-R19, G, E, X and X1 in the compounds of Formulae 1-25 are as defined above in the Summary of the Invention or as defined below in the Schemes. Compounds of Formulae Ia-If are various subsets of the compounds of Formula I, and all substituents for Formulae Ia-If are as defined above for Formula I.
Compounds of Formula I where R6 is other than H can be prepared by the reaction of compounds of Formula I (R6 is H) with a compound of Formula 1 in the presence of a proton acceptor as depicted in Scheme 1.
Scheme 1
R° ■X
(R6 = H) Proton acceptor (R6 is other ^ H)
X is halogen, alkylsulfonate, arylsulfonate, or R -X is an anhydride of a carboxylic acid or sulfonic acid or R -X is an alkyl or aryl isocyanate.
Compounds of Formula 1 can be highly varied and include alkylating agents such as alkyl halides, alkyl sulfonates and the like; acylating agents such as acyl halides and acyl anhydrides and pyrocarbonates; sulfonylating agents such as sulfonyl halides and sulfonic anhydrides; and carbamoylating reagents such as alkyl and aryl isocyanates. Typical Scheme 1 reactions involve mixing a compound of Formula I (R6 is H) with one to ten molar equivalents of a compound of Formula 1 in the presence of one molar equivalent of a proton acceptor. Typical proton acceptors include sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, alkyl lithiums, lithium amides (such as lithium diisopropylamide) amines (such as pyridine, triethylamine and 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU)) and hydroxide bases (such as sodium hydroxide and potassium hydroxide).
Scheme 1 reactions are usually carried out in a solvent, including polar aprotic solvents (such as tetrahydrofuran, NN-dimethylformamide, NN-dimethylacetamide and 1 -methyl-2-pyrrolidinone), alcohols such as methanol, ethanol and 2-propanol, or water. In some cases, a solvent is not used. Scheme 1 reactions are typically run at temperatures ranging from 0 °C to the reflux temperature of the solvent and the reactions are usually complete within 2 to 48 hours. The products of Formula I (R6 is other than H) can be isolated by chromatography, crystallization or, in some cases, by the addition of water to the reaction followed by filtration of the product. Compounds of Formula I where R5 is other than H can be prepared by the reaction of a compound of Formula I (where R5 is H) with a compound of Formula 2 in the presence of a proton acceptor as depicted in Scheme 2. 10 Scheme 2
R5 — X
(R5 = H) proton acceptor (R5 is other ^ H)
Procedures for Scheme 2 reactions are completely analogous to those already described for Scheme 1 reactions and compounds of Formula 2 are completely analogous to compounds of Formula 1.
Reactions of compounds of Formula I (where R5 and R6 are H) with alkylating, acylating and sulfonylating agents of Formula 1 or 2 as described for Schemes 1 and 2 typically occur to give compounds of Formula I where R6 is not H. Analogous reactions to give the alternative regioisomer of a compound of Formula I (R5 is other than H, R6 is H) usually requires that the R3 group be sterically demanding (e.g., t-butyl) and that the R4 group be small (e.g., H or Me).
Alternatively, the preparation of compounds of Formula I where R5 is other than H and R6 is H can be achieved using the three-step protocol outlined in Scheme 3.
Scheme 3
Step i
O. o
Y°Y o
(R5 = R6 = H) proton acceptor (R5 = H, R6 = C(O)O-f-Bu)
Step ii
(Rθ H, R6 = C(0)0-?-Bu) proton acceptor' (R5 is other than H, R6 = C(O)O-t-Bu)
Step iii acid
(R5 is other than H, solvent (R5 is other than H, R6 = C(0)0-/-Bu) R6 = H)
Step i of Scheme 3 is an example of a Scheme 1 reaction using di-tert-butyl pyrocarbonate (3) as the compound of Formula 1. In Step ii of Scheme 3, the product of Step i reacts with a compound of Formula 2 as described in Scheme 2. In Step iii of Scheme 3, the product of Step ii reacts with an acid, which results in the removal of the 11 t-butoxy carbonyl group and the formation of compounds of Formula I (R5 is other than H, R6 is H). Acids used in Step iii reactions include trifluoroacetic and hydrochloric acids. One skilled in the art will recognize that many methods are available for carrying out reactions depicted in Step iii of Scheme 3 (see, e.g., Protective Groups in Organic Synthesis, 2nd Edition, T. W. Greene and P. G. M. Wuts, 1991, pp. 327-330.)
The reaction of a compound of Formula I (R5 and R6 are H) with greater than two molar equivalents of a compound of Formula 1 and greater than two molar equivalents of a proton acceptor will sometimes produce compounds of Formula I where R5 and R6 are other than H. In these cases, heating of the reaction to form the compounds of Formula I (R5 and R6 are other than H) may be required (e.g. above ambient temperature), otherwise, the conditions for these reactions will be analogous to those described for Scheme 1 reactions.
The definitions of compounds of Formula 1 and Formula 2 are the same; the use of the separate identifiers (i.e., 1 and 2) simply distinguishes the introduction of R6 and R5 substituents, respectively. Compounds of Formula 1 and Formula 2 are usually available from commercial sources. One skilled in the art will recognize that a variety of methods can be used to prepare compounds of Formula 1 and Formula 2 that may not be commercially available (e.g. alcohols can be converted to alkyl halides and alkyl sulfonates, carboxylic acids can be converted into acid chlorides and acid anhydrides, sulfonic acids can be converted into sulfonyl halides and sulfonic anhydrides, and amines can be converted into isocyanates).
Compounds of Formula I where R5 and R6 are H and E is other than CR16R17can be prepared by the reaction of compounds of Formula 4 with between 2 to 10 molar equivalents of cyanamide in the presence of a base (such as piperidine) as depicted in Scheme 4.
Scheme 4
H2N-CN I
Figure imgf000013_0001
base (R5 = R6 = R8 = H)
(Rz )m
4 (E is other than CR16R17) Scheme 4 reactions are usually performed in a solvent such as tetrahydrofuran,
1 ,2-dimethoxyethane, alcohols (such as methanol or ethanol), aromatic hydrocarbons (such as benzene or toluene), or by using the base (usually piperidine) as a solvent. Mixtures of solvents may also be employed. Reactions are typically carried out at temperatures ranging from 0 °C to 150 °C, with the refluxing temperatures of the solvent being preferred. Reactions are typically complete in 1 to 72 hours. 12
A variety of procedures are known for preparing compounds of Formula 4. For instance they can be prepared via a Heck reaction of an appropriately substituted iodide or triflate with an α,β-unsaturated aldehyde or ketone. Alternatively, they can be prepared via the condensation of an aldehyde or ketone with an appropriately substituted phosphorane. Scheme 5 depicts the formation of compounds of Formula 4 via an aldol (or Claisen-Schmidt) condensation (followed by dehydration to the unsaturated products of Formula 4).
Scheme 5
Figure imgf000014_0002
Figure imgf000014_0001
(Rz )m base (-H20)
(E is other than CR16R17)
In Scheme 5 reactions, compounds of Formula 5 react with compounds of Formula 6 (1 to 50 molar equivalents) in the presence of between 0.1 and 2.0 equivalents of a suitable base (including aqueous sodium hydroxide, aqueous potassium hydroxide, aluminum t-butoxide and sodium hydride). For compounds of Formula 5, where G forms an aromatic ring, the hydrogen atom bonded to E is relatively acidic and, in these cases, the use of greater than one molar equivalent of base is preferred. In Scheme 5 reactions, the loss of a water molecule from the aldol product usually occurs under the conditions of the aldol reaction, however, in the rare cases where the aldol is stable to the reaction conditions, then the aldol intermediate can be dehydrated using known methods (see, e.g., Bull. Chem. Soc. Japan, (1989), vol. 62, 180). Scheme 5 reactions are usually conducted in a polar solvent such as water, methanol, ethanol, tetrahydrofuran, 1,2-dimethoxyethane, NN-dimethylformamide, dioxane, acetonitrile or in a mixture of solvents. It is sometimes advantageous to use compounds of Formula 6 as the solvent. Reaction temperatures can range from 20 °C to the reflux temperature of the solvent and the reactions are usually complete in 2 to 48 hours. A great number of the compounds of Formula 5 can be obtained from commercial sources (for example, when G forms a phenyl ring, then compounds of Formula 5 [where E is O] are comprised of the well-known salicylaldehydes [R3 is H], o-hydroxyacetophenones [R3 is Me] and o-hydroxybenzophenones [R3 is optionally substituted phenyl]. Salicylaldehydes of Formula 5 (E is O, R3 is H), can be prepared by the 13
Duff reaction (see: J. Chem. Soc, (1932), p. 1987; Chem. Pharm. Bull, (1983), 31, 1751) as depicted in Scheme 6.
Scheme 6
(Rl hexamethylenetetramine *- 5
Figure imgf000015_0001
OH acid catalyst
(R3 = H) Rz
ø-Hydroxy phenyl alkyl ketones of Formula 5 (E is O, R3 is optionally substituted alkyl) and o-hydroxy phenyl aryl ketones of Formula 5 (E is O, R3 is optionally substituted aryl) can be prepared by a number of methods, including the Friedel-Crafts acylation (see Chem. Revs., (1955), vol. 55, p. 229) depicted in Scheme 7. Phenols of Formula 7 may be obtained from commercial suppliers.
Scheme 7
O
R3' "Cl
A1C13 (R3 is other than H)
Preparations of compounds of Formula 5 a (compounds of Formula 5 where G forms a thiophene ring and E is O) can be achieved using the two-step protocol depicted in Scheme 8.
Scheme 8
Step i
OMe
acylation j-J
Figure imgf000015_0003
reaction
Figure imgf000015_0002
Figure imgf000015_0004
Step ii BBr3
10
Figure imgf000015_0005
14
In Step i of Scheme 8, the methoxy thiophenes of Formula 9 are acylated using either the Nilsmeier reagent (POC^/NN-dimethylformamide ) to give compounds of Formula 10 (R3 is H) or by a Friedel-Crafts acylation procedure (R3COCl/AlCl3) to give compounds of Formula 10 (R3 is other than H). Procedures for conducting Step i of Scheme 8 are well-known to those skilled in the art (see, e.g., Chem. Rev., (1955), vol. 55, p. 229 and J. Chem. Soc, Section C (1967), p. 779).
In Step ii of Scheme 8, the methyl ether is removed using boron tribromide in a solvent such as dichloromethane (for an example, see Org. Synth., Collect, vol. V, (1973), p. 412). One skilled in the art will recognize that there are many alternative procedures for the de-methylation reaction depicted in Step ii of Scheme 8.
Compounds of Formula 5b (compounds of Formula 5 where G forms a pyridine ring and E is O) can be prepared by the four-step sequence depicted in Scheme 9.
Scheme 9
Step i
(R! )n
OH (R! )n
OH
LiAlH4 (R2 ' Ν' C02H
(RZ M „o CH20H
11 12
Step ii
(R*
12 oxidation
(R2
Figure imgf000016_0001
15 R3-M (Rl
OH
Step iii
14
R3
(R2 π^T N
Figure imgf000017_0001
HO
13
Step iv
(R!
13 oxidation
Figure imgf000017_0002
R3
(R2 )n
Figure imgf000017_0003
5b O
(R3 is other than H)
In Step i of Scheme 9, carboxylic acids of Formula 11 are reduced to diols of Formula 12 using 0.5 to 5 molar equivalents of lithium aluminum hydride in a suitable solvent (typically ether or tetrahydrofuran) at a temperature ranging from 0 °C to the reflux temperature of the solvent. In Step ii of Scheme 9, compounds of Formula 12 are oxidized to aldehydes of
Formula 5b (R3 is H) using an oxidant such as activated manganese dioxide in a solvent such as methylene chloride or toluene at temperatures ranging from ambient to the refluxing temperature of the solvent. One skilled in the art will recognize that a variety of oxidation procedures are available for use in Scheme 9, Step ii reactions, including the use of pyridinium chlorochromate, dimethyl sulfoxide/oxalyl chloride (Swern reagent) and tetrapropylammonium perruthenate.
In Step iii of Scheme 9, aldehydes of Formula 5b (R3 is H) react with a compound of Formula 14 to form secondary alcohols of Formula 13. Compounds of Formula 14 include Grignard reagents (M = Mg halide) and organolithiums (M is Li). Formation of compounds of Formula 13 usually requires the use of greater than 2 molar equivalents of a compound of Formula 14 and the reactions are typically carried out in solvents such as ether, tetrahydrofuran, hexane or toluene. Reactions are usually run at temperatures ranging from -78 °C to room temperature and require between 0.5 and 48 hours for completion.
In Step iv of Scheme 9, carbinols of Formula 13 are oxidized to ketones of Formula 5b (R3 is other than H) using procedures that are analogous to those previously described for Step ii of Scheme 9.
Compounds of Formula 5 c (compounds of Formula 5 where G forms a non-aromatic ring, E is O and R3 is H) can be prepared using the synthetic pathway depicted in Scheme 10. 16 Scheme 10
Stepi
(R')n
C02Et
NaBH4
Figure imgf000018_0001
Figure imgf000018_0002
(R )m (R^)m
15 16
Step ii
f-Bu(Me)2SiCl C02Et
16 proton acceptor
Figure imgf000018_0003
(R^)m
17
Step iii
CH2OH
17 reduction
Figure imgf000018_0004
(R )m
18
Step iv
CHO oxidation
18
Figure imgf000018_0005
)m
19
Stepv
(RX)n CHO
19 fluoride ion
Figure imgf000018_0006
OH
(R2)m
5c
In Step i of Scheme 10, keto-esters of Formula 15 are reduced to alcohols of Formula 16 using sodium borohydride in a polar solvent such as ethanol at temperatures 17 ranging from 0 °C to 78 °C for times ranging from 1 hour to 3 days. One skilled in the art will recognize that alternative reduction procedures are available for the conversion of a compound of Formula 15 to a compound of Formula 16 (using, e.g., aluminum triisopropoxide, Baker's yeast or hydrogen with a platinum or nickel catalyst, see Helv. Chim. Acta, (1952), vol. 35, p. 2406).
In Step ii of Scheme 10, alcohols of Formula 16 are protected as tert-butyldimethylsilyl ethers using procedures that are well-known in the literature (see, e.g., J. Org. Chem., (1966), vol. 61, p. 3794).
The esters of Formula 17 are reduced to primary alcohols of Formula 18 using preferably lithium aluminum hydride in an ethereal solvent, or diisobutylaluminum hydride in dichloromethane, tetrahydrofuran or toluene as depicted in Step iii of Scheme 10. Numerous procedures for analogous ester reductions are available in the chemical literature (see, e.g., Tetrahedron Lett. (1995), p. 2097 and Synlett, (1993), p. 27).
In Step iv of Scheme 10, the primary alcohols of Formula 18 are oxidized to aldehydes of Formula 19 using oxidants such as the Swera reagent (dimethyl sulfoxide, oxalyl chloride), pyridinium chlorochromate (PCC) or (rc-Pr^NRuO^ These are standard procedures for organic synthesis and are well-known to those skilled in the art (for two examples, see J. Org. Chem., (1992), vol. 57, p. 4512 and Tetrahedron-Asymmetry, (1995), p. 2131). In Step v of Scheme 10, silyl ethers of Formula 19 are converted to alcohols of
Formula 5c using a fluoride-ion source such as tetrabutylammonium fluoride, potassium fluoride, aqueous hydrofluoric acid or pyridine- hydrofluoric acid. Alternatively, non-fluoride-ion de-silylation procedures are available as well (see, e.g., J. Am. Chem. Soc, (1985), vol. 107, p. 4577). The preparation of compounds of Formula 5d (compounds of Formula 5 where E is O and R3 is other than H) can be achieved using procedures depicted in Scheme 11.
Scheme 11
Step i R3_M
14
19
Figure imgf000019_0001
(R2 )m
20 18
Step ii oxidation 20
Figure imgf000020_0001
(R )m
21
Step iii fluoride ion
21 or acid
Figure imgf000020_0002
)m
5d
(R >3J : is other than H)
In Step i of Scheme 11, aldehydes of Formula 19 are treated with between 1 and 5 molar equivalents of an organometallic compound of Formula 14 to give alcohols of Formula 20 using procedures analogous to those described previously for Scheme 9 reactions. For a related example, see Tetrahedron Lett., (1995), p. 3091.
In Step ii of Scheme 11, alcohols of Formula 20 are oxidized to ketones of Formula 21 using oxidation procedures analogous to those described previously for Scheme 10, Step iv reactions.
In Step iii of Scheme 11, removal of the silyl protecting group from compounds of Formula 21 to form alcohols of Formula 5 is realized via procedures which are completely analogous to those already described for Scheme 10, Step v reactions.
Compounds of Formula 5e (compounds of Formula 5 where E is S) can be prepared using procedures depicted by Scheme 12.
Scheme 12
R3
(Rl
1) BuLi, TMEDA O *-
O SH
Figure imgf000020_0003
)m 2) (R2 )m
R3 2 Λ x1
2 23 5e G forms an aromatic ring
X is a leaving group such as halogen, alkoxy or dialkylamino, or the compound of Formula 23 is an acid anhydride 19
Scheme 12 reactions involve the reaction of mercaptans of Formula 22 with typically 2 molar equivalents of n-butyllithium and 2 molar equivalents of N,N,N,N-tetramethylenediamine (TMEDA) in a solvent such as tetrahydrofuran or cyclohexane at temperatures ranging from -78 °C to the refluxing temperature of the solvent for 0.25 to 12 hours, followed by treatment with compounds of Formula 23 (1-2 molar equivalents) at 0 °C to ambient temperature. The products of Formula 5e are typically isolated by acidification of the reaction medium followed by extractive work-up. For the preparation of compounds of Formula 5e where R3 is H, compounds of Formula 23 are typically N,N-dimethylformamide or N-formylpiperidine. Alternatively, when R3 is not H, compounds of Formula 5e may be prepared via nitriles of Formula 24 as shown in Scheme 13.
Scheme 13
1) H-BuLi, TMEDA ,
22 >■ 5e (Rό is other than H)
2) R3 - CΝ (24) 3) H30+
In Scheme 13 reactions, compounds of Formula 22 are treated with «-butyllithium and N,N,N,N-tetramethylethylenediamine (TMEDA) in a manner analogous to that described for Scheme 12 reactions, followed by treatment with one equivalent of a nitrile of Formula 24. When the reaction with compounds of Formula 24 is complete (usually in 1 to 24 hours at temperatures ranging from 0 °C to the refluxing temperature of the solvent), the resulting imine is hydrolyzed to the ketones of Formula 5e with aqueous acid followed by extractive work-up. More detailed procedures for Scheme 12 and 13 reactions can be found in: J. Am. Chem. Soc, (1989), vol. Ill, p. 2327 andJ. Heterocycl. Chem., (1995), vol. 32, p. 1683. Compounds of Formula I where R5 and R6 are H and E is CR16R17 can be prepared by the reaction of diamines of Formula 25 with reagents such as diphenyl cyanocarbonimidate or dimethyl cyanodithioiminocarbonate as depicted in Scheme 14.
Scheme 14
(R')n RJ ΝH2
Λ R
O CN
G o \ ^-R8 (PhO) C=N
O θNH2 (R° = R° = H, E ; CR16R17)
(R2)
Figure imgf000021_0001
R 16/ R1
25
Scheme 14 reactions are usually performed in a solvent such as an alcohol (e.g., -propanol or ethanol), tetrahydrofuran or aromatic hydrocarbon (e.g., benzene or toluene). 20
Mixtures of solvents may also be employed. Reactions are typically carried out at temperatures ranging from O °C to 150 °C, with the reflux temperature of the solvent being preferred. Reactions are typically complete in 1 to 72 hours.
Diamines of Formula 25 can be prepared by known methods (e.g., Chem. Pharm. Bull, (1966), vol. 14, p. 324) or by methods known to one skilled in the art.
It is recognized that some reagents and reaction conditions described above for preparing compounds of Formula I may not be compatible with certain functionalities present in the intermediates. In these instances, the incorporation of protection/deprotection sequences or functional group interconversions into the synthesis will aid in obtaining the desired products. The use and choice of the protecting groups will be apparent to one skilled in chemical synthesis (see, for example, Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). One skilled in the art will recognize that, in some cases, after the introduction of a given reagent as it is depicted in any individual scheme, it may be necessary to perform additional routine synthetic steps not described in detail to complete the synthesis of compounds of Formula I. One skilled in the art will also recognize that it may be necessary to perform a combination of the steps illustrated in the above schemes in an order other than that implied by the particular sequence presented to prepare the compounds of Formula I.
