WO1999011129A1 - Enantiomerically enriched compositions and their pesticidal use - Google Patents

Enantiomerically enriched compositions and their pesticidal use Download PDF

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Publication number
WO1999011129A1
WO1999011129A1 PCT/US1998/017747 US9817747W WO9911129A1 WO 1999011129 A1 WO1999011129 A1 WO 1999011129A1 US 9817747 W US9817747 W US 9817747W WO 9911129 A1 WO9911129 A1 WO 9911129A1
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Prior art keywords
phenyl
pyridinyl
chr
methyl
alkyl
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PCT/US1998/017747
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French (fr)
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Richard James Brown
Albert Loren Casalnuovo
Dominic Ming-Tak Chan
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E.I. Du Pont De Nemours And Company
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Priority to AU92065/98A priority Critical patent/AU9206598A/en
Publication of WO1999011129A1 publication Critical patent/WO1999011129A1/en

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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
    • A01N43/647—Triazoles; Hydrogenated triazoles
    • A01N43/653—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • 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
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
    • A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
    • 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
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero atoms

Definitions

  • This invention relates to certain enantiomerically enriched compositions, their N-oxides, agriculturally suitable salts and compositions, and methods of their use as fungicides and arthropodicides.
  • the control of plant diseases caused by fungal plant pathogens is extremely important in achieving high crop efficiency. Plant disease damage to ornamental, vegetable, field, cereal, and fruit crops can cause significant reduction in productivity and thereby result in increased costs to the consumers.
  • the control of arthropod pests is also 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.
  • compositions comprising pesticidal compounds of Formula I including all geometric and stereoisomers, N-oxides, and agriculturally suitable salts thereof, agricultural formulations containing them and their use as fungicides and arthropodicides:
  • V is H, halogen, C C 3 alkyl, CN, NO 2 or C r C 3 alkoxy;
  • U is halogen, C r C alkyl or C r C 2 haloalkyl;
  • YZ is a group consisting of (a) 5 or more atoms independently selected from the group C, N, O, S, Si and Ge, provided that at least 2 of said atoms are C, and (b) additional atoms independently selected from H, F, Cl, Br and I;
  • A is O; S; N; NR 3 ; or CR 4 ;
  • G is C or N; provided that when G is C, then A is O, S or NR 3 and the floating double bond is attached to G; and when G is N, then A is N or CR 4 and the floating double bond is attached to A; W is O or S;
  • X is OR 1 ; SCO ⁇ R 1 ; halogen; C r C 6 alkyl; C r C 6 haloalkyl; C 3 -C 6 cycloalkyl; cyano;
  • R 1 is C r C 6 alkyl; C r C 6 haloalkyl; C 2 -C 6 alkenyl; C 2 -C 6 haloalkenyl; C 2 -C 6 alkynyl; C 2 -Cg haloalkynyl; C 3 -C 6 cycloalkyl; C 2 -C 4 alkylcarbonyl; or C 2 -C 4 alkoxycarbonyl;
  • R 2 is H; C C 6 alkyl; C r C 6 haloalkyl; C 2 -C 6 alkenyl; C 2 -C 6 haloalkenyl; C 2 -C 6 alkynyl; C 2 -C 6 haloalkynyl; C 3 -C 6 cycloalkyl; C 2 -C 4 alkylcarbonyl; C 2 -C 4 alkoxycarbonyl; hydroxy; C r C alkoxy; or acetyloxy; R 3 is H; C r C 6 alkyl; C r C 6 haloalkyl; C 2 -C 6 alkenyl; C 2 -C 6 haloalkenyl; C 2 -C 6 alkynyl; C 2 -Cg haloalkynyl; C 3 -C 6 cycloalkyl; C 2 -C alkylcarbonyl; or C 2 -C 4 alkoxycarbonyl; R 4 is
  • R 5 is C r C 6 alkyl, C r C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C -C 6 haloalkynyl or C 3 -C 6 cycloalkyl; each R6 is H, C r C 6 alkyl, C r C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -Cg haloalkynyl, C 3 -C 6 cycloalkyl, C 2 -C 4 alkylcarbonyl, C 2 -C 4 alkoxycarbonyl, hydroxy, C C 2 alk
  • compositions of this invention are characterized by having at least a 20% enantiomeric excess ("ee") of the more active of the two atropic isomer types resulting from the hindered rotation around the bond between T and the phenyl group to which it is bound (i.e., at least a 60:40 ratio of the more active to the less active atropic isomer type).
  • ee enantiomeric excess
  • the more active isomer type corresponds with respect to the relative positions of U, T and YZ to the structural atropic isomer of 2,4-dihydro-5-methoxy-2-methyl-4-[6-methyl-2- [3-(trifluoromethyl)phenoxy]phenyl]-3H-l,2,4-triazol-3-one which has the longer retention time (as measured herein) in a chiral separation using a column with a chiral stationary phase having R,R configuration and derived from 4-(3,5-dinitrobenzamido)tetrahydrophenanthrene covalently bound to 5 ⁇ m 3-propyl silica with a mobile phase employing a solvent consisting of 80% by volume hexane and 20% by volume 2-propanol.
  • IbrT 4 forT 5 : and forT 6 : where the groups shown define a distorted tetrahedron, the view is along the bond between the phenyl group and the moiety T, and the solid line represents the foreground and the dashed line the background.
  • compositions comprising intermediates of Formula II: wherein Y a is -O ⁇ , -C ⁇ 2 X a or -CH(CH 3 )X a ; X a is Cl, Br, I or OH; and T, U and V are defined as in Formula I.
  • compositions of the invention are characterized by having at least a 20 % enantiomeric excess of the structural atropic isomer corresponding to the more active Formula I isomer above (i.e., with Y a in the YZ position).
  • Stereoisomers comprising enantiomers and diastereomers, are isomers of identical constitution but differing in the arrangement of their atoms in space.
  • Atropic enantiomers (atropisomers) are stereoisomers resulting from restricted rotation about single bonds where the rotational barrier is high enough to permit isolation of stable isomeric species.
  • the bond between the phenyl group and the moiety T is an axis of chiralty and the substituents on T and the groups U and Y-Z define a distorted tetrahedron about that axis. Because these groups are all different and are sufficiently large to hinder rotation about the axis of chirality, the rotational isomers can be isolated as stable species.
  • the compounds of this invention may contain other stereogenic axes or centers in addition to the chiral axis just described.
  • individual structures of Formula I may encompass diastereomers as well as enantiomers.
  • the terms enantiomeric excess or enantiomeric enrichment used here refer to the excess of one of the rotational isomers (described above) relative to the other and without regard to the presence of other stereogenic axes or centers.
  • 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).
  • the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers.
  • the enantiomerically enriched compositions of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form.
  • the salts of the more active atropic isomers of the invention include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfiiric, 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, sulfiiric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids.
  • the salts of the more fungicidally active atropic isomers 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 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 enantiomerically enriched compositions for reasons of better activity and/or ease of synthesis are:
  • a 1 is O; S; NR 15 ; or a direct bond
  • a 2 is O; NR 15 ; or a direct bond
  • each Z is independently selected from: i) C r C 10 alkyl, C 2 -C 10 alkenyl, and C 2 -C 10 alkynyl each substituted with R 9 and optionally substituted with one or more R 10 ; ii) C 3 -Cg cycloalkyl, C 3 -C 8 cycloalkenyl and phenyl each substituted with R 9 and optionally substituted with one or more R 10 ; iii) a ring system selected from 3 to 14-membered monocyclic, fused bicyclic and fused tricyclic nonaromatic heterocyclic ring systems and 5 to 14-membered monocyclic, fused bicyclic and fused tricyclic aromatic heterocyclic ring systems, each heterocyclic ring system containing 1 to 6 heteroatoms independently selected from the group nitrogen, oxygen,
  • R 9 is phenyl, benzyl, benzoyl, phenoxy, pyridinyl, pyridinyloxy, thienyl, thienyloxy, furanyl, pyrimidinyl, or pyrimidinyloxy each optionally substituted with one of R ⁇ R ⁇ or both R ⁇ and R 12 ; each R 10 is independently halogen; C r C 4 alkyl; C r C haloalkyl; C r C 4 alkoxy; nitro; or cyano; or when R 9 and an R 10 are attached to adjacent atoms on Z, R 9 and said adjacently attached R 10 can be taken together as -OCH 2 O- or -OCH 2 CH 2 O-; each CH 2 group of said taken together R 9 and R 10 optionally substituted with 1-2 halogen;
  • J is attached to Z; J is -CH 2 -; -CH 2 CH 2 -; -OCH 2 -; -CH 2 O-; -SCH 2 -; -CH 2 S-; -N(R 16 )CH 2 -; or
  • R 1 1 and R 12 are each independently 1 -2 halogen; C r C 4 alkyl; C r C 4 haloalkyl; C 2 -C 6 alkenyl; C 2 -C(, haloalkenyl; C 2 -C6 alkynyl; C 2 -C 6 haloalkynyl; C 2 -C 6 alkoxyalkyl; C 2 -Cg alkylthioalkyl; C 3 -Cg alkoxyalkynyl; C -C[Q tetrahydropyranyloxyalkynyl; benzyloxymethyl; C C 4 alkoxy; C C 4 haloalkoxy; C -Cg alkenyloxy; C 3 -Cg haloalkenyloxy; C 3 -Cg alkynyloxy; Gj-Cg
  • S(O) 2 OR 26 S(O) 2 N(R 6) 2 ; OS(O) 2 R 27 ; N(R 26 )S(O) 2 R 27 ; or phenyl, phenoxy, benzyl, benzyloxy, phenylsulfonyl, phenylethynyl or pyridinylethynyl, each optionally substituted with halogen, C C 4 alkyl, C r C 4 haloalkyl, Cj-C 4 alkoxy,
  • R 16 , R 17 , and R 18 are each independently H; C r C 3 alkyl; C 3 -C 6 cycloalkyl; or phenyl optionally substituted with halogen, C j -C alkyl, C C 4 haloalkyl, C j -C alkoxy,
  • R 22 , R 23 , and R 24 are each independently C C6 alkyl; C 2 - alkenyl; C C 4 alkoxy; or phenyl; each R 25 is independently C C 4 alkyl; C C 4 haloalkyl; C2- 4 alkenyl; C C 4 alkoxy; or phenyl; each R 26 is independently H; C r C 6 alkyl; C r C 6 haloalkyl; C 2 -C 6 alkenyl; C 2 -C 6 haloalkenyl; C 2 -Cg alkynyl; C 2 -Cg haloalkynyl; C 3 -Cg cycloalkyl; or phenyl or benzyl, each optionally substituted on the phenyl ring with halogen, C j -C4 alkyl, C j -C 4 haloalkyl, C
  • the view is along the bond between the phenyl group and the moiety T, and the solid line represents the foreground and the dashed line the background (i.e., T is T 1 ).
  • G is N; A is N; R 2 is CH 3 ; X is OR 1 ; R 1 is CH 3 ; and
  • W is O.
  • compositions of Formula I compounds selected from the group:
  • compositions of this invention (whether of Formula I or of Formula II) have at least a 50%> enantiomeric excess; more preferably at least a 75% enantiomeric excess; still more preferably at least a 90% enantiomeric excess; and the most preferably at least a 94% enantiomeric excess of the more active Formula I isomer or its corresponding Formula II intermediate.
  • enantiomerically pure embodiments of the more active Formula I isomer or its corresponding Formula II intermediate are enantiomerically pure embodiments of the more active Formula I isomer or its corresponding Formula II intermediate.
  • alkyl used either alone or in compound words such as “alkylthio” or “haloalkyl” includes straight-chain or branched alkyl, such as, methyl, ethyl, H-propyl, z ' -propyl, or the different butyl, pentyl or hexyl isomers.
  • 1-2 CH 3 indicates that the substituent can be methyl or, when there is a hydrogen attached to the same atom, the substituent and said hydrogen can both be methyl.
  • Alkenyl includes straight-chain or branched alkenes such as vinyl, 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.
  • Alkylene denotes a straight-chain alkanediyl. Examples of “alkylene” include CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 CH 2 .
  • Alkoxy includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers.
  • Alkoxyalkyl denotes alkoxy substitution on alkyl. Examples of “alkoxyalkyl” include CH 3 OCH 2 , CH 3 OCH 2 CH 2 , CH 3 CH 2 OCH 2 , CH 3 CH 2 CH 2 CH 2 OCH 2 and CH 3 CH 2 OCH 2 CH 2 .
  • Alkoxyalkoxy denotes alkoxy substitution on alkoxy.
  • Alkenyloxy includes straight-chain or branched alkenyloxy moieties.
  • alkynyloxy includes straight-chain or branched alkynyloxy moieties. Examples of “alkynyloxy” include HC ⁇ CCH 2 O, CH 3 C ⁇ CCH 2 O and CH 3 C_ ⁇ CCH 2 CH 2 O.
  • Alkylthio includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers.
  • Alkylthioalkyl denotes alkylthio substitution on alkyl. Examples of “alkylthioalkyl” include CH 3 SCH 2 , CH 3 SCH 2 CH 2 , CH 3 CH 2 SCH 2 , CH 3 CH 2 CH 2 CH 2 SCH 2 and CH 3 CH 2 SCH 2 CH 2 .
  • Alkylthioalkylthio denotes alkylthio substitution on alkylthio.
  • alkylthioalkoxy denotes alkylthio substitution on alkoxy.
  • Alkylsulfinyl includes both enantiomers of an alkylsulfinyl group. Examples of “alkylsulfinyl” 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.
  • Alkenylthio is defined analogously to the above examples.
  • Cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Cycloalkenyl includes groups such as cyclopentenyl and cyclohexenyl as well as groups with more than one double bond such as 1 ,3- and 1 ,4-cyclohexadienyl.
  • Trialkylsilylalkoxyalkoxy denotes trialkylsilylalkoxy substitution on alkoxy. Examples of “trialkylsilylalkoxyalkoxy” includes, for example,- (CH 3 ) SiCH 2 CH 2 OCH 2 O.
  • aromatic carbocyclic ring system includes fully aromatic carbocycles and carbocycles in which at least one ring of a polycyclic ring system is aromatic (where aromatic indicates that the Huckel rule is satisfied).
  • nonaromatic carbocyclic ring system denotes fully saturated carbocycles as well as partially or fully unsaturated carbocycles where the Huckel rule is not satisfied by any of the rings in the ring system.
  • aromatic heterocyclic ring system includes fully aromatic heterocycles and heterocycles in which at least one ring of a polycyclic ring system is aromatic (where aromatic indicates that the Huckel rule is satisfied).
  • nonaromatic heterocyclic ring system denotes fully saturated heterocycles as well as partially or fully unsaturated heterocycles where the Huckel rule is not satisfied by any of the rings in the ring system.
  • the heterocyclic ring systems can be attached through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.
  • Z examples include CH 3 ; CH 2 C1; CH Br; cyclopropyl; phenyl; naphthalenyl; anthracenyl; phenanthrenyl; lH-pyrrolyl; furanyl; thienyl; lH-pyrazolyl; lH-imidazolyl; isoxazolyl; oxazolyl; isothiazolyl; thiazolyl; lH-l,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;
  • 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.
  • halogen either alone or in compound words such as “haloalkyl” includes fluorine, chlorine, bromine or iodine.
  • 1-2 halogen indicates that one or two of the available positions for that substituent may be halogen which are independently selected.
  • alkyl may be partially or fully substituted with halogen atoms which may be the same or different.
  • haloalkyl include F 3 C, C1C ⁇ 2 , CF 3 CH 2 and CF 3 CC1 2 .
  • haloalkenyl “haloalkynyl", “haloalkoxy”, and the like, are defined analogously to the term “haloalkyl”.
  • haloalkynyl examples include HC ⁇ CCHCl, CF 3 C ⁇ C, CC1 3 G__C and FCH 2 C__$CH 2 .
  • haloalkoxy examples include CF 3 O, CCl 3 CH 2 O, HCF 2 CH 2 CH 2 O and CF 3 CH 2 O.
  • haloalkylthio examples include CC1 3 S, CF 3 S, CC1 3 CH 2 S and C1CH 2 CH 2 CH 2 S.
  • haloalkylsulfmyl examples 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 .
  • the total number of carbon atoms in a substituent group is indicated by the "Cj-Cj" prefix where i and j are numbers from 1 to 10.
  • C j -C 3 alkylsulfonyl designates methylsulfonyl through propylsulfonyl.
  • alkylcarbonyl examples include C(O)CH 3 , C(O)CH 2 CH 2 CH 3 and C(O)CH(CH 3 ) 2 .
  • alkoxycarbonyl examples include
  • This invention also relates to fungicidal formulations which comprise a fungicidally effective amount of the enantiomerically enriched compositions described above and which include at least one of a surfactant, a solid diluent or a liquid diluent.
  • the preferred fungicidal formulations of the present invention are those which comprise the above preferred enantiomerically enriched compositions.
  • This invention also relates to a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof, or to the plant seed or seedling, a fungicidally effective amount of the enantiomerically enriched compositions of the invention (e.g., as a fungicidal formulation described herein).
  • the preferred methods of use are those involving the above preferred enantiomerically enriched compositions.
  • This invention also relates to arthropodicidal formulations which comprise arthropodicidally effective amounts of the enantiomerically enriched compositions described above and which includes at least one of a surfactant, a solid diluent or a liquid diluent.
  • the preferred arthropodicidal formulations of the present invention are those which comprise the above preferred enantiomerically enriched compositions.
  • This invention also relates to a method for controlling arthropods comprising contacting the arthropods or their environment with an arthropodicidally effective amount of the enantiomerically enriched compositions of the invention (e.g., as an arthropodicidal formulation described herein).
  • the preferred methods of use are those involving the above preferred enantiomerically enriched compositions.
  • the compounds of Formula I can be prepared by one or more of the following methods and variations as described in Schemes 1-46.
  • the definitions of T, A, G, U, V, W, X, Y, Z, R*-R 13 , R 15 -R 18 , R 2 -R 34 , m, n, p, q, r and s in the compounds of Formulae 1-62 below are as defined above in the Summary of the Invention or as defined below in Schemes 1-46.
  • Compounds of Formulae Ia-Iy are various subsets of the compounds of Formula I, and all substituents for Formulae Ia-Iy are as defined above for Formula I.
  • Kinetic resolutions of intermediates containing atropic centers may also be effected by enantioselective processes in which one enantiomer is more reactive than the other enantiomer. Such processes may result in the selective destruction or degradation of one enantiomer to a simpler derivative, or selective conversion of one enantiomer into a more complex derivative.
  • Kinetic resolutions can be effected by enzymatic processes or by chemical conversions using chiral auxiliaries. Such kinetic resolution techniques are well known to one skilled in the art.
  • Compounds in which the stereochemistry is undefined in Scheme 1-46 may either be racemic mixtures or specific enantiomers depending on the context of any given synthesis.
  • Absolute configurations of the atropic centers can be described using the R or S descriptors using the Cahn-Ingold-Prelog system.
  • One skilled in the art will recognize that the assignment of priority among the substituents U, Y-Z, and the substituents on T in compounds of formula I may result in the description of the atropic center of the active enantiomer to be R in some cases and S in others. However, for any given T, the relative configuration among the substituents for the active enantiomer is expected to be the same for any U and Y-Z combination.
  • the active atropic enantiomers of compounds of Formula I can be correlated to a specific intermediate of known optical activity, that is indicated in the disclosure.
  • a compound of Formula I wherein T is T 1 and R 2 is H may exist as tautomer la or lb, or both la and lb.
  • Procedures 1) to 5 describe syntheses involving construction of the heterocycle after the formation of the aryl moiety.
  • Procedure 5) describes syntheses of the aryl moiety with the T-moiety already in place.
  • Suitable solvents are selected from the group consisting of polar aprotic solvents such as acetonitrile, dimethylformamide or dimethyl sulfoxide; ethers such as tetrahydrofuran, dimethoxyethane, or diethyl ether; ketones such as acetone or 2-butanone; hydrocarbons such as toluene or benzene; and halocarbons such as dichloromethane or chloroform.
  • polar aprotic solvents such as acetonitrile, dimethylformamide or dimethyl sulfoxide
  • ethers such as tetrahydrofuran, dimethoxyethane, or diethyl ether
  • ketones such as
  • Method 1 a protic cosolvent
  • Suitable Lewis acids include trimethylsilyl triflate and tetrafluoroboric acid.
  • the alkyl trichloroacetimidates can be prepared from the appropriate alcohol and trichloroacetonitrile as described in the literature (J. Danklmaier and H. H ⁇ nig, Synth. Commun., (1990), 20, 203).
  • a trialkyloxonium tetrafluoroborate e.g., Meerwein's salt
  • the use of trialkyloxonium salts as powerful alkylating agents is well known in the art (see U. Schollkopf, U. Groth, C. Deng, Angew. Chem., Int. Ed. Engl, (1981), 20, 798).
  • Appropriate bases include alkali metal alkoxides such as potassium tert-butoxide, inorganic bases such as sodium hydride and potassium carbonate, pyridine, or tertiary amines such as triethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and triethylenediamine.
  • alkali metal alkoxides such as potassium tert-butoxide
  • inorganic bases such as sodium hydride and potassium carbonate
  • pyridine or tertiary amines such as triethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and triethylenediamine.
  • the nucleophiles of Formula 6 are N-substituted hydroxylamines (HO- ⁇ HR 2 ) and substituted hydrazines (H ⁇ (R 3 )- ⁇ HR 2 ). Examples of such nucleophiles are N-methylhydroxylamine and methylhydrazine.
  • Esters of Formula 5a can be prepared from copper (I)-catalyzed reaction of malonate esters with substituted iodobenzenes of Formula 8 according to methods adapted from A. Osuka, T. Kobayashi and H. Suzuki, Synthesis , (1983), 67, and illustrated in Scheme 3.
  • R C ⁇ -C 4 alkyl
  • the malonate esters of Formula 5a can be prepared by treating phenyl acetic acid esters of Formula 9a with a dialkyl carbonate or alkyl chloroformate in the presence of a suitable base such as, but not limited to, sodium metal and sodium hydride (Scheme 4).
  • a suitable base such as, but not limited to, sodium metal and sodium hydride (Scheme 4).
  • a suitable base such as, but not limited to, sodium metal and sodium hydride
  • Esters of Formula 9a (compounds of Formula 9 wherein E 1 is OR) can be prepared from acid-catalyzed alcoholysis of phenyl acetonitriles of Formula 10 or by esterification of phenyl acetic acids of Formula 1 1 as illustrated in Scheme 5 (see Org. Synth., Coll. Vol. I, (1941), 270).
  • R C 1 -C 4 alkyl
  • Phenyl acetic acid esters of Formula 9b (compounds of Formula 9a wherein Y is Y 1 ) can also be prepared by copper (I)-catalyzed condensation of phenyl halides of Formula 12 with compounds of Formula 13 as described in EP-A-307,103 and illustrated below in Scheme 6.
  • Compounds of Formula 12 can be prepared by the Arndt-Eistert synthesis starting from benzoic acids of Formula 14 as illustrated in Scheme 7, (see F. Arndt, B. Eistert, Ber. 68, 200 (1935); T. Aoyama, T. Shioiri, Tetrahedron Letters 21, 4461 (1980)).
  • a halogenating agent such as thionyl chloride
  • an alkylating agent such as diazomethane
  • Compounds of Formula 14 can be prepared from nitrobenzoic acids of Formula 15 by a modification of the Sandmeyer Reaction as taught in S. Kanoh, H. JViuramoto, N. Kobayashi, M. Motoi and H. Suda, Bull. Chem. Soc. Jpn. 60, 3659 (1987) and M. P. Doyle, J. Org. Chem. 42, 2426 (1977) (Scheme 8).
  • esters of Formula 9c can also be prepared by forming the Y 2 bridge using conventional nucleophilic substitution chemistry (Scheme 9). Displacement of an appropriate leaving group (Lg) in electrophiles of Formula 17 or 18 with a nucleophilic ester of Formula 16 affords compounds of Formula 9c.
  • a base for example sodium hydride, is used to generate the corresponding alkoxide or thioalkoxide of the compound of Formula 16.
  • R C!-C 4 alkyl
  • R28 OH, SH, CH 2 OH, CH 2 SH ⁇ 2 - _ 0 -, -OCH 2 -, -SCHR 15 -, -CH 0-, -CU 2 S(p) n -
  • Lg Br, Cl, I, OS0 2 CH 3 , OS0 2 (4-Me-Ph)
  • Compounds of Formula 16 can be prepared from compounds of Formula 12 by methods taught in Chem. Pharm. Bull. 33 (12), 5184 (1985) orJ. Org. Chem. 53 (2) 439, (1988). For example, treatment of compounds of Formula 12 with a metal hydroxide, such as sodium hydroxide, in a polar protic solvent in the presence of a metal species such as copper yields compound 16a (compounds of Formula 16 where R 28 is OH).
  • Compounds of Formula 16b (compounds of Formula 16 where R 28 is CH 2 OH or CH 2 SH) can be prepared by metal -halogen exchange in compounds of Formula 12 followed by quenching with the appropriate electrophile.
  • reducing agents sodium borohydride (NaBH 4 ), sodium cyanoborohydride (NaCNBH 4 ) and diisobutylaluminum hydride (DIBAL-H) (Scheme 10).
  • Suitable inert solvents are methanol, ethanol, methylene chloride and THF, (see M. Hudlicky, Reductions in Organic Chemistry; John Wiley & Sons: New York, (1986)).
  • esters of Formula 9d can also be prepared by forming the Y 3 bridge from substituted hydroxylamines 16d and carbonyl compounds 19.
  • the hydroxylamines 16d are in turn prepared from esters 16c.
  • Compounds of Formula 16c where the Lg is Br, Cl, I, OSO 2 CH 3 or OSO 2 (4-Me-Ph) can be prepared from compounds of Formula 16b, (see March, J. Advanced Organic Chemistry; 3rd ed., John Wiley: New York, (1985). This method has been described in EP-A-600,835 and is illustrated in Scheme 11.
  • Lg 1 Cl, Br, -S0 2 Q, or -OS0 2 Q
  • Compounds of Formula 20a can be prepared from compounds of Formula Id (compounds of Formula 1 wherein X 1 is OH) by reaction with halogenating agents such as thionyl chloride or phosphorus oxybromide to form the corresponding ⁇ -halo-substituted derivatives (Scheme 13).
  • halogenating agents such as thionyl chloride or phosphorus oxybromide
  • compounds of Formula Id can be treated with an alkylsulfonyl halide or haloalkylsulfonyl anhydride, such as methane sulfonyl chloride, />-toluenesulfonyl chloride, and trifluoromethanesulfonyl anhydride, to form the corresponding ⁇ -alkylsulfonate of Formula 20b.
  • the reaction with the sulfonyl halides may be performed in the presence of a suitable base (e.g., triethylamine).
  • sulfonyl compounds of Formula 20c can be prepared by oxidation of the corresponding thio compound of Formula 21 using well-known methods for the oxidation of sulfur (see Schrenk, K. in The Chemistry ofSulphones and Sulphoxides; Patai, S. et al., Eds.; Wiley: New York, (1988)).
  • Suitable oxidizing reagents include met ⁇ -chloro-peroxybenzoic acid, hydrogen peroxide and Oxone® (KHSO 5 ).
  • halo-compounds of Formula 20d can be prepared from hydrazides of Formula 22 as illustrated in Scheme 15.
  • the compound of Formula 22 is treated with excess of a thionyl halide such as thionyl chloride.
  • the product formed first is the ring-closed compound of Formula 23 which can be isolated or converted in situ to the compound of Formula 20d; see P. Molina, A. Tarraga, A. Espinosa, Synthesis, (1989), 923 for a description of this process.
  • the hydrazides of Formula 22 can be prepared as illustrated in Scheme 16. Condensation of the isocyanate of Formula 24 with the hydrazine of Formula H 2 NNR R 29 in an inert solvent such as tetrahydrofiiran affords the hydrazide.
  • R 1 -halide such as iodomethane or propargyl bromide
  • R C j-C 4 alkyl
  • the carbonylating agents can be alkyl chloroformates or dialkyl carbonates. Some of these carbonylating reactions may require the addition of a base to effect reaction.
  • Appropriate bases include alkali metal alkoxides such as potassium tert-butoxide, inorganic bases such as sodium hydride and potassium carbonate, pyridine, or tertiary amines such as triethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or triethylenediamine.
  • Suitable solvents include polar aprotic solvents such as acetonitrile, dimethylformamide, or dimethyl sulfoxide; ethers such as tetrahydrofiiran, dimethoxyethane or diethyl ether; ketones such as acetone or 2-butanone; hydrocarbons such as toluene or benzene; or halocarbons such as dichloromethane or chloroform.
  • the reaction temperature can vary between 0 °C and 150 °C and the reaction time can be from 1 to 72 hours depending on the choice of base, solvent, temperature, and substrates.
  • Treatment of an aniline of Formula 27 with phosgene, thiophosgene, NN'-carbonyldiimidazole, or NN'-thiocarbonyldiimidazole produces the isocyanate or isothiocyanate of Formula 28.
  • a base can be added for reactions with phosgene or thiophosgene.
  • Subsequent treatment of the iso(thio)cyanate with an R 2 -substituted hydrazine produces the N-amino-urea of Formula 26.
  • Compounds of formula 28a can be treated with alkyl hydrazinocarboxyla.es to provide compounds of Formula 28b. Subsequent treatment with excess base followed by alkylation according to Method 4 , Scheme 1 provides compounds of Formula (+/-)-21a.
  • Compounds of Formula (+/-)-21a can be resolved by treatment with a suitable enantiomerically pure reagent to provide a mixture of two diastereomers of Formula 21b, which can be separated by, for example, fractional crystallization, distillation or chromatography. Subsequent removal of the chiral auxiliary will allow isolation of enantiomerically enriched (+)-21a or (-)-21a.
  • Suitable enantiomerically pure reagents include, but are not limited to, acid chlorides or anhydrides, chloroformates, alkyl halides or sulfonates or iso(thio)cyanates. Removal of the chiral auxiliary R* is dependent on the nature of R* and conditions appropriate for removal of any particular R* are well-known in the art.
  • Scheme 20a illustrates this resolution sequence with an acid chloride as the enantiomerically pure reagent and the subsequent removal of the chiral auxiliary can be accomplished by reaction with alkali metal hydroxides or alkoxides.
  • R* enantiomerically pure moiety
  • X OR! or SR 1
  • Lg 3 Br, I, R 2 OS0 2 -, -OS0 2 Me Floating double bond attached to A
  • Base induced cyclization of compounds of Formula 28b provides a racemic mixture of compounds of Formula 28c.
  • Resolution of compounds of Formula 28c can be achieved by reaction with a chiral amine followed by fractional crystallization. Acidification of the diastereomerically enriched salts allows the isolation of enantiomerically enriched compounds of Formula (+)-28c or (-)-28c.
  • resolution sequences are well known in the art. For a general reference, see J. Jacques, A. Collet and S. H. Wilen, Enantiomers, Racemates, and Resolutions, John Wiley & Sons, New York, N. Y. 1981.
  • Alkylation with two equivalents of a suitable alkylating agent R 2 -Lg 3 provides compounds of Formula 2 Id, which can be converted by methods previously described in Scheme 20a to compounds of Formula Ic.
  • Lg 3 Br, I, R2 ⁇ S0 2 -, MeS0 2 0-
  • Compounds of Formula 29 can be prepared by contacting benzyl halides, mesylates or tosylates of Formula 30 with various nucleophiles (Scheme 22).
  • the appropriate alcohol or thiol is treated with a base, for example sodium hydride, to form the corresponding alkoxide or thioalkoxide which acts as the nucleophile.
  • Lg Br, Cl, I, OS0 2 CH 3 , OS0 2 (4-Me-Ph)
  • Compounds of Formula 30 can be prepared from corresponding nitrobenzyl alcohols of Formula 30a (compounds of Formula 30 where the Lg group has been replaced with OH) by reaction with halogenating agents such as thionyl chloride or phosphorus oxybromide to form the corresponding ⁇ -halo-substituted derivatives (Scheme 23).
  • halogenating agents such as thionyl chloride or phosphorus oxybromide
  • Compounds of Formula 30a can also be treated with an alkylsulfonyl halide or haloalkylsulfonyl anhydride, such as methane sulfonyl chloride, /?-toluenesulfonyl chloride, and trifluoromethanesulfonyl anhydride, to form the corresponding ⁇ -alkylsulfonate of Formula 30.
  • the reaction with the sulfonyl halides may be performed in the presence of a suitable base (e.g., triethylamine).
  • Compounds of Formula 30a can be prepared by reduction of nitrobenzoic acids of Formula 31 with a suitable reducing agent, such as borane in tetrahydrofiiran or dimethyl sulfide as taught in M. Pavia, W. H. Moos and F. M. Hershenson, J. Org. Chem. 55, 560, (1990) or C. F. Lane, H. L. Myatt, j. Daniels and H. B. Hopps J. Org. Chem. 39, 3052, (1974) (Scheme 24).
  • a suitable reducing agent such as borane in tetrahydrofiiran or dimethyl sulfide as taught in M. Pavia, W. H. Moos and F. M. Hershenson, J. Org. Chem. 55, 560, (1990) or C. F. Lane, H. L. Myatt, j. Daniels and H. B. Hopps J. Org. Chem. 39,
  • Formula lf compounds can be prepared by reaction of Formula 28 iso(thio)cyanates with Formula 35 esters. As described above, base may be added to accelerate the reaction and subsequent cyclization to Formula 1 f compounds.
  • compounds of Formula 34c may be prepared by reaction of isocyanates of Formula 28 with compounds of Formula 35b to provide compounds of Formula 34b, followed by Method 4. Scheme 25
  • the (thio)ureas of Formula 32 can be prepared by either of the methods illustrated in Scheme 26.
  • an iso(thio)cyanate of Formula 28 can be condensed with an amine of Formula R 2 -NH 2 to form the (thio)urea.
  • the anilines and iso(thio)cyanates of Formulae 27 and 28, respectively, are commercially available or prepared by well-known methods.
  • isothiocyanates can be prepared by methods described inJ. Heterocycl. Chem., (1990), 27, 407.
  • Isocyanates can be prepared as described in March, J. Advanced Organic Chemistry; 3rd ed., John Wiley: New York, (1985), pp 944, 1166.
  • thionating reagents such as P S5 or Lawesson's reagent [2,4-bis(4- methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulfide] as illustrated in Scheme 27 (see Bull. Soc. Chim. Belg., (1978), 87, 2
  • Compounds of Formula Ik (compounds of Formula I wherein Y is Y 4 ) can be prepared by displacing the appropriate leaving group (Lg) in electrophiles of Formula 36 with various nucleophiles (Scheme 29).
  • a base for example sodium hydride
  • Suitable enantiomerically pure reagents include, but are not limited to, acid chlorides or anhydrides, chloroformates, alkyl halides or sulfonates or iso(thio)cyanates. Removal of the chiral auxiliary R* is dependent on the nature of R* and conditions appropriate for removal of any particular R* are well-known in the art.
  • Compounds of Formula Im (compounds of Formula I where T is T 1 , X is OR 1 , R 1 is CH 3 , R 2 is CH 3 , W is O, A is N, G is N, Y 5 is -O-, -OCH 2 - or -SCHR 15 -) can be prepared by forming the Y 5 bridge using conventional nucleophilic substitution chemistry (Scheme 30). Displacement of an appropriate leaving group (Lg) in electrophiles of Formula 17 or 18 with nucleophilic compounds of Formula 37 affords compounds of Formula Im.
  • a base for example sodium hydride, is used to generate the corresponding alkoxide or thioalkoxide of the compounds of Formula 37.
  • Compounds of racemic (+/-) Formula 37 may also be resolved by conversions to acids or bases. These acids or bases can then be converted into diastereomeric salts by treatment with enantiomerically pure acids or bases. Separation of the diastereomeric salts, when possible, followed by removal of the acid or base functionality affords the resolved compounds of Formula 37.
  • Reagents for the conversion of compounds of Formula 37 to acids or bases include, but are not limited to, anhydrides, diacids, diesters, amino acids, and sulfur trioxide. For further details about this resolution strategy see J. Jacques, A. Collet, and S. H. Wilen, Enantiomers, Racemates and Resolutions (Krieger Publishing Co., Malabar, FL 1994).
  • Benzyl halides of Formula 38 can be prepared by radical halogenation of the corresponding alkyl compound of Formula 39a, see WO 96/38425. Benzyl halides can also be prepared by the acidic cleavage of the corresponding methyl ether of Formula 39b under conditions which provide the halide, see Scheme 31. Methods for preparing the corresponding compounds of Formula 38a wherein T is T 2 are described in WO 94/05620. Methods for preparing the corresponding compounds of Formula 38a wherein T is T 3 are described in EP-A-254,426, EP-A-299,694 and AU-A-55899/90.
  • compounds of Formula 38 can be prepared from the corresponding alcohol of Formula 40 by reaction with halogenating agents such as thionyl chloride or phosphorus oxybromide to form the corresponding ⁇ -halo-substituted derivatives.
  • halogenating agents such as thionyl chloride or phosphorus oxybromide
  • compounds of Formula 40 can be treated with an alkylsulfonyl halide or haloalkylsulfonyl anhydride, such as methane sulfonyl chloride, /? -toluenesulfonyl chloride, and trifluoromethanesulfonyl anhydride, to form the corresponding ⁇ -alkylsulfonate of Formula 41.
  • an alkylsulfonyl halide or haloalkylsulfonyl anhydride such as methane sulfonyl chloride, /? -toluenesulfonyl chloride, and trifluoromethanesulfonyl anhydride, to form the corresponding ⁇ -alkylsulfonate of Formula 41.
  • the reaction with the sulfonyl halides may be performed in the presence of a suitable base (e.g., triethylamine) see Scheme 32
  • (+/-) - 40b (+) - 40b or (-) - 40b
  • R* enantiomerically pure moiety
  • Compounds of Formula 40 can be prepared by reducing esters of Formula 44 or aldehydes of Formula 43 with an appropriate reducing agent, (M. Hudlicky, Reductions in Organic Chemistry; John Wiley & Sons pp. 147-160, (1986)).
  • an appropriate reducing agent M. Hudlicky, Reductions in Organic Chemistry; John Wiley & Sons pp. 147-160, (1986)
  • DIBAL-H diisobutylaluminum hydride
  • compounds of Formula 44 contain an enantiomerically pure moiety R* they can be obtained as diasteromerically enriched compounds of formula 44.
  • R C]-C alkyl or R*
  • R* enantiomerically pure moiety
  • Racemic compounds of Formula 43 may also be resolved by kinetic resolution of the cyanohydrins formed by enantioselective hydrocyanation (Scheme 34a).
  • Treatment of compounds of Formula 43 with hydrogen cyanide in the presence of a chiral catalyst will provide diastereomerically enriched cyanohydrins of Formula 43a which can be separated from unreacted 43 or the diastereomeric cyanohydrin 43b to afford 43a in high diastereomeric excess.