One skilled in the art will also recognize that compounds of Formula I and the intermediates described herein can be subjected to various electrophilic, nucleophilic, radical, organometallic, oxidation, and reduction reactions to add substituents or modify existing substituents.
Without further elaboration, it is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever. Percentages are by weight except for chromatographic solvent mixtures or where otherwise indicated. Parts and percentages for chromatographic solvent mixtures are by volume unless otherwise indicated. lH NMR spectra are reported in ppm downfield from tetramethylsilane; s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, ABq = AB quartet and br s = broad singlet. Title compounds in Examples 1 -5 are named according to the rules of Chemical Abstracts 9 Collective Index which require an endocyclic double bond in the 1,3,5-benzoxadiazocine ring. However, NMR data indicates that the double bond is exocyclic in Me2SO-(i6 solutions. EXAMPLE 1
Step A: Preparation of 4-f 2-hydroxyphenyl)-3-buten-2-one
Sodium hydroxide (89 mL of a 1.0 N solution, 89 mmol) was added to a stirred solution of salicylaldehyde (8.65 mL, 81 mmol) and acetone (60 mL) at a temperature less 21 than 30 °C. After stirring at 23 °C for two days, hydrochloric acid (95 mL of a 1.0 N solution) was added dropwise with ice-water bath cooling. The resulting solid product was removed by filtration, washed with several portions of water and dried to give 11.4 g of 4-(2-hydroxyphenyl)-3-buten-2-one, as a yellow solid, mp 136-138 °C. JH NMR (300 MHz, Me2SO- 6) δ 10.2 (s,lH), 7.78 (d,lH), 7.60 (dd,lH), 7.25 (dt,lH), 6.95-6.78 (m,3H), 2.30 (s,3H).
Step B: Preparation of re/-r(2R,6R)-3.6-dihvdro-2-methyl-2.6-methano-2H-l.3.5- benzoxadiazocin-4-vncyanamide A solution of 0.25 g (1.5 mmol) of the product of the previous step, cyanamide (0.3 g, 3.1 mmol), 1 ,2-dimethoxyethane (2 mL) and piperidine (two drops) was heated at reflux for 5 h, cooled to ambient temperature, diluted with 1, 2 -dimethoxy ethane (5 mL) and filtered. The solid product was washed with 1,2-dimethoxyethane and dried to give O.ll g of the title compound as a white solid, mp >220 °C. JΗ NMR (300 MHz, Me2SO-</6) δ 8.66 (br s,2H), 7.27-7.18 (m,2H), 6.92 (t,lH), 6.82 (d,lH), 4.50 (m,lH), 2.15 (m,2H), 1.68 (t,3H). EXAMPLE 2
Preparation of re/-["(2R.6R)-5-(6-chloro-3-pyridinylmethyl)-5,6-dihvdro-2-methyl-2,6- methano-2H- 1,3.5 -benzoxadiazocin-4- yll cyanamide Sodium hydride (18 mg of a 60% in oil suspension, 0.45 mmol) was added to a solution of 0.10 g (0.45 mmol) of the product of Step B, Example 1 and 1.5 mL of NN-dimethylformamide with ice-water bath cooling. The resulting mixture was stirred at 23 °C for 0.75 hours and then a solution of 2-chloro-5-(chloromethyl)pyridine (82 mg of 88% pure material, 0.45 mmol) and NN-dimethylformamide (1.5 mL) was added at 5 °C. The resulting mixture was stirred at 5 °C for 1 h and then at 23 °C for 18 h. The reaction was quenched with ethanol (1 mL) at 5 °C and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (3 X 100 mL) and the combined organic layers were washed with water (4 X 100 mL), dried over anhydrous magnesium sulfate and concentrated to give 0.21 g of a crude product that was chromatographed on silica gel using 1:1 hexane-ethyl acetate to give 60 mg of the title compound as a solid, mp 216 °C (dec). !Η ΝMR (300 MHz, Me2SO- 6) δ 8.67 (s, >1H), 8.40 (d,lH), 7.79 (dd,lH), 7.3-7.2 (m,2H), 6.95-6.80 (m,2H), 4.87 (d,lH), 4.67 (m,lH), 4.58 (d,lH), 2.37 (d of multiplets,lH), 2.20 (distorted d,lH), 1.79 (s,3H).
EXAMPLE 3 Preparation of re/-r2R.6R)-5-acetyl-N-cvano-5,6-dihydro-2-methyl-2.6-methano-2H-l .3.5- benzoxadiazocin-4-amine Sodium hydride (74 mg of a 60% suspension in mineral oil, 1.8 mmol), was added to a solution of 0.42 g (1.8 mmol) of the product from Step B, Example 1 and NN-dimethylformamide (11 mL) at 5 °C. After stirring for 1 h at 5 °C, acetic anhydride (0.26 mL, 2.8 mmol) was added at 5 °C. The viscous reaction mixture was stirred at 23 °C 22 for 18 h and then water (25 mL) was added. The resulting precipitate was filtered, washed with water and dried to give 0.30 g of the title compound as a white solid, mp 219-221 °C. *H NMR (300 MHz, Me2SO- 6) δ 9.35 (s,lH), 7.33-7.22 (m,2H), 6.96 (t,lH), 6.87 (d,lH), 5.78 (m,lH), 2.48 (s,3H), 2.37 (dd,lH), 2.23 (dd,lH), 1.80 (s,3H). EXAMPLE 4
Step A: Preparation of 4-(2-hvdroxy-5-chlorophenyl)-3-buten-2-one
Aqueous sodium hydroxide (10.5 mL, 1.0 N) was added to a solution of 5-chlorosalicylaldehyde (1.5 g, 9.6 mmol) and acetone (7 mL) at ambient temperature. After 18 h, the reaction was cooled to 5 °C and then 12.5 mL of 1 N aqueous hydrochloric acid was added dropwise. The resulting solid product was removed by filtration and washed with 1 N aqueous hydrochloric acid. After drying, 1.7 g of the title compound was isolated as a tan solid, mp 157 °C (dec). !H ΝMR (300 MHz, Me2SO- 6) δ 10.54 (s,lH), 7.75-7.65 (overlapping doublets,2H), 7.26 (dd,lH), 6.94 (s,lH), 6.90 (d,lH), 2.30 (s,3H). Step B: Preparation of re/-r(2R.6R)-8-chloro-3,6-dihydro-2-methyl-2.6-methano-2H- 1 ,3 ,5-benzoxadiazocin-4-yl]cyanamide
A solution of 1.45 g of the product from the above procedure, 0.62 g (15 mmol) of cyanamide, 11 mL of 1 ,2-dimethoxyethane and 4 drops of piperidine was heated at reflux for 8 h, and then cooled to ambient temperature. The resulting solid product was removed by filtration, washed with 20 mL of 1,2-dimethoxyethane and dried to give 0.63 g of the title compound as a white solid, mp >220 °C. JΗ ΝMR (300 MHz, Me2SO- 6) δ 8.76 (s,lH), 8.63 (br s,lH), 7.35-7.20 (m,2H), 6.86 (d,lH), 4.52 (m,lH), 2.2 (ABq,2H), 1.68 (s,3H).
EXAMPLE 5 Preparation of rg/-[(lR.5R)-l, 2,5,6-tetrahydro-l.5-methano-2.4-benzodiazocin- 3 -yl] cyanamide To a solution of 1.29 g (7.93 mmol) of re/-(lR,3R)-l ,2,3,4-tetrahydro-
1,3-naphthalenediamine (prepared according to Chem. Pharm. Bull, (1966), vol. 14, p. 324) in 70 mL of 2-propanol was added 1.87 g (7.93 mmol) of diphenyl cyanocarbonimidate. The mixture was refluxed for 4 h. After cooling 0.93 g of the title compound was filtered off, mp > 250 °C. !H ΝMR (300 MHz, Me2SO-</6) δ 8.16 (br s,lH), 7.83 (br s,lH), 7.20 (m,4H), 4.40 (br s,lH), 3.94 (br s,lH), 2.84 (m,2H), 2.02 (m,2H).
By the procedures described herein together with methods known in the art, the following compounds of Tables 1 to 58 and of Index Tables A, B, C and D can be prepared. The following abbreviations are used in the Tables which follow: n = normal, c = cyclo, Me = methyl, Et = ethyl, Pr = propyl, Ph = phenyl, OMe = methoxy, OEt = ethoxy, SO2Me = methylsulfonyl, SO2Et = ethylsulfonyl, 23
COMe = COEt = SO2-(4-Me-Ph) =
O O O
Figure imgf000025_0001
CH3CH2
Figure imgf000025_0002
H3C =oV 2-CH2-pyridinyl = 3-CH2-pyridinyl = 4-CH -pyridinyl =
N-
Figure imgf000025_0003
Nc
N' CH — CH2—
Figure imgf000025_0005
6-Cl-2-CH2-pyridinyl = 6-Cl-3-CH2-pyridinyl = 2-CH2-furanyl =
Cl
Figure imgf000025_0004
N* O cr N CH— - - CH2-
CH— CH2-c-Pr = 2 -pyridinyl = 4-pyridinyl : t CH2-, N-
'N' ^ and
Figure imgf000025_0006
STRUCTURES FOR TABLES 1-54
R"
R1 R
Figure imgf000025_0008
Figure imgf000025_0007
Structure for Tables 1-28 Structure for Tables 29-41
"CN
• >
Figure imgf000025_0010
Figure imgf000025_0009
Structure for Tables 42-43 Structure for Tables 44 24
R°
R
'CN .N 'CN
Figure imgf000026_0002
,N
'R3 ■oΛ
Figure imgf000026_0001
ΕC
Structure for Table 45 Structure for Table 46
R°
CN 'CN
Figure imgf000026_0004
,N„
Figure imgf000026_0005
'RJ
Figure imgf000026_0003
oΛ R7
Structure for Table 47 Structure for Table 48
Figure imgf000026_0006
Figure imgf000026_0007
Structure for Table 49 Structure for Table 50
R°
R
'CN
Figure imgf000026_0009
-N„
'RJ ■oΛ
Figure imgf000026_0008
R7
Structure for Table 51 Structure for Table 52
R° N-.
.N 'CN
Figure imgf000026_0010
,N„
'RJ ■oΛ
R7
Figure imgf000026_0011
Structure for Table 53 Structure for Table 54 25
^CN !
'RJ
Figure imgf000027_0001
Figure imgf000027_0002
Structure for Table 55 Structure for Table 56
R°
I
Ri ,N N
CN
L -^R8 NT^ ^ R5
Figure imgf000027_0003
R7
Figure imgf000027_0004
Structure for Table 57 Structure for Table 58
TABLE 1
= H, R = - H, E = = 0,
Column 1 Column 2
R R! R£ R^ R3. R! R£ R6
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-furanyl
6 H Me H «-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C02-«-Pr H Me H S02NMe2
9 H Me H COEt H Me H CH2SiMe3 0 H Me H CO-w-Pr H Me H 2-pyridinyl 1 H Me H Ph H Me H 4-pyridinyl 2 H Me H CH2Ph Me Me H H 3 H Me H S02Me Me Me H Me 4 H Me H S02CF3 Me Me H COMe 5 H Me H S02Ph Me Me H C02Me
Figure imgf000027_0005
6 H Me H S02-(4-Me-Ph) Me Me H S02Me 26
Column 1 Column 2 nl R4 R5 R6 R R! R£ R6
H Me H S02Et H Me Me H
H Me H C0CF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Figure imgf000028_0001
27
Column 1 Column 2
El El E£ El El El El El
52 Me Me Me H Ph Ph Me H 3 Me Me Me Me Ph Ph H Me 4 Me Me COMe COMe Ph CF3 H H 5 H H H H H H Me Me 6 H H H Me H H COMe COMe 7 H H H COMe H H C02Me C02Me 8 H H H C02Me H H S0 Me S02Me 9 H H H S02Me H H Me H
TABLE 2
= C 1, R2 : = H, E = = O,
Column 1 Column 2
El El E El El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-furanyl
6 H Me H H-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C02-«-Pr H Me H S02NMe2
9 H Me H COEt H Me H CH2SiMe3 0 H Me H CO-n-Pr H Me H 2-pyridinyl 1 H Me H Ph H Me H 4-pyridinyl 2 H Me H CH2Ph Me Me H H 3 H Me H S02Me Me Me H Me 4 H Me H S02CF3 Me Me H COMe 5 H Me H S02Ph Me Me H C02Me 6 H Me H S02-(4-Me-Ph) Me Me H S02Me 7 H Me H S02Et H Me Me H 8 H Me H COCF3 H Me Me Me 9 H Me H CH2CF3 H Me COMe COMe 0 H Me H CONHMe H Me C02Me C02Me 1 H Me H CONHEt H Me S02Me S02Me
Figure imgf000029_0001
2 H Me H CONHPh H Et H H 28
Column 1 Column 2
El El El El El El El El
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
Figure imgf000030_0001
H H H Me H H COMe COMe 29
Column 1 Column 2
El El El El El El El El 7 H H H COMe H H C02Me C02Me 8 H H H C02Me H H S02Me S02Me 9 H H H S02Me H H Me H
TABLE 3
= H [, R2= C1, E = = 0,
Column 1 Column 2
El El El El El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-furanyl
6 H Me H M-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C02-«-Pr H Me H S02NMe2
9 H Me H COEt H Me H CH2SiMe3 0 H Me H CO-w-Pr H Me H 2-pyridinyl 1 H Me H Ph H Me H 4-pyridinyl 2 H Me H CH2Ph Me Me H H 3 H Me H S02Me Me Me H Me 4 H Me H S02CF3 Me Me H COMe 5 H Me H S02Ph Me Me H C02Me 6 H Me H S02-(4-Me-Ph) Me Me H S02Me 7 H Me H S02Et H Me Me H 8 H Me H COCF3 H Me Me Me 9 H Me H CH2CF3 H Me COMe COMe 0 H Me H CONHMe H Me C02Me C02Me 1 H Me H CONHEt H Me S02Me S02Me 2 H Me H CONHPh H Et H H 3 H Me H CH2CH=CH2 H Et H Me 4 H Me H CH2C≡CH H Et H COMe 5 H Me H CH2CH=CHMe H Et H C02Me 6 H Me H CH2C≡CMe H Et H S02Me
Figure imgf000031_0001
7 H Me H 2-CH2-pyridinyl H Ph H H 30
Column 1 Column 2
El El El El El El El El
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
H H H Me H H COMe COMe
H H H COMe H H C02Me C02Me
H H H C02Me H H S02Me S02Me
Figure imgf000032_0001
H H H S02Me H H Me H 31
TABLE 4
= Cl, R2= - Cl, E = = o,
Column 1 Column 2
El El El El El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-furanyl
6 H Me H H-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C02-n-Pr H Me H S02NMe
9 H Me H COEt H Me H CH2SiMe3 0 H Me H CO-n-Pr H Me H 2-pyridinyl 1 H Me H Ph H Me H 4-pyridinyl 2 H Me H CH2Ph Me Me H H 3 H Me H S02Me Me Me H Me 4 H Me H S02CF3 Me Me H COMe 5 H Me H S02Ph Me Me H C02Me 6 H Me H S02-(4-Me-Ph) Me Me H S02Me 7 H Me H S02Et H Me Me H 8 H Me H COCF3 H Me Me Me 9 H Me H CH2CF3 H Me COMe COMe 0 H Me H CONHMe H Me C02Me C02Me 1 H Me H CONHEt H Me S02Me S02Me 2 H Me H CONHPh H Et H H 3 H Me H CH2CH=CH2 H Et H Me 4 H Me H CH2C≡CH H Et H COMe 5 H Me H CH2CH=CHMe H Et H C02Me 6 H Me H CH2C≡CMe H Et H S02Me 7 H Me H 2-CH2-pyridinyl H Ph H H 8 H Ph H Me Me Me C02Me C02Me 9 H Ph H COMe Me Et H H 0 H Ph H C02Me Me Et H Me 1 H Ph H S02Me Me Et H Me 2 H Et Me H Me Et H COMe
Figure imgf000033_0001
3 H Et Me Me Me Et H C02Me 32
Column 1 Column 2
El El El El El El El El
34 H Et COMe COMe Me Et H S02Me
35 H Et C02Me C02Me Me Ph H H
36 H Et S02Me S02Me Me Ph H Me
37 H Ph Me H Me Ph H COMe
38 H Ph Me Me Me Ph H C02Me
39 H Ph COMe COMe Me Ph H S02Me
40 H Ph C02Me C02Me Me CF3 H H
41 H Ph S02Me S02Me Me CF3 H Me
42 H CF3 H H Me CF3 H COMe
43 H CF3 H Me Me CF3 H C02Me
44 H CF3 H COMe Me CF3 H S02Me
45 H CF3 H C02Me Ph Me H H
46 H CF3 H S02Me Ph Me H Me
47 H CF3 Me H Ph Me Me H
48 H CF3 Me Me Ph Et H H
49 H CF3 COMe COMe Ph Et Me H
50 H CF3 C02Me C02Me Ph Et H Me
51 H CF3 S02Me S02Me Ph Ph H H
52 Me Me Me H Ph Ph Me H
53 Me Me Me Me Ph Ph H Me
54 Me Me COMe COMe Ph CF3 H H
55 H H H H H H Me Me
56 H H H Me H H COMe COMe
57 H H H COMe H H C02Me C02Me
58 H H H C02Me H H S02Me S02Me
59 H H H S02Me H H Me H
TAE 5LE 5
RJ = F R2= H, E = O,
Column 1 Column 2
El El El El El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
Figure imgf000034_0001
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl 33
Column 1 Column 2
El El El El El El El El
H Me H Et H Me H 2-CH2-furanyl
H Me H n-Pr H Me H CH2-c-Pr
H Me H C02Et H Me H CH2OMe
H Me H C02-«-Pr H Me H S0 NMe2
H Me H COEt H Me H CH2SiMe3
H Me H CO-n-Pr H Me H 2-pyridinyl
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
H Me H S02Me Me Me H Me
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2G≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
Figure imgf000035_0001
H Ph COMe COMe Me Ph H S02Me 34
Column 1 Column 2
El El El El El Bl El El
40 H Ph C02Me C02Me Me CF3 H H
41 H Ph S02Me S02Me Me CF3 H Me
42 H CF3 H H Me CF3 H COMe
43 H CF3 H Me Me CF3 H C02Me
44 H CF3 H COMe Me CF3 H S02Me
45 H CF3 H C02Me Ph Me H H
46 H CF3 H S02Me Ph Me H Me
47 H CF3 Me H Ph Me Me H
48 H CF3 Me Me Ph Et H H
49 H CF3 COMe COMe Ph Et Me H
50 H CF3 C02Me C02Me Ph Et H Me
51 H CF3 S02Me S02Me Ph Ph H H
52 Me Me Me H Ph Ph Me H
53 Me Me Me Me Ph Ph H Me
54 Me Me COMe COMe Ph CF3 H H
55 H H H H H H Me Me
56 H H H Me H H COMe COMe
57 H H H COMe H H C02Me C02Me
58 H H H C02Me H H S02Me S02Me
59 H H H S02Me H H Me H
Figure imgf000036_0001
TAE 5LE 6
R1 = H, R2= F, E = O,
Column 1 Column 2
El El El El El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-furanyl
6 H Me H «-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C02-«-Pr H Me H S02NMe2
9 H Me H COEt H Me H CH2SiMe3
Figure imgf000036_0002
0 H Me H CO-n-Pr H Me H 2-pyridinyl 35
Column 1 Column 2
El El El El El El El El
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
H Me H S02Me Me Me H Me
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H CQ2Me Ph Me H
Figure imgf000037_0001
H 36
Column 1 Column 2
El El El El El El El El 6 H CF3 H S02Me Ph Me H Me 7 H CF3 Me H Ph Me Me H 8 H CF3 Me Me Ph Et H H 9 H CF3 COMe COMe Ph Et Me H 0 H CF3 C02Me C02Me Ph Et H Me
51 H CF3 S02Me S02Me Ph Ph H H 2 Me Me Me H Ph Ph Me H 3 Me Me Me Me Ph Ph H Me 4 Me Me COMe COMe Ph CF3 H H 5 H H H H H H Me Me 6 H H H Me H H COMe COMe 7 H H H COMe H H C02Me C02Me 8 H H H C02Me H H S02Me S02Me 9 H H H S02Me H H Me H
TAI ΪLE 7
= F , R2= F, E = O,
Column 1 Column 2
El El El El El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH -pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-furanyl
6 H Me H n-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C02-«-Pr H Me H S02NMe2
9 H Me H COEt H Me H CH2SiMe3 0 H Me H CO-«-Pr H Me H 2-pyridinyl 1 H Me H Ph H Me H 4-pyridinyl 2 H Me H CH2Ph Me Me H H 3 H Me H S02Me Me Me H Me 4 H Me H S02CF3 Me Me H COMe 5 H Me H S02Ph Me Me H C02Me 6 H Me H S02-(4-Me-Ph) Me Me H
Figure imgf000038_0001
S02Me 37
Column 1 Column 2
El El El El _ BL. El El
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Figure imgf000039_0001
38
Column 1 Column 2
El El El El El El El El
52 Me Me Me H Ph Ph Me H
53 Me Me Me Me Ph Ph H Me 4 Me Me COMe COMe Ph CF3 H H 5 H H H H H H Me Me 6 H H H Me H H COMe COMe 7 H H H COMe H H C02Me C02Me 8 H H H C02Me H H S02Me S02Me 9 H H H S02Me H H Me H
TABLE 8
= B r, R2= - H, E = = O,
Column 1 Column 2
El El El El El El El El
1 H Me H H H Me H 3-CH -pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-furanyl
6 H Me H M-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C02-«-Pr H Me H S02NMe2
9 H Me H COEt H Me H CH2SiMe3 0 H Me H CO-w-Pr H Me H 2-pyridinyl 1 H Me H Ph H Me H 4-pyridinyl 2 H Me H CH2Ph Me Me H H 3 H Me H S02Me Me Me H Me 4 H Me H S02CF3 Me Me H COMe 5 H Me H S02Ph Me Me H C02Me 6 H Me H S02-(4-Me-Ph) Me Me H S02Me 7 H Me H S02Et H Me Me H 8 H Me H COCF3 H Me Me Me 9 H Me H CH2CF3 H Me COMe COMe 0 H Me H CONHMe H Me C02Me C02Me 1 H Me H CONHEt H Me S02Me S02Me
Figure imgf000040_0001
2 H Me H CONHPh H Et H H 39
Column 1 Column 2
El El El El El El El El
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
Figure imgf000041_0001
H H H Me H H COMe COMe 40
Column 1 Column 2
El El El El El El El El
57 H H H COMe H H C02Me C02Me
58 H H H C02Me H H S02Me S02Me
59 H H H S02Me H H Me H
TABLE 9
^ = B *, R2= Br, E = = o,
Column 1 Column 2
El El El El El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH -pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-furanyl
6 H Me H w-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C02-«-Pr H Me H S02NMe2
9 H Me H COEt H Me H CH2SiMe3
10 H Me H CO-n-Pr H Me H 2-pyridinyl
11 H Me H Ph H Me H 4-pyridinyl
12 H Me H CH2Ph Me Me H H
13 H Me H S02Me Me Me H Me
14 H Me H S02CF3 Me Me H COMe
15 H Me H S02Ph Me Me H C02Me
16 H Me H S02-(4-Me-Ph) Me Me H S02Me
17 H Me H S02Et H Me Me H
18 H Me H COCF3 H Me Me Me
19 H Me H CH2CF3 H Me COMe COMe
20 H Me H CONHMe H Me C02Me C02Me
21 H Me H CONHEt H Me S02Me S02Me
22 H Me H CONHPh H Et H H
23 H Me H CH2CH=CH2 H Et H Me
24 H Me H CH2C≡CH H Et H COMe
25 H Me H CH2CH=CHMe H Et H C02Me
26 H Me H CH2C≡CMe H Et H S02Me
27 H Me H 2-CH2-pyridinyl H Ph H H
Figure imgf000042_0001
41
Column 1 Column 2
El El El El El El El El
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
H H H Me H H COMe COMe
H H H COMe H H C02Me C02Me
H H H C02Me H H S02Me S02Me
Figure imgf000043_0001
H H H S02Me H H Me H 42 TABLE 10 = Br, R2- = Br, E = = 0,
Column 1 Column 2
El El El El El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH -pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-furanyl
6 H Me H M-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C02-«-Pr H Me H S02NMe2
9 H Me H COEt H Me H CH2SiMe3 0 H Me H CO-«-Pr H Me H 2-pyridinyl 1 H Me H Ph H Me H 4-pyridinyl 2 H Me H CH2Ph Me Me H H 3 H Me H S02Me Me Me H Me 4 H Me H S02CF3 Me Me H COMe 5 H Me H S02Ph Me Me H C02Me 6 H Me H S02-(4-Me-Ph) Me Me H S02Me 7 H Me H S02Et H Me Me H 8 H Me H COCF3 H Me Me Me 9 H Me H CH2CF3 H Me COMe COMe 0 H Me H CONHMe H Me C02Me C02Me 1 H Me H CONHEt H Me S02Me S02Me 2 H Me H CONHPh H Et H H 3 H Me H CH2CH=CH2 H Et H Me 4 H Me H CH2C≡CH H Et H COMe 5 H Me H CH2CH=CHMe H Et H C02Me 6 H Me H CH2C≡CMe H Et H S02Me 7 H Me H 2-CH2-pyridinyl H Ph H H 8 H Ph H Me Me Me C02Me C02Me 9 H Ph H COMe Me Et H H 0 H Ph H C02Me Me Et H Me 1 H Ph H S02Me Me Et H Me 2 H Et Me H Me Et H COMe
Figure imgf000044_0001
3 H Et Me Me Me Et H C02Me 43
Column 1 Column 2
El El El El El El El El
34 H Et COMe COMe Me Et H S02Me
35 H Et C02Me C02Me Me Ph H H
36 H Et S02Me S02Me Me Ph H Me
37 H Ph Me H Me Ph H COMe
38 H Ph Me Me Me Ph H C02Me
39 H Ph COMe COMe Me Ph H S02Me
40 H Ph C02Me C02Me Me CF3 H H
41 H Ph S02Me S02Me Me CF3 H Me
42 H CF3 H H Me CF3 H COMe
43 H CF3 H Me Me CF3 H C02Me
44 H CF3 H COMe Me CF3 H S02Me
45 H CF3 H C02Me Ph Me H H
46 H CF3 H S02Me Ph Me H Me
47 H CF3 Me H Ph Me Me H
48 H CF3 Me Me Ph Et H H
49 H CF3 COMe COMe Ph Et Me H
50 H CF3 C02Me C02Me Ph Et H Me
51 H CF3 S02Me S02Me Ph Ph H H
52 Me Me Me H Ph Ph Me H
53 Me Me Me Me Ph Ph H Me
54 Me Me COMe COMe Ph CF3 H H
55 H H H H H H Me Me
56 H H H Me H H COMe COMe
57 H H H COMe H H C02Me C02Me
58 H H H C02Me H H S02Me S02Me
59 H H H S02Me H H Me H
TAB LE U
R' = 0 Me, R2= H, E = O,
Column 1 Column 2
El El El El El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
Figure imgf000045_0001
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl 44
Column 1 Column 2
El El El El El El E El
H Me H Et H Me H 2-CH2-ftιranyl
H Me H «-Pr H Me H CH2-c-Pr
H Me H C02Et H Me H CH2OMe
H Me H C0 -n-Pr H Me H S02NMe2
H Me H COEt H Me H CH2SiMe3
H Me H CO-n-Pr H Me H 2-pyridinyl
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
H Me H S02Me Me Me H Me
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
Figure imgf000046_0001
H Ph COMe COMe Me Ph H S02Me 45
Column 1 Column 2
El El El El El El El El
40 H Ph C02Me C02Me Me CF3 H H
41 H Ph S02Me S02Me Me CF3 H Me
42 H CF3 H H Me CF3 H COMe
43 H CF3 H Me Me CF3 H C02Me
44 H CF3 H COMe Me CF3 H S02Me
45 H CF3 H C02Me Ph Me H H
46 H CF3 H S02Me Ph Me H Me 7 H CF3 Me H Ph Me Me H 8 H CF3 Me Me Ph Et H H 9 H CF3 COMe COMe Ph Et Me H
50 H CF3 C02Me C02Me Ph Et H Me
51 H CF3 S02Me S02Me Ph Ph H H
52 Me Me Me H Ph Ph Me H
53 Me Me Me Me Ph Ph H Me
54 Me Me COMe COMe Ph CF3 H H 5 H H H H H H Me Me 6 H H H Me H H COMe COMe 7 H H H COMe H H C02Me C02Me 8 H H H C02Me H H S02Me S02Me 9 H H H S02Me H H Me H
TAB LE 12
= IV Ie, R2= = H, E = O,
Column 1 Column 2
E El El El El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-furanyl
6 H Me H H-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C0 -«-Pr H Me H S02NMe2
9 H Me H COEt H Me H CH2SiMe3
Figure imgf000047_0001
0 H Me H CO-w-Pr H Me H 2-pyridinyl 46
Column 1 Column 2
El El El El El R4 El El
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
H Me H S02Me Me Me H Me
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H
Figure imgf000048_0001
H 47
Column 1 Column 2
El El El El El El El El
46 H CF3 H S02Me Ph Me H Me
47 H CF3 Me H Ph Me Me H
48 H CF3 Me Me Ph Et H H
49 H CF3 COMe COMe Ph Et Me H
50 H CF3 C02Me C02Me Ph Et H Me
51 H CF3 S02Me S02Me Ph Ph H H
52 Me Me Me H Ph Ph Me H
53 Me Me Me Me Ph Ph H Me
54 Me Me COMe COMe Ph CF3 H H 5 H H H H H H Me Me 6 H H H Me H H COMe COMe 7 H H H COMe H H C02Me C02Me 8 H H H C02Me H H S02Me S02Me 9 H H H S02Me H H Me H
TAB LE 13
= H [, R = Me, E = O,
Column 1 Column 2
El El El El El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-furanyl
6 H Me H «-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C0 -«-Pr H Me H S02NMe2
9 H Me H COEt H Me H CH2SiMe3 0 H Me H CO-«-Pr H Me H 2-pyridinyl 1 H Me H Ph H Me H 4-pyridinyl 2 H Me H CH2Ph Me Me H H 3 H Me H S02Me Me Me H Me 4 H Me H S02CF3 Me Me H COMe 5 H Me H S02Ph Me Me H C02Me
Figure imgf000049_0001
6 H Me H S02-(4-Me-Ph) Me Me H S02Me 48
Column 1 Column 2
El El El El Bl El El s!
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Figure imgf000050_0001
49
Column 1 Colun ιn 2
El El El El El El El El
52 Me Me Me H Ph Ph Me H
53 Me Me Me Me Ph Ph H Me
54 Me Me COMe COMe Ph CF3 H H
55 H H H H H H Me Me
56 H H H Me H H COMe COMe
57 H H H COMe H H C02Me C02Me
58 H H H C02Me H H S02Me S02Me
59 H H H S02Me H H Me H
TABLE 14
R1 -^ le, R2- = Me, E = O,
Column 1 Column 2
E! El El El El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-furanyl
6 H Me H w-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C02-n-Pr H Me H S0 NMe2
9 H Me H COEt H Me H CH2SiMe3
10 H Me H CO-«-Pr H Me H 2-pyridinyl
11 H Me H Ph H Me H 4-pyridinyl
12 H Me H CH2Ph Me Me H H
13 H Me H S02Me Me Me H Me
14 H Me H S02CF3 Me Me H COMe
15 H Me H S02Ph Me Me H C02Me
16 H Me H S02-(4-Me-Ph) Me Me H S02Me
17 H Me H S02Et H Me Me H
18 H Me H COCF3 H Me Me Me
19 H Me H CH2CF3 H Me COMe COMe
20 H Me H CONHMe H Me C02Me C02Me
21 H Me H CONHEt H Me S02Me S02Me
Figure imgf000051_0001
22 H Me H CONHPh H Et H H 50
Column 1 Column 2
El El El El El El El El
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
Figure imgf000052_0001
H H H Me H H COMe COMe 51
Column 1 Column 2
El El El El El El El El 7 H H H COMe H H C02Me C02Me 8 H H H C02Me H H S02Me S02Me 9 H H H S02Me H H Me H
TABLE 15
= t- Bu, R2= H, E = 0,
Column 1 Column 2
El El El El El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-fiιranyl
6 H Me H w-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C02-«-Pr H Me H S02NMe2
9 H Me H COEt H Me H CH2SiMe3 0 H Me H CO-«-Pr H Me H 2-pyridinyl 1 H Me H Ph H Me H 4-pyridinyl 2 H Me H CH2Ph Me Me H H 3 H Me H S02Me Me Me H Me 4 H Me H S02CF3 Me Me H COMe 5 H Me H S02Ph Me Me H C02Me 6 H Me H S02-(4-Me-Ph) Me Me H S02Me 7 H Me H S02Et H Me Me H 8 H Me H COCF3 H Me Me Me 9 H Me H CH2CF3 H Me COMe COMe 0 H Me H CONHMe H Me C02Me C02Me 1 H Me H CONHEt H Me S02Me S02Me 2 H Me H CONHPh H Et H H 3 H Me H CH2CH=CH2 H Et H Me 4 H Me H CH2C≡CH H Et H COMe 5 H Me H CH2CH=CHMe H Et H C02Me 6 H Me H CH2C≡CMe H Et H S02Me
Figure imgf000053_0001
7 H Me H 2-CH2-pyridinyl H Ph H H 52
Column 1 Column 2
El El El El El El El El
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
H H H Me H H COMe COMe
H H H COMe H H C02Me C02Me
H H H C02Me H H S02Me S02Me
H H H S02Me H H Me H
Figure imgf000054_0001
53 TABLE 16 = t-Bu, R = t-Bu, E = O,
Column 1 Column 2
El El El El El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-furanyl
6 H Me H «-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C02-«-Pr H Me H S02NMe2
9 H Me H COEt H Me H CH2SiMe3 0 H Me H CO-«-Pr H Me H 2-pyridinyl 1 H Me H Ph H Me H 4-pyridinyl 2 H Me H CH2Ph Me Me H H 3 H Me H S02Me Me Me H Me 4 H Me H S02CF3 Me Me H COMe 5 H Me H S02Ph Me Me H C02Me 6 H Me H S02-(4-Me-Ph) Me Me H S02Me 7 H Me H S02Et H Me Me H 8 H Me H COCF3 H Me Me Me 9 H Me H CH2CF3 H Me COMe COMe 0 H Me H CONHMe H Me C02Me C02Me 1 H Me H CONHEt H Me S02Me S02Me 2 H Me H CONHPh H Et H H 3 H Me H CH2CH=CH2 H Et H Me 4 H Me H CH2C≡CH H Et H COMe 5 H Me H CH2CH=CHMe H Et H C02Me 6 H Me H CH2C≡CMe H Et H S02Me 7 H Me H 2-CH2-pyridinyl H Ph H H 8 H Ph H Me Me Me C02Me C02Me 9 H Ph H COMe Me Et H H 0 H Ph H C02Me Me Et H Me 1 H Ph H S02Me Me Et H Me 2 H Et Me H Me Et H COMe
Figure imgf000055_0001
3 H Et Me Me Me Et H C02Me 54
Column 1 Column 2
El El El El E El El El
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
H H H Me H H COMe COMe
H H H COMe H H C02Me C02Me
H H H C02Me H H S02Me S02Me
H H H S02Me H H Me H
TAB LE 17 2, R2= H, E = O,
Column 1 Column 2
El El El El El El El El
H Me H H H Me H 3-CH2-pyridinyl
H Me H Me H Me H 4-CH2-pyridinyl
H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
Figure imgf000056_0001
H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl 55
Column 1 Column 2
El El El El El El El El
H Me H Et H Me H 2-CH2-furanyl
H Me H H-Pr H Me H CH2-c-Pr
H Me H C02Et H Me H CH2OMe
H Me H C02-«-Pr H Me H S02NMe2
H Me H COEt H Me H CH2SiMe3
H Me H CO-«-Pr H Me H 2-pyridinyl
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
H Me H S02Me Me Me H Me
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
Figure imgf000057_0001
H Ph COMe COMe 1 Me Ph H S02Me 56
Column 1 Column 2
El El El El El El El El
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S0 Me S0 Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
H H H Me H H COMe COMe
H H H COMe H H C02Me C02Me
H H H C02Me H H S02Me S02Me
H H H S02Me H H Me H
TAB LE 18 O, R2= H, E = O,
Column 1 Column 2
El El El El El El El El
H Me H H H Me H 3-CH2-pyridinyl
H Me H Me H Me H 4-CH -pyridinyl
H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
H Me H Et H Me H 2-CH2-foranyl
H Me H n-Pr H Me H CH2-c-Pr
H Me H C02Et H Me H CH2OMe
H Me H C02-«-Pr H Me H S02NMe2
H Me H COEt H Me H CH2SiMe3
Figure imgf000058_0001
H Me H CO-«-Pr H Me H 2-pyridinyl 57
Column 1 Column 2
El El El El El El El El
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
H Me H S02Me Me Me H Me
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
Figure imgf000059_0001
H CF3 H C02Me 1 Ph Me H H 58
Column 1 Column 2
El s! El El El El El El 6 H CF3 H S02Me Ph Me H Me 7 H CF3 Me H Ph Me Me H 8 H CF3 Me Me Ph Et H H 9 H CF3 COMe COMe Ph Et Me H 0 H CF3 C02Me C02Me Ph Et H Me
51 H CF3 S02Me S02Me Ph Ph H H
52 Me Me Me H Ph Ph Me H 3 Me Me Me Me Ph Ph H Me 4 Me Me COMe COMe Ph CF3 H H 5 H H H H H H Me Me 6 H H H Me H H COMe COMe 7 H H H COMe H H C02Me C02Me 8 H H H C02Me H H S02Me S02Me 9 H H H S02Me H H Me H
TAB LE 19
= C F3, R2 = H, E = O,
Column 1 Column 2
El El El El El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridir
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridir
5 H Me H Et H Me H 2-CH2-fiιranyl
6 H Me H «-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C02-«-Pr H Me H S02NMe2
9 H Me H COEt H Me H CH2SiMe3 0 H Me H CO-«-Pr H Me H 2-pyridinyl 1 H Me H Ph H Me H 4-pyridinyl 2 H Me H CH2Ph Me Me H H 3 H Me H S02Me Me Me H Me 4 H Me H S02CF3 Me Me H COMe 5 H Me H S02Ph Me Me H C02Me
Figure imgf000060_0001
6 H Me H S02-(4-Me-Ph) Me Me H S02Me 59
Column 1 Column 2
El El El El El El El El
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Figure imgf000061_0001
60
Column 1 Column 2
El El El El El El El El 2 Me Me Me H Ph Ph Me H 3 Me Me Me Me Ph Ph H Me 4 Me Me COMe COMe Ph CF3 H H 5 H H H H H H Me Me 6 H H H Me H H COMe COMe 7 H H H COMe H H C02Me C02Me 8 H H H C02Me H H S02Me S02Me 9 H H H S02Me H H Me H
TABLE 20
= C 1, R2= • H, E = = s,
Column 1 Column 2
El El El El El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH -pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-furanyl
6 H Me H n-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C02-n-Pr H Me H S02NMe2
9 H Me H COEt H Me H CH2SiMe3 0 H Me H CO-M-Pr H Me H 2-pyridinyl 1 H Me H Ph H Me H 4-pyridinyl 2 H Me H CH2Ph Me Me H H 3 H Me H S02Me Me Me H Me 4 H Me H S02CF3 Me Me H COMe 5 H Me H S02Ph Me Me H C02Me 6 H Me H S02-(4-Me-Ph) Me Me H S02Me 7 H Me H S02Et H Me Me H 8 H Me H COCF3 H Me Me Me 9 H Me H CH2CF3 H Me COMe COMe 0 H Me H CONHMe H Me C02Me C02Me 1 H Me H CONHEt H Me S02Me S02Me
Figure imgf000062_0001
2 H Me H CONHPh H Et H H 61
Column 1 Column 2
El Bl Bl El El El El El
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
Figure imgf000063_0001
H H H Me H H COMe COMe 62
Column 1 Column 2
El El El El Bl El El El 7 H H H COMe H H C02Me C02Me 8 H H H C02Me H H S02Me S02Me 9 H H H S02Me H H Me H
TABLE 21
= H [, R = C1, E = = s,
Column 1 Column 2
El El El El El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-furanyl
6 H Me H H-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C02-«-Pr H Me H S02NMe2
9 H Me H COEt H Me H CH2SiMe3 0 H Me H CO-«-Pr H Me H 2-pyridinyl 1 H Me H Ph H Me H 4-pyridinyl 2 H Me H CH2Ph Me Me H H 3 H Me H S02Me Me Me H Me 4 H Me H S02CF3 Me Me H COMe 5 H Me H S02Ph Me Me H C02Me 6 H Me H S02-(4-Me-Ph) Me Me H S02Me 7 H Me H S02Et H Me Me H 8 H Me H COCF3 H Me Me Me 9 H Me H CH2CF3 H Me COMe COMe 0 H Me H CONHMe H Me C02Me C02Me 1 H Me H CONHEt H Me S02Me S02Me 2 H Me H CONHPh H Et H H 3 H Me H CH2CH=CH2 H Et H Me 4 H Me H CH2C≡CH H Et H COMe 5 H Me H CH2CH=CHMe H Et H C02Me 6 H Me H CH2C≡CMe H Et H S02Me
Figure imgf000064_0001
7 H Me H 2-CH2-pyridinyl H Ph H H 63
Column : Column 2
El El El El El El El El