  • Regeneration of chiral 43* from 43a can be accomplished by base hydrolysis. See H. Danla, Synlett. 1991, 263 for recent advances in asymmetric synthesis of cyanohydrins.
  • Esters of Formula 44 can be prepared from anthranilic acid esters of Formula 45 according to the procedures described in Scheme 35.
  • Esters 45 can be prepared from readily accessible anthranilic acids by esterification techniques well known in the art. If compounds of Formula 45 contain an enantiomerically pure moiety R* they can be treated as indicated in Scheme 35 to obtain a mixture of diastereomers of Formula 44. Separation of the diastereomers of Formula 44 would provide diasteromerically enriched compounds of formula 44.
  • Compounds of Formula 45 which contain an enantiomerically pure moiety R* when treated as indicated in Scheme 35 may effect a stereoselective synthesis of compounds of Formula 44 by stereoinduction of the resulting atropic center in compounds of Formula 44.
  • R* enantiomerically pure moiety
  • a formaldehyde equivalent i.e., dimethylformamide or methyl chloroformate
  • compounds of Formula 48 can be prepared from compounds of Formula 46 by metallation using an alkyllithium followed by quenching with a trialkoxy borane, (Scheme 38), see Organic Synthesis via Boranes; Wiley: New York, (1975).
  • Scheme 38
  • R C ⁇ -C alkyl
  • R* enantiomerically pure moiety
  • R 34 P(C 6 H 5 ) 3 + (Cl, Br or I) ⁇ O
  • R 34 P(0(CrC 4 alkyl)) 2
  • the olefin of Formula Ip can also be prepared by reversing the reactivity of the reactants in the Wittig or Horner-Emmons condensation.
  • 2-alkylphenyl derivatives of Formula 56 can be converted into the co ⁇ esponding dibromo-compounds of Formula 57a as illustrated in Scheme 42 (see Synthesis, (1988), 330).
  • the dibromo- compounds can be hydrolyzed to the carbonyl compounds of Formula 57b, which in turn can be condensed with a phosphorus-containing nucleophile of Formula 58 or 59 to afford the olefins of Formula Ip.
  • NBS N-bromosuccinimide 57b
  • the O-substituted hydroxylamine can be condensed with the carbonyl compound of Formula 60 to yield oximes of Formula Ir directly.
  • Carbamates of Formula lu can be prepared by reacting benzyl alcohols of Formula 61 with iso(thio)cyanates of Formula 62 (Scheme 44). A base such as triethylamine can be added to catalyze the reaction.
  • Compounds of Formula Iw may be prepared by methods described in EP-A-178,826, EP-A-341,845 and EP-A-464,381.
  • organobismuth reagents in the preparation of diaryl ethers is well known in the art (see Tetrahedron Lett., (1986), 27, 3619, and Tetrahedron Lett., (1987), 28, 887).
  • Boronic acids are well known in the literature (see Acta Chem. Scand. 1993, 47, 221 and references therein).
  • the use of boronic acids in the preparation of diaryl ethers is known in the art (see Tetrahedron Lett., (1998), 39, 3933).
  • Step A The title compound of Step A (100.0 g, 447.9 mmol) was suspended in ethyl acetate (1 L) and added dropwise, via mechanical pump, over 3.5 h to a stirring solution of phosgene (177 g, 1.79 moles) in ethyl acetate (1.5 L) which was heated at reflux. After the addition was complete, the mixture was heated at reflux for a further 3 hr, cooled to room temperature and stirred overnight. The solution was concentrated under reduced pressure and the residue was dissolved in ethyl acetate and water and extracted four times with ethyl acetate.
  • Step B Preparation of 5-chloro-2,4-dihydro-4-(2-hvdroxy-6-methylphenyl)-2-methyl-
  • Step D Preparation of 2,4-dihvdro-4-(2-hydroxy-6-methylphenyl)-5-methoxy-2- methyl-3H- 1 ,2,4-triazol-3-one To a stirred solution of the title compound of Step C (133.5 g, 557.0 mmol) in tetrahydrofiiran (1.5 L) was added dropwise sodium methoxide (25% by weight in methanol, 382 mL, 1.67 moles).
  • Step F Separation of enantiomers of 2,4-dihvdro-5-methoxy-2-methyl-4-r2-methyl-6-
  • Step B Preparation of 2,4-dihvdro-4-r2-(3-iodophenoxy)-6-methylphenyl]-5- methoxy-2-methyl-3H-1.2.4-triazol-3-one
  • 2,4-dihydro-4-(2-hydroxy-6-methylphenyl)-5-methoxy-2-methyl-3H- l,2,4-triazol-3-one (3.0 g, 12.76 mmol)
  • methylene chloride 60 mL
  • Step C Separation of enantiomers of 2,4-dihydro-4-r2-(3-iodophenoxy)-6- methylphenyll-5-methoxy-2-methyl-3H- 1 ,2,4-triazol-3-one Separations of enantiomers of the title compound from Step B were carried out on a
  • the individual enantiomers were obtained by collecting fractions from the ⁇ PLC outlet and concentrated in vacuo. The residues were redissolved in methylene chloride and transferred to scintillation vials and further dried by evaporation and under high vacuum.
  • the crude material was purified by flash chromatography on silica gel (gradient from 1 : 1 ethyl acetate hexane to 100% ethyl acetate as eluant) to provide a mixture of two diastereomers in a 1 : 1 ratio as a colorless oil. Trituration in ether provide a solid which was enriched in one diastereomer (15.4 g). This material was fractionally crystallized from methanol (2 recrystallizations) to provide a single Diastereomer A, mp 147 °C.
  • Step B Preparation of (aS)-2,4-dihvdro-4-(2-hvdroxy-6-methylphenyl)-5-methoxy-2- methyl-3H- 2,4-triazol-3-one
  • aS aS-2,4-dihvdro-4-(2-hvdroxy-6-methylphenyl)-5-methoxy-2- methyl-3H- 2,4-triazol-3-one
  • Step E Preparation of (aS)-2.4-dihvdro-5-methoxy-2-methyl-4-r2-methyl-6-rr3-r4- methylphenyl)-L2,4-thiadiazol-5-vnoxy]phenvn-3H-l,2,4-triazol-3-one
  • the title compound from Step B 800 mg
  • the title compound from Step D 720 mg
  • the mixture was diluted with 25 mL of water and extracted with ethyl ether (3x25 mL). The combined extracts were dried (Mg SO 4 ), filtered and concentrated by rotary evaporation. The crude material was purified by flash chromatography on silica gel (hexane/ethyl acetate 2:1 to 1 : 1 gradient as eluant).
  • Step B Preparation of (aR)-2 > 4-dihvdro-5-methoxy-2-methyl-4-r2-methyl-6-r[3-r4- methylphenyl)- 1 ,2,4-thiadiazol-5-v ⁇ oxylphenyll-3H- 1 ,2,4-triazol-3-one
  • the title compound from Step A (306 mg) and the title compound from Step D, Example 3 (274 mg) were dissolved in 20 mL of dimethylformamide and 200 mg of potassium carbonate was added. The mixture was stirred at room temperature for 64 h. The mixture was diluted with 20 mL of water and extracted with ethyl ether (3x20 mL).
  • Example 3 To a solution of the title compound from Step B, Example 3 (0.79 g) in methylene chloride (16 mL) was added triphenylbismuth (2.98 g, Aldrich Chemical Co.), anhydrous cupric acetate (0.61 g), and triethylamine (0.70 g). After stirring at room temperature for 70 h, the crude reaction mixture was directly subjected to flash chromatography purification (silica gel, 30-40% ethyl acetate in hexane) to give the title compound (0.95 g, 90%), melting at 61-64 °C.
  • Enantiomer V (a5)-2,4-dihydro-5-methoxy-2-methyl-4-(2-methyl-6-phenoxyphenyl)-3H- l,2,4-triazol-3-one, same compound as Example 5, elution time 21 min, and Enantiomer VI (aR)-2,4-dihydro-5-methoxy-2-methyl-4-(2-methyl-6-phenoxyphenyl)-3H-l,2,4-triazol-3- one, same compound as Example 6, elution time 27 min.
  • Step A Preparation of raS-r2-(R*)11-4-r2-rrr(7.7-dimethyl-6-oxobicvclor2.2.1 Iheptan-
  • Step B Preparation of (aS)-2,4-dihydro-4-(2-hvdroxy-6-methylphenyl)-5-methoxy-2 - methyl-3H-l .2.4-triazol-3-one
  • Diastereomer C from Step A (12.85 g) was suspended in 100 mL of methanol and 14.6 mL of 30% sodium methoxide in methanol was added. The reaction mixture was stirred at ambient temperature for 4 h. The mixture was concentrated in vacuo to remove most of the methanol and the remainder was diluted with 200 mL of ethyl acetate and washed with 100 mL of IN hydrochloric acid, 50 mL of water, then 100 mL of saturated sodium chloride solution.
  • Step E Preparation of (aS)-4-[2-r(5-chloro-4-methyl-2-thiazolyl)oxy1-6- methylphenyl]-2.4-dihvdro-5-methoxy-2-methyl-3H-1.2,4-triazol-3-one
  • 2-methylsulfonyl-4-methyl-5-chlorothiazole (4.44 g)
  • (aS)-2,4- dihydro-4-(2-hydroxy-6-methylphenyl)-5-methoxy-2-methyl-3H- 1 ,2,4-triazol-3-one (96%) ee), (4.1 g,), (prepared as in Steps A-B) in 60 mL of acetonitrile was added 7.2 g of potassium carbonate.
  • Step A Preparation of 4-( l-dimethylethyl)-2-(methylthio)thiazole
  • Step B Preparation of 5-bromo-4-(l .1 -dimethylethyl)-2-(methylthio)thiazole A solution of 2-methylthio-4-( 1 , 1 -dimethylethyl)thiazole (prepared similarly as above)
  • Step C Preparation of 5-bromo-4-( 1 , 1 -dimethylethyl)-2-(methylsulfonvDthiazole
  • Step B A solution of the material obtained in Step B (18.35 g) was dissolved in 150 mL of dichloromethane was cooled in an ice water bath and treated with 32% peracetic acid
  • Step D Preparation of (aS)-4-r2-rF5-bromo-4-( 1 , 1 -dimethvIethyl)-2-thiazolyl)oxy1-6- methylphenvn-2,4-dihvdro-5-methoxy-2-methyl-3H-l,2,4-triazol-3-one
  • 2-methylsulfonyl-4-(l,l-dimethylethyl)-5-bromothiazole (8.76 g)
  • (aS)-2,4-dihydro-4-(2-hydroxy-6-methylphenyl)-5-methoxy-2-methyl-3H- 1 ,2,4-triazol-3-one (96% ee), (6.9 g,), (prepared as in Steps A-B, Example ) in 150 mL of acetonitrile was added 12.2 g of potassium carbonate.
  • the mixture was heated to reflux for 2 days.
  • the reaction mixture was cooled, concentrated to remove most of the acetonitrile, diluted with ethyl acetate, washed with water, then saturated sodium chloride solution, dried (MgSO 4 ), filtered and concentrated.
  • the residue was flash chromatographed (silica gel, 40-50% ethyl acetate in hexane). The residue was triturated in ether/hexane to give the titled compound as an off- white solid (5.6 g), mp 97-99 °C.
  • the ratio of diastereomers can be obtained via integration of their respective ⁇ Me singlets ((aS)-2,4-dihydro-5-methoxy-2- methyl-4-[2-methyl-6-(sulfooxy)phenyl]-3H-l,2,4-triazol-3-one ⁇ - methylbenzenemethanamine: ⁇ 3.27, undesired diastereomer: ⁇ 3.31).
  • Symmetry Operation Codes a 1/2 - X, -Y, l/2+Z e X, Y, 1+Z b 3/2 - X , - Y , l/2+Z f X , Y , - 1+Z c l/2+X , l/2 - Y, - Z g 1 - X, 1 /2+Y , 1/2 - Z d 3/2 -X, - Y, - 1/2+Z
  • Step B Preparation of (a-Sy2,4-dihvdro-4-f2-hvdroxy-6-methvIphenv0-5-methoxy-2- methyl-3H- 1 ,2,4-triazol-3-one
  • ⁇ PLC analysis (Chirobiotic T column purchased from Astec (i.e., Advanced Separations Technologies, Inc.)), 80/20 ⁇ exanes/EtO ⁇ , 1.0 mL/min, 40 °C; 9.64 min (aS)-2,4-dihydro-4-(2-hydroxy-6- methylphenyl)-5-methoxy-2-methyl-3H-l,2,4-triazol-3-one, 1 1.3 min (aR)-2,4-dihydro-4-(2- hydroxy-6-methylphenyl)-5-methoxy-2-methyl-3H-l,2,4-triazol-3-one showed 94% ee.
  • Step C Preparation of 5-chloro-4- 2-(chloromethyl)-6-methylphenyll-2,4-dihvdro-2- methyl-3H- 1 ,2,4-triazol-3-one
  • the crude material from Step B (237.6 g) was dissolved in 3 L of ethyl acetate.
  • the solution was cooled to 10-15 °C and 1,1-dimethylhydrazine was added dropwise, resulting in a white suspension.
  • the addition funnel was rinsed into the reaction vessel with 250 mL of ethyl acetate, the cooling bath was removed and the slurry held at room temperature until used in a second operation.
  • Step D Preparation of 2,9-dimethyl-5H-r 1 ,2.4 " jtriazolor4,3- ⁇ ir3, 1 Ibenzothiazin-
  • Step E Preparation of 2,9-dimethyl-5H-[ 1 ,2,4]triazolor4,3-fll ⁇ 3 ⁇ lbenzothiazin- l(2H)-one 4,4-dioxide
  • a suspension of 2,9-dimethyl-5H-[l,2,4]triazolo[4,3-__][3,l]benzothiazin-l(2H)-one (400 g) in 1.6 L of acetic acid was added an aqueous solution of sodium tungstate (17.6 g in 10 mL) and the mixture heated to 55 °C. Hydrogen peroxide (30%, 425 g) was added dropwise over a 1 h period while maintaining a temperature about 70 °C.
  • Step F Preparation of 4-r2-r(bromosulfonyl)methyll-6-methylphenyll-2,4-dihydro-5- methoxy-2-methyl-3H- 1.2.4-triazol-3-one To a suspension of 2,9-dimethyl-5H-[l,2,4]triazolo[4,3-_.][3,l]benzothiazin-l(2H)-one
  • Step I Preparation of l-[4-(trifluoromethyl)-2-pyridinyl1ethanone oxime
  • Step K Separation of enantiomers of 2.4-dihydro-5-methoxy-2-methyl-4-r2-methyl-6- rrrri-r4-(trifluoromethylV2-pyridinyllethylidenelaminoloxy1methyllphenyl]- 3H- 1 ,2,4-triazol-3-one A sample of 2,4-dihydro-5-methoxy-2-methyl-4-[2-methyl-6-[[[[l-[4-
  • the dioxane was removed by rotary evaporation and the residue was diluted with 400 mL of IN hydrochloric acid. The pH was adjusted to 3 by the addition of concentrated hydrochloric acid and ice was added to cool. The aqueous mixture was extracted with dichloromethane (3 X 200 mL). The combined organic phases were washed with 500 mL aqueous sodium bicarbonate, dried (MgSO ⁇ , filtered and concentrated to yield a pale yellow solid. The crude product was triturated in hexanes and filtered to yield the title compound (34.1 g) as a white solid, mp 132-134 °C.
  • Step B Preparation of faS-.2- ( R* ⁇ l1-4-r2-ITr [Y7,7-dimethyl-6- oxobicvclor2.2.1 Iheptan- 1 -yl)methyllsulfonvnoxy1methyll-6-methylphenyl1- 2.4-dihvdro-5-methoxy-2-methyl-3H-1.2.4-triazol-3-one
  • Diastereomer E ! H NMR (CDC1 3 ) ⁇ 7.4 (m, 3H), 5.21 (AB quartet, 2H), 3.97 (s, 3H), 3.47 (s, 3H), 3.46 (d, IH), 2.85 (d, IH), 2.4 (m, 2H), 2.18 (s, 3H), 2.1 (m, 2H), 1.93 (d, IH), 1.6 (m, IH), 1.4 (m, IH), 1.07 (s, 3H), 0.81 (s, 3H).
  • Diastereomer F ! H NMR (CDC1 3 ) ⁇ 7.4 (m, 3H), 5.19 (AB quartet, 2H), 3.95 (s, 3H), 3.52 (d, IH), 3.47 (s, 3H), 2.94 (d, IH), 2.4 (m, 2H), 2.18 (s, 3H), 2.1 (m, 2H), 1.93 (d, IH), 1.6 (m, IH), 1.4 (m, IH), 1.08 (s, 3H), 0.86 (s, 3H).
  • Step C Preparation of (aR -2.4-dihvdro-5-methoxy-2-methyl-4-r2-methyl-6-[rf I " 1 -F3- (trifluoromethyl phenyllethylidene1aminoloxylmethyllphenyl]-3H- 1.2,4- triazol-3-one
  • sodium hydride 50% oil dispersion
  • Diastereomer E from Step B, in 10 mL of tetrahydrofiiran was added and the mixture stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate (2x25 mL). The combined extracts were dried (MgSO 4 ), filtered and concentrated to an amber oil. The crude product was purified by applying to silica gel and eluting with 1 : 1 hexanes/ethyl acetate to recover the product. Removal of solvents gave 240 mg of the title compound as a colorless oil.
  • Step D Preparation of ( aS)-2.4-dihvdro-5-methoxy-2-methyl-4-r2-methyl-6-rrrri-r3-
  • Diastereomer F (230 mg), from Example 12, Step B, in 5 mL of tetrahydrofiiran was added and the mixture stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate (2x25 mL). The combined extracts were dried (MgSO ), filtered and concentrated to an amber oil. The crude product was purified by applying to silica gel and eluting with 1 : 1 hexanes/ethyl acetate to recover the product. Removal of solvents gave the title compound as a colorless oil. Trituration in ether/hexanes gave 110 mg of the title compound as a white crystalline solid, mp 125-129 °C.
  • V H
  • Y -O-
  • V H
  • Y -CH 2 0-
  • V H
  • Y -OCH 2 -
  • V H
  • V H
  • V H
  • V H
  • Y -CH 2 S-
  • V H
  • V H
  • V H
  • Y -CH 2 CH 2 -
  • V H
  • V H
  • V H
  • V H
  • V H
  • Y -SCH 2 - Z
  • V 3-CH 3
  • Y -O-
  • V 3-CH 3
  • Y -OCH 2 -
  • V 3-CH 3
  • V 3-CH3
  • V 3-CH3
  • V 3-CH3
  • V 3-CH3
  • Y -CH 2 S-
  • V 3-CH3
  • V 3-CH3
  • V 3-CH 3
  • Y -CH 2 CH 2 -
  • V 3-CH3
  • V 3-CH3
  • V 3-CH 3

Abstract

Compositions of Formula (I) compounds, N-oxides and/or agriculturally suitable salts, are disclosed which are enriched in the more active isomer type with respect to the relative positions of U, T and YZ and are useful as fungicides and arthropodicides, wherein U, T, V, Y and Z are as defined in the disclosure. Also disclosed are formulations containing the enantiomerically enriched compositions; methods for controlling plant diseases caused by fungal plant pathogens which involve applying an effective amount of the compositions; and methods for controlling arthropods which involve contacting the arthropods or their environment with an effective amount of the compositions.