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
H H H Me H H COMe COMe
H H H COMe H H C02Me C02Me
H H H C02Me H H S02Me S02Me
Figure imgf000065_0001
H H H S02Me H H Me H 64 TABLE 22
R1 = F, R2= H, E = S,
Column 1 Column 2
El El El El El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-turanyl
6 H Me H n-Pr H Me H CH2-oPr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C02-n-Pr H Me H S02NMe2
9 H Me H COEt H Me H CH2SiMe3
10 H Me H CO-n-Pr H Me H 2-pyridinyl
11 H Me H Ph H Me H 4-pyridinyl
12 H Me H CH2Ph Me Me H H
13 H Me H S02Me Me Me H Me
14 H Me H S02CF3 Me Me H COMe
15 H Me H S02Ph Me Me H C02Me
16 H Me H S02-(4-Me-Ph) Me Me H S02Me
17 H Me H S02Et H Me Me H
18 H Me H COCF3 H Me Me Me
19 H Me H CH2CF3 H Me COMe COMe
20 H Me H CONHMe H Me C02Me C02Me
21 H Me H CONHEt H Me S02Me S02Me
22 H Me H CONHPh H Et H H
23 H Me H CH2CH=CH2 H Et H Me
24 H Me H CH2C≡CH H Et H COMe
25 H Me H CH2CH=CHMe H Et H C02Me
26 H Me H CH2C≡CMe H Et H S02Me
27 H Me H 2-CH2-pyridinyl H Ph H H
28 H Ph H Me Me Me C02Me C02Me
29 H Ph H COMe Me Et H H
30 H Ph H C02Me Me Et H Me
31 H Ph H S02Me Me Et H Me
32 H Et Me H Me Et H COMe
Figure imgf000066_0001
33 H Et Me Me Me Et H CQ2Me 65
Column 1 Column 2
R3 R4 R5 El R3 R4 El El
34 H Et COMe COMe Me Et H S02Me
35 H Et C02Me C02Me Me Ph H H
36 H Et S02Me S02Me Me Ph H Me
37 H Ph Me H Me Ph H COMe
38 H Ph Me Me Me Ph H C02Me
39 H Ph COMe COMe Me Ph H S02Me
40 H Ph C02Me C02Me Me CF3 H H
41 H Ph S02Me S02Me Me CF3 H Me
42 H CF3 H H Me CF3 H COMe
43 H CF3 H Me Me CF3 H C02Me
44 H CF3 H COMe Me CF3 H S02Me
45 H CF3 H C02Me Ph Me H H
46 H CF3 H S02Me Ph Me H Me
47 H CF3 Me H Ph Me Me H
48 H CF3 Me Me Ph Et H H
49 H CF3 COMe COMe Ph Et Me H
50 H CF3 C02Me C02Me Ph Et H Me
51 H CF3 S02Me S02Me Ph Ph H H
52 Me Me Me H Ph Ph Me H
53 Me Me Me Me Ph Ph H Me
54 Me Me COMe COMe Ph CF3 H H
55 H H H H H H Me Me
56 H H H Me H H COMe COMe
57 H H H COMe H H C02Me C02Me
58 H H H C02Me H H S02Me S02Me
Figure imgf000067_0001
59 H H H S02Me H H Me H
TABLE 23
R1 = H, R2= F, E = S,
Column 1 Column 2
El El El El El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
Figure imgf000067_0002
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl 66
Column 1 Column 2
El El El El El El El El
H Me H Et H Me H 2-CH2-foranyl
H Me H n-Pr H Me H CH2-c-Pr
H Me H C02Et H Me H CH2OMe
H Me H C02-«-Pr H Me H S02NMe2
H Me H COEt H Me H CH2SiMe3
H Me H CO-n-Pr H Me H 2-pyridinyl
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
H Me H S02Me Me Me H Me
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
Figure imgf000068_0001
H Ph COMe COMe Me Ph H S02Me 67
Column 1 Column 2
El El El El El El El El
40 H Ph C02Me C02Me Me CF3 H H
41 H Ph S02Me S02Me Me CF3 H Me
42 H CF3 H H Me CF3 H COMe
43 H CF3 H Me Me CF3 H C02Me
44 H CF3 H COMe Me CF3 H S02Me
45 H CF3 H C02Me Ph Me H H 6 H CF3 H S02Me Ph Me H Me
47 H CF3 Me H Ph Me Me H 8 H CF3 Me Me Ph Et H H 9 H CF3 COMe COMe Ph Et Me H
50 H CF3 C02Me C02Me Ph Et H Me
51 H CF3 S02Me S02Me Ph Ph H H 2 Me Me Me H Ph Ph Me H 3 Me Me Me Me Ph Ph H Me 4 Me Me COMe COMe Ph CF3 H H 5 H H H H H H Me Me 6 H H H Me H H COMe COMe 7 H H H COMe H H C02Me C02Me 8 H H H C02Me H H S02Me S02Me 9 H H H S02Me H H Me H
TAB LE 24
= Br, R = - H, E = = s,
Column 1 Column 2
El El El El El El El El
1 H Me H H H Me H 3-CH -pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-furanyl
6 H Me H H-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C02-«-Pr H Me H S02NMe2
9 H Me H COEt H Me H CH2SiMe3
Figure imgf000069_0001
0 H Me H CO-w-Pr H Me H 2-pyridinyl 68
Column 1 Column 2
Bl El El El El El El El
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
H Me H S02Me Me Me H Me
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2G≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH -pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
Figure imgf000070_0001
69
Columr l l Column 2
El El El El El El El El
46 H CF3 H S02Me Ph Me H Me
47 H CF3 Me H Ph Me Me H
48 H CF3 Me Me Ph Et H H 9 H CF3 COMe COMe Ph Et Me H
50 H CF3 C02Me C02Me Ph Et H Me
51 H CF3 S02Me S02Me Ph Ph H H
52 Me Me Me H Ph Ph Me H 3 Me Me Me Me Ph Ph H Me 4 Me Me COMe COMe Ph CF3 H H 5 H H H H H H Me Me 6 H H H Me H H COMe COMe 7 H H H COMe H H C02Me C02Me 8 H H H C02Me H H S02Me S02Me 9 H H H S02Me H H Me H
TAB LE 25
= H [, R2= Br, E = = s,
Column 1 Column 2
El El El El El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-ruranyl
6 H Me H w-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C02-«-Pr H Me H S02NMe2
9 H Me H COEt H Me H CH2SiMe3 0 H Me H CO-n-Pr H Me H 2-pyridinyl 1 H Me H Ph H Me H 4-pyridinyl 2 H Me H CH2Ph Me Me H H 3 H Me H S02Me Me Me H Me 4 H Me H S02CF3 Me Me H COMe 5 H Me H S02Ph Me Me H C02Me
Figure imgf000071_0001
6 H Me H S02-(4-Me-Ph) Me Me H S02Me 70
Column 1 Column 2
Bl El El El El El El El
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Figure imgf000072_0001
71
Column 1 Column 2
R3 R4 R5 El R3 R El El
52 Me Me Me H Ph Ph Me H
53 Me Me Me Me Ph Ph H Me
54 Me Me COMe COMe Ph CF3 H H
55 H H H H H H Me Me
56 H H H Me H H COMe COMe
57 H H H COMe H H C02Me C02Me
58 H H H C02Me H H S02Me S02Me
Figure imgf000073_0001
59 H H H S02Me H H Me H
TABLE 26
R1 = H, R2= OMe, E = O,
Column Column 2
R3 R4 R5 El R3 R4 El _ R6
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl 3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl 4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl 5 H Me H Et H Me H 2-CH2-fiιranyl 6 H Me H H-Pr H Me H CH2-c-Pr 7 H Me H C02Et H Me H CH2OMe H Me H C02-n-Pr H Me H S02NMe2
9 H Me H COEt H Me H CH2SiMe3 10 H Me H CO-n-Pr H Me H 2-pyridinyl 11 H Me H Ph H Me H 4-pyridinyl 12 H Me H CH2Ph Me Me H H 13 H Me H S02Me Me Me H Me 14 H Me H S02CF3 Me Me H COMe 15 H Me H S02Ph Me Me H C02Me 16 H Me H S02-(4-Me-Ph) Me Me H S02Me 17 H Me H S02Et H Me Me H 18 H Me H COCF3 H Me Me Me 19 H Me H CH2CF3 H Me COMe COMe 20 H Me H CONHMe H Me C02Me C02Me 21 H Me H CONHEt H Me S0 Me S02Me 22 H Me H CONHPh H Et H H 72
Column 1 Column 2
El El El Bl El El El El
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
Figure imgf000074_0001
H H H Me H H COMe COMe 73
Column 1 Column 2
El El El El El El El El 7 H H H COMe H H C02Me C02Me 8 H H H C02Me H H S02Me S02Me 9 H H H S02Me H H Me H
TABLE 27
= H [, R2= OEt, E = O,
Column 1 Column 2
El El El El El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-fiιranyl
6 H Me H «-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C02-n-Pr H Me H S02NMe2
9 H Me H COEt H Me H CH2SiMe3 0 H Me H CO-«-Pr H Me H 2-pyridinyl 1 H Me H Ph H Me H 4-pyridinyl 2 H Me H CH2Ph Me Me H H 3 H Me H S02Me Me Me H Me 4 H Me H S02CF3 Me Me H COMe 5 H Me H S02Ph Me Me H C02Me 6 H Me H S02-(4-Me-Ph) Me Me H S02Me 7 H Me H S02Et H Me Me H 8 H Me H COCF3 H Me Me Me 9 H Me H CH2CF3 H Me COMe COMe 0 H Me H CONHMe H Me C02Me C02Me 1 H Me H CONHEt H Me S02Me S02Me 2 H Me H CONHPh H Et H H 3 H Me H CH2CH=CH2 H Et H Me 4 H Me H CH2C≡CH H Et H COMe 5 H Me H CH2CH=CHMe H Et H C02Me 6 H Me H CH2C≡CMe H Et H S02Me
Figure imgf000075_0001
7 H Me H 2-CH2-pyridinyl H Ph H H 74
Column 1 Column 2
El El El El El El El El
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C0 Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
H H H Me H H COMe COMe
H H H COMe H H C02Me C02Me
H H H C02Me H H S02Me S02Me
Figure imgf000076_0001
H H H SQ2Me H H Me H ' 75
TABLE 28
= H, R2 = = NO2, E = O,
Column 1 Column 2
El El El El El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH -pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-foranyl
6 H Me H n-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C02-«-Pr H Me H S0 NMe2
9 H Me H COEt H Me H CH2SiMe3 0 H Me H CO-«-Pr H Me H 2-pyridinyl 1 H Me H Ph H Me H 4-pyridinyl 2 H Me H CH2Ph Me Me H H 3 H Me H S02Me Me Me H Me 4 H Me H S02CF3 Me Me H COMe 5 H Me H S02Ph Me Me H C02Me 6 H Me H S02-(4-Me-Ph) Me Me H S02Me 7 H Me H S02Et H Me Me H 8 H Me H COCF3 H Me Me Me 9 H Me H CH2CF3 H Me COMe COMe 0 H Me H CONHMe H Me C02Me C02Me 1 H Me H CONHEt H Me S02Me S02Me 2 H Me H CONHPh H Et H H 3 H Me H CH2CH=CH2 H Et H Me 4 H Me H CH2C≡CH H Et H COMe 5 H Me H CH2CH=CHMe H Et H C02Me 6 H Me H CH2C≡CMe H Et H S02Me 7 H Me H 2-CH2-pyridinyl H Ph H H 8 H Ph H Me Me Me C02Me C02Me 9 H Ph H COMe Me Et H H 0 H Ph H C02Me Me Et H Me 1 H Ph H S02Me Me Et H Me 2 H Et Me H Me Et H COMe
Figure imgf000077_0001
3 H Et Me Me Me Et H C02Me 76
Column 1 Column 2
El El El El El El El El
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
H H H Me H H COMe COMe
H H H COMe H H C02Me C02Me
H H H C02Me H H S02Me S02Me
H H H S02Me H H Me H
TAB LE 29 R2 = = H,
Column 1 Column 2
El El El El El El El El
H Me H H H Me H 3-CH2-pyridinyl
H Me H Me H Me H 4-CH2-pyridinyl
H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
Figure imgf000078_0001
H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl 77
Column 1 Colum ιn 2
E! El El El El El El El
H Me H Et H Me H 2-CH2-furanyl
H Me H H-Pr H Me H CH2-c-Pr
H Me H C02Et H Me H CH2OMe
H Me H C0 -«-Pr H Me H S02NMe2
H Me H COEt H Me H CH2SiMe3
H Me H CO-κ-Pr H Me H 2-pyridinyl
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
H Me H S02Me Me Me H Me
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
Figure imgf000079_0001
H Ph COMe COMe Me Ph H S02Me 78
Column 1 Column 2
El El El El El El El El
40 H Ph C02Me C02Me Me CF3 H H
41 H Ph S02Me S02Me Me CF3 H Me
42 H CF3 H H Me CF3 H COMe
43 H CF3 H Me Me CF3 H C02Me
44 H CF3 H COMe Me CF3 H S02Me
45 H CF3 H C02Me Ph Me H H
46 H CF3 H S02Me Ph Me H Me
47 H CF3 Me H Ph Me Me H
48 H CF3 Me Me Ph Et H H
49 H CF3 COMe COMe Ph Et Me H
50 H CF3 C02Me C02Me Ph Et H Me
51 H CF3 S02Me S02Me Ph Ph H H
52 Me Me Me H Ph Ph Me H
53 Me Me Me Me Ph Ph H Me
54 Me Me COMe COMe Ph CF3 H H
55 H H H H H H Me Me 6 H H H Me H H COMe COMe 7 H H H COMe H H C02Me C02Me 8 H H H C02Me H H S02Me S02Me 9 H H H S02Me H H Me H
TAB LE 30
= H , R2 = = C1,
Column 1 Column 2
El El El El El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-fiιranyl
6 H Me H H-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C02-«-Pr H Me H S02NMe2
9 H Me H COEt H Me H CH2SiMe3
Figure imgf000080_0001
0 H Me H CO-n-Pr H Me H 2-pyridinyl 79
Column 1 Column 2
Bl El El El El El El El
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
H Me H S02Me Me Me H Me
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
Figure imgf000081_0001
80
Column 1 Column 2
El El El El El El El El
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
H H H Me H H COMe COMe
H H H COMe H H C02Me C02Me
H H H C02Me H H S02Me S02Me
H H H S02Me H H Me H
TAB LE 31 2 = H,
Column 1 Column 2
El El El El El El El El
H Me H H H Me H 3-CH2-pyridinyl
H Me H Me H Me H 4-CH2-pyridinyl
H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
H Me H Et H Me H 2-CH2-furanyl
H Me H «-Pr H Me H CH2-c-Pr
H Me H C02Et H Me H CH2OMe
H Me H C02-n-Pr H Me H S02NMe
H Me H COEt H Me H CH2SiMe3
H Me H CO-n-Pr H Me H 2-pyridinyl
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
H Me H S02Me Me Me H Me
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
Figure imgf000082_0001
H Me H S02-(4-Me-Ph) Me Me H S02Me 81
Column 1 Column 2
El El El El El El El El
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me SQ2Me Ph Ph H H
Figure imgf000083_0001
82
Column 1 Column 2
El El El El El El El El
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
H H H Me H H COMe COMe
H H H COMe H H C02Me C02Me
H H H C02Me H H S02Me S02Me
H H H S02Me H H Me H
TABLE 32 R = = F,
Column 1 Column 2
El El El El El El El El
H Me H H H Me H 3-CH2-pyridinyl
H Me H Me H Me H 4-CH2-pyridinyl
H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
H Me H Et H Me H 2-CH2-furanyl
H Me H «-Pr H Me H CH2-c-Pr
H Me H C02Et H Me H CH2OMe
H Me H C0 -«-Pr H Me H S02NMe2
H Me H COEt H Me H CH2SiMe3
H Me H CO-n-Pr H Me H 2-pyridinyl
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
H Me H S02Me Me Me H Me
H Me H S02CF3 Me Me H COMe
H Me H SQ2Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
Figure imgf000084_0001
H Me H CONHPh H Et H H 83
Column 1 Column 2
£_ El E! El El El El El
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
Figure imgf000085_0001
H H H Me H H COMe COMe 84
Column 1 Column 2
El El El El El El El El
H H H COMe H H C02Me C02Me
H H H C02Me H H S02Me S02Me
H H H S02Me H H Me H
TABLE 33 R2 = H,
Column 1 Column 2
E El El El El El El El
H Me H H H Me H 3-CH2-pyridinyl
H Me H Me H Me H 4-CH2-pyridinyl
H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
H Me H Et H Me H 2-CH2-fiiranyl
H Me H «-Pr H Me H CH2-c-Pr
H Me H C02Et H Me H CH2OMe
H Me H C02-«-Pr H Me H S02NMe2
H Me H COEt H Me H CH2SiMe3
H Me H CO-n-Pr H Me H 2-pyridinyl
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
H Me H S02Me Me Me H Me
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
Figure imgf000086_0001
H Me H 2-CH2-pyridinyl H Ph H H 85
Column 1 Column 2
El El El El El El El El
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
H H H Me H H COMe COMe
H H H COMe H H C02Me C02Me
H H H C02Me H H S02Me S02Me
H H H S02Me H H Me H
Figure imgf000087_0001
86 TABLE 34 R2 = = Br,
Column 1 Column 2
El El El El El El El El
H Me H H H Me H 3-CH2-pyridinyl
H Me H Me H Me H 4-CH2-pyridinyl
H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
H Me H Et H Me H 2-CH2-turanyl
H Me H n-Pr H Me H CH2-c-Pr
H Me H C02Et H Me H CH2OMe
H Me H C02-«-Pr H Me H S02NMe2
H Me H COEt H Me H CH2SiMe3
H Me H CO-«-Pr H Me H 2-pyridinyl
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
H Me H S02Me Me Me H Me
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
Figure imgf000088_0001
H Et Me Me Me Et H C02Me 87
Column 1 Column 2
El El El El El El El El
34 H Et COMe COMe Me Et H S02Me
35 H Et C02Me C02Me Me Ph H H
36 H Et S02Me S02Me Me Ph H Me
37 H Ph Me H Me Ph H COMe
38 H Ph Me Me Me Ph H C02Me
39 H Ph COMe COMe Me Ph H S02Me
40 H Ph C02Me C02Me Me CF3 H H
41 H Ph S02Me S02Me Me CF3 H Me
42 H CF3 H H Me CF3 H COMe
43 H CF3 H Me Me CF3 H C02Me
44 H CF3 H COMe Me CF3 H S02Me
45 H CF3 H C02Me Ph Me H H
46 H CF3 H S02Me Ph Me H Me
47 H CF3 Me H Ph Me Me H
48 H CF3 Me Me Ph Et H H
49 H CF3 COMe COMe Ph Et Me H
50 H CF3 C02Me C02Me Ph Et H Me
51 H CF3 S02Me S02Me Ph Ph H H
52 Me Me Me H Ph Ph Me H
53 Me Me Me Me Ph Ph H Me
54 Me Me COMe COMe Ph CF3 H H
55 H H H H H H Me Me
56 H H H Me H H COMe COMe
57 H H H COMe H H C02Me C02Me
58 H H H C02Me H H S02Me S02Me
59 H H H S02Me H H Me H
Figure imgf000089_0001
TAB LE 35
R1 = H, R2 = OMe,
Column 1 Column 2
El l El El El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH -pyridinyl
Figure imgf000089_0002
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl 88
Column 1 Colum ιn 2
El El El El El El El El
H Me H Et H Me H 2-CH2-fiιranyl
H Me H w-Pr H Me H CH2-c-Pr
H Me H C02Et H Me H CH2OMe
H Me H C02-n-Pr H Me H S02NMe2
H Me H COEt H Me H CH2SiMe3
H Me H CO-«-Pr H Me H 2-pyridinyl
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
H Me H S02Me Me Me H Me
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
Figure imgf000090_0001
H Ph COMe COMe Me Ph H S02Me 89
Column 1 Column 2
El El El Bl El El El El
40 H Ph C02Me C02Me Me CF3 H H
41 H Ph S02Me S02Me Me CF3 H Me
42 H CF3 H H Me CF3 H COMe
43 H CF3 H Me Me CF3 H C02Me
44 H CF3 H COMe Me CF3 H S02Me
45 H CF3 H C02Me Ph Me H H
46 H CF3 H S02Me Ph Me H Me
47 H CF3 Me H Ph Me Me H
48 H CF3 Me Me Ph Et H H
49 H CF3 COMe COMe Ph Et Me H
50 H CF3 C02Me C02Me Ph Et H Me
51 H CF3 S02Me S02Me Ph Ph H H