Description

TITLE ENANTIOMERICALLY ENRICHED COMPOSITIONS AND THEIR PESTICIDAL USE
BACKGROUND OF THE INVENTION This invention relates to certain enantiomerically enriched compositions, their N-oxides, agriculturally suitable salts and compositions, and methods of their use as fungicides and arthropodicides.
The control of plant diseases caused by fungal plant pathogens is extremely important in achieving high crop efficiency. Plant disease damage to ornamental, vegetable, field, cereal, and fruit crops can cause significant reduction in productivity and thereby result in increased costs to the consumers. The control of arthropod pests is also 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.
World Patent Publications WO 95/14009 and WO 97/00612 disclose certain racemic fungicides. SUMMARY OF THE INVENTION
This invention involves compositions comprising pesticidal compounds of Formula I including all geometric and stereoisomers, N-oxides, and agriculturally suitable salts thereof, agricultural formulations containing them and their use as fungicides and arthropodicides:
Figure imgf000003_0001
wherein
Figure imgf000003_0002
Figure imgf000004_0001
T4 ^ T5 or T6 ;
V is H, halogen, C C3 alkyl, CN, NO2 or CrC3 alkoxy; U is halogen, CrC alkyl or CrC2 haloalkyl;
YZ is a group consisting of (a) 5 or more atoms independently selected from the group C, N, O, S, Si and Ge, provided that at least 2 of said atoms are C, and (b) additional atoms independently selected from H, F, Cl, Br and I;
A is O; S; N; NR3; or CR4;
G is C or N; provided that when G is C, then A is O, S or NR3 and the floating double bond is attached to G; and when G is N, then A is N or CR4 and the floating double bond is attached to A; W is O or S;
X is OR1; SCO^R1; halogen; CrC6 alkyl; CrC6 haloalkyl; C3-C6 cycloalkyl; cyano;
NH2; NHR1; N(C C6 alkyl)Rl; NH(CrC6 alkoxy); or N(CrC6 alkoxy)R1; R1 is CrC6 alkyl; CrC6 haloalkyl; C2-C6 alkenyl; C2-C6 haloalkenyl; C2-C6 alkynyl; C2-Cg haloalkynyl; C3-C6 cycloalkyl; C2-C4 alkylcarbonyl; or C2-C4 alkoxycarbonyl;
R2 is H; C C6 alkyl; CrC6 haloalkyl; C2-C6 alkenyl; C2-C6 haloalkenyl; C2-C6 alkynyl; C2-C6 haloalkynyl; C3-C6 cycloalkyl; C2-C4 alkylcarbonyl; C2-C4 alkoxycarbonyl; hydroxy; CrC alkoxy; or acetyloxy; R3 is H; CrC6 alkyl; CrC6 haloalkyl; C2-C6 alkenyl; C2-C6 haloalkenyl; C2-C6 alkynyl; C2-Cg haloalkynyl; C3-C6 cycloalkyl; C2-C alkylcarbonyl; or C2-C4 alkoxycarbonyl; R4 is H; halogen; CrC6 alkyl; CrC6 haloalkyl; C2-C6 alkenyl; C2-C6 haloalkenyl;
C2-C6 alkynyl; C2-C6 haloalkynyl; or C3-C6 cycloalkyl; R5 is CrC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C -C6 haloalkynyl or C3-C6 cycloalkyl; each R6 is H, CrC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-Cg haloalkynyl, C3-C6 cycloalkyl, C2-C4 alkylcarbonyl, C2-C4 alkoxycarbonyl, hydroxy, C C2 alkoxy or acetyloxy, provided that at least one R6 is other than hydroxy, CrC2 alkoxy or acetyloxy; m is 0, 1 or 2; and s is 0 or 1.
These compositions of this invention are characterized by having at least a 20% enantiomeric excess ("ee") of the more active of the two atropic isomer types resulting from the hindered rotation around the bond between T and the phenyl group to which it is bound (i.e., at least a 60:40 ratio of the more active to the less active atropic isomer type).
The more active isomer type corresponds with respect to the relative positions of U, T and YZ to the structural atropic isomer of 2,4-dihydro-5-methoxy-2-methyl-4-[6-methyl-2- [3-(trifluoromethyl)phenoxy]phenyl]-3H-l,2,4-triazol-3-one which has the longer retention time (as measured herein) in a chiral separation using a column with a chiral stationary phase having R,R configuration and derived from 4-(3,5-dinitrobenzamido)tetrahydrophenanthrene covalently bound to 5 μm 3-propyl silica with a mobile phase employing a solvent consisting of 80% by volume hexane and 20% by volume 2-propanol.
The more active isomer corresponds, with respect to the relative positions of U, YZ and the substituents on T, to the following projections of the compounds of Formula I:
Figure imgf000005_0001
IbrT4: forT5: and forT6:
Figure imgf000005_0002
Figure imgf000005_0003
Figure imgf000005_0004
where the groups shown define a distorted tetrahedron, the view is along the bond between the phenyl group and the moiety T, and the solid line represents the foreground and the dashed line the background.
This invention further pertains to compositions comprising intermediates of Formula II: wherein Ya is -OΗ, -CΗ2Xa or -CH(CH3)Xa; Xa is Cl, Br, I or OH; and T, U and V are defined as in Formula I.
Figure imgf000005_0005
These compositions of the invention are characterized by having at least a 20 % enantiomeric excess of the structural atropic isomer corresponding to the more active Formula I isomer above (i.e., with Ya in the YZ position).
DETAILS OF THE INVENTION Stereoisomers, comprising enantiomers and diastereomers, are isomers of identical constitution but differing in the arrangement of their atoms in space. Atropic enantiomers (atropisomers) are stereoisomers resulting from restricted rotation about single bonds where the rotational barrier is high enough to permit isolation of stable isomeric species. In the present invention, the bond between the phenyl group and the moiety T is an axis of chiralty and the substituents on T and the groups U and Y-Z define a distorted tetrahedron about that axis. Because these groups are all different and are sufficiently large to hinder rotation about the axis of chirality, the rotational isomers can be isolated as stable species. In the absence of other stereogenic centers or axes, these rotational isomers are nonsuperimposable mirror images and are therefore enantiomers. The projection of the groups U, Y-Z, and the substituents on T, obtained when viewing the enantiomer along the chiral axis, precisely defines the absolute configuration of the enantiomer. Using these projections and a set of rules (known in the art) for assigning substituent priorities, the well-known Cahn-Ingold- Prelog R and S descriptors can be used to denote the configuration of the enantiomers. For a more comprehensive discussion of atropisomerism and stereoisomerism, see E. L. Eliel, S. H. Wilen and L. N. Mander, Stereochemistry of Organic Compounds (John Wiley & Sons, New York, N. Y. 1994).
The compounds of this invention may contain other stereogenic axes or centers in addition to the chiral axis just described. As a result, individual structures of Formula I may encompass diastereomers as well as enantiomers. The terms enantiomeric excess or enantiomeric enrichment used here refer to the excess of one of the rotational isomers (described above) relative to the other and without regard to the presence of other stereogenic axes or centers. Furthermore, 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. The enantiomerically enriched compositions of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form.
The salts of the more active atropic isomers of the invention include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfiiric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids. The salts of the more fungicidally active atropic isomers 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 phenol. Preferred enantiomerically enriched compositions for reasons of better activity and/or ease of synthesis are:
Preferred 1. The enantiomerically enriched compositions above wherein: V is bonded to the 3- or 4-position of the phenyl ring; Y is -0-; -S(O)n-; -NR^-; -C(=O)-; -CH(ORl5)-; -CHR8-; -CHR8CHR8-; -CR8=CR8-; -C≡C-; -CHR15O-; -OCHR15-; -CHR15S(O)n-; -S(O)nCHR15-; -CHR15N-; -CHR15O-N=C(R7)-; -(R7)C=N-OCH(R15)-; -C(R7)=N-O-; -O-N=C(R7)-; -CHR15OC(=O)N(R15)-; -CHRl5θC(=S)N(R15)-; -CHR15OC(=O)O-; -CHR15OC(=S)O-; -CHR15OC(=O)S-; -CHR15OC(=S)S-;
-CHR15SC(=O)N(R15)-; -CHR15SC(=S)N(R15)-; -CHR15SC(=O)O-; -CHR15SC(=S)O-; -CHR15SC(=O)S-; -CHRI 5SC(=S)S-; -CHR15SC(=NR15)S-; -CHR15N(R15)C(=O)N(R15)-; -CHR15O-N(Rl5)C(=O)N(R15)-; -CHR15O-N(R15)C(=S)N(R15)-; -CHR15O-N=C(R7)NR15-; -CHR15O-N=C(R7)OCH2-; -CHR15O-N=C(R7)-N=N-;
-CHR 15O-N=C(R7)-C(=O)-; -CHR 15θ-N=C(R7)-C(=N-OR15)-; -CHR15O-N=C(R7)-C(R7)=N-A -A3-; -CHR15O-N=C(-C(R )=N-A2-Z l )-; -CHR15O-N=C(R7)-CH2O-; -CHR15O-N=C(R7)-CH2S-; -O-CH2CH2O-N=C(R7)-; -CHR15O-C(R15)=C(R7)-; -CHR!5θ-C(R7)=N-; -CHR15S-C(R7)=N-; -C(R7)=N-NR15-; -CH=N-N=C(R7)-;
-CHR 15N(R 15)-N=C(R7)-; -CHR l 5N(COCH3)-N=C(R7)-; -OC(=S)NR15C(=O)-; -CHR8-C(=W1)-A1-; -CHR8CHR8-C(=W )-A1-; -CR =CR8-C(=W )-A1-; -C≡C-C(=W1)-A1-; -N=CR8-C(=W1)-A1-; or a direct bond; and the directionality of the Y linkage is defined such that the moiety depicted on the left side of the linkage is bonded to the phenyl ring and the moiety on the right side of the linkage is bonded to Z; Z1 is H or -A3-Z; W1 is O or S;
A1 is O; S; NR15; or a direct bond; A2 is O; NR15; or a direct bond;
A3 is -C(=O)-; -S(O)2-; or a direct bond; each R7 is independently H; C Cβ alkyl; Cj-Cβ haloalkyl; C Cg alkoxy; C C6 haloalkoxy; CrC6 alkylthio; CrC6 alkylsulfinyl; CrC6 alkylsulfonyl; C C6 haloalkylthio; C C6 haloalkylsulfinyl; CrC6 haloalkylsulfonyl; C2-C6 alkenyl; C2-C6 haloalkenyl; C2-C6 alkynyl; C2-C6 haloalkynyl; C3-C6 cycloalkyl; C2-C4 alkylcarbonyl; C -C4 alkoxycarbonyl; halogen; cyano; nitro; hydroxy; amino; NH(CrC6 alkyl); N(CrC6 alkyl)2; or moφholinyl; each R8 is independently H; 1-2 CH3; C2-C3 alkyl; CrC3 alkoxy; C3-C6 cycloalkyl; formylamino; C2-C4 alkylcarbonylamino; C2-C alkoxycarbonylamino; NH2C(O)NH; (CrC3 alkyl)NHC(O)NH; (CrC3 alkyl)2NC(O)NH;
N(CrC3 alkyl)2; piperidinyl; moφholinyl; 1-2 halogen; cyano; or nitro; each Z is independently selected from: i) CrC10 alkyl, C2-C10 alkenyl, and C2-C10 alkynyl each substituted with R9 and optionally substituted with one or more R10; ii) C3-Cg cycloalkyl, C3-C8 cycloalkenyl and phenyl each substituted with R9 and optionally substituted with one or more R10; iii) a ring system selected from 3 to 14-membered monocyclic, fused bicyclic and fused tricyclic nonaromatic heterocyclic ring systems and 5 to 14-membered monocyclic, fused bicyclic and fused tricyclic aromatic heterocyclic ring systems, each heterocyclic ring system containing 1 to 6 heteroatoms independently selected from the group nitrogen, oxygen, and sulfur, provided that each heterocyclic ring system contains no more than 4 nitrogens, no more than 2 oxygens, and no more than 2 sulfurs, each nonaromatic or aromatic heterocyclic ring system substituted with R9 and optionally substituted with one or more R10; iv) a multicyclic ring system selected from 8 to 14-membered fused-bicyclic and fused-tricyclic ring systems which are an aromatic carbocyclic ring system, a nonaromatic carbocyclic ring system, or a ring system containing one or two nonaromatic rings that each include one or two J1 as ring members and one or two ring members independently selected from C(=O) and S(O)2, and any remaining rings as aromatic carbocyclic rings, each multicyclic ring system substituted with R9 and optionally substituted with one or more R10; and v) adamantyl substituted with R9 and optionally substituted with one or more RIO; each J1 is independently selected from the group -CHR13-, -NR13-, -O-, and -S(O)p-; R9 is H; 1-2 halogen; CrC6 alkyl; CrC6 haloalkyl; CrC6 alkoxy; CrC6 haloalkoxy; C2-C6 alkenyl; C2-C6 haloalkenyl; C2-C6 alkynyl; CrC6 alkylthio; CrC6 haloalkylthio; CrC6 alkylsulfinyl; CrC6 alkylsulfonyl; C3-C6 cycloalkyl; C3-C6 alkenyloxy; CO2(CrC6 alkyl); NH(CrC6 alkyl); N(CrC6 alkyl)2;
-C(R18)=NOR17; cyano; nitro; SF5; SiR22R23R24; or GeR22R23R24; or R9 is phenyl, benzyl, benzoyl, phenoxy, pyridinyl, pyridinyloxy, thienyl, thienyloxy, furanyl, pyrimidinyl, or pyrimidinyloxy each optionally substituted with one of R^ R^ or both R^ and R12; each R10 is independently halogen; CrC4 alkyl; CrC haloalkyl; CrC4 alkoxy; nitro; or cyano; or when R9 and an R10 are attached to adjacent atoms on Z, R9 and said adjacently attached R10 can be taken together as -OCH2O- or -OCH2CH2O-; each CH2 group of said taken together R9 and R10 optionally substituted with 1-2 halogen; or when Y and an R10 are attached to adjacent atoms on Z and Y is -CHR15O-N=C(R7)-, -O-N=C(R7)-, -O-CH2CH2O-N=C(R7)-, -CHR15O-C(Rl5)=C(R7)-, -CH=N-N=C(R7)-, -CHR15N(R15)-N=C(R7)- or -CHR>5N(COCH3)-N=C(R7)-, R7 and said adjacently attached R10 can be taken together as -(CH2)r-J- such that
J is attached to Z; J is -CH2-; -CH2CH2-; -OCH2-; -CH2O-; -SCH2-; -CH2S-; -N(R16)CH2-; or
-CH2N(R16)-; each CH2 group of said J optionally substituted with 1 to 2 CH3; R1 1 and R12 are each independently 1 -2 halogen; CrC4 alkyl; CrC4 haloalkyl; C2-C6 alkenyl; C2-C(, haloalkenyl; C2-C6 alkynyl; C2-C6 haloalkynyl; C2-C6 alkoxyalkyl; C2-Cg alkylthioalkyl; C3-Cg alkoxyalkynyl; C -C[Q tetrahydropyranyloxyalkynyl; benzyloxymethyl; C C4 alkoxy; C C4 haloalkoxy; C -Cg alkenyloxy; C3-Cg haloalkenyloxy; C3-Cg alkynyloxy; Gj-Cg haloalkynyloxy; C2-C6 alkoxyalkoxy; C5-C9 trialkylsilylalkoxyalkoxy; C2-Cg alkylthioalkoxy; CrC alkylthio; CrC4 haloalkylthio; CrC4 alkylsulfinyl;
CrC4 haloalkylsulfinyl; CrC4 alkylsulfonyl; CrC4 haloalkylsulfonyl; C3-C6 alkenylthio; C3-C6 haloalkenyl thio; C2-Cg alkylthioalkyl thio; nitro; cyano; thiocyanato; hydroxy; N(R 6)2; SF5; Si(R 5)3; Ge(R25)3; (R 5)3Si-C=C-; OSi(R25)3; OGe(R25)3; C(=O)R26; C(=S)R26; C(=O)OR26; C(=S)OR26;
C(=O)SR26; C(=S)SR26; C(=O)N(R26)2; C(=S)N(R26)2; OC(=O)R26;
OC(=S)R26; SC(=O)R26; SC(=S)R26; N(R 6)C(=O)R26; N(R26)C(=S)R26;
OC(=O)OR27; OC(=O)SR27; OC(=O)N(R26)2; SC(=O)OR27; SC(=O)SR27;
S(O)2OR26; S(O)2N(R 6)2; OS(O)2R27; N(R26)S(O)2R27; or phenyl, phenoxy, benzyl, benzyloxy, phenylsulfonyl, phenylethynyl or pyridinylethynyl, each optionally substituted with halogen, C C4 alkyl, CrC4 haloalkyl, Cj-C4 alkoxy,
C C4 haloalkoxy, nitro or cyano; each R13 is independently H; CrC6 alkyl; Cι-C6 haloalkyl; or phenyl optionally substituted with halogen, CrC alkyl, CrC4 haloalkyl, CrC4 alkoxy, CrC4 haloalkoxy, nitro or cyano; each R15 is independently H; CrC3 alkyl; C3-Ce cycloalkyl; or phenyl or benzyl, each optionally substituted on the phenyl ring with halogen, C C alkyl, C C haloalkyl, Cj-C4 alkoxy, C C4 haloalkoxy, nitro or cyano; or when Y is -CHR15N(R15)C(=O)N(R15)-, the two R15 attached to nitrogen atoms on said group can be taken together as -(CH2)q-; or when Y is -CHR15O-N=C(R7)NR15-, R7 and the adjacently attached R15 can be taken together as -CH2-(CH2)q-; -O-(CH2)q-; -S-(CH2)q-; or -N(CrC3 alkyl)-(CH2)q-; with the directionality of said linkage defined such that the moiety depicted on the left side of the linkage is bonded to the carbon and the moiety on the right side of the linkage is bonded to the nitrogen;
R16, R17, and R18 are each independently H; CrC3 alkyl; C3-C6 cycloalkyl; or phenyl optionally substituted with halogen, Cj-C alkyl, C C4 haloalkyl, Cj-C alkoxy,
Cj-C4 haloalkoxy, nitro or cyano; R22, R23, and R24 are each independently C C6 alkyl; C2- alkenyl; C C4 alkoxy; or phenyl; each R25 is independently C C4 alkyl; C C4 haloalkyl; C2- 4 alkenyl; C C4 alkoxy; or phenyl; each R26 is independently H; CrC6 alkyl; CrC6 haloalkyl; C2-C6 alkenyl; C2-C6 haloalkenyl; C2-Cg alkynyl; C2-Cg haloalkynyl; C3-Cg cycloalkyl; or phenyl or benzyl, each optionally substituted on the phenyl ring with halogen, Cj-C4 alkyl, Cj-C4 haloalkyl, CrC4 alkoxy, CrC4 haloalkoxy, nitro or cyano; R27 is independently C C6 alkyl; CrC6 haloalkyl; C2-CG alkenyl; C2-C6 haloalkenyl; C2-Cg alkynyl; C2-C6 haloalkynyl; C3-C6 cycloalkyl; or phenyl or benzyl, each optionally substituted on the phenyl ring with halogen, CrC4 alkyl, Cι~C haloalkyl, Cj-C4 alkoxy, C C4 haloalkoxy, nitro or cyano; n and p are each independently 0, 1 or 2; r is 0 or 1 ; and q is 2 or 3.
Preferred 2. Enantiomerically enriched compositions of Preferred 1 above wherein: U is CH3;
Y is Y is -O-; -S(O)n-; -NR15-; -CHR8-; -CHR8CHR8-; -CR8=CR8-; -CHR15O-; -OCHR15-; -CHR15S(O)n-; -S(O)nCHR15-; -CHR15N-; -CHR15O-N=C(R7)-; -(R )C=N-OCH(R15)-; -CHR1 OC(=S)N(R15)-; -CHR15SC(=S)N(R15)-;
-CHR15O-N=C(R7)-C(=N-OR1 )-; -CHR15O-N=C(R7)-CH2O-; -CHR15O-N=C(R7)-CH2S-; -CHR15O-C(R7)=N-; -CHR15S-C(R7)=N-; -C(R7)=N-NR15-; -C(R7)=N-N=C(R7)-; or a direct bond; and the directionality of the Y linkage is defined such that the moiety depicted on the left side of the linkage is bonded to the phenyl ring and the moiety on the right side of the linkage is bonded to Z; and Z is naphthalenyl, tetrahydronaphthalenyl, phenyl, or 5- or 6- membered aromatic heterocyclic ring systems each substituted with R9 and optionally substituted with one or more R10. Preferred 3. Enantiomerically enriched compositions of Preferred 2 above wherein the relative positions of U, YZ and the substituents on T correspond to the following projections of the compounds of Formula I:
Figure imgf000010_0001
where the groups shown define a distorted tetrahedron, the view is along the bond between the phenyl group and the moiety T, and the solid line represents the foreground and the dashed line the background (i.e., T is T1).
Preferred 4. Enantiomerically enriched compositions of Preferred 2 wherein the relative positions of U, YZ and the substituents on T correspond to one of the following projections of the compounds of Formula I:
Figure imgf000011_0001
where the groups shown define a distorted tetrahedron, the view is along the bond between the phenyl group and the moiety T, and the solid line represents the foreground and the dashed line the background (i.e., T is T2, τ3, T4, T5 or τ ). Preferred 5. Enantiomerically enriched compositions of Preferred 3 above wherein:
G is N; A is N; R2 is CH3; X is OR1; R1 is CH3; and
W is O.
Most preferred are enantiomerically enriched compositions of Formula I compounds selected from the group:
(aS)-4-[2-(3-fluorophenoxy)-6-methylphenyl]-2,4-dihydro-5-methoxy-2- methyl-3H-l,2,4-triazol-3-one;
(aS)-2,4-dihydro-5-methoxy-2-methyl-4-[2-methyl-6-(3- methylphenoxy)phenyl]-3H- 1 ,2,4-triazol-3-one; (aS)-2,4-dihydro-5-methoxy-2-methyl-4-(2-methyl-6-phenoxyphenyl)-3H- l,2,4-triazol-3-one; (aS)-2,4-dihydro-5-methoxy-2-methyl-4-[2-methyl-6-(4- methylphenoxy)phenyl]-3H- 1 ,2,4-triazol-3-one; (aS)-2,4-dihydro-5-methoxy-2-methyl-4-[2-methyl-6-[3-
(trifluoromethyl)phenoxy]phenyl]-3H- 1 ,2,4-triazol-3-one; (aS)-(2,4-dihydro-5-methoxy-2-methyl-4-[2-methyl-6-[[[[l-[4-
(trifluoromethyl)-2-pyridinyl]ethylidene]amino]oxy]methyl]phenyl]-3H- l,2,4-triazol-3-one; (aS)-4-[2-[[[[l-[2-fluoro-5- (trifluoromethyl)phenyl]ethylidene]amino]oxy]methyl]-6- methylphenyl]-2,4-dihydro-5-methoxy-2-methyl-3H-l,2,4-triazol-3-one; (aS)-4-[2-[[[[l-(2-fluoro-5-methylphenyl)ethylidene]amino]oxy]methyl]-6- methylphenyl]-2,4-dihydro-5-methoxy-2-methyl-3H-l,2,4-triazol-3-one; (aS)-4-[2-[3-(2-fluorophenoxy)phenoxy]-6-methylphenyl]-2,4-dihydro-5- methoxy-2-methyl-3H- 1 ,2,4-triazol-3-one;
(aS)-4-[2-[[4-(3,5-difluorophenyl)-5-methyl-2-thiazolyl]oxy]-6- methylphenyl]-2,4-dihydro-5-methoxy-2-methyl-3H-l,2,4-triazol-3-one; (a5)-2-[[6-[2-( 1 ,5-dihydro-3-methoxy- 1 -methyl-5-oxo-4H- 1 ,2,4-triazol-4-yl)-
3-methylphenoxy]-4-pyrimidinyl]oxy]benzonitrile; (aS)-4-[2-[[4-( 1 , 1 -dimethylethyl)-2-thiazolyl]oxy]-6-methylphenyl]-2,4- dihydro-5-methoxy-2-methyl-3H- 1 ,2,4-triazol-3-one; (_ιS)-4-[2-[(5-bromo-2-thiazolyl)oxy]-6-methylphenyl]-2,4-dihydro-5- methoxy-2-methyl-3H- 1 ,2,4-triazol-3-one; (aS)-2,4-dihydro-4-[2-[(5-iodo-2-thiazolyl)oxy]-6-methylphenyl]-5-methoxy- 2-methyl-3H-l ,2,4-triazol-3-one;
(aS)-2,4-dihydro-5-methoxy-2-methyl-4-[2-methyl-6-[[6-(2,4,6- trifluorophenoxy)-4-pyrimidinyl]oxy]phenyl]-3H-l,2,4-triazol-3-one; (aS)-2,4-dihydro-5-methoxy-2-methyl-4-[2-methyl-6-[[[[ 1 -[3-
(trifluoromethyl)phenyl] ethylidene] amino] oxy] methyljpheny 1] -3H- l,2,4-triazol-3-one;
(aS)-2,4-dihydro-5-methoxy-2-methyl-4-[2-methyl-6-[[2-methyl-5-(l- methylethyl)phenoxy]methyl]phenyl]-3H-l,2,4-triazol-3-one; (aS)-2,4-dihydro-5-methoxy-2-methyl-4-[2-methyl-6-[[[[l-(3- methylphenyl)ethylidene]amino]oxy]methyl]phenyl]-3H-l,2,4-triazol-3- one;
(aS)-4-[2-[(2,5-dimethylphenoxy)methyl]-6-methylphenyl]-2,4-dihydro-5- methoxy-2-methyl-3H- 1 ,2,4-triazol-3-one; (aS)-2,4-dihydro-5-methoxy-2-methyl-4-[2-methyl-6-[[[[ 1 -(4- methylphenyl)ethylidene]amino]oxy]methyl]phenyl]-3H-l,2,4-triazol-3- one; and
(aS)-4-[2-[[5-bromo-4-( 1 , 1 -dimethylethyl)-2-thiazolyl)oxy]-6-methylphenyl]-
2,4-dihydro-5-methoxy-2-methyl-3H- 1 ,2,4-triazol-3-one. Preferred are intermediates of Formula II wherein T is T ' . Particularly preferred are intermediates wherein U is methyl, V is hydrogen or methyl, X is OR1, R1 is methyl, R2 is methyl and W is O.
Preferably the compositions of this invention (whether of Formula I or of Formula II) have at least a 50%> enantiomeric excess; more preferably at least a 75% enantiomeric excess; still more preferably at least a 90% enantiomeric excess; and the most preferably at least a 94% enantiomeric excess of the more active Formula I isomer or its corresponding Formula II intermediate. Of particular note are enantiomerically pure embodiments of the more active Formula I isomer or its corresponding Formula II intermediate. 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, H-propyl, z'-propyl, or the different butyl, pentyl or hexyl isomers. The term "1-2 CH3" indicates that the substituent can be methyl or, when there is a hydrogen attached to the same atom, the substituent and said hydrogen can both be methyl. "Alkenyl" includes straight-chain or branched alkenes such as vinyl, 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. "Alkylene" denotes a straight-chain alkanediyl. Examples of "alkylene" include CH2CH2CH2, CH2CH2CH2CH2, CH2CH2CH2CH2CH2. "Alkenylene" denotes a straight-chain alkenediyl containing one olefinic bond. Examples of "alkenylene" include CH2CH=CH, CH2CH2CH=CH, CH2CH=CHCH2 and CH2CH=CHCH2CH2. "Alkoxy" includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers. "Alkoxyalkyl" denotes alkoxy substitution on alkyl. Examples of "alkoxyalkyl" include CH3OCH2, CH3OCH2CH2, CH3CH2OCH2, CH3CH2CH2CH2OCH2 and CH3CH2OCH2CH2. "Alkoxyalkoxy" denotes alkoxy substitution on alkoxy. "Alkenyloxy" includes straight-chain or branched alkenyloxy moieties. Examples of "alkenyloxy" include H2C=CHCH2O, (CH3)2C=CHCH2O, (CH3)CH=CHCH2O, (CH3)CH=C(CH3)CH2O and CH2=CHCH2CH2O. "Alkynyloxy" includes straight-chain or branched alkynyloxy moieties. Examples of "alkynyloxy" include HC≡CCH2O, CH3C≡CCH2O and CH3C_≡CCH2CH2O. "Alkylthio" includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers. "Alkylthioalkyl" denotes alkylthio substitution on alkyl. Examples of "alkylthioalkyl" include CH3SCH2, CH3SCH2CH2, CH3CH2SCH2, CH3CH2CH2CH2SCH2 and CH3CH2SCH2CH2. "Alkylthioalkylthio" denotes alkylthio substitution on alkylthio. Analogously, "alkylthioalkoxy" denotes alkylthio substitution on alkoxy. "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. "Alkenylthio" is defined analogously to the above examples. "Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. "Cycloalkenyl" includes groups such as cyclopentenyl and cyclohexenyl as well as groups with more than one double bond such as 1 ,3- and 1 ,4-cyclohexadienyl. "Trialkylsilylalkoxyalkoxy" denotes trialkylsilylalkoxy substitution on alkoxy. Examples of "trialkylsilylalkoxyalkoxy" includes, for example,- (CH3) SiCH2CH2OCH2O. The term "aromatic carbocyclic ring system" includes fully aromatic carbocycles and carbocycles in which at least one ring of a polycyclic ring system is aromatic (where aromatic indicates that the Huckel rule is satisfied). The term "nonaromatic carbocyclic ring system" denotes fully saturated carbocycles as well as partially or fully unsaturated carbocycles where the Huckel rule is not satisfied by any of the rings in the ring system. The term "aromatic heterocyclic ring system" includes fully aromatic heterocycles and heterocycles in which at least one ring of a polycyclic ring system is aromatic (where aromatic indicates that the Huckel rule is satisfied). The term "nonaromatic heterocyclic ring system" denotes fully saturated heterocycles as well as partially or fully unsaturated heterocycles where the Huckel rule is not satisfied by any of the rings in the ring system. The heterocyclic ring systems can be attached through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen. Examples of Z include CH3; CH2C1; CH Br; cyclopropyl; phenyl; naphthalenyl; anthracenyl; phenanthrenyl; lH-pyrrolyl; furanyl; thienyl; lH-pyrazolyl; lH-imidazolyl; isoxazolyl; oxazolyl; isothiazolyl; thiazolyl; lH-l,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; 1,2,4,5-tetrazinyl; lH-indolyl; benzofuranyl; benzo[b]thiophenyl; lH-indazolyl; lH-benzimidazolyl; benzoxazolyl; benzo thiazolyl; quinolinyl; isoquinolinyl; cinnolinyl; phthalazinyl; quinazolinyl; quinoxalinyl; 1 ,8-naphthyridinyl; pteridinyl; 2,3-dihydro-lH-indenyl; 1 ,2,3,4-tetrahydronaphthalenyl;
6,7,8,9-tetrahydro-5H-benzocycloheptenyl; 5,6,7,8,9, 10-hexahydrobenzocyclooctenyl; 2 ,3 -dihydro-3 -oxobenzofuranyl ; 1 ,3 -dihydro- 1 -oxoisobenzo furanyl ; 2,3-dihydro-2-oxobenzofuranyl; 3,4-dihydro-4ι-oxo-2H-l-benzopyranyl; 3,4-dihydro-l-oxo-lH-2-benzopyranyl; 3,4-dihydro-3-oxo-lH-2-benzopyranyl; 3,4-dihydro-2-oxo-2H- 1 -benzopyranyl; 4-oxo-4H- 1 -benzopyranyl; 2-oxo-2H-l-benzopyranyl; 2,3,4,5-tetrahydro-5-oxo-l-benzoxepinyl; 2,3,4,5-tetrahydro-2-oxo- 1 -benzoxepinyl; 2,3-dihydro- 1 ,3-dioxo- lH-isoindolyl; 1 ,2,3,4-tetrahydro- 1 ,3-dioxoisoquinolinyl; 3,4-dihydro-2,4-dioxo-2H- 1 ,3-benzoxazinyl; 2-oxo- 1 ,3-benzodioxyl; 2,3-dihydro- 1 , 1 ,3-trioxo- 1 ,2-benzisothiazolyl; 9H-fluorenyl; azulenyl; and thiazolo[2,3-c]-l,2,4-triazolyl; each group substituted with R9 and optionally substituted with one or more R10. 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.
The term "halogen", either alone or in compound words such as "haloalkyl", includes fluorine, chlorine, bromine or iodine. The term "1-2 halogen" indicates that one or two of the available positions for that substituent may be halogen which are independently selected. 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, C1CΗ2, CF3CH2 and CF3CC12. The terms "haloalkenyl", "haloalkynyl", "haloalkoxy", 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, CC13G__C and FCH2C__€CH2. 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. The total number of carbon atoms in a substituent group is indicated by the "Cj-Cj" prefix where i and j are numbers from 1 to 10. For example, Cj-C3 alkylsulfonyl designates methylsulfonyl through propylsulfonyl. Examples of "alkylcarbonyl" include C(O)CH3, C(O)CH2CH2CH3 and C(O)CH(CH3)2. Examples of "alkoxycarbonyl" include
CH3OC(=O), CH3CH2OC(=O), CH3CH2CH2OC(=O), (CH3)2CHOC(=O) and the different butoxy- or pentoxycarbonyl isomers. In the above recitations, when a compound of Formula I is comprised of one or more heterocyclic rings, all substituents are attached to these rings through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.
When a group contains a substituent which can be hydrogen, for example R9 or R13, then, when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted.
This invention also relates to fungicidal formulations which comprise a fungicidally effective amount of the enantiomerically enriched compositions described above and which include at least one of a surfactant, a solid diluent or a liquid diluent. The preferred fungicidal formulations of the present invention are those which comprise the above preferred enantiomerically enriched compositions. This invention also relates to a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof, or to the plant seed or seedling, a fungicidally effective amount of the enantiomerically enriched compositions of the invention (e.g., as a fungicidal formulation described herein). The preferred methods of use are those involving the above preferred enantiomerically enriched compositions. This invention also relates to arthropodicidal formulations which comprise arthropodicidally effective amounts of the enantiomerically enriched compositions described above and which includes at least one of a surfactant, a solid diluent or a liquid diluent. The preferred arthropodicidal formulations of the present invention are those which comprise the above preferred enantiomerically enriched compositions.
This invention also relates to a method for controlling arthropods comprising contacting the arthropods or their environment with an arthropodicidally effective amount of the enantiomerically enriched compositions of the invention (e.g., as an arthropodicidal formulation described herein). The preferred methods of use are those involving the above preferred enantiomerically enriched compositions.
DETAILS OF THE SYNTHESIS The compounds of Formula I can be prepared by one or more of the following methods and variations as described in Schemes 1-46. The definitions of T, A, G, U, V, W, X, Y, Z, R*-R13, R15-R18, R 2-R34, m, n, p, q, r and s in the compounds of Formulae 1-62 below are as defined above in the Summary of the Invention or as defined below in Schemes 1-46. Compounds of Formulae Ia-Iy are various subsets of the compounds of Formula I, and all substituents for Formulae Ia-Iy are as defined above for Formula I. Compounds of Formula 1-62 in Schemes 1-46 are depicted, for ease of illustration, without stereochemistry indicated. One skilled in the art will recognize that not all intermediates depicted can exhibit atropic stereochemical behavior; however, they may contain stereochemical centers in substituents which are symbolized by the letters listed above and defined as in the Summary of the Invention. Such stereocenters, in combination with atropic centers in intermediates later in a synthetic sequence, may allow separation of diastereomers by fractional crystallization, distillation or kinetic resolution techniques. Separation of racemic mixtures of atropic enantiomers may be effected by chromatography with a chiral stationary phase. Kinetic resolutions of intermediates containing atropic centers may also be effected by enantioselective processes in which one enantiomer is more reactive than the other enantiomer. Such processes may result in the selective destruction or degradation of one enantiomer to a simpler derivative, or selective conversion of one enantiomer into a more complex derivative. Kinetic resolutions can be effected by enzymatic processes or by chemical conversions using chiral auxiliaries. Such kinetic resolution techniques are well known to one skilled in the art. Compounds in which the stereochemistry is undefined in Scheme 1-46 may either be racemic mixtures or specific enantiomers depending on the context of any given synthesis. Resolution of any diastereomeric or enantiomeric material illustrated in the Schemes is implied. In some instances, specific sequences of diastereomeric separations or operations are illustrated to demonstrate methods for obtaining resolved intermediates. Enantiomeric purity of materials will be expressed as % enantiomeric excess, which is a measure of enantiomeric enrichment relative to the racemic mixture of atropic enantiomers. Optical rotations are expressed as (+) or (-) and are reported as specific rotations using the sodium D-line. One skilled in the art will recognize that optical rotations are empirical measurements and do not provide information about the absolute configuration of the atropic center. Absolute configurations of the atropic centers can be described using the R or S descriptors using the Cahn-Ingold-Prelog system. One skilled in the art will recognize that the assignment of priority among the substituents U, Y-Z, and the substituents on T in compounds of formula I may result in the description of the atropic center of the active enantiomer to be R in some cases and S in others. However, for any given T, the relative configuration among the substituents for the active enantiomer is expected to be the same for any U and Y-Z combination. When the active atropic enantiomers of compounds of Formula I can be correlated to a specific intermediate of known optical activity, that is indicated in the disclosure.
For a general reference on stereochemistry, see E. L. Eliel, S. H. Wilen and L. N. Mander Stereochemistry of Organic Compounds, (John Wiley & Sons, New York, N. Y.
1994). For a general reference on enantiomers, racemates and resolutions, see J. Jacques, A. Collet, and S. H. Wilen, Enantiomers, Racemates, and Resolutions, (John Wiley & Sons, New York, N. Y. ,1981).
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 T is T1 and R2 is H may exist as tautomer la or lb, or both la and lb. The present invention comprises all tautomeric forms of compounds of Formula I where T = T1.
Figure imgf000017_0001
la lb
The compounds of Formula I where T = T1 can be prepared as described below in Procedures 1) to 5). Procedures 1) to 4) describe syntheses involving construction of the heterocycle after the formation of the aryl moiety. Procedure 5) describes syntheses of the aryl moiety with the T-moiety already in place. 1) Alkylation Procedures
The compounds of Formula Ic, compounds of Formula I where T = T1, are prepared by treating compounds of Formula 1 with an appropriate alkyl transfer reagent in an inert solvent with or without additional acidic or basic reagents or other reagents (Scheme 1). Suitable solvents are selected from the group consisting of polar aprotic solvents such as acetonitrile, dimethylformamide or dimethyl sulfoxide; ethers such as tetrahydrofuran, dimethoxyethane, or diethyl ether; ketones such as acetone or 2-butanone; hydrocarbons such as toluene or benzene; and halocarbons such as dichloromethane or chloroform.