52 Me Me Me H Ph Ph Me H
53 Me Me Me Me Ph Ph H Me
54 Me Me COMe COMe Ph CF3 H H
55 H H H H H H Me Me
56 H H H Me H H COMe COMe
57 H H H COMe H H C02Me C02Me
58 H H H C02Me H H S02Me S02Me
59 H H H S02Me H H Me H
Figure imgf000091_0001
TAB LE 36
R1 = OMe, R2 = H,
Column 1 Column 2
El El Bl Bl El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH -pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-fiιranyl
6 H Me H n-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C0 -n-Pr H Me H S02NMe2
9 H Me H COEt H Me H CH2SiMe3
Figure imgf000091_0002
10 H Me H CO-«-Pr H Me H 2-pyridinyl 90
Column 1 Column 2
El El El El El El El El
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
H Me H S02Me Me Me H Me
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
Figure imgf000092_0001
91
Column 1 Column 2
El El El El El El El El
46 H CF3 H S02Me Ph Me H Me 7 H CF3 Me H Ph Me Me H
48 H CF3 Me Me Ph Et H H 9 H CF3 COMe COMe Ph Et Me H
50 H CF3 C02Me C02Me Ph Et H Me
51 H CF3 S02Me S0 Me Ph Ph H H 2 Me Me Me H Ph Ph Me H 3 Me Me Me Me Ph Ph H Me 4 Me Me COMe COMe Ph CF3 H H 5 H H H H H H Me Me 6 H H H Me H H COMe COMe 7 H H H COMe H H C02Me C02Me 8 H H H C02Me H H S02Me S02Me 9 H H H S02Me H H Me H
TAB LE 37
= < le, R2 = Me,
Column 1 Column 2
El El El El El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-ftιranyl
6 H Me H n-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C02-«-Pr H Me H S02NMe2
9 H Me H COEt H Me H CH2SiMe3 0 H Me H CO-w-Pr H Me H 2-pyridinyl 1 H Me H Ph H Me H 4-pyridinyl 2 H Me H CH2Ph Me Me H H 3 H Me H S02Me Me Me H Me 4 H Me H S02CF3 Me Me H COMe 5 H Me H S02Ph Me Me H C02Me
Figure imgf000093_0001
6 H Me H S02-(4-Me-Ph) Me Me H S02Me 92
Column 1 Column 2
R_ El El El El El El El
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C0 Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S0 Me SQ2Me Ph Ph H
Figure imgf000094_0001
H 93
Column 1 Column 2
El El El El El El El El
52 Me Me Me H Ph Ph Me H
53 Me Me Me Me Ph Ph H Me
54 Me Me COMe COMe Ph CF3 H H
55 H H H H H H Me Me
56 H H H Me H H COMe COMe
57 H H H COMe H H C02Me C02Me
58 H H H C02Me H H S02Me S02Me
59 H H H S02Me H H Me H
Figure imgf000095_0001
TABLE 38
R1 = Me, R2 = H,
Column I Column 2
E_ El El El El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-furanyl
6 H Me H n-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C02-M-Pr H Me H S02NMe2
9 H Me H COEt H Me H CH2SiMe3
10 H Me H CO-w-Pr H Me H 2-pyridinyl
11 H Me H Ph H Me H 4-pyridinyl
12 H Me H CH2Ph Me Me H H
13 H Me H S02Me Me Me H Me
14 H Me H S02CF3 Me Me H COMe
15 H Me H S02Ph Me Me H C02Me
16 H Me H S02-(4-Me-Ph) Me Me H S02Me
17 H Me H S02Et H Me Me H
18 H Me H COCF3 H Me Me Me
19 H Me H CH2CF3 H Me COMe COMe
20 H Me H CONHMe H Me C02Me C02Me
21 H Me H CONHEt H Me S02Me S02Me
Figure imgf000095_0002
22 H Me H CONHPh H Et H H 94
Column 1 Column 2
El El El El El El El El
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S0 Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
Figure imgf000096_0001
H H H Me H H COMe COMe 95
Column 1 Column 2 si El El El El El El El
57 H H H COMe H H C02Me C02Me
58 H H H C02Me H H S02Me S02Me
59 H H H S02Me H H Me H
Figure imgf000097_0001
TABLE 39
R1 = H, R2 = Me,
Column 1 Column 2
El El El El El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridir
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridiιι
5 H Me H Et H Me H 2-CH2-furanyl
6 H Me H «-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C02-«-Pr H Me H S02NMe2
9 H Me H COEt H Me H CH2SiMe3
10 H Me H CO-n-Pr H Me H 2 -pyridinyl
11 H Me H Ph H Me H 4-pyridinyl
12 H Me H CH2Ph Me Me H H
13 H Me H S02Me Me Me H Me
14 H Me H S02CF3 Me Me H COMe
15 H Me H S02Ph Me Me H C02Me
16 H Me H S02-(4-Me-Ph) Me Me H S02Me
17 H Me H S02Et H Me Me H
18 H Me H COCF3 H Me Me Me
19 H Me H CH2CF3 H Me COMe COMe
20 H Me H CONHMe H Me C02Me C02Me
21 H Me H CONHEt H Me S02Me S02Me
22 H Me H CONHPh H Et H H
23 H Me H CH2CH=CH2 H Et H Me
24 H Me H CH2C≡CH H Et H COMe
25 H Me H CH2CH=CHMe H Et H C02Me
26 H Me H CH2C≡CMe H Et H S02Me
27 H Me H 2-CH2-pyridinyl H Ph H H
Figure imgf000097_0002
96
Column '. Column 2
El El E£ Bl El El El Bl
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
H H H Me H H COMe COMe
H H H COMe H H C02Me C02Me
H H H C02Me H H S02Me S02Me
Figure imgf000098_0001
H H H S02Me 1 H H Me H 97 TABLE 40
R1 = H, R2 = OCF,
Column 1 Column 2
Bl El __! Bl E El Bl E^
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-furanyl
6 H Me H w-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C02-«-Pr H Me H S02NMe2
9 H Me H COEt H Me H CH2SiMe3
10 H Me H CO-n-Pr H Me H 2-pyridinyl
11 H Me H Ph H Me H 4-pyridinyl
12 H Me H CH2Ph Me Me H H
13 H Me H S02Me Me Me H Me
14 H Me H S02CF3 Me Me H COMe
15 H Me H S02Ph Me Me H C02Me
16 H Me H S02-(4-Me-Ph) Me Me H S02Me
17 H Me H S02Et H Me Me H
18 H Me H COCF3 H Me Me Me
19 H Me H CH2CF3 H Me COMe COMe
20 H Me H CONHMe H Me C02Me C02Me
21 H Me H CONHEt H Me S02Me S02Me
22 H Me H CONHPh H Et H H
23 H Me H CH2CH=CH2 H Et H Me
24 H Me H CH2C≡CH H Et H COMe
25 H Me H CH2CH=CHMe H Et H C02Me
26 H Me H CH2C≡CMe H Et H S02Me
27 H Me H 2-CH2-pyridinyl H Ph H H
28 H Ph H Me Me Me C02Me C02Me
29 H Ph H COMe Me Et H H
30 H Ph H C02Me Me Et H Me
31 H Ph H S02Me Me Et H Me
32 H Et Me H Me Et H COMe
Figure imgf000099_0001
33 H Et Me Me Me Et H C02Me 98
Column 1 Column 2
E El E E . Bl El El Bl
34 H Et COMe COMe Me Et H S02Me
35 H Et C02Me C02Me Me Ph H H
36 H Et S02Me S02Me Me Ph H Me
37 H Ph Me H Me Ph H COMe
38 H Ph Me Me Me Ph H C02Me
39 H Ph COMe COMe Me Ph H S02Me
40 H Ph C02Me C02Me Me CF3 H H
41 H Ph S02Me S02Me Me CF3 H Me
42 H CF3 H H Me CF3 H COMe
43 H CF3 H Me Me CF3 H C02Me
44 H CF3 H COMe Me CF3 H S02Me 5 H CF3 H C02Me Ph Me H H
46 H CF3 H S02Me Ph Me H Me
47 H CF3 Me H Ph Me Me H 8 H CF3 Me Me Ph Et H H 9 H CF3 COMe COMe Ph Et Me H
50 H CF3 C02Me C02Me Ph Et H Me
51 H CF3 S02Me S02Me Ph Ph H H 2 Me Me Me H Ph Ph Me H 3 Me Me Me Me Ph Ph H Me 4 Me Me COMe COMe Ph CF3 H H 5 H H H H H H Me Me 6 H H H Me H H COMe COMe 7 H H H COMe H H C02Me C02Me 8 H H H C02Me H H S02Me S02Me 9 H H H S02Me H H Me H
TAB LE 41
= H , R2 = - CF3,
Column 1 Column 2
El E£ E^ E El El E^
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
Figure imgf000100_0001
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl 99
Column 1 Column 2
B2 El El E . E El El Bl
H Me H Et H Me H 2-CH2-furanyl
H Me H H-Pr H Me H CH2-c-Pr
H Me H C02Et H Me H CH2OMe
H Me H C02-«-Pr H Me H S02NMe2
H Me H COEt H Me H CH2SiMe3
H Me H CO-κ-Pr H Me H 2-pyridinyl
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
H Me H S02Me Me Me H Me
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
Figure imgf000101_0001
H Ph COMe COMe Me Ph H S02Me 100
Column 1 Column 2
Bl El Bl El El El El El
40 H Ph C02Me C02Me Me CF3 H H
41 H Ph S02Me S02Me Me CF3 H Me
42 H CF3 H H Me CF3 H COMe
43 H CF3 H Me Me CF3 H C02Me
44 H CF3 H COMe Me CF3 H S02Me
45 H CF3 H C02Me Ph Me H H
46 H CF3 H S02Me Ph Me H Me
47 H CF3 Me H Ph Me Me H
48 H CF3 Me Me Ph Et H H
49 H CF3 COMe COMe Ph Et Me H
50 H CF3 C02Me C02Me Ph Et H Me
51 H CF3 S02Me S02Me Ph Ph H H
52 Me Me Me H Ph Ph Me H
53 Me Me Me Me Ph Ph H Me
54 Me Me COMe COMe Ph CF3 H H
55 H H H H H H Me Me
56 H H H Me H H COMe COMe
57 H H H COMe H H C02Me C02Me
58 H H H C02Me H H S02Me S02Me
59 H H H S02Me H H Me H
Figure imgf000102_0001
TAB LE 42
R1 = OH, R2 = OH,
Column 1 Column 2
El El E£ E^ E El __! E^
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-fiiranyl
6 H Me H H-Pr H Me H CH2-oPr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C02-n-Pr H Me H S0 NMe2
9 H Me H COEt H Me H CH2SiMe3
Figure imgf000102_0002
10 H Me H CO-«-Pr H Me H 2-pyridinyl 101
Column 1 Column 2
El El E£ Bl Bl El E! E^
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
H Me H S02Me Me Me H Me
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
Figure imgf000103_0001
102
Column 1 Colun τn 2
El El Bl E^ El El El s
46 H CF3 H S02Me Ph Me H Me
47 H CF3 Me H Ph Me Me H
48 H CF3 Me Me Ph Et H H
49 H CF3 COMe COMe Ph Et Me H
50 H CF3 C02Me C02Me Ph Et H Me
51 H CF3 S02Me S02Me Ph Ph H H
52 Me Me Me H Ph Ph Me H
53 Me Me Me Me Ph Ph H Me
54 Me Me COMe COMe Ph CF3 H H
55 H H H H H H Me Me
56 H H H Me H H COMe COMe
57 H H H COMe H H C02Me C02Me
58 H H H C02Me H H S02Me S02Me
59 H H H S02Me H H Me H
TAB LE 43
R^ C Me, R2 = OMe,
Column 1 Column 2
Si El El E^ El El El El
1 H Me H H H Me H 3-CH2-pyridinyl
2 H Me H Me H Me H 4-CH2-pyridinyl
3 H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
4 H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
5 H Me H Et H Me H 2-CH2-fiιranyl
6 H Me H n-Pr H Me H CH2-c-Pr
7 H Me H C02Et H Me H CH2OMe
8 H Me H C02-«-Pr H Me H S02NMe2
9 H Me H COEt H Me H CH2SiMe3
10 H Me H CO-w-Pr H Me H 2-pyridinyl
11 H Me H Ph H Me H 4-pyridinyl
12 H Me H CH2Ph Me Me H H
13 H Me H S02Me Me Me H Me
14 H Me H S02CF3 Me Me H COMe
15 H Me H S02Ph Me Me H C02Me
Figure imgf000104_0001
16 H Me H S02-(4-Me-Ph) Me Me H S02Me 103
Column 1 Column 2
El El El El El El El El
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me SQ2Me Ph Ph H H
Figure imgf000105_0001
104
Column 1 Column 2
El El El El El El El El
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
H H H Me H H COMe COMe
H H H COMe H H C02Me C02Me
H H H C02Me H H S02Me S02Me
H H H S02Me H H Me H
TABLE 44 R2= Cl,
Column 1 Column 2
El El El El El El El
H Me H H H Me H 3-CH -pyridinyl
H Me H Me H Me H 4-CH2-pyridinyl
H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
H Me H Et H Me H 2-CH2-furanyl
H Me H n-Pr H Me H CH2-c-Pr
H Me H C02Et H Me H CH2OMe
H Me H C02-«-Pr H Me H S02NMe2
H Me H COEt H Me H CH2SiMe3
H Me H CO-«-Pr H Me H 2-pyridinyl
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
H Me H S02Me Me Me H Me
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
Figure imgf000106_0001
H Me H CONHPh H Et H H 105
Column 1 Column 2
El El El El El El El Bl
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
Figure imgf000107_0001
H H H Me H H COMe COMe 106
Column 1 Column 2
El El El El El El El El
H H H COMe H H C02Me C02Me
H H H C02Me H H S02Me S02Me
H H H S02Me H H Me H
TABLE 45
Column 1 Column 2
El El El El El El El El
H Me H H H Me H 3-CH2-pyridinyl
H Me H Me H Me H 4-CH2-pyridinyl
H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
H Me H Et H Me H 2-CH2-furanyl
H Me H w-Pr H Me H CH2-c-Pr
H Me H C02Et H Me H CH2OMe
H Me H C02-«-Pr H Me H S02NMe2
H Me H COEt H Me H CH2SiMe3
H Me H CO-n-Pr H Me H 2-pyridinyl
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
H Me H S02Me Me Me H Me
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
Figure imgf000108_0001
107
Column 1 Column 2
El El El El El El El El
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
H H H Me H H COMe COMe
H H H COMe H H C02Me C02Me
H H H C02Me H H S02Me S02Me
Figure imgf000109_0001
H H H S02Me H H Me H 108
TABLE 46
Column 1 Column 2
El El El El El Bl El El
H Me H H H Me H 3-CH2-pyridinyl
H Me H Me H Me H 4-CH2-pyridinyl
H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
H Me H Et H Me H 2-CH2-furanyl
H Me H w-Pr H Me H CH2-c-Pr
H Me H C02Et H Me H CH2OMe
H Me H C02-«-Pr H Me H S02NMe2
H Me H COEt H Me H CH2SiMe3
H Me H CO-w-Pr H Me H 2-pyridinyl
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
H Me H S02Me Me Me H Me
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
Figure imgf000110_0001
H Et COMe COMe Me Et H S02Me 109
Column 1 Column 2
El El El El El El El El
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
H H H Me H H COMe COMe
H H H COMe H H C02Me C02Me
H H H C02Me H H S02Me S02Me
H H H S02Me H H Me H
TAB LE 47
Column 1 Column 2
El El El R6 El Bl El El
H Me H H H Me H 3-CH2-pyridinyl
H Me H Me H Me H 4-CH2-pyridinyl
H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
H Me H Et H Me H 2-CH2-furanyl
Figure imgf000111_0001
H Me H w-Pr H Me H CH2-c-Pr 110
Column 1 Column 2
El El E! E! El El El El
H Me H C02Et H Me H CH2OMe
H Me H C02-«-Pr H Me H S0 NMe
H Me H COEt H Me H CH2SiMe3
H Me H CO-n-Pr H Me H 2-pyridinyl
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
H Me H S02Me Me Me H Me
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C0 Me C02Me Me CF3 H H
Figure imgf000112_0001
H Ph S02Me S02Me Me CF3 H Me 111
Column 1 Column 2
El El El El El El El El
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
H H H Me H H COMe COMe
H H H COMe H H C02Me C02Me
H H H C02Me H H S02Me S02Me
H H H S02Me H H Me H
TAB LE 48
Column 1 Column 2
El El El El Bl El El El
H Me H H H Me H 3-CH2-pyridinyl
H Me H Me H Me H 4-CH2-pyridinyl
H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
H Me H Et H Me H 2-CH2-fiιranyl
H Me H w-Pr H Me H CH2-c-Pr
H Me H C02Et H Me H CH2OMe
H Me H C02-n-Pr H Me H S0 NMe
H Me H COEt H Me H CH2SiMe3
H Me H CO-w-Pr H Me H 2-pyridinyl
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
Figure imgf000113_0001
H Me H S02Me Me Me H Me 112
Column 1 Column 2
El El El El El El El El
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H
Figure imgf000114_0001
H 113
Column 1 Column 2
El El El El El El El El
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
H H H Me H H COMe COMe
H H H COMe H H C02Me C02Me
H H H C02Me H H S02Me S02Me
H H H S02Me H H Me H
TAB LE 49
Column 1 Column 2
El El El El El El El El
H Me H H H Me H 3-CH -pyridinyl
H Me H Me H Me H 4-CH2-pyridinyl
H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
H Me H Et H Me H 2-CH2-furanyl
H Me H n-Pr H Me H CH2-c-Pr
H Me H C0 Et H Me H CH2OMe
H Me H C0 -«-Pr H Me H S02NMe2
H Me H COEt H Me H CH2SiMe3
H Me H CO-«-Pr H Me H 2-pyridinyl
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
H Me H S02Me Me Me H Me
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
Figure imgf000115_0001
H Me H CONHMe H Me C02Me C02Me 114
Column 1 Column 2
El El El El El El El El
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
Figure imgf000116_0001
H H H H H H Me Me 115
Column 1 Coluπ in 2
El Bl El El El El El El
H H H Me H H COMe COMe
H H H COMe H H C02Me C02Me
H H H C02Me H H S02Me S02Me
H H H S02Me H H Me H
TABLE 50
Column 1 Column 2
El El El El El R! El El
H Me H H H Me H 3-CH2-pyridinyl
H Me H Me H Me H 4-CH2-pyridinyl
H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
H Me H Et H Me H 2-CH2-furanyl
H Me H w-Pr H Me H CH2-oPr
H Me H C02Et H Me H CH2OMe
H Me H C02-«-Pr H Me H S02NMe2
H Me H COEt H Me H CH2SiMe3
H Me H CO-M-Pr H Me H 2-pyridinyl
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
H Me H S02Me Me Me H Me
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
Figure imgf000117_0001
H Me H 2-CH2-pyridinyl H Ph H H 116
Column 1 Column 2
El El El El El El El El
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
H H H Me H H COMe COMe
H H H COMe H H C02Me C02Me
H H H C02Me H H S02Me S02Me
H H H S02Me H H Me H
Figure imgf000118_0001
117 TABLE 51
Column 1 Column 2
El El El El El E1 E! _ R_6
H Me H H H Me H 3-CH2-pyridinyl
H Me H Me H Me H 4-CH2-pyridinyl
H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
H Me H Et H Me H 2-CH2-furanyl
H Me H H-Pr H Me H CH2-c-Pr
H Me H C02Et H Me H CH2OMe
H Me H C0 -«-Pr H Me H S02NMe2
H Me H COEt H Me H CH2SiMe3
H Me H CO-M-Pr H Me H 2-pyridinyl
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
H Me H S02Me Me Me H Me
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-ρyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
Figure imgf000119_0001
H Et COMe COMe Me Et H S02Me 00 00 o o £ £
£ .3 _?