Scheme 1
Methods 1-4
Figure imgf000018_0002
Figure imgf000018_0001
Ic
X^ OH orSH X = OR1 or SR1
Method 1: Ql-CH=N (Q1 = H or (CH3)3Si)
2
Method 2:
Lewis acid
Figure imgf000018_0003
Method 3: (R1)30+ BF4-
4
Method 4: (R1)2S04; R1OS02Q; or R^-hal; optional base (hal = F, Cl, Br, or I) (Q = C ΓC6 alkyl, C rC6 haloalkyl)
For example, compounds of Formula Ic, compounds of Formula I where T = T1, can be prepared by the action of diazoalkane reagents of Formula 2 such as diazomethane (Q1 = H) or trimethylsilyldiazomethane (Q1 = (CH3)3Si) on compounds of Formula 1 (Method 1). Use of trimethylsilyldiazomethane requires a protic cosolvent such as methanol. For examples of these procedures, see Chem. Pharm. Bull., (1984), 32, 3759. As indicated in Method 2, compounds of Formula Ic, compounds of Formula I where T = T1, can also be prepared by contacting carbonyl compounds of Formula 1 with alkyl trichloroacetimidates of Formula 3 and a Lewis acid catalyst. Suitable Lewis acids include trimethylsilyl triflate and tetrafluoroboric acid. The alkyl trichloroacetimidates can be prepared from the appropriate alcohol and trichloroacetonitrile as described in the literature (J. Danklmaier and H. Hόnig, Synth. Commun., (1990), 20, 203).
Compounds of Formula Ic, compounds of Formula I where T = T1, can also be prepared from compounds of Formula 1 by treatment with a trialkyloxonium tetrafluoroborate (e.g., Meerwein's salt) of Formula 4 (Method 3). The use of trialkyloxonium salts as powerful alkylating agents is well known in the art (see U. Schollkopf, U. Groth, C. Deng, Angew. Chem., Int. Ed. Engl, (1981), 20, 798).
Other alkylating agents which can convert compounds of Formula 1 to compounds of Formula Ic where T = T1, are dialkyl sulfates such as dimethyl sulfate, haloalkyl sulfonates such as methyl trifluoromethanesulfonate, and alkyl halides such as iodomethane and propargyl bromide (Method 4). These alkylations can be conducted with or without additional base. Appropriate bases include alkali metal alkoxides such as potassium tert-butoxide, inorganic bases such as sodium hydride and potassium carbonate, pyridine, or tertiary amines such as triethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and triethylenediamine. See R. E. Benson, T. L. Cairns, J. Am. Chem. Soc, (1948), 70, 2115 for alkylation examples using agents of this type.
Compounds of Formula la (compounds of Formula 1 wherein G = C, W = O and X1 = OH) can be prepared by condensation of malonates or malonate derivatives of Formula 5 with an ambident nucleophile of Formula 6 (Scheme 2). The nucleophiles of Formula 6 are N-substituted hydroxylamines (HO-ΝHR2) and substituted hydrazines (HΝ(R3)-ΝHR2). Examples of such nucleophiles are N-methylhydroxylamine and methylhydrazine. The malonate esters of Formula 5 (E = O(C C4 alkyl)) can be prepared by methods described hereinafter. The esters of Formula 5 can also be activated by first hydrolyzing the ester to form the corresponding carboxylic acid, and then converting the acid into the acid chloride (E = Cl) using thionyl chloride or oxalyl chloride, or into the acyl imidazole (E = 1-imidazolyl) by treating with 1,1 -carbonyldiimidazole. Scheme 2
Figure imgf000020_0001
E = 0(C i -C4 alkyl), Cl, 1 -imidazolyl l a
Esters of Formula 5a can be prepared from copper (I)-catalyzed reaction of malonate esters with substituted iodobenzenes of Formula 8 according to methods adapted from A. Osuka, T. Kobayashi and H. Suzuki, Synthesis , (1983), 67, and illustrated in Scheme 3.
Scheme 3
Figure imgf000020_0002
5a R = Cι-C4 alkyl
Additionally, the malonate esters of Formula 5a can be prepared by treating phenyl acetic acid esters of Formula 9a with a dialkyl carbonate or alkyl chloroformate in the presence of a suitable base such as, but not limited to, sodium metal and sodium hydride (Scheme 4). For example, see J. Am. Chem. Soc, (1928), 50, 2758.
Scheme 4
Figure imgf000020_0003
9a E ! = OR R = Cι-C4 alkyl
Esters of Formula 9a (compounds of Formula 9 wherein E1 is OR) can be prepared from acid-catalyzed alcoholysis of phenyl acetonitriles of Formula 10 or by esterification of phenyl acetic acids of Formula 1 1 as illustrated in Scheme 5 (see Org. Synth., Coll. Vol. I, (1941), 270).
Scheme 5
Figure imgf000021_0001
10 9a 11
R = C1-C4 alkyl
Phenyl acetic acid esters of Formula 9b (compounds of Formula 9a wherein Y is Y1) can also be prepared by copper (I)-catalyzed condensation of phenyl halides of Formula 12 with compounds of Formula 13 as described in EP-A-307,103 and illustrated below in Scheme 6.
Scheme 6
Figure imgf000021_0002
Compounds of Formula 12 can be prepared by the Arndt-Eistert synthesis starting from benzoic acids of Formula 14 as illustrated in Scheme 7, (see F. Arndt, B. Eistert, Ber. 68, 200 (1935); T. Aoyama, T. Shioiri, Tetrahedron Letters 21, 4461 (1980)). For example, treatment of benzoic acids of Formula 14 with a halogenating agent such as thionyl chloride followed by addition of an alkylating agent such as diazomethane yields an intermediate that can be quenched with R-OH in an appropriate solvent to afford the desired ester 12. Scheme 7
Figure imgf000022_0001
Compounds of Formula 14 can be prepared from nitrobenzoic acids of Formula 15 by a modification of the Sandmeyer Reaction as taught in S. Kanoh, H. JViuramoto, N. Kobayashi, M. Motoi and H. Suda, Bull. Chem. Soc. Jpn. 60, 3659 (1987) and M. P. Doyle, J. Org. Chem. 42, 2426 (1977) (Scheme 8). Nitrobenzoic acids of Formula 15 where U = CH3 and V = H are commercially available as are the corresponding anthranilic acids (where the nitro group is replaced by an amino group). Where U = CH3 and V = 5-CH3 the compound can be prepared by nitration and reduction of commercially available 2,5-dimethylbenzoic acid as taught in A.N. Fugiwara, E. M. Acton, Can. J. Chem. 48, 1346 (1970).
Scheme 8
Figure imgf000022_0002
15 14
Some esters of Formula 9c can also be prepared by forming the Y2 bridge using conventional nucleophilic substitution chemistry (Scheme 9). Displacement of an appropriate leaving group (Lg) in electrophiles of Formula 17 or 18 with a nucleophilic ester of Formula 16 affords compounds of Formula 9c. A base, for example sodium hydride, is used to generate the corresponding alkoxide or thioalkoxide of the compound of Formula 16. Scheme 9
Figure imgf000023_0001
16 9c
R = C!-C4 alkyl
R28 = OH, SH, CH2OH, CH2SH γ2 - _0-, -OCH2-, -SCHR15-, -CH 0-, -CU2S(p)n-
Lg = Br, Cl, I, OS02CH3, OS02(4-Me-Ph)
Compounds of Formula 16 can be prepared from compounds of Formula 12 by methods taught in Chem. Pharm. Bull. 33 (12), 5184 (1985) orJ. Org. Chem. 53 (2) 439, (1988). For example, treatment of compounds of Formula 12 with a metal hydroxide, such as sodium hydroxide, in a polar protic solvent in the presence of a metal species such as copper yields compound 16a (compounds of Formula 16 where R28 is OH). Compounds of Formula 16b (compounds of Formula 16 where R28 is CH2OH or CH2SH) can be prepared by metal -halogen exchange in compounds of Formula 12 followed by quenching with the appropriate electrophile. For example, treatment of compounds of Formula 12 with a suitable alkyllithium such as /.-Butyllithium in an inert solvent such as ether or tetrahydrofuran (THF) followed by quenching with an electrophile such as paraformaldehyde would yield compound of Formula 16b (where R28 is CH2OH), (see B. J. Wakefield Organolithium Methods; Academic Press: New York, (1988)). Alternatively quenching the metalated species with a formaldehyde equivalent D-CHO (where D is (CH3)2N, or OMe) followed by reduction of the aldehyde with a suitable reducing agent yields compounds of Formula 16b. Examples of such reducing agents are sodium borohydride (NaBH4), sodium cyanoborohydride (NaCNBH4) and diisobutylaluminum hydride (DIBAL-H) (Scheme 10). Suitable inert solvents are methanol, ethanol, methylene chloride and THF, (see M. Hudlicky, Reductions in Organic Chemistry; John Wiley & Sons: New York, (1986)). Scheme 10
Figure imgf000024_0001
Some esters of Formula 9d can also be prepared by forming the Y3 bridge from substituted hydroxylamines 16d and carbonyl compounds 19. The hydroxylamines 16d are in turn prepared from esters 16c. Compounds of Formula 16c where the Lg is Br, Cl, I, OSO2CH3 or OSO2(4-Me-Ph) can be prepared from compounds of Formula 16b, (see March, J. Advanced Organic Chemistry; 3rd ed., John Wiley: New York, (1985). This method has been described in EP-A-600,835 and is illustrated in Scheme 11. Esters of Formula 9d can be used to prepare compounds of Formula Id wherein T = T2 or T3 by methods described in EP-A-600,835.
Scheme 1 1
Figure imgf000024_0002
16d B = CHR1 ONH2 • HC1 Y3 = -CHRl ON=C(R7)-
2) Displacement and Conjugate Addition/Elimination Procedures Compounds of Formula Ic, compounds of Formula I where T = T1, can also be prepared by reaction of Formula 20 compounds with alkali metal alkoxides (R1O"M+) or alkali metal thioalkoxides (R^'M -) in a suitable solvent (Scheme 12). The leaving group Lg1 in the amides of Formula 20 is any group known in the art to undergo a displacement reaction of this type. Examples of suitable leaving groups include chlorine, bromine, and sulfonyl and sulfonate groups. Examples of suitable inert solvents are dimethylformamide or dimethyl sulfoxide. Scheme 12
Figure imgf000025_0001
20 Ic
Lg1 = Cl, Br, -S02Q, or -OS02Q
Q = CrC6 alkyl or Cj-Cg haloalkyl M = K or Na
Compounds of Formula 20a can be prepared from compounds of Formula Id (compounds of Formula 1 wherein X1 is OH) by reaction with halogenating agents such as thionyl chloride or phosphorus oxybromide to form the corresponding β-halo-substituted derivatives (Scheme 13). Alternatively, compounds of Formula Id can be treated with an alkylsulfonyl halide or haloalkylsulfonyl anhydride, such as methane sulfonyl chloride, />-toluenesulfonyl chloride, and trifluoromethanesulfonyl anhydride, to form the corresponding β-alkylsulfonate of Formula 20b. The reaction with the sulfonyl halides may be performed in the presence of a suitable base (e.g., triethylamine).
Scheme 13
Figure imgf000025_0002
Id 20a Lg1 = Cl or Br
Q = Cl-C6 alkyl or C rC6 haloalkyl 20b Lg! = -OS02Q hal = Br, Cl or F
As illustrated in Scheme 14, sulfonyl compounds of Formula 20c (compounds of Formula 20 where Lg1 is QSO2-) can be prepared by oxidation of the corresponding thio compound of Formula 21 using well-known methods for the oxidation of sulfur (see Schrenk, K. in The Chemistry ofSulphones and Sulphoxides; Patai, S. et al., Eds.; Wiley: New York, (1988)). Suitable oxidizing reagents include metα-chloro-peroxybenzoic acid, hydrogen peroxide and Oxone® (KHSO5).
Scheme 14
oxidizing agent
Figure imgf000026_0001
Figure imgf000026_0002
21 20c
Q = CrC6 alkyl or C^Cg haloalkyl
Alternatively, halo-compounds of Formula 20d (compounds of Formula 20 wherein A = N, G = N, and W = O) can be prepared from hydrazides of Formula 22 as illustrated in Scheme 15. When R29 = C(=S)S(Cι-C4 alkyl), the compound of Formula 22 is treated with excess of a thionyl halide such as thionyl chloride. The product formed first is the ring-closed compound of Formula 23 which can be isolated or converted in situ to the compound of Formula 20d; see P. Molina, A. Tarraga, A. Espinosa, Synthesis, (1989), 923 for a description of this process.
Alternatively, when R29 = R2 as defined above, the hydrazide of Formula 22 is cyclized with phosgene to form the cyclic urea of Formula 20d wherein hal = Cl. This procedure is described in detail inJ. Org. Chem., (1989), 54, 1048.
R29
Figure imgf000027_0001
20d hal = Cl, Br, I
The hydrazides of Formula 22 can be prepared as illustrated in Scheme 16. Condensation of the isocyanate of Formula 24 with the hydrazine of Formula H2NNR R29 in an inert solvent such as tetrahydrofiiran affords the hydrazide.
Scheme 16
Figure imgf000027_0002
24 22
R29 = C(=S)S(Cj-C4 alkyl) or R2 3) Conjugate Addition/Cvclization Procedures
In addition to the methods disclosed above, compounds of Formula I wherein T is T1, X = SR1 and G = C (Formula Ie) can be prepared by treating a ketenedithioacetal of Formula 25 with an ambident nucleophile of Formula 6 (Scheme 17). The nucleophiles of Formula 6 are described above.
Scheme 17
kyl)
Figure imgf000028_0001
Figure imgf000028_0002
25 Ie
Ketene dithioacetals of Formula 25a (compounds of Formula 25 wherein R30 is CO2(CrC4 alkyl)) or 25b (compounds of Formula 25 wherein R30 is C(=O)NHQ2) can be prepared by condensing phenyl acetic acid esters of Formula 9a or amides of Formula 9e, (compounds of Formula 9 wherein E1 is NHQ2) respectively, with carbon disulfide in the presence of a suitable base, followed by reaction with two equivalents of an R1 -halide, such as iodomethane or propargyl bromide (Scheme 18).
Scheme 18
Figure imgf000028_0003
9a 25a
R = C j-C4 alkyl
Figure imgf000029_0001
Q2 = H, CrC6 alkyl, C rC6 alkoxy
Compounds of Formula le (compounds of Formula 1 wherein A = N and G = N) can be prepared by condensation of N-amino-ureas of Formula 26 with a carbonylating agent (Scheme 19). The carbonylating agents are carbonyl or thiocarbonyl transfer reagents such as phosgene, thiophosgene, diphosgene (ClC(=O)OCCl3), triphosgene (Cl3COC(=O)OCCl3), NN'-carbonyldiimidazole, N,N-thiocarbonyldiimidazole, and l, -carbonyldi(l,2,4-triazole). Alternatively, the carbonylating agents can be alkyl chloroformates or dialkyl carbonates. Some of these carbonylating reactions may require the addition of a base to effect reaction. Appropriate bases include alkali metal alkoxides such as potassium tert-butoxide, inorganic bases such as sodium hydride and potassium carbonate, pyridine, or tertiary amines such as triethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or triethylenediamine. Suitable solvents include polar aprotic solvents such as acetonitrile, dimethylformamide, or dimethyl sulfoxide; ethers such as tetrahydrofiiran, dimethoxyethane or diethyl ether; ketones such as acetone or 2-butanone; hydrocarbons such as toluene or benzene; or halocarbons such as dichloromethane or chloroform. The reaction temperature can vary between 0 °C and 150 °C and the reaction time can be from 1 to 72 hours depending on the choice of base, solvent, temperature, and substrates.
Scheme 19
Figure imgf000029_0002
26 le
Q3 and Q4 are independently Cl, OCCl3, 0(C rC4 alkyl), 1-imidazolyl, 1,2,4-triazolyl X1 = OH or SH χ2 = O or S N-Amino-ureas of Formula 26 can be prepared as illustrated in Scheme 20. Treatment of an aniline of Formula 27 with phosgene, thiophosgene, NN'-carbonyldiimidazole, or NN'-thiocarbonyldiimidazole produces the isocyanate or isothiocyanate of Formula 28. A base can be added for reactions with phosgene or thiophosgene. Subsequent treatment of the iso(thio)cyanate with an R2-substituted hydrazine produces the N-amino-urea of Formula 26.
Scheme 20
Figure imgf000030_0001
w = o, S 26
Compounds of formula 28a can be treated with alkyl hydrazinocarboxyla.es to provide compounds of Formula 28b. Subsequent treatment with excess base followed by alkylation according to Method 4 , Scheme 1 provides compounds of Formula (+/-)-21a. Compounds of Formula (+/-)-21a can be resolved by treatment with a suitable enantiomerically pure reagent to provide a mixture of two diastereomers of Formula 21b, which can be separated by, for example, fractional crystallization, distillation or chromatography. Subsequent removal of the chiral auxiliary will allow isolation of enantiomerically enriched (+)-21a or (-)-21a. Suitable enantiomerically pure reagents include, but are not limited to, acid chlorides or anhydrides, chloroformates, alkyl halides or sulfonates or iso(thio)cyanates. Removal of the chiral auxiliary R* is dependent on the nature of R* and conditions appropriate for removal of any particular R* are well-known in the art. (Scheme 20a illustrates this resolution sequence with an acid chloride as the enantiomerically pure reagent and the subsequent removal of the chiral auxiliary can be accomplished by reaction with alkali metal hydroxides or alkoxides.) Alkylation of the enantiomerically enriched 21 a with alkylating reagents provides compounds of Formula 21 c which can be treated according to Schemes 14 and 12 to provide compounds of Formula Ic (where G = N, A = N, and the floating double bond is attached to A).
Scheme 20A
4
Figure imgf000031_0001
28a 28b
Figure imgf000031_0002
Figure imgf000031_0003
21b (-)-21a
R2-Lg3 Scheme 14 Scheme 12
Figure imgf000031_0005
Figure imgf000031_0004
21c Ic
R = Cι-C4 alkyl W = O, A = N, X = O, S, G = N
R* = enantiomerically pure moiety X = OR! or SR1
Lg3 = Br, I, R2OS02-, -OS02Me Floating double bond attached to A
Base induced cyclization of compounds of Formula 28b provides a racemic mixture of compounds of Formula 28c. Resolution of compounds of Formula 28c can be achieved by reaction with a chiral amine followed by fractional crystallization. Acidification of the diastereomerically enriched salts allows the isolation of enantiomerically enriched compounds of Formula (+)-28c or (-)-28c. Such resolution sequences are well known in the art. For a general reference, see J. Jacques, A. Collet and S. H. Wilen, Enantiomers, Racemates, and Resolutions, John Wiley & Sons, New York, N. Y. 1981. Alkylation with two equivalents of a suitable alkylating agent R2-Lg3 provides compounds of Formula 2 Id, which can be converted by methods previously described in Scheme 20a to compounds of Formula Ic.
Scheme 20b
Figure imgf000032_0001
(+/-)-28c
1) Chiral Amine
2) Separate
3) Acidify
Figure imgf000032_0002
(+) - 28c or 21d (-) - 28c
Lg3 = Br, I, R2θS02-, MeS020-
Anilines of Formula 27a (compounds of Formula 27 where Y = Y4) can be prepared from nitro compounds of Formula 29 by reduction methods well known in the art, Scheme 21 (see M. Hudlicky, Reductions in Organic Chemistry; John Wiley & Sons pp. 69-76 (1986)). Scheme 21
"reduction"
Figure imgf000033_0001
Figure imgf000033_0002
29 27a
Y = -CH20-, -CHR150-N= C(R7)-, -CH2S(0)n-
Compounds of Formula 29 can be prepared by contacting benzyl halides, mesylates or tosylates of Formula 30 with various nucleophiles (Scheme 22). The appropriate alcohol or thiol is treated with a base, for example sodium hydride, to form the corresponding alkoxide or thioalkoxide which acts as the nucleophile.