2 ft vo I
H s s o I a υ al a s o s ,-J 1 a ^ a a a ^ a a s s s o al ft '£. ft a a ft u o o o υ o U o CΛ υ oj o CM a a CJ u a a u C aJ D υ J CJ
C 3 4) 4) 4) wo 4) 4) 4) a a s s O s a in U al a a a a a a a a a a s a a s a a s o s U al PP υ o υ o
"al ft ft ft ft ft ft ft ft ft ft 4) 4)
CJ u υ u u s s s w ω 43 43 43
W ft ft ft ft υ a a a a a ^1 s s s s
CN co 43 43 43 43 43 43 43 43 43 43
Figure imgf000120_0001
ft ft ft ft ft ft ft ft ft ft a a a a oo al S S S S S S S W al
3 vo I S S S s s vo I 4) S rt al CM S CM s o o o o a 2 o o o a s o s s o a al S o cS w
Figure imgf000120_0002
u 00 υ CJ o oo CJ υ oo u o CJ o o CΛ υ o υ o υ υ
4) 4) 4) 4) 4) o I s s 4) o 4) s S S „ ) 4) s al s s o o s s o s s Ά 3 m I o 2 o "o al a a a a a a
U
Figure imgf000120_0003
υ CΛ υ δ CJ δ X a a a a 4 oo
Figure imgf000120_0004
υ o o rt υ CΛ υ U
al W P [SJ ^ ft ^ ft ^ ^ ft ^ ft ft ft pH ft H ft ft ft ft υ o o cj u o u u cj o ^ ^ ^ x x x x x *! S S S S S S o i
Ov al a a a a a a a a a a a a a a a a a rt rt rt a a a a a ^1 a a a a a a o ιn vo t^ oo σv © HH M co -*-f "n vo t^ oo σ © —, c co ^j- ιn vo t~~ oo σv HH CM co *--f >n vo co co co co cθ '--f "* ---f ---r *^ '--r '--]- *-r --t '--t- -n ιn ιn -n ιn ιn ιn ιn ιn ιn
119
Column 1 Column 2
El El El El El El El El
H Me H C02Et H Me H CH2OMe
H Me H C02-w-Pr H Me H S02NMe2
H Me H COEt H Me H CH2SiMe3
H Me H CO-w-Pr H Me H 2-pyridinyl
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
H Me H S02Me Me Me H Me
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH -pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
Figure imgf000121_0001
120
Column 1 Column 2
El El El El El El El El
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
H H H Me H H COMe COMe
H H H COMe H H C02Me C02Me
H H H C02Me H H S02Me S02Me
H H H S02Me H H Me H
TAB LE 53
Column 1 Column 2
El El El El El El El El
H Me H H H Me H 3-CH2-pyridinyl
H Me H Me H Me H 4-CH2-pyridinyl
H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
H Me H Et H Me H 2-CH2-furanyl
H Me H n-Pr H Me H CH2-c-Pr
H Me H C02Et H Me H CH2OMe
H Me H C0 -«-Pr H Me H S02NMe2
H Me H COEt H Me H CH2SiMe3
H Me H CO-n-Pr H Me H 2-pyridinyl
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
Figure imgf000122_0001
H Me H S02Me Me Me H Me 121
Column 1 Column 2
El El El El El El El El
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
H Me H CONHMe H Me C02Me C02Me
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH-=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H
Figure imgf000123_0001
H 122
Columr L l Colun ιn 2
El El El El El El El El
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
H H H H H H Me Me
H H H Me H H COMe COMe
H H H COMe H H C02Me C02Me
H H H C02Me H H S02Me S02Me
H H H S02Me H H Me H
TAB LE 54
Column 1 Column 2
El El El El El El El El
H Me H H H Me H 3-CH2-pyridinyl
H Me H Me H Me H 4-CH2-pyridinyl
H Me H COMe H Me H 6-Cl-2-CH2-pyridinyl
H Me H C02Me H Me H 6-Cl-3-CH2-pyridinyl
H Me H Et H Me H 2-CH2-_uranyl
H Me H n-Pr H Me H CH2-c-Pr
H Me H C02Et H Me H CH2OMe
H Me H C02-«-Pr H Me H S02NMe2
H Me H COEt H Me H CH2SiMe3
H Me H CO-«-Pr H Me H 2-pyridinyl
H Me H Ph H Me H 4-pyridinyl
H Me H CH2Ph Me Me H H
H Me H S02Me Me Me H Me
H Me H S02CF3 Me Me H COMe
H Me H S02Ph Me Me H C02Me
H Me H S02-(4-Me-Ph) Me Me H S02Me
H Me H S02Et H Me Me H
H Me H COCF3 H Me Me Me
H Me H CH2CF3 H Me COMe COMe
Figure imgf000124_0001
H Me H CONHMe H Me CQ2Me C02Me 123
Column 1 Column 2
El El El El El El El El
H Me H CONHEt H Me S02Me S02Me
H Me H CONHPh H Et H H
H Me H CH2CH=CH2 H Et H Me
H Me H CH2C≡CH H Et H COMe
H Me H CH2CH=CHMe H Et H C02Me
H Me H CH2C≡CMe H Et H S02Me
H Me H 2-CH2-pyridinyl H Ph H H
H Ph H Me Me Me C02Me C02Me
H Ph H COMe Me Et H H
H Ph H C02Me Me Et H Me
H Ph H S02Me Me Et H Me
H Et Me H Me Et H COMe
H Et Me Me Me Et H C02Me
H Et COMe COMe Me Et H S02Me
H Et C02Me C02Me Me Ph H H
H Et S02Me S02Me Me Ph H Me
H Ph Me H Me Ph H COMe
H Ph Me Me Me Ph H C02Me
H Ph COMe COMe Me Ph H S02Me
H Ph C02Me C02Me Me CF3 H H
H Ph S02Me S02Me Me CF3 H Me
H CF3 H H Me CF3 H COMe
H CF3 H Me Me CF3 H C02Me
H CF3 H COMe Me CF3 H S02Me
H CF3 H C02Me Ph Me H H
H CF3 H S02Me Ph Me H Me
H CF3 Me H Ph Me Me H
H CF3 Me Me Ph Et H H
H CF3 COMe COMe Ph Et Me H
H CF3 C02Me C02Me Ph Et H Me
H CF3 S02Me S02Me Ph Ph H H
Me Me Me H Ph Ph Me H
Me Me Me Me Ph Ph H Me
Me Me COMe COMe Ph CF3 H H
Figure imgf000125_0001
H H H H H H Me Me rΛ ω ) ) H- II II CΛ CΛ CΛ
VO oo OS
CΛ μp X PP ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft fL a a a a |^ VO VO ffi Ov t
O o o Ov
2 2 ct a a a rt
I σv ft O _≠ rt ft rt ft o o a a a a ft Ov rt 2 2 " a (I ( 2I a ™ a a a is* o o n π
55 o o o a a a a p> o w 2 2 w 2 ST - to 23 P P CD 2 CD 2 a
ET 2 CD a w w a a I σ 3 ES
o to O 2 to o O O ft ft rt ft ft Ir?. rt 2 rt2 rt2 a rt a 2 rt rt2 2 ct a a a w 2 a 2
2 ct 1 σv rt 2t !
H w t-1
2 2 tn •ft 2 2 2 P W c-ι 2 ct 2ct 2ct 2o 2ct rt2 2rt 2ct c2t 2ct 2ct 2ct rt2 2ct 2rt I I +■ σ x a a a a c_*ι PS, o o o
2 2 a a a P3 a | a a | | 2 a 2 2 a 2 a a a t a a a a pi π CΛ o o π o g o o o o 2 to O to o o pi w "■ c 2t 2 rt ~ w 2 ct I ~o 3 ^ | p | a a 2 ct o 2 2 a a a a I** O. 2 2 2 ct ct
CD CD CD ) to 3 t*o Λ O a a 2 a a I**, 2 2 2 a 2 O rt rt rt rt ^ rt a^ 2ct 2ct 2t a a a w^- rt2 a1^ oo O
Figure imgf000126_0001
a t O to o p O 1 σiv H rt ct
CΛ vo vo
© o
00 00 t
125
Column 1 Column 2
E! E1 EZ El El El EZ El
H COMe Me H Me COMe Me H
H COMe Et H Me COMe Et H
H COMe Me Me Me COMe Me Me
H S02Me Me H Me S02Me Me H
H C02Me Me H Me C02Me Me H
TABLE 57 R 8 = R17 = H,
Column 1 Column 2
R 4 R5 R6 R7 R16 R4 R5 R6 R7 R16
I I H H H H Me H H H H
F I Me H H H Me Me H H H
I I H Me H H Me H Me H H
F 1 COMe H H H Me COMe H H H
F I H COMe H H Me H COMe H H
I I COMe COMe H H Me COMe COMe H H
I I H H Me H Me H H Me H
I I Me H Me H Me Me H Me H
F I Me Me Me H Me Me Me Me H
F 1 COMe H Me H Me COMe H Me H
I 1 H COMe Me H Me H COMe Me H
F 1 H S02Me Me H Me H S02Me Me H
F I H H H Me Me H H H Me
F 1 Me H H Me Me Me H H Me
F I COMe H H Me Me COMe H H Me
F 1 H H Me Me Me H H Me Me
E 1 H H H Et Me H H H Et
E [ H H Et H Me H H Et H
E [ Me H Et H Me Me H Et H
H [ COMe H Et H Me COMe H Et H
H [ H Me Et H Me H Me Et H
Figure imgf000127_0001
E [ H COMe Et H Me H COMe Et H 126 TABLE 58
R3 = H,
Column 1 Column 2
El El El R18 El El El Ell
1 H H H H Me H H H
2 H H H Me Me H H Me
3 H H H Et Me H H Et
4 H Me H H Me Me H H
5 H H Me H Me H Me H
6 H Me Me H Me Me Me H
7 H Me H Me Me Me H Me
8 H H Me Me Me H Me Me
9 H Me Me Me Me Me Me Me
10 H COMe H H Me COMe H H
11 H COMe H Me Me COMe H Me
12 H H COMe H Me H COMe H
13 H H COMe Me Me H COMe Me
14 H COMe COMe Me Me COMe COMe Me
15 H H S02Me Me Me H S02Me Me
Figure imgf000128_0001
Formu lation/Utilitv
Compounds of this invention will generally be used as a formulation or composition with an agriculturally suitable carrier comprising at least one of a liquid diluent, a solid diluent or a surfactant. The formulation or composition ingredients are selected to be consistent with the physical properties of the active ingredient, mode of application and environmental factors such as soil type, moisture and temperature. Useful formulations include liquids such as solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions and/or suspoemulsions) and the like which optionally can be thickened into gels. Useful formulations further include solids such as dusts, powders, granules, pellets, tablets, films, and the like which can be water-dispersible ("wettable") or water-soluble. Active ingredient can be (micro)encapsulated and further formed into a suspension or solid formulation; alternatively the entire formulation of active ingredient can be encapsulated (or "overcoated"). Encapsulation can control or delay release of the active ingredient. Sprayable formulations can be extended in suitable media and used at spray volumes from about one to several hundred liters per hectare. High-strength compositions are primarily used as intermediates for further formulation. 127
The formulations will typically contain effective amounts of active ingredient, diluent and surfactant within the following approximate ranges which add up to 100 percent by weight.
Weight Percent
Active
Ingredient Diluent Surfactant
Water-Dispersible and 5-90 0-94 1-15
Water-soluble Granules, Tablets and
Powders.
Suspensions, Emulsions, 5-50 40-95 0-15
Solutions (including Emulsifiable
Concentrates)
Dusts 1-25 70-99 0-5
Figure imgf000129_0001
Granules and Pellets 0.01-99 5-99.99 0-15
High Strength Compositions 90-99 0-10 0-2
Typical solid diluents are described in Watkins, et al., Handbook of Insecticide Dust Diluents and Carriers, 2nd Ed., Dorland Books, Caldwell, New Jersey. Typical liquid diluents are described in Marsden, Solvents Guide, 2nd Ed., Interscience, New York, 1950. McCutcheon 's Detergents and Emulsifiers Annual, Allured Publ. Corp., Ridgewood, New Jersey, as well as Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964, list surfactants and recommended uses. All formulations can contain minor amounts of additives to reduce foam, caking, corrosion, microbiological growth and the like, or thickeners to increase viscosity.
Surfactants include, for example, polyethoxylated alcohols, polyethoxylated alkylphenols, polyethoxylated sorbitan fatty acid esters, dialkyl sulfosuccinates, alkyl sulfates, alkylbenzene sulfonates, organosilicones, NN-dialkyltaurates, lignin sulfonates, naphthalene sulfonate formaldehyde condensates, polycarboxylates, and polyoxyethylene/polyoxypropylene block copolymers. Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, starch, sugar, silica, talc, diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate, and sodium sulfate. Liquid diluents include, for example, water, NN-dimethylformamide, dimethyl sulfoxide, N-alkylpyrrolidone, ethylene glycol, polypropylene glycol, paraffins, alkylbenzenes, alkylnaphthalenes, oils of olive, castor, linseed, tung, sesame, corn, peanut, cotton-seed, soybean, rape-seed and coconut, fatty acid esters, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy-4-methyl-2-pentanone, and alcohols such as methanol, cyclohexanol, decanol and tetrahydrofurfuryl alcohol. Solutions, including emulsifiable concentrates, can be prepared by simply mixing the ingredients. Dusts and powders can be prepared by blending and, usually, grinding as in a hammer mill or fluid-energy mill. Suspensions are usually prepared by wet-milling; see, for 128 example, U.S. 3,060,084. Granules and pellets can be prepared by spraying the active material upon preformed granular carriers or by agglomeration techniques. See Browning, "Agglomeration", Chemical Engineering, December 4, 1967, pp 147-48, Perry's Chemical Engineer's Handbook, 4th Ed., McGraw-Hill, New York, 1963, pages 8-57 and following, and WO 91/13546. Pellets can be prepared as described in U.S. 4,172,714.
Water-dispersible and water-soluble granules can be prepared as taught in U.S. 4,144,050, U.S. 3,920,442 and DE 3,246,493. Tablets can be prepared as taught in U.S. 5,180,587, U.S. 5,232,701 and U.S. 5,208,030. Films can be prepared as taught in GB 2,095,558 and U.S. 3,299,566. For further information regarding the art of formulation, see U.S. 3,235,361, Col. 6, line 16 through Col. 7, line 19 and Examples 10-41; U.S. 3,309,192, Col. 5, line 43 through Col. 7, line 62 and Examples 8, 12, 15, 39, 41, 52, 53, 58, 132, 138-140, 162-164, 166, 167 and 169-182; U.S. 2,891,855, Col. 3, line 66 through Col. 5, line 17 and Examples 1-4; Klingman, Weed Control as a Science, John Wiley and Sons, Inc., New York, 1961, pp 81-96; and Hance et al., Weed Control Handbook, 8th Ed., Blackwell Scientific Publications, Oxford, 1989.
In the following Examples, all percentages are by weight and all formulations are prepared in conventional ways. Compound numbers refer to compounds in Index Tables A-C. Example A
Wettable Powder
Compound 1 65.0% dodecylphenol polyethylene glycol ether 2.0% sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0% montmorillonite (calcined) 23.0%.
Example B
Granule
Compound 4 10.0% attapulgite granules (low volatile matter,
0.71/0.30 mm; U.S.S. No. 25-50 sieves) 90.0%.
Example C
Extruded Pellet
Compound 1 25.0% anhydrous sodium sulfate 10.0% crude calcium ligninsulfonate 5.0% sodium alkylnaphthalenesulfonate 1.0% calcium/magnesium bentonite 59.0%. 129
Example D Emulsifiable Concentrate
Compound 4 20.0% blend of oil soluble sulfonates and polyoxyethylene ethers 10.0% isophorone 70.0%.
The compounds of this invention exhibit activity against a wide spectrum of foliar-feeding, fruit-feeding, stem or root feeding, seed-feeding, aquatic and soil-inhabiting arthropods (term "arthropods" includes insects, mites and nematodes) which are pests of growing and stored agronomic crops, forestry, greenhouse crops, ornamentals, nursery crops, stored food and fiber products, livestock, household, and public and animal health. Those skilled in the art will appreciate that not all compounds are equally effective against all growth stages of all pests. Nevertheless, all of the compounds of this invention display activity against pests that include: eggs, larvae and adults of the Order Lepidoptera; eggs, foliar-feeding, fruit-feeding, root-feeding, seed-feeding larvae and adults of the Order Coleoptera; eggs, immatures and adults of the Orders Hemiptera and Homoptera; eggs, larvae, nymphs and adults of the Order Acari; eggs, immatures and adults of the Orders Thysanoptera, Orthoptera and Dermaptera; eggs, immatures and adults of the Order Diptera; and eggs, juveniles and adults of the Phylum Nematoda. The compounds of this invention are also active against pests of the Orders Hymenoptera, Isoptera, Siphonaptera, Blattaria, Thysanura and Psocoptera; pests belonging to the Class Arachnida and Phylum Platyhelminthes. Specifically, the compounds are active against southern corn rootworm (Diabrotica undecimpunctata howardi), aster leafhopper (Mascrosteles fascifrons), boll weevil (Anthonomus grandis), two-spotted spider mite (Tetranychus urticae), fall armyworm (Spodoptera frugiperdd), black bean aphid (Aphis fabae), green peach aphid (Myzus persica), cotton aphid (Aphis gossypii), Russian wheat aphid (Diuraphis noxid), English grain aphid (Sitobion avenae), tobacco budworm (Heliothis virescens), rice water weevil (Lissorhoptrus oryzophilus), rice leaf beetle (Oulema oryzae), whitebacked planthopper (Sogatella furcifera), green leafhopper (Nephotettix cincticeps), brown planthopper (Nilaparvata lugens), small brown planthopper (Laodelphax striatellus), rice stem borer (Chilo suppressalis), rice leafroller (Cnaphalocrocis medinalis), black rice stink bug (Scotinophara luridd), rice stink bug (Oebalus pugnax), rice bug (Leptocorisa chinensis), slender rice bug (Cletus puntiger), and southern green stink bug (Nezara viridula). The compounds are active on mites, demonstrating ovicidal, larvicidal and chemosterilant activity against such families as Tetranychidae including Tetranychus urticae, Tetranychus cinnabarinus, Tetranychus mcdanieli, Tetranychus paciβcus, Tetranychus turkestani, Byrobia rubrioculus, Panonychus ulmi, Panonychus citri, Eotetranychus carpini borealis, Eotetranychus, hicoriae, Eotetranychus sexmaculatus, Eotetranychus yumensis, 130
Eotetranychus banksi and Oligonychus pratensis; Tenuipalpidae including Brevipalpus lewisi, Brevipalpus phoenicis, Brevipalpus californicus and Brevipalpus obovatus; Eriophyidae including Phyllocoptruta oleivora, Eriophyes sheldoni, Aculus cornutus, Epitrimerus pyri and Eriophyes mangiferae. See WO 90/10623 and WO 92/00673 for more detailed pest descriptions.