Scheme 22
Figure imgf000033_0003
Lg = Br, Cl, I, OS02CH3, OS02(4-Me-Ph)
Compounds of Formula 30 can be prepared from corresponding nitrobenzyl alcohols of Formula 30a (compounds of Formula 30 where the Lg group has been replaced with OH) by reaction with halogenating agents such as thionyl chloride or phosphorus oxybromide to form the corresponding β-halo-substituted derivatives (Scheme 23). Compounds of Formula 30a can also be treated with an alkylsulfonyl halide or haloalkylsulfonyl anhydride, such as methane sulfonyl chloride, /?-toluenesulfonyl chloride, and trifluoromethanesulfonyl anhydride, to form the corresponding β-alkylsulfonate of Formula 30. The reaction with the sulfonyl halides may be performed in the presence of a suitable base (e.g., triethylamine). Scheme 23
Figure imgf000034_0001
Compounds of Formula 30a can be prepared by reduction of nitrobenzoic acids of Formula 31 with a suitable reducing agent, such as borane in tetrahydrofiiran or dimethyl sulfide as taught in M. Pavia, W. H. Moos and F. M. Hershenson, J. Org. Chem. 55, 560, (1990) or C. F. Lane, H. L. Myatt, j. Daniels and H. B. Hopps J. Org. Chem. 39, 3052, (1974) (Scheme 24).
Scheme 24
Figure imgf000034_0002
Compounds of Formula lf (compounds of Formula 1 wherein A = CR4, G = N, and X = O) can be prepared by the methods illustrated in Scheme 25. Ureas of Formula 32 are reacted with activated 2-halocarboxylic acid derivatives such as 2-halocarboxylic acid chlorides, 2-halocarboxylic acid esters or 2-haloacyl imidazoles of Formula 33. The initial acylation on the aniline nitrogen is followed by an intramolecular displacement of the 2-halo group to effect cyclization. Base may be added to accelerate the acylation and/or the subsequent cyclization. Suitable bases include triethylamine and sodium hydride. Alternatively, Formula lf compounds can be prepared by reaction of Formula 28 iso(thio)cyanates with Formula 35 esters. As described above, base may be added to accelerate the reaction and subsequent cyclization to Formula 1 f compounds. Compounds of Formula lg (where T = T5, s = 0) may be prepared by reaction of isocyanates of Formula 28 with compounds of Formula 35a to provide compounds of Formula 34. Reaction of compounds of Formula 34 with alkylating agents according to the previously described Method 4 (Scheme 1) allows formation of compounds of Formula 34a. Similarly, compounds of Formula 34c may be prepared by reaction of isocyanates of Formula 28 with compounds of Formula 35b to provide compounds of Formula 34b, followed by Method 4. Scheme 25
CHR4— hal
Figure imgf000035_0001
Figure imgf000035_0002
The (thio)ureas of Formula 32 can be prepared by either of the methods illustrated in Scheme 26. The anilines of Formula 27 can be contacted with an isocyanate or isothiocyanate of Formula R2N=C=W as described above. Alternatively, an iso(thio)cyanate of Formula 28 can be condensed with an amine of Formula R2-NH2 to form the (thio)urea. The anilines and iso(thio)cyanates of Formulae 27 and 28, respectively, are commercially available or prepared by well-known methods. For example, isothiocyanates can be prepared by methods described inJ. Heterocycl. Chem., (1990), 27, 407. Isocyanates can be prepared as described in March, J. Advanced Organic Chemistry; 3rd ed., John Wiley: New York, (1985), pp 944, 1166.
Scheme 26
Figure imgf000036_0001
28 W = O or S
4) Thionation Procedures
Compounds of Formula If (compounds of Formula Ic wherein W = S) can be prepared by treating compounds of Formula lg (compounds of Formula Ic wherein W = O) with thionating reagents such as P S5 or Lawesson's reagent [2,4-bis(4- methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulfide] as illustrated in Scheme 27 (see Bull. Soc. Chim. Belg., (1978), 87, 229; and Tetrahedron Lett., (1983), 24, 3815).
Scheme 27
Figure imgf000036_0002
If lg X ^ ORi or SR1 5) Aryl Moiety Synthesis Procedures
Compounds of Formula Ik (compounds of Formula I wherein Y is Y4) can be prepared by displacing the appropriate leaving group (Lg) in electrophiles of Formula 36 with various nucleophiles (Scheme 29).
Scheme 29
Figure imgf000037_0001
HS-Z; base 36 Ik
Y4 = -CH 0-, -CH150-N=C(R7)-, -CH S(0)n- The appropriate alcohol or thiol is treated with a base, for example sodium hydride, to form the corresponding alkoxide or thioalkoxide which acts as the nucleophile. Compounds of Formula Ik (compounds of Formula I wherein T = T2 and Y = Y4 is as defined in Scheme 29) can be prepared according to methods described in the following references: for Y4 = -CH2O-, EP-A-278,595 and EP-A-472,224; for Y4 = -CH2S(O)n-, EP-A-379,098; for Y4 = -CHR15O-N=C(R7)-, EP-A-370,629 and WO 94/05620. Compounds of Formula Ik (compounds of Formula I wherein T = T3 and Y = Y4 is as defined in Scheme 29) can be prepared according to methods described in the following references: for Y4 = -CH2O-, EP-A-253,213, EP-A-498,188 and EP-A-554,767; for Y4 = CH2S(O)n, EP-A-374,811; for Y4 = -CHR O-N=C(R7)-, EP-A-414,153, EP-A-472,300, EP-A-515,901, and WO 92/18494.
Compounds of racemic (+/-) Formula 37 (Scheme 30) can be resolved into the separated enantiomers (+) - 37 and (-) - 37, in some cases, by treatment with a suitable enantiomerically pure reagent to provide a mixture of two diastereomers of Formula 37a, which can sometimes be separated by, for example, fractional crystallization, distillation or chromatography. Subsequent removal of the chiral auxiliary will allow isolation of enantiomerically enriched (+) - 37 or (-) - 37. Suitable enantiomerically pure reagents include, but are not limited to, acid chlorides or anhydrides, chloroformates, alkyl halides or sulfonates or iso(thio)cyanates. Removal of the chiral auxiliary R* is dependent on the nature of R* and conditions appropriate for removal of any particular R* are well-known in the art. (Scheme 30 illustrates this resolution sequence with an acid chloride as the enantiomerically pure reagent and the subsequent removal of the chiral auxiliary can be accomplished by reaction with alkali metal hydroxides or alkoxides.) When R3 * = OH, U = methyl and V = H, (+) - 37 when reacted as described subsequently in Scheme 30 leads to the active enantiomer of compounds of Formula Im. A similar diastereomeric resolution sequence can be performed on (+/-) - 37b, where T = T2, T3, T4, T5 or T6. Reaction with electrophiles of Formula 17 or 18 with compounds of Formula (+) - 37b or (-) - 37b provides compounds of Formula Im where T = T2, T3, T4, T5 or T6.
Compounds of Formula Im (compounds of Formula I where T is T1, X is OR1, R1 is CH3, R2 is CH3, W is O, A is N, G is N, Y5 is -O-, -OCH2- or -SCHR15-) can be prepared by forming the Y5 bridge using conventional nucleophilic substitution chemistry (Scheme 30). Displacement of an appropriate leaving group (Lg) in electrophiles of Formula 17 or 18 with nucleophilic compounds of Formula 37 affords compounds of Formula Im. A base, for example sodium hydride, is used to generate the corresponding alkoxide or thioalkoxide of the compounds of Formula 37.
Scheme 30
Figure imgf000038_0001
(+/-) - 37 37a R31 = OH or SH W! = O or S
Figure imgf000038_0002
(+) - 37 or (-) - 37
Figure imgf000038_0003
Figure imgf000039_0001
Compounds of racemic (+/-) Formula 37 may also be resolved by conversions to acids or bases. These acids or bases can then be converted into diastereomeric salts by treatment with enantiomerically pure acids or bases. Separation of the diastereomeric salts, when possible, followed by removal of the acid or base functionality affords the resolved compounds of Formula 37. Reagents for the conversion of compounds of Formula 37 to acids or bases include, but are not limited to, anhydrides, diacids, diesters, amino acids, and sulfur trioxide. For further details about this resolution strategy see J. Jacques, A. Collet, and S. H. Wilen, Enantiomers, Racemates and Resolutions (Krieger Publishing Co., Malabar, FL 1994). A specific example of this method is shown in Scheme 30A. Treatment of racemic (+/-)-37b (R31 = OH) with a sulfiir trioxide reagent (sulfur trioxide or sulfur trioxide adducts such as sulfur trioxide dimethylformamide or sulfur trioxide pyridine) followed by a chiral amine gives diastereomeric sulfates. Separation of these sulfates, typically by crystallization, followed by acid hydrolysis affords the resolved compounds (+)-37b and (-)-37b.
Scheme 30a
Figure imgf000039_0002
(+/-) - 37b R31 = OH
Figure imgf000039_0003
Benzyl halides of Formula 38 can be prepared by radical halogenation of the corresponding alkyl compound of Formula 39a, see WO 96/38425. Benzyl halides can also be prepared by the acidic cleavage of the corresponding methyl ether of Formula 39b under conditions which provide the halide, see Scheme 31. Methods for preparing the corresponding compounds of Formula 38a wherein T is T2 are described in WO 94/05620. Methods for preparing the corresponding compounds of Formula 38a wherein T is T3 are described in EP-A-254,426, EP-A-299,694 and AU-A-55899/90.
Scheme 31
Figure imgf000040_0001
38
39a R32 = H 39b R32 = OCH3
Figure imgf000040_0002
Alternatively compounds of Formula 38 can be prepared from the corresponding alcohol of Formula 40 by reaction with halogenating agents such as thionyl chloride or phosphorus oxybromide to form the corresponding β-halo-substituted derivatives.
Alternatively, compounds of Formula 40 can be treated with an alkylsulfonyl halide or haloalkylsulfonyl anhydride, such as methane sulfonyl chloride, /? -toluenesulfonyl chloride, and trifluoromethanesulfonyl anhydride, to form the corresponding β-alkylsulfonate of Formula 41. The reaction with the sulfonyl halides may be performed in the presence of a suitable base (e.g., triethylamine) see Scheme 32.
Compounds of racemic (+/-) Formula 40 (Scheme 32) can be resolved into the separated enantiomers (+) - 40 and (-) - 40 by treatment with a suitable enantiomerically pure reagent to provide a mixture of two diastereomers of Formula 40a, which can be separated by, for example, fractional crystallization, distillation or chromatography. Subsequent removal of the chiral auxiliary will allow isolation of enantiomerically enriched (+) - 40 or (-) - 40. Suitable enantiomerically pure reagents include, but are not limited to, acid chlorides or anhydrides, chloroformates, alkyl halides or sulfonates or iso(thio)cyanates. Removal of the chiral auxiliary R* is dependent on the nature of R* and conditions appropriate for removal of any particular R* are well-known in the art. (Scheme 32 illustrates this resolution sequence with an acid chloride as the enantiomerically pure reagent and the subsequent removal of the chiral auxiliary can be accomplished by reaction with alkali metal hydroxides or alkoxides.) Reaction of compounds of Formula (+/-)-40 with chiral sulfonates such as enantiomerically enriched camphorsulfonyl chloride, followed by separation of the resulting diastereomers results in compounds of Formula 41a which are diastereomerically resolved. Subsequent reaction of compounds of Formula 41a containing such chiral sulfonates according to procedures outlined in Scheme 29 would result in enantiomerically enriched compounds of the present invention. A similar diastereomeric resolution sequence can be performed on (+/-) - 40b, where T = T2, T3, T4, T5 or T6. Subsequent treatment of the enantiomerically enriched (+) - 40 or (-) - 40 with the reagents previously described will provide enantiomerically enriched compounds of formula 38 or 41. For a recent review of kinetic resolutions of secondary alcohols, see Angew. Chem. Int. Ed., Engl. 1997 36, 2731.
Figure imgf000041_0001
*camphorsulfonyl chloride
(+/-) - 40
38 Lg2 = Cl, Br
R*COCl 41 Lg2 = OS02 or OS02 (4-Me.Ph) base
41a Lg2 = *camphorS(02)0
Figure imgf000041_0002
The active enantiomers of the present invention contain the atropic stereochemistry which corresponds to (+)-40, when U = CH3 and V = H.
Figure imgf000042_0001
(+/-) - 40b (+) - 40b or (-) - 40b
R* = enantiomerically pure moiety
Compounds of Formula 42a wherein T = T3 can be used to prepare compounds of Formula Io wherein T = T4 and Y3 = -CHR15O-N=C(R7)- according to methods described in EP-A-585,751 and illustrated in Scheme 33. Compounds of Formula 42a are treated with N-hydroxyphthalimide. Treatment of this intermediate with HΝR6R5 yields compounds of Formula 42b wherein T3 is converted to T4 and B is CHR15ONH . Treatment of compounds of Formula 42b with compounds of Formula 19 provides compounds of Formula Io.
Scheme 33
Figure imgf000042_0002
2) aq. HNR6R5
Compounds of Formula 40 can be prepared by reducing esters of Formula 44 or aldehydes of Formula 43 with an appropriate reducing agent, (M. Hudlicky, Reductions in Organic Chemistry; John Wiley & Sons pp. 147-160, (1986)). For example, diisobutylaluminum hydride (DIBAL-H) can be used to reduce 44 in an inert solvent such as methylene chloride, diethyl ether or tetrahydrofiiran. If compounds of Formula 44 contain an enantiomerically pure moiety R* they can be obtained as diasteromerically enriched compounds of formula 44. Reduction of these diasteromerically enriched compounds according to Scheme 34 would lead to enantiomerically enriched compounds of formula 40. Compounds of Formula 43 can be reduced with sodium borohydride in a protic solvent such as methanol or ethanol, Scheme 34. Compounds of Formula 43 may also be reduced with a chiral reducing agent. Differences in rate between the two atropic enantiomers of Formula 43 would effect a kinetic resolution, allowing compounds of Formula 40 to be obtained in an enantioselective fashion. Examples of chiral reducing agents include oxazalolidines/borane complexes (J. Org. Chem. 1991, 56, 751) binaphthol aluminum hydride complexes (J. Am. Chem. Soc. 1979, 101, 3129) and hydroxyalkyl benzimidazole borohydride complexes (Syn. Comm. 1998, 28, 99). For reductions of prochiral aldehydes using chiral hydride reagents, see Tetrahedron Lett. 1989, 30, 627 and J. Am. Chem. Soc. 1979, 101, 3129.
Scheme 34
Figure imgf000043_0001
43 40 44
R = C]-C alkyl or R*
R* = enantiomerically pure moiety
Racemic compounds of Formula 43 may also be resolved by kinetic resolution of the cyanohydrins formed by enantioselective hydrocyanation (Scheme 34a). Treatment of compounds of Formula 43 with hydrogen cyanide in the presence of a chiral catalyst will provide diastereomerically enriched cyanohydrins of Formula 43a which can be separated from unreacted 43 or the diastereomeric cyanohydrin 43b to afford 43a in high diastereomeric excess. Regeneration of chiral 43* from 43a can be accomplished by base hydrolysis. See H. Danla, Synlett. 1991, 263 for recent advances in asymmetric synthesis of cyanohydrins.
Scheme 34a
Figure imgf000044_0001
Esters of Formula 44 can be prepared from anthranilic acid esters of Formula 45 according to the procedures described in Scheme 35. Esters 45 can be prepared from readily accessible anthranilic acids by esterification techniques well known in the art. If compounds of Formula 45 contain an enantiomerically pure moiety R* they can be treated as indicated in Scheme 35 to obtain a mixture of diastereomers of Formula 44. Separation of the diastereomers of Formula 44 would provide diasteromerically enriched compounds of formula 44. Compounds of Formula 45 which contain an enantiomerically pure moiety R* when treated as indicated in Scheme 35 may effect a stereoselective synthesis of compounds of Formula 44 by stereoinduction of the resulting atropic center in compounds of Formula 44.
R
Figure imgf000044_0002
R* = enantiomerically pure moiety Compounds of Formula 43 can be prepared either by metal-halogen exchange in compounds of Formula 46a (when R33 = Cl, Br, I) or by metallation of compounds of Formula 46b (when R33 is H) with alkyllithium reagents in an inert solvent. Quenching of the metalated species with a formaldehyde equivalent (i.e., dimethylformamide or methyl chloroformate) yields compound of Formula 43 (see Scheme 36).
Scheme 36
Figure imgf000045_0001
43
46a R3 = C1, Br or l 46b R3 = H
Compounds of Formula 46 are prepared from commercially available anilines of Formula 47 according to the procedures described for the synthesis of 44, Scheme 37.
Figure imgf000045_0002
47
46
Compounds of Formula 37a (Compounds of Formula 37 where R31 = OH) can be prepared by the oxidative work-up of intermediate boronic acids of Formula 48. In turn compounds of Formula 48 can be prepared from compounds of Formula 46 by metallation using an alkyllithium followed by quenching with a trialkoxy borane, (Scheme 38), see Organic Synthesis via Boranes; Wiley: New York, (1975). Scheme 38
Figure imgf000046_0001
R = Cι-C alkyl
Figure imgf000046_0002
37a
Alternatively compounds of Formula 37c (compounds of Formula 37 wherein U = CH3, V = H and R31 = OH) can be prepared according to the route outlined in Scheme 39. Commercially available anilines of Formula 49a (where U = CH3 and P is a protecting group) are converted to the triazolone of Formula 50 according to the procedures described above. If P in compounds of Formula 49a contains an enantiomerically pure moiety R* then treatment of compounds of Formula 49a according to Scheme 39 may effect stereoselection of the resulting atropic center in compounds of Formula 50. Separation of the diastereomers of compounds of Formula 50 followed by deprotection and methanolysis would allow formation of the enantiomerically enriched compounds of formula 37c. Deprotection of the oxygen followed by alcoholysis yields compounds of Formula 37c.
Alternatively compounds of Formula 49b (where P is a protecting group) are converted to the triazolone 51 as previously described. Metallation at the ortho-position followed by quenching with an electrophile such as Mel yields compound of Formula 52 which is deprotected to yield compound of Formula 37c, Scheme 39. If P in compounds of Formula 51 contains an enantiomerically pure moiety R* then treatment of compounds of Formula 51 according to Scheme 39 may effect stereoselection in the alkylation to afford diastereotopic enrichment of compounds of Formula 52. Separation of the mixture of diastereomers of Formula 52, followed by deprotection affords enantiomerically enriched compounds of Formula 37c. When treated with compounds of Formula 17 or 18 as described in Scheme 30, (+) - 37c leads to the more active atropic enantiomer of compounds of Formula Im. Scheme 39
Figure imgf000047_0001
1) separate
2) "deprotect"
3) CH3θH/NaOMe
Figure imgf000047_0002
37c
t
Figure imgf000047_0003
P = protecting group or R*
R* = enantiomerically pure moiety
Compounds of Formula 37d (compounds of Formula 37 where U = CH3 and V = 3-Me and R31 = OH) can be prepared from compounds of Formula 54 by procedures already described. Compounds of Formula 54 are prepared by nitration of commercially available
2,5-dimethylphenol 53 as taught in M. Quertani, P. Girard and H. B. Kagan, Tetrahedron
Letters, 23, 4315 (1982), Scheme 40.