Compounds of this invention can also be mixed with one or more other insecticides, fungicides, nematocides, bactericides, acaricides, growth regulators, chemosterilants, semiochemicals, repellents, attractants, pheromones, feeding stimulants or other biologically active compounds to form a multi-component pesticide giving an even broader spectrum of agricultural protection. Examples of such agricultural protectants with which compounds of this invention can be formulated are: insecticides such as abamectin, acephate, acetamiprid, azinphos-methyl, bifenthrin, buprofezin, carbofuran, chlorfenapyr, chlorpyrifos, chlorpyrifos-methyl, cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, deltamethrin, diafenthiuron, diazinon, diflubenzuron, dimethoate, esfenvalerate, ethiprole, fenoxycarb, fenpropathrin, fenvalerate, fipronil, flucythrinate, tau-fluvalinate, fonophos, imidacloprid, indoxacarb, isofenphos, malathion, metaldehyde, methamidophos, methidathion, methomyl, methoprene, methoxychlor, indoxacarb, monocrotophos, oxamyl, parathion, parathion-methyl, permethrin, phorate, phosalone, phosmet, phosphamidon, pirimicarb, profenofos, pymetrozine, rotenone, spinosad, sulprofos, tebufenozide, tefluthrin, terbufos, tetrachlorvinphos, thiacloprid, thiamethoram, thiodicarb, tralomethrin, trichlorfon and triflumuron; fungicides such as azoxystrobin, benomyl, blasticidin-S, Bordeaux mixture (tribasic copper sulfate), bromuconazole, captafol, captan, carbendazim, chloroneb, chlorothalonil, copper oxychloride, copper salts, cymoxanil, cyproconazole, cyprodinil (CGA 219417), diclomezine, dicloran, difenoconazole, dimethomorph, diniconazole, diniconazole-M, dodine, edifenphos, epoxiconazole (BAS 480F), famoxadone, fenarimol, fenbuconazole, fenpiclonil, fenpropidin, fenpropimorph, fluazinam, fluquinconazole, flusilazole, flutolanil, flutriafol, folpet, fosetyl-aluminum, furalaxyl, hexaconazole, ipconazole, iprobenfos, iprodione, isoprothiolane, kasugamycin, kresoxim-methyl, mancozeb, maneb, mepronil, metalaxyl, metconazole, S-methyl 7-benzothiazolecarbothioate (CGA 245704), myclobutanil, neo-asozin (ferric methanearsonate), oxadixyl, penconazole, pencycuron, probenazole, prochloraz, propiconazole, pyrifenox, pyroquilon, spiroxamine (KWG4168), sulfur, tebuconazole, tetraconazole, thiabendazole, thiophanate-methyl, thiram, triadimefon, triadimenol, tricyclazole, triticonazole, validamycin and vinclozolin; nematocides such as aldoxycarb and fenamiphos; bactericides such as streptomycin; acaricides such as amitraz, chinomethionat, chlorobenzilate, cyhexatin, dicofol, dienochlor, etoxazole, fenazaquin, fenbutatin oxide, fenpropathrin, fenpyroximate, hexythiazox, propargite, pyridaben and tebufenpyrad; and biological agents such as Bacillus thuringiensis, 131
Bacillus thuringiensis delta endotoxin, baculovirus, and entomopathogenic bacteria, virus and fungi.
In certain instances, combinations with other arthropodicides having a similar spectrum of control but a different mode of action will be particularly advantageous for resistance management.
Preferred for better control of pests (use rate or spectrum) or resistance management are mixtures of a compound of this invention with an arthropodicide selected from the group indoxacarb, imidacloprid, fipronil, acetamprid, pymetrozine and thiacloprid. Specifically preferred mixtures (compound numbers refer to compounds in Index Tables A-D) are selected from the group: compound 1 and acetamprid; compound 1 and chlorfenapyr; compound 1 and fipronil; compound 1 and imidacloprid; compound 1 and indoxacarb; compound 1 and methomyl; compound 1 and pymetrozine; compound 1 and spinosad; compound 1 and thiacloprid; compound 52 and acetamprid; compound 52 and chlorfenapyr; compound 52 and fipronil; compound 52 and imidacloprid; compound 52 and indoxacarb; compound 52 and methomyl; compound 52 and pymetrozine; compound 52 and spinosad; and compound 52 and thiacloprid.
Arthropod pests are controlled and protection of agronomic, horticultural and specialty crops, animal and human health is achieved by applying one or more of the compounds of this invention, in an effective amount, to the environment of the pests including the agronomic and/or nonagronomic locus of infestation, to the area to be protected, or directly on the pests to be controlled. Thus, the present invention further comprises a method for the control of foliar and soil inhabiting arthropods and nematode pests and protection of agronomic and/or nonagronomic crops, comprising applying one or more of the compounds of the invention, or compositions containing at least one such compound, in an effective amount, to the environment of the pests including the agronomic and/or nonagronomic locus of infestation, to the area to be protected, or directly on the pests to be controlled. A preferred method of application is by spraying. Alternatively, granular formulations of these compounds can be applied to the plant foliage or the soil. Other methods of application include direct and residual sprays, aerial sprays, seed coats, microencapsulations, systemic uptake, baits, eartags, boluses, foggers, fumigants, aerosols, dusts and many others. The compounds can be incorporated into baits that are consumed by the arthropods or in devices such as traps and the like.
The compounds of this invention can be applied in their pure state, but most often application will be of a formulation comprising one or more compounds with suitable carriers, diluents, and surfactants and possibly in combination with a food depending on the contemplated end use. A preferred method of application involves spraying a water dispersion or refined oil solution of the compounds. Combinations with spray oils, spray oil 132 concentrations, spreader stickers, adjuvants, other solvents, and synergists such as piperonyl butoxide often enhance compound efficacy.
The rate of application required for effective control will depend on such factors as the species of arthropod to be controlled, the pest's life cycle, life stage, its size, location, time of year, host crop or animal, feeding behavior, mating behavior, ambient moisture, temperature, and the like. Under normal circumstances, application rates of about 0.01 to 2 kg of active ingredient per hectare are sufficient to control pests in agronomic ecosystems, but as little as 0.001 kg/hectare may be sufficient or as much as 8 kg/hectare may be required. For nonagronomic applications, effective use rates will range from about 1.0 to 50 mg/square meter but as little as 0.1 mg/square meter may be sufficient or as much as 150 mg/square meter may be required.
The following TESTS demonstrate the control efficacy of compounds of this invention on specific pests. "Control efficacy" represents inhibition of arthropod development (including mortality) that causes significantly reduced feeding. The pest control protection afforded by the compounds is not limited, however, to these species. See Index Tables A-D for compound descriptions. The following abbreviations are used in the Index Tables which follow: Me = methyl, Et = ethyl, Ph = phenyl, OMe = methoxy, NO2 = nitro, COMe = acetyl, S(O)2Me = methylsulfonyl and 6-Cl-3-CH2-pyridinyl =
Figure imgf000134_0001
The abbreviation "dec" indicates that the compound appeared to decompose on melting. The abbreviation "Ex." stands for "Example" and is followed by a number indicating in which example the compound is prepared.
INDEX TABLE A
R6
R
8 X ^ J; "^CN
9 x 2 R- < R X 10 1 i <4
Cmpd Ri R El l mo . °α
No.
1 (Ex. 1) H H Me H H >220*
2 (Ex. 4) 8-C1 H Me H H >220*
Figure imgf000134_0002
3 8-C1 10-Cl Me H H >220* 133
Cmpd Ri R_: R4 R5 R6 mp (°C)
No. (Ex. 2) H H Me H 6-Cl-3-CH2- 216 (dec) pyridinyl
5 8-Br 10-Br Me H H >225*
6 8-NO2 H Me H H >225* (Ex. 3) H H Me H COMe 219-221
8 H H Me H Me >220*
9 H H Me H MeSO2 >225*
10 H H Et H H 240-245
11 H H Ph H H 253-256
Figure imgf000135_0002
12 H H
Figure imgf000135_0003
H H >225*
CH3
Figure imgf000135_0001
13 9-MeO 10-MeO Me H H >225*
14 H H Me H CO2Me 199 (dec)
15 H H Me Me Me 187 (dec)
16 8-F3CO H Me H H >225*
17 10-Me H Me H H >225*
18 8-t-Bu 10-t-Bu Me H H >225*
19 H H Me H 2-CH2- >225* pyridinyl
20 8-Me H Me H H >225*
21 H H CF3 H H 137-138
22 H H Me H Et >225*
23 H H Me H CH2-Ph >225*
24 10-F H Me H H >225*
25 H H Me H CH2CH=CH2 208-210
26 H H Me H CH2SiMe 186-189
27 H H Me H CH2CO2Me >225*
28 H H Me H CH2C≡CH 204 (d)
29 H H Me H COEt 196-198
30 H H Me H CO-n-Pr 198-199
31 10-MeO H Me H H 250
32 H H Me H CO-t-Pr 206-209
Figure imgf000135_0004
33 H H Me
Figure imgf000135_0005
H COCF3 oil* 134
Cmpd E_i E: R R5 R6 mp (°c . No.
34 8-NH2 H Me H H 234-235
35 9-Cl H Me H H >225*
36 9-F H Me H COMe 207-210
37 9-F H Me H Me >225*
38 9-F H Me H CO2Me 209-211
39 7-MeO H Me H H >225*
40 7-C1 9-Cl Me H H >225*
41 9-F H Me H H >225*
Figure imgf000136_0002
42 H H H
Figure imgf000136_0003
H H 208-210
*See Index Table E for *H NMR data.
INDEX TABLE B
Figure imgf000136_0001
Cmpd No. Ed Z R8 mp r°o
43 Et Me H 249-252
44 Me Me H 258-261
45 Me Et H 219-221
46 H Me H 220-230
47 H Et H 249-252
INDEX TABLE C
H
1
H ••"R7 ^ ^CN
^
) , XH
Cmpd No. R EZ R8 mp (°C)
48 Me Me H 248-249
Figure imgf000136_0004
49 Me H Me 279-280 135 INDEX TABLE D
Figure imgf000137_0001
Cmpd R4 R5 R6 R7 R8 R16 R17 mp TO
No. (Ex. 5) H H H H H H H >250
51 H H H H Me H H 254-256
52 H H H Me H H H 286-287
53 H H COMe H H H H 218-220
54 H COMe H H H H H 225-227
55 H Me H H H H H 234-238
56 Me H H H H H H 272-273
57 H H H H H Me H 235-241
58 Me H H Me H H H 250-255
INDEX TABLE E
Figure imgf000137_0002
Cmpd No. --H NMR Data (Me2SO- 6 solution unless indicated otherwise)3 δ 8.66 (br s,2H), 7.27-7.18 (m,2H), 6.92 (t,lH), 6.82 (d,lH), 4.50 (m,lH), 2.15 (m,2H),
1.68 (t,3H). δ 8.76 (s,l), 8.63 (br s,lH), 7.35-7.20 (m,2H), 6.86 (d,lH), 4.52 (m,lH),
2.16 (AB q,2H), 1.68 (s,3H). δ 8.90 (s,lH), 8.72 (s,lH), 7.54 (d,lH), 7.28 (d,lH), 4.60 (narrow m,lH), 2.22 (m,2H),
1.74 (s,3H). δ 8.90 (s,lH), 8.69 (br s, IH), 7.75 (d,lH), 7.44 (d,lH), 4.58 (m,lH), 2.21 (m,2H),
1.73 (s,3H). δ 8.96 (s,lH), 8.75 (br s,lH), 8.24 (d,lH), 8.10 (ddJH), 7.06 (d,lH), 4.70 (m,lH),
2.35-2.20 (m,2H), 1.74 (s,3H). δ 8.40 (sJH), 7.35 (d-lH), 7.25 (tJH), 6.93 (tJH), 6.85 (d,lH), 4.56 (mJH),
3.00 (s,3H), 2.34 (dd,lH), 2.20 (dd, IH), 1.76 (s,3H). δ 9.61 (s,lH), 7.35-7.25 (m,2H)), 7.01 (t,lH), 6.91 (d,lH), 5.62 (apparent t, IH),
3.47 (s,3H), 2.43 (ddJH), 2.33 (ddJH), 1.81 (s,3H). 136
12 δ 8.88 (br s,lH) 8.19 (s,lH), 7.24 (apparent t, 2H), 6.96 (t,lH), 6.89 (dJH),
4.83 (s,2H), 4.54 (br sJH), 4.30 (d,lH), 4.10 (dJH), 3.82 (dJH), 3.67 (d,lH), 2.33 (ddJH), 2.16 (br d,lH), 1.09 (s,3H).
13 δ 8.67 (s,lH), 8.62 (mJH), 6.92 (d,lH), 6.63 (dJH), 4.42 (m,lH), 3.74 (s,3H),
3.65 (s,3H), 2.12 (s,2H), 1.70 (s,3H).
16 δ 8.79 (s,lH), 8.65 (brs, IH), 7.25-7.15 (overlapping s and d,2H), 6.93 (d,lH), 4.55 (br s,lH), 2.18 (d,2H), 1.69 (s,3H).
17 δ 8.63 (br s,2H), 7.07 (apparent d, 2H), 6.82 (t,lH), 4.47 (apparent s, IH), 2.13 (d,2H),
2.10 (s,3H), 1.70 (s,3H).
18 δ 8.71 (sJH), 8.59 (br dJH), 7.16 (dJH), 7.12 (d,lH), 4.44 (m,lH), 2.10 (m,2H), 1.72
(s,3H), 1.33 (s,9H), 1.26 (s,9H).
19 δ 8.61 (sJH), 8.57 (d,lH), 7.78 (dt,lH), 7.35-7.20 (m,4H), 6.90-6.82 (m,2H), 4.98
(dJH), 4.67 (m,lH), 4.61 (dJH), 2.44 (dd,lH), 2.22 (br dJH), 1.81 (s,3H).
20 δ 8.61 (br s,2H), 7.05-6.98 (m,2H), 6.71 (d,lH), 4.42 (m,lH), 2.23 (s,3H), 2.11 (d,2H),
1.66 (s,3H).
22 δ 8.37 (s,lH), 8.40 (dJH), 7.24 (t,lH), 6.92 (t,lH), 6.85 (d,lH), 4.67 (s,lH), 3.72-3.62
(mJH), 3.4-3.25 (m,lH), 2.20 (m,2H), 1.76 (s,3H), 1.13 (t,3H).
23 δ 8.59 (s,lH), 7.4-7.1 (m,7H), 6.86 (apparent d, 2H), 4.94 (d,lH), 4.53 (m,lH), 4.45
(d,lH), 2.27 (dd,lH), 2.20 (d,lH), 1.80 (s,3H).
24 δ 8.79 (s,lH), 8.74 (d,lH), 7.20-7.05 (m,2H), 6.98-6.88 (m,lH), 4.56 (br s,lH), 2.21
(m,2H), 1.72 (s,3H). 27 δ 8.72 (s,lH), 7.41 (dd,lH), 7.22 (dt,lH), 6.91 (t,lH), 6.85 (d,lH), 4.71 (br t,lH), 4.34
(ABq,2H), 3.66 (s,3H), 2.32 (dd,lH), 2.22 (br dJH), 1.80 (s,3H). 33 δ 7.61 (d,lH), 7.31 (tJH), 6.99 (t,lH), 6.91 (d,lH), 6.74 (br s,lH), 6.15 (t,lH), 2.52
(d,lH), 2.22 (dd,lH), 1.94 (s,3H). 37 (CDC13) δ 7.11 (ddJH), 6.7-6.6 (m,2H), 6.18 (br s,lH), 4.29 (t,lH), 3.09 (s,3H), 2.33 (dd,lH),
2.25 (dd,lH), 1.81 (s,3H).
39 δ 8.66 (br s,lH), 8.55 (sJH), 7.17 (t,lH), 6.57 (d,lH). 6.43 (dJH), 4.74 (br s-lH), 3.82
(s,3H), 2.04 (m,2H), 1.68 (s,3H).
40 δ 9.01 (br s,lH), 8.80 (s.lH), 7.21 (d,lH). 6.99 (dJH), 4.79 (br sJH), 2.17 (m,2H),
1.71 (s,3H).
41 δ 8.75 (s,lH), 8.67 (m,lH), 7.27 (t,lH), 6.78 (dt,lH), 6.70 (dd,lH), 4.52 (m,lH), 2.15
(m,2H), 1.68 (s,3H). a H NMR data are in ppm downfϊeld from tetramethylsilane. Couplings are designated by (s)-singlet, (d)-doublet, (t)-triplet, (q)-quartet, (m)-multiρlet, (dd)-doublet of doublets, (ABq)-AB quartet and (br s)-broad singlet. 137
BIOLOGICAL EXAMPLES OF THE INVENTION TEST A Com Planthopper Test
Test Unit: The test unit consists of a plastic cup containing about 17 g of sterilized, unfertilized sassafras soil. One fungicide treated pre-germinated Pioneer variety 3394 com seed is placed in a 1/2 inch depression in the soil and covered. The test unit is watered with 3ml of distilled water and placed in a closed plexiglass box inside a greenhouse operating at 24 degrees centigrade and 36% relative humidity for 2 days at which time it is ready for test. Before compound application, the test unit is watered with an additional 3 mL of distilled water which is allowed to soak in, after which a fine layer of white quartz sand is poured onto the surface of the soil to aid in the identification of live and dead insects at the conclusion of the test.
Compound Application: Test compounds are formulated at 250 ppm in 75% acetone in water. The test solution is administered with a traveling belt sprayer equipped with a single 800 IE flat fan nozzle situated about 1 inch above the top of the germinated com plant. The sprayer is operated at 30 PSI spray pressure and a belt speed of 55 feet per minute. Sprayed test units are placed in a ventilated fume hood for about 45 minutes to dry.
Insect Infesting/Compound Evaluation: Sprayed test units are infested with 15 - 20 third instar nymphs of the corn planthopper, Peregrinus maidis (Ashmead) (Homoptera:Delphacidae) which have been raised on com in a growth chamber operating at 26 degrees centigrade and 77% relative humidity and 12:12 light;dark photoperiod. Three untreated and three solvent treated test units serve as controls. Infested test units are held in a growth chamber operating at 20 degrees centigrade and 70 % relative humidity with a 16:8 ligh dark photoperiod. Test units are visually assessed for live and dead insects at 7 days post treatment. Mortality is adjusted for control mortality, if any, by Abbott's formula. Of the compounds tested, the following gave mortality of 80% or greater: 1, 4, 7, 8, 10, 14, 15, 22, 25, 26, 27, 28, 29, 30, 32, 35, 37,38, 42, 44, 46, 50, 52, 53, 54.
TEST B Green Leafhopper Test (Combined Contact and Systemic Test) Test Unit: Rice seedlings are raised in a nursery box. Five rice seedlings (1,5 leaf stage, about 10 cm tall) are transplanted into a '/_ oz. plastic cup containing Kumiai brown artificial soil.
Compound Application: Seven mL of a 100 ppm solution of the test compound in 2.5:97.5 acetone:water (prepared by dissolving the test compound in acetone and then diluting the resulting solution with water) is drenched onto the soil of each test unit by automatic pipet. There are 4 replications per test. After application, the test units are covered with a vinyl sheet and held in a growth chamber at 27 degrees centigrade and 65% relative humidity for 24 hours. A 100 ppm solution of the test compound in 138
75:25 acetone: water is then sprayed onto the test unit using an air atomizing spray nozzle at a pressure of 2.0 kg/cm2. A turntable sprayer is used for the application to all 4 replicated test units at a time, and the spray is carried-out over a 45-second time interval in which time the turntable has made 7.5 rotations and approximately 50 mL of the test solution has been sprayed. The treated test units are then held to dry for 2 hours.
Insect Infesting / Evaluation: After drying, the test units are placed into conical shaped test units and the surface of the soil is covered with 2 to 3 mm of quartz sand to aid in the evaluation of live and dead insects at the conclusion of the test. Eight green leafhopper nymphs (3rd-4m instar) are infested into each test unit using an aspirator. The test units are then held in a growth chamber at 27 degrees centigrade and 65% relative humidity. Insect mortality is evaluated at 6 days post-infestation. Of the compounds tested, the following gave mortality of 80% or greater: 1, 7, 8, 10, 14, 15, 22, 28, 29, 30, 32, 35, 42, 44, 46, 50.
TEST C Brown Planthopper Test (Combined Contact and Systemic Test) Test units are prepared and test compound is applied in the same manner as described for the green leafhopper test. After covering the soil with 2-3 mm of quartz sand, eight brown planthopper nymphs (3rd-4m instar) are infested into each test unit using an aspirator. The test units are then held in a growth chamber at 27 degrees centigrade and 65% relative humidity. Insect mortality is evaluated at 6 days post-infestation. Of the compounds tested, the following gave mortality of 80% or greater: 1 , 7, 8, 10, 14, 15, 19, 22, 25, 26, 27, 28, 29, 30, 32, 35, 42, 44, 46, 50.