Figure imgf000048_0001
P = protecting group
Compounds of Formula I wherein Y is -CR8=CR8- can be prepared as illustrated n
Scheme 41. Treatment of compounds of Formula 36a (compounds of Formula 36 where Lg is Cl, Br or I) with triphenylphosphine or a trialkylphosphite produces the corresponding phosphonium salt (Formula 55a) or phosphonate (Formula 55b), respectively. Condensation of the phosphorus compound with a base and a carbonyl compound of Formula Z(R8)C=O affords the olefin of Formula Ip. Compounds of Formula Ip wherein T = T2 may be prepared by methods described in EP-A-203,606, EP-A-474,042, EP-A-528,245 and FR 2,670,781.
Compounds of Formula Ip wherein T = T3 may be prepared by methods described in
EP-A-253,213 and EP-A-254,426.
Scheme 41
Figure imgf000048_0002
P(0(CrC4 alkyl ))3 55
36a
55a R34 = P(C6H5)3+ (Cl, Br or I) ■ O
55b R34 = P(0(CrC4 alkyl))2
Figure imgf000048_0003
The olefin of Formula Ip can also be prepared by reversing the reactivity of the reactants in the Wittig or Horner-Emmons condensation. For example, 2-alkylphenyl derivatives of Formula 56 can be converted into the coπesponding dibromo-compounds of Formula 57a as illustrated in Scheme 42 (see Synthesis, (1988), 330). The dibromo- compounds can be hydrolyzed to the carbonyl compounds of Formula 57b, which in turn can be condensed with a phosphorus-containing nucleophile of Formula 58 or 59 to afford the olefins of Formula Ip.
Scheme 42
Figure imgf000049_0001
2) morpholine 56 57 cone. HC1, H20
57a R34 = C(Br) R8
NBS = N-bromosuccinimide 57b R 4 = C(=0)R8
M
Figure imgf000049_0002
ip
59
Oximes of Formula Ir (Formula I wherein Y is -C(R7)=N-O-CHR15) can be prepared from carbonyl compounds of Formula 60 by condensation with hydroxylamine, followed by O-alkylation with electrophiles of Formula ZCHR15-(C1, Br, or I) (Scheme 43).
Alternatively, the O-substituted hydroxylamine can be condensed with the carbonyl compound of Formula 60 to yield oximes of Formula Ir directly. Compounds of Formula Ir wherein T = T2, T3, or T4 may be prepared by methods described in EP-A-499,823 and EP-A-596,254. Scheme 43
Figure imgf000050_0001
Carbamates of Formula lu can be prepared by reacting benzyl alcohols of Formula 61 with iso(thio)cyanates of Formula 62 (Scheme 44). A base such as triethylamine can be added to catalyze the reaction. Compounds of Formula lu wherein T = T2, T3, or T4 may be prepared by methods described in WO 93/07116.
Scheme 44
Figure imgf000050_0002
61 lu
Compounds of Formula Iw may be prepared by methods described in EP-A-178,826, EP-A-341,845 and EP-A-464,381.
Compounds of Formula Ix as defined in Scheme 45 may be prepared by methods described in EP-A-398,692.
Scheme 45
Figure imgf000050_0003
Ix
Iw γ6 = _o__ -CH2CH2-, -CR8=CR8-, -CH20-, -OCH2-, -CH2S(0)n- or -S(0)nCHR15-
Compounds of Formula Iy (compounds of Formula I wherein Y7 = -O-) can be prepared by treating compounds of Formula 62 with a triarylbismuth compound or a substituted phenylboronic acid in the presence of cupric acetate and a tertiary amine such as pyridine or triethylamine as illustrated in Scheme 46. The use of organobismuth reagents in the preparation of diaryl ethers is well known in the art (see Tetrahedron Lett., (1986), 27, 3619, and Tetrahedron Lett., (1987), 28, 887). Boronic acids are well known in the literature (see Acta Chem. Scand. 1993, 47, 221 and references therein). The use of boronic acids in the preparation of diaryl ethers is known in the art (see Tetrahedron Lett., (1998), 39, 3933).
Scheme 46
Figure imgf000051_0001
Et3N, Cu(OAc)2
62 iy γ7 = _0- 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. H NMR spectra are reported in ppm downfield from tetramethylsilane; s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets and br s = broad singlet.
Except where indicated, analyses of enantiomeric excesses (% ee) were carried out on an HP 1090 HPLC equipped with a (R,R) Whelk-01 column analytical HPLC column (Whelk-01 is derived from 4-(3,5-dinitrobenzamido)tetrahydrophenanthrene, covalently bound to 5 μm 3-propyl silica, 25 cm X 4.6 mm ID, Code no. 786201, Regis Technologies Inc., Morton Grove, IL, USA, column temperature = 40 °C, detector λ= 230, 254 nm) using solvent mixtures, flow rates and elution times as indicated for each example.
EXAMPLE 1 Step A: Preparation of N-(2-methoxy-6-methylphenvD-2,2- dimethylhvdrazinecarboxamide To a stirred solution of phosgene (108 g, 1.09 moles) in ethyl acetate (750 mL) at 0 °C was added dropwise 2-methoxy-6-methylaniline (125.0 g, 911 mmol) dissolved in ethyl acetate (250 mL) over 20 min. The reaction mixture was slowly warmed to room temperature and was then heated at reflux for 1 h. The solution was cooled to room temperature and was concentrated under reduced pressure to provide the crude isocyanate as a dark red liquid which was redissolved in ethyl acetate (1 L) and cooled to 0 °C. 1,1-Dimethylhydrazine (55.0 g, 911 mmol) was added dropwise over 30 min and then the mixture was allowed to warm to room temperature and stir overnight. The mixture was cooled, filtered, and the solid was washed with ethyl acetate and dried to provide 200.0 g of the title compound of Step A as a white solid melting at 151-153 °C. *H ΝMR (CDC13) δ 7.58 (br s,lH), 7.10 (t,lH), 6.84 (d,lH), 6.74 (d,lH), 5.22 (br s,lH), 3.80 (s,3H), 2.63 (s,6H), 2.31 (s,3H). Step B: Preparation of 5-chloro-2,4-dihydro-4-(2-methoxy-6-methylphenyl)-2-methyl- 3H-1.2.4-triazol-3-one
The title compound of Step A (100.0 g, 447.9 mmol) was suspended in ethyl acetate (1 L) and added dropwise, via mechanical pump, over 3.5 h to a stirring solution of phosgene (177 g, 1.79 moles) in ethyl acetate (1.5 L) which was heated at reflux. After the addition was complete, the mixture was heated at reflux for a further 3 hr, cooled to room temperature and stirred overnight. The solution was concentrated under reduced pressure and the residue was dissolved in ethyl acetate and water and extracted four times with ethyl acetate. The combined organic phases were washed with saturated aqueous ΝaCl, dried (MgSO ), filtered and concentrated to afford 1 1 1.4 g of the title compound of Step B as a pale yellow solid melting at 132-134 °C. Η ΝMR (CDC13) δ 7.34 (t,lΗ), 6.93 (d,lH), 6.85 (d,lH), 3.79 (s,3H), 3.54 (s,3H), 2.20 (s,3H). Step C: Preparation of 5-chloro-2,4-dihydro-4-(2-hvdroxy-6-methylphenyl)-2-methyl-
3H-1.2.4-triazol-3-one To a stirring solution of the title compound of Step B (15.0 g, 59.3 mmol) in benzene (200 mL) at 0 °C was added aluminum chloride (23.7 g, 178 mmol) in small portions. The mixture was warmed to room temperature and stirred for 2 days. The mixture was poured over ice and water and then extracted four times with ethyl acetate. The combined organic phases were washed with saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to an oil that was purified by flash column chromatography on silica gel to provide 13.6 g of the title compound of Step C as a pale orange solid melting at 175-178 °C. 1 Η NMR (CDC13) δ 8.11 (s,lΗ), 6.92 (t,lH), 6.71 (d,lH), 6.41 (d,lH), 3.56 (s,3H), 2.12 (s,3H). Step D: Preparation of 2,4-dihvdro-4-(2-hydroxy-6-methylphenyl)-5-methoxy-2- methyl-3H- 1 ,2,4-triazol-3-one To a stirred solution of the title compound of Step C (133.5 g, 557.0 mmol) in tetrahydrofiiran (1.5 L) was added dropwise sodium methoxide (25% by weight in methanol, 382 mL, 1.67 moles). The mixture was heated at reflux for 3 h, cooled to room temperature and then diluted with aqueous ammonium chloride and ethyl acetate. The aqueous layer was acidified (pΗ 4-5) with IN ΗC1 and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to a dark brown solid which was triturated with ethyl acetate to afford 75.0 g of the title compound of Step D as a white solid melting at 194- 196 °C . l Η NMR (Me2SO-c.6) δ 9.91 (s,lΗ), 7.17 (t,lH), 6.78 (m,2H), 3.84 (s,3H), 3.30 (s,3H), 2.03 (s,3H). Step E: Preparation of 2,4-dihvdro-5-methoxy-2-methyl-4-r2-methyl-6-r3-
(trifluoromethyl)phenoxy phenyl1-3H- 1 ,2,4-triazol-3-one To a solution of the title compound of Step D (0.50 g, 2.13 mmol) in methylene chloride (15 mL) was added 3-trifluoromethylbenzeneboronic acid (0.88 g), anhydrous cupric acetate (0.38 g), and triethylamine (0.43 g). After stirring at room temperature for 27 h, the crude reaction mixture was directly subjected to flash chromatography purification (silica gel, 30% to 38% ethyl acetate in hexane) to give the title compound (0.39 g, 47%), melting at 95-96 °C. Η NMR (CDC13) δ 7.35 (m,3Η), 7.14 (m,3H), 6.86 (d,lH), 3.82 (s,3H), 3.37 (s,3H), 2.28 (s,3H).
Step F: Separation of enantiomers of 2,4-dihvdro-5-methoxy-2-methyl-4-r2-methyl-6-
[3-(trifluoromethyl)phenoxy1phenvH-3H-l ,2,4-triazol-3-one A racemic mixture of the title compound of Step E was separated on the ΗPLC column described above into the two component enantiomers. Six 25 μL portions of a 2-propanol solution of title compound of Step E (8.8 mg/mL) were injected onto the ΗPLC column and fractions of Enantiomer I ((aR)-2,4-dihydro-5-methoxy-2-methyl-4-[2-methyl-6-[3- (trifluoromethyl)phenoxy]phenyl]-3H-l,2,4-triazol-3-one >99% ee by ΗPLC) [4: 1 hexanes/2-propanol, flow rate 0.7 ml/min, elution time 8.2 min] and Enantiomer II ((aS)-2,4- dihydro-5-methoxy-2-methyl-4-[2-methyl-6-[3-(trifluoromethyl)phenoxy]phenyl]-3H- 1,2,4- triazol-3-one approximately 97% ee by ΗPLC) [4: 1 hexanes/2-propanol, flow rate 0.7 ml/min, elution time 9.8 min] were collected separately at the ΗPLC outlet. Dilution of these samples to 25 mL with 2-propanol gave concentrations of 22.2 μg/mL of Enantiomer I and 22.6 μg/mL of Enantiomer II, respectively, as determined by gas chromatography. The concentrations of Enantiomers I and II were determined by GC analysis by comparing the peak areas of the samples to those obtained from a series of standards of known concentration. GC analyses were performed on an HP 5890 Series II instrument equipped with an HP-1 column (5 m X 530 μm; Program: 200 °C, lmin, 10 deg/min, 250 °C; Column flow rate = 10 mL/min He) and FID. Under these conditions the title compound of Step E eluted as a single peak at 1.71 min. The samples were evaporated to dryness in vacuo as thin films.
Samples of the two enantiomers showed no significant formation of the other enantiomer after two days at ambient temperature in 2-propanol. A sample of Enantiomer II in toluene showed no significant change in enantiomeric excess after 24 h at 105 °C, analyzed by the HPLC analysis described above.
EXAMPLE 1A
Preparation of (aS)-2 ,4-dihydro-5 -methoxy-2-meth yl-4- [2 -me thyl-6- \3 -
(trifluoromethyl)phenoxylphenyl1-3H- 1 ,2,4-triazol-3-one To a solution of (aS)-2,4-dihydro-4-(2-hydroxy-6-methylphenyl)-5-methoxy-2-methyl-
3H-l,2,4-triazol-3-one (92% ee), (0.50 g, 2.13 mmol), (similarly prepared as in Steps A-B, Example 3) in methylene chloride (12 mL) was added powdered, activated 3 A molecular sieves 1.4 g), 3-trifluoromethylbenzeneboronic acid (0.82 g), anhydrous cupric acetate (0.39 g), and triethylamine (1.08 g). After stirring at room temperature for 18 h, the reaction mixture was filtered and concentrated in vαcuo. The crude reaction product was directly subjected to flash chromatography purification (silica gel, 30% to 38% ethyl acetate in hexane) to give, after trituration in cold hexanes, the titled compound (0.27 g, 33% yield), melting at 72-74 °C. Η NMR (CDC13) δ 7.35 (m,3Η), 7.14 (m,3H), 6.86 (d,lH), 3.82 (s,3H), 3.37 (s,3H), 2.28 (s,3H). HPLC analysis as above showed the material to be 94% ee. EXAMPLE 2
Step A: Preparation of 3-iodobenzeneboronic acid
To a solution of 1,3-diiodobenzene (25.0 g, 76 mmol), in diethyl ether (60 mL) and tetrahydrofiiran (70 mL) at -78 °C was added dropwise a solution of «-BuLi in hexane (2.5 M, 30 mL) over 20 min under nitrogen. After a further 20 min of stirring, triisopropylborate (19.9 mL) was added to the orange slurry while maintaining the temperature below -60 °C. After a further 10 min of stirring, the reaction was allowed to warm to room temperature where a clear brown solution resulted. After stirring at room temperature for 21 h, the cloudy orange solution was poured slowly into a solution of aqueous hydrochloric acid (7%, 250 mL). After stirring for 25 min, the layers were separated and the aqueous layer was extracted with 150 mL of diethyl ether. The combined organic layers were dried (MgSO4), filtered, and concentrated to an orange solid, which was triturated with hexane to give 15.98 g of the title compound as a light tan solid, mp 190-192°C.
Step B: Preparation of 2,4-dihvdro-4-r2-(3-iodophenoxy)-6-methylphenyl]-5- methoxy-2-methyl-3H-1.2.4-triazol-3-one To a solution of 2,4-dihydro-4-(2-hydroxy-6-methylphenyl)-5-methoxy-2-methyl-3H- l,2,4-triazol-3-one (3.0 g, 12.76 mmol), (similarly prepared as in Steps A-D, Example 1) in methylene chloride (60 mL) was added title compound of step A (6.33 g), anhydrous cupric acetate (2.32 g), and triethylamine (2.63 g). After stirring at room temperature for 27 h, an additional 2.6 g of 3-iodobenzene boronic acid was added, followed by an additional 5.2 g after a total of 123 h of stirring. After a total of 147 h of stirring, the crude reaction mixture was directly subjected to flash chromatography purification (silica gel, 40% ethyl acetate in hexane) to give the title compound (1.63 g, 29%), melting at 127-129 °C. !Η NMR (CDC13) δ 7.42 (d,lH), 7.31 (m,2H), 7.09 (d, IH), 7.00 (m,2H), 6.82 (d,lH), 3.85 (s,3H), 3.39 (s,3H), 2.26 (s,3H).
Step C: Separation of enantiomers of 2,4-dihydro-4-r2-(3-iodophenoxy)-6- methylphenyll-5-methoxy-2-methyl-3H- 1 ,2,4-triazol-3-one Separations of enantiomers of the title compound from Step B were carried out on a
Varian VISTA 5500 ΗPLC equipped with a Chiralcel OD column (25 cm x 2 cm i.d., cellulose tris(3,5-dimethylphenyl)carbamate stationary phase, Part No.14045, Chiral Technologies, Inc., USA) using a solution of 5% 2-propanol and 95% hexane as mobile phase (detector λ= 270 nm). About 100 mg of the title compound from Step B was added to a 10-mL volumetric flask. About 8 mL of the mobile phase and 5 drops of 2-propanol were added. The solution was then sonicated for 20 minutes and then injected into the ΗPLC in lmL fractions. The individual enantiomers (Enantiomer III, retention time = 25 min, Enantiomer IV, retention time = 31 min) were obtained by collecting fractions from the ΗPLC outlet and concentrated in vacuo. The residues were redissolved in methylene chloride and transferred to scintillation vials and further dried by evaporation and under high vacuum. The enantiomeric purity of the recovered materials was determined by the general ΗPLC method: Enantiomer III [(aS)-2,4-dihydro-4-[2-(3-iodophenoxy)-6-methylphenyl]-5-methoxy-2- methyl-3H-l,2,4-triazol-3-one ,4:1 hexanes/2-propanol, flow rate 0.8 mL/ min elution time 12.2 min] >99% ee.; Enantiomer IV [(aR)-2,4-dihydro-4-[2-(3-iodophenoxy)-6- methylphenyl]-5-methoxy-2-methyl-3H-l ,2,4-triazol-3-one, 4: 1 hexanes/2-propanol, flow rate 0.8 mL/min, elution time 9.9 min] 97.5% ee. EXAMPLE 3 Step A: Preparation and separation of the mixture of diastereomers of T2-π ,5-dihydro-
3-methoxy- 1 -methyl-5-oxo-4H- 1 ,2,4-triazol-4-yl)-3-methylphenyll 6- methoxy-α-methyl-2-naphthaleneacetate S-(+)-6-Methoxy-α-methyl-2-naphthaleneacetic acid (23.03 g) was treated with 75 mL of oxalyl chloride at room temperature for 1 hour. The excess oxalyl chloride was removed by rotary evaporation. The crude acid chloride was dissolved in 100 mL of tetrahydrofiiran and added dropwise to a solution of 2,4-dihydro-4-(2-hydroxy-6-methylphenyl)-5-methoxy- 2-methyl-3H-l,2,4-triazol-3-one (similarly prepared as in Steps A-D, Example 1) (23.5- g) and triethylamine (14 mL) in 500 mL of tetrahydrofiiran. After addition was complete, the mixture was allowed to stir at room temperature for 1 h. The precipitated triethylamine hydrochloride was removed by filtration and the filtrate was concentrated to yield an orange oil. The crude material was purified by flash chromatography on silica gel (gradient from 1 : 1 ethyl acetate hexane to 100% ethyl acetate as eluant) to provide a mixture of two diastereomers in a 1 : 1 ratio as a colorless oil. Trituration in ether provide a solid which was enriched in one diastereomer (15.4 g). This material was fractionally crystallized from methanol (2 recrystallizations) to provide a single Diastereomer A, mp 147 °C. lH NMR (CDC13) δ 7.7 (m, 3H), 7.3 (m, 2H), 7.15 (m, 4H), 3.99 (q, IH), 3.93 (s, 3H), 3.61 (s, 3H), 3.10 (s, 3H), 2.15 (s, 3H), 1.61 (d, 3H). The ether-soluble material (12 g.) was enriched in the other Diastereomer B (4: 1 mixture). This material was fractionally crystallized from methanol to give 3.15 g of a white solid (4:1 mixture). The mother liquors were fractionally crystallized from ether to give 4.3 g of a white solid (8:1 mixture). This material was recrystallized from ethyl acetate/ hexane to give 4.0 g of a white solid