Claims

139CLAIMS What is claimed is:
1. A compound selected from Formula I, N-oxides and agriculturally suitable salts thereof,
Figure imgf000141_0001
I wherein:
A is CR7R8;
E is O, S, CR16R17 or ΝR17;
G is a fused 5- or 6-membered ring which may be aromatic or non-aromatic, optionally containing one or two heteroatoms selected from the group nitrogen, oxygen and sulfur; each R1 is independently selected from the group halogen, cyano, nitro, formyl, Cj-Cg alkyl, C3-C.5 cycloalkyl, C2-Cg alkenyl, C2-C6 alkynyl, C-i-Cg alkoxy, Cj-C6 haloalkyl, C2-Cg haloalkenyl, C2-Cg haloalkynyl, C Cg haloalkoxy; CrC6 alkylthio, CrC6 haloalkylthio, CrC6 alkylsulfinyl, C 1 -C6 haloalkylsulfmyl, C 1 -Cg alkylsulfonyl, C 1 -C6 haloalkylsulfonyl,
C2-Cg alkylcarbonyl, C2-Cg alkoxycarbonyl, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl, Cj-Cg alkylamino, and C2-C8 dialkylamino; each R2 is independently selected from the group halogen, nitro, Cj-Cg alkyl, Cj-Cg haloalkyl and Cj-Cg alkoxy; or R1 and R2, when on adjacent atoms, can be taken together along with the atoms to which they are attached to form a 5- or 6- membered ring which may be aromatic or non-aromatic, optionally containing one or two hetero atoms selected from nitrogen, oxygen and sulfur, and optionally substituted with (R10)q; R3 and R4 are each independently selected from the group H; C3- cycloalkyl; C C6 haloalkyl; C2-Cg alkenyl; C2-C6 alkynyl; C2-C6 alkylcarbonyl;
C2-C6 alkoxycarbonyl; C2-C6 alkylaminocarbonyl; C3-C8 dialkylaminocarbonyl; Q; and Cj-C6 alkyl optionally substituted with cyano, Cj-Cg alkoxy, Ci-Cg haloalkoxy or Q; R5 and R6 are each independently selected from the group H; C3-C6 cycloalkyl; CrC6 haloalkyl; C2-C6 alkenyl; C2-C6 haloalkenyl; C2-C6 alkynyl; 140
C2-C6 haloalkynyl; RnC(=Y); R12SO2; (R9)2NSO2; Q; and CrC6 alkyl optionally substituted with cyano, C3-C6 cycloalkyl, Cj-Cg alkoxy, Cj-Cg haloalkoxy, R1 O, R12S, R12SO2, (R9)2NSO2, R"C(=Y), (R13)(R14)(R15)Si or Q; Y is O, S or NR9;
R7 is H, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, CrC6 haloalkyl, C -Cg alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-Cg alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl, Q or Cj-Cg alkyl optionally substituted with Q; or R3 and R7 can be taken together along with the carbon atoms to which they are attached to form a 4-, 5-, 6- or 7-membered ring; or
R4 and R7 can be taken together along with the carbon atoms to which they are attached to form a 4-, 5-, 6- or 7-membered ring; R8 is H or CrC6 alkyl; or R7 and R8 can be taken together as =CR18R19; each R9 is independently selected from the group H, Cj-Cg alkyl, Cj-Cg haloalkyl, C╬╣-C6 alkoxy, Cj-Cg haloalkoxy or phenyl optionally substituted with (R10)p; each R10 is independently selected from the group halogen, cyano, nitro, formyl, SF5, Cj-Cg alkyl, C3-C6 cycloalkyl, C -C6 alkenyl, C2-Cg alkynyl, C1-C6 alkoxy, Cj-Cg haloalkyl, C2-C6 haloalkenyl, C2-Cg haloalkynyl, C Cg haloalkoxy; C 1 -C6 alkylthio, C ╬╗ -C6 haloalkylthio, C ╬╗ -C6 alkylsulfinyl,
Cj-Cg haloalkylsulfmyl, Cj-C6 alkylsulfonyl, Cj-Cg haloalkylsulfonyl, C2-C╬▓ alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-Cg alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl, Cj-Cg alkylamino and C2-Cg dialkylamino; each R11 is independently selected from the group H, hydroxy, amino, Cj-C6 alkyl, Cj-Cg haloalkyl, C Cg alkoxy, Cj-Cg haloalkoxy, Cj-C6 alkylthio, Cj-C6 haloalkylthio, C Cg alkylamino, C -Cg dialkylamino, QNH and Q; each Q is a phenyl or a 5- or 6-membered heterocydic ring which may be aromatic or non-aromatic, containing 1 to 4 heteroatoms selected from the group nitrogen, oxygen and sulfur, provided that each heterocydic ring contains no more than 2 oxygens and no more than 2 sulfurs, each phenyl or heterocydic ring optionally substituted with (R10)p; each R12 is independently selected from the group Cj-Cg alkyl, C Cg haloalkyl, Cj-Cg alkoxy, Cj-Cg haloalkoxy and phenyl optionally substituted with (R10)p; R13, R14 and R15 are each independently Cj-C alkyl or phenyl; Rl6 is H or CrC6 alkyl;
R17 is H; C3-C6 cycloalkyl; CrC6 haloalkyl; C2-C6 alkenyl; C2-C6 alkynyl; C2-Cg alkylcarbonyl; C2-C6 alkoxycarbonyl; C2-C6 alkylaminocarbonyl; 141
C3-C8 dialkylaminocarbonyl; Q; and Cj-C6 alkyl optionally substituted with cyano, Ci-Cg alkoxy, Cj-Cg haloalkoxy or Q; R1 is H or CrC6 a_kyl;
R19 is H, CrC6 alkyl, CrC6 haloalkyl, CrC6 alkoxy, CrC6 haloalkoxy or phenyl optionally substituted with (R10)p; m and n are each independently 0, 1 or 2; each p is 0, 1, 2, 3, 4 or 5; and q is 0, 1, 2, 3 or 4; provided that a compound of Formula I is other than (2╬▒,6╬▒)-(3,6-dihydro-2-methyl-2,6-methano-2H-l,3,5-benzoxadiazocin-
4-yl)-cyanamide.
2. The compound of Claim 1 wherein:
E is O or CR16R17;
R3 is Η or C]-C6 alkyl optionally substituted with 1-3 halogen or R3 is phenyl optionally substituted with (R10)p;
R7 is Η or CrC6 alkyl;
R8 is Η; or
R7 and R8 can be taken together as =CR18R19;
R17 is Η or CrC3 alkyl; R18 is H, CrC3 alkyl; and
R19 is H, CrC3 alkyl.
3. The compound of Claim 2 wherein:
G is a fused cyclohexyl, cyclopentyl, phenyl, naphthalenyl, thienyl, pyridinyl or quinolinyl ring; R3 is H or C ! -C6 alkyl; and
R4 is H or CH3.
4. The compound of Claim 3 wherein:
G is a fused phenyl ring; each R1 is independently selected from the group consisting of halogen, C1-C3 alkyl, CrC3 haloalkyl and CrC3 haloalkoxy;
R5 and R6 are each independently H, CrC6 alkyl, CrC6 alkylcarbonyl, C2-C6 alkoxycarbonyl, CrC3 alkylsulfonyl, 3-pyridinylmethyl optionally substituted with 1-2 halogens or 5-thiazolylmethyl optionally substituted with halogen; and p and q are each independently 0, 1 or 2. 142
5. An arthropodicidal composition comprising an arthropodicidally effective amount of a compound selected from Formula I, N-oxides and agriculturally suitable salts thereof,
, R6
1 R. 1
(R1 X^ 7 \ /Νy\γ^Ν "\cN
G N, , \R5
(R2)ώ ^ E \
Figure imgf000144_0001
R4
I wherein: A is CR7R8;
E is O, S, CR16R17 or NR17;
G is a fused 5- or 6-membered ring which may be aromatic or non-aromatic, optionally containing one or two heteroatoms selected from the group nitrogen, oxygen and sulfur; each R1 is independently selected from the group halogen, cyano, nitro, formyl, Cj-C6 alkyl, C3-Cg cycloalkyl, C -C£ alkenyl, C2-Cg alkynyl, C Cg alkoxy, Cj-C6 haloalkyl, C -Cg haloalkenyl, C2-Cg haloalkynyl, Cj-Cg haloalkoxy; CrC6 alkylthio, CrC6 haloalkylthio, CrC6 alkylsulfinyl, Cj-Cg haloalkylsulfmyl, Cj-Cg alkylsulfonyl, Cj-Cg haloalkylsulfonyl, C2-Cg alkylcarbonyl, C2-Cg alkoxycarbonyl, C2-Cg alkylaminocarbonyl,
C3-Cg dialkylaminocarbonyl, Cj-Cg alkylamino, and C2-Cg dialkylamino; each R2 is independently selected from the group halogen, nitro, Cj-Cg alkyl, Cj-Cg haloalkyl and Cj-Cg alkoxy; or R1 and R2, when on adjacent atoms, can be taken together along with the atoms to which they are attached to form a 5- or 6- membered ring which may be aromatic or non-aromatic, optionally containing one or two hetero atoms selected from nitrogen, oxygen and sulfur, and optionally substituted with (R10)q; R3 and R4 are each independently selected from the group H; C3-Cg cycloalkyl; CrC6 haloalkyl; C2-C6 alkenyl; C2-C6 alkynyl; C2-C6 alkylcarbonyl; 2-Cg alkoxycarbonyl; C2-C6 alkylaminocarbonyl; C3-Cg dialkylaminocarbonyl;
Q; and Cj-Cg alkyl optionally substituted with cyano, Cj-Cg alkoxy, Cj-Cg haloalkoxy or Q; R5 and R6 are each independently selected from the group H; C3- cycloalkyl; C Cg haloalkyl; C2-Cg alkenyl; C2-C6 haloalkenyl; C2-C6 alkynyl; C2-C6 haloalkynyl; R1 !C(=Y); R12SO2; (R9)2NSO2; Q; and CrC6 alkyl 143 optionally substituted with cyano, C -Cg cycloalkyl, Cj-Cg alkoxy, C Cg haloalkoxy, R12O, R12S, R12SO2, (R9)2NSO2, RnC(=Y), (R13)(R14)(Rl5)Si or Q; Y is O, S or NR9; R7 is H, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, CrC6 haloalkyl,
C2-C6 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-Cg alkylaminocarbonyl, C3~Cg dialkylaminocarbonyl, Q or Cj-Cg alkyl optionally substituted with Q; or R3 and R7 can be taken together along with the carbon atoms to which they are attached to form a 4-, 5-, 6- or 7-membered ring; or R4 and R7 can be taken together along with the carbon atoms to which they are attached to form a 4-, 5-, 6- or 7-membered ring; R8 is H or CrC6 alkyl; or R7 and R8 can be taken together as =CR18R19; each R9 is independently selected from the group H, Cj-C6 alkyl, CrC6 haloalkyl, C Cg alkoxy, C C6 haloalkoxy or phenyl optionally substituted with (R10)p; each R10 is independently selected from the group halogen, cyano, nitro, formyl, SF5, Cj-Cg alkyl, C3-C6 cycloalkyl, C2-Cg alkenyl, C2-C╬▓ alkynyl, C C6 alkoxy, Cj-Cg haloalkyl, C2- haloalkenyl, C2-Cg haloalkynyl, C Cg haloalkoxy; CrC6 alkylthio, CrC6 haloalkylthio, CrC6 alkylsulfinyl, C j -Cg haloalkylsulfmyl, C j -C6 alkylsulfonyl, C j -Cg haloalkylsulfonyl,
C2-Cg alkylcarbonyl, C2-Cg alkoxycarbonyl, C2-C6 alkylaminocarbonyl, C3-C dialkylaminocarbonyl, Cj-Cg alkylamino and C2-Cg dialkylamino; each R1 J is independently selected from the group H, hydroxy, amino, C Cg alkyl, Cj-Cg haloalkyl, C Cg alkoxy, Cj-C6 haloalkoxy, C Cg alkylthio, C Cg haloalkylthio, C Cg alkylamino, C2-Cg dialkylamino, QNH and Q; each Q is a phenyl or a 5- or 6-membered heterocydic ring which may be aromatic or non-aromatic, containing 1 to 4 heteroatoms selected from the group nitrogen, oxygen and sulfur, provided that each heterocydic ring contains no more than 2 oxygens and no more than 2 sulfurs, each phenyl or heterocydic ring optionally substituted with (R10)p; each R12 is independently selected from the group Cj-Cg alkyl, C Cg haloalkyl, Cj-C6 alkoxy, Cj-Cg haloalkoxy and phenyl optionally substituted with (R10)p; R13, R14 and R15 are each independently C Cg alkyl or phenyl; R16 is H or CrC6 alkyl; R17 is H; C3-C6 cycloalkyl; CrC6 haloalkyl; C2-C6 alkenyl; C2-C6 alkynyl;
C2-C6 alkylcarbonyl; C2-C6 alkoxycarbonyl; C2-Cg alkylaminocarbonyl; C3-C8 dialkylaminocarbonyl; Q; and Cj-Cg alkyl optionally substituted with cyano, C C6 alkoxy, Cj-Cg haloalkoxy or Q; 144
R18 is H or CrC6 alkyl;
R19 is H, Cj-Cg alkyl, Cj-Cg haloalkyl, Cj-C6 alkoxy, Cj-Cg haloalkoxy or phenyl optionally substituted with (R10)p; m and n are each independently 0, 1 or 2; each p is 0, 1, 2, 3, 4 or 5; and q is 0, 1, 2, 3 or 4; and at least one of a surfactant, a solid diluent or a liquid diluent.
6. A method for controlling arthropods comprising contacting the arthropods or their environment with an arthropodicidally effective amount of a compound selected from Formula I, N-oxides and agriculturally suitable salts thereof,
R┬░
ΝΝ . CN
Figure imgf000146_0001
,
(R2)rή v. •RJ
I wherein:
A is CR7R8;
E is O, S, CR16R17 or NR17;
G is a fused 5- or 6-membered ring which may be aromatic or non-aromatic, optionally containing one or two heteroatoms selected from the group nitrogen, oxygen and sulfur; each R1 is independently selected from the group halogen, cyano, nitro, formyl, C Cg alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-CG alkynyl, C C^ alkoxy, Cj-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, Cj-Cg haloalkoxy; CrC6 alkylthio, CrC6 haloalkylthio, CrC6 alkylsulfinyl,
Cj- haloalkylsulfmyl, Cj-Cg alkylsulfonyl, Cj-C6 haloalkylsulfonyl, C2-C6 alkylcarbonyl, C2-Cg alkoxycarbonyl, C2-CG alkylaminocarbonyl, C3-Cg dialkylaminocarbonyl, Cj-Cg alkylamino, and C2-Cg dialkylamino; each R2 is independently selected from the group halogen, nitro, Cj-Cg alkyl, C C6 haloalkyl and Cj-Cg alkoxy; or
R1 and R2, when on adjacent atoms, can be taken together along with the atoms to which they are attached to form a 5- or 6- membered ring which may be aromatic or non-aromatic, optionally containing one or two hetero atoms selected from nitrogen, oxygen and sulfur, and optionally substituted with (R10)q; 145
R3 and R4 are each independently selected from the group H; C3-C6 cycloalkyl; C1-C6 haloalkyl; C2-C6 alkenyl; C2-Cg alkynyl; C2-C6 alkylcarbonyl; C2-Cg alkoxycarbonyl; C2-Cg alkylaminocarbonyl; C3-Cg dialkylaminocarbonyl; Q; and Cj-C6 alkyl optionally substituted with cyano, C Cg alkoxy, Cj-C╬▓ haloalkoxy or Q;
R5 and R6 are each independently selected from the group H; C3-Cg cycloalkyl; Cj- haloalkyl; C2-Cg alkenyl; C2-Cg haloalkenyl; C2-Cg alkynyl; C2-C6 haloalkynyl; RπC(=Y); R12SO2; (R9)2NSO2; Q; and CrC6 alkyl optionally substituted with cyano, C3-C6 cycloalkyl, Cj-Cg alkoxy, Cj-Cg haloalkoxy, Rl2O, R12S, R12SO2, (R9)2NSO2, R1 1C(=Y), (R13)(R14)(R!5)Si or Q; Y is O, S or NR9;
R7 is H, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, CrC6 haloalkyl, C -C6 alkylcarbonyl, C2-Cg alkoxycarbonyl, C2-C6 alkylaminocarbonyl, C3-Cg dialkylaminocarbonyl, Q or C Cg alkyl optionally substituted with Q; or
R3 and R7 can be taken together along with the carbon atoms to which they are attached to form a 4-, 5-, 6- or 7-membered ring; or R4 and R7 can be taken together along with the carbon atoms to which they are attached to form a 4-, 5-, 6- or 7-membered ring; R8 is H or C,-C6 alkyl; or
R7 and R8 can be taken together as =CR18R19; each R9 is independently selected from the group H, C Cg alkyl, C Cg haloalkyl, Cj-Cg alkoxy, C1-C6 haloalkoxy or phenyl optionally substituted with (R10)p; each R10 is independently selected from the group halogen, cyano, nitro, formyl, SF5, C╬╣-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, CrC6 alkoxy, CrC6 haloalkyl, C2-Cg haloalkenyl, C2-Cg haloalkynyl, Cj-Cg haloalkoxy; Cj-C^ alkylthio, Cj-C6 haloalkylthio, Cj-Cg alkylsulfinyl, Cj-Cg haloalkylsulfinyl, Cj-Cg alkylsulfonyl, C haloalkylsulfonyl, C2-C6 alkylcarbonyl, C2-Cg alkoxycarbonyl, C2-Cg alkylaminocarbonyl, C3-Cg dialkylaminocarbonyl, Cj-Cg alkylamino and C2-Cg dialkylamino; each R11 is independently selected from the group H, hydroxy, amino, Cj-Cg alkyl, C haloalkyl, Cj-Cg alkoxy, Cj-C6 haloalkoxy, C C^ alkylthio, C Cg haloalkylthio, C Cg alkylamino, C2-Cg dialkylamino, QNH and Q; each Q is a phenyl or a 5- or 6-membered heterocydic ring which may be aromatic or non-aromatic, containing 1 to 4 heteroatoms selected from the group nitrogen, oxygen and sulfur, provided that each heterocydic ring contains no more than 2 oxygens and no more than 2 sulfurs, each phenyl or heterocydic ring optionally substituted with (R10)p; 146 each R12 is independently selected from the group C Cg alkyl, C]-C6 haloalkyl, Cj-Cg alkoxy, C Cg haloalkoxy and phenyl optionally substituted with (R10)p; R13, R14 and R15 are each independently Cj-Cg alkyl or phenyl; R16 is H or CrC6 alkyl; R17 is H; C3-C6 cycloalkyl; CrC6 haloalkyl; C2-C6 alkenyl; C2-C6 alkynyl;
C2-Cg alkylcarbonyl; C2-Cg alkoxycarbonyl; C2-C6 alkylaminocarbonyl; C3-Cg dialkylaminocarbonyl; Q; and C Cg alkyl optionally substituted with cyano, Cj-Cg alkoxy, Cj-Cg haloalkoxy or Q; R18 is H or CrC6 alkyl; R19 is H, CrC6 alkyl, CrC6 haloalkyl, CrC6 alkoxy, CrC6 haloalkoxy or phenyl optionally substituted with (R10)p; m and n are each independently 0, 1 or 2; each p is 0, 1, 2, 3, 4 or 5; and q is 0, 1, 2, 3 or 4.
PCT/US1999/000882 1998-03-13 1999-01-13 Benzoxadiazocinyl arthropodicides WO1999046266A1 (en)

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CN113292574A (en) * 2020-02-21 2021-08-24 四川大学 Chiral polycyclic tropane compounds, preparation method and application thereof

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EP0580553A2 (en) * 1992-07-22 1994-01-26 Ciba-Geigy Ag Oxadiazine derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0580553A2 (en) * 1992-07-22 1994-01-26 Ciba-Geigy Ag Oxadiazine derivatives

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113292574A (en) * 2020-02-21 2021-08-24 四川大学 Chiral polycyclic tropane compounds, preparation method and application thereof

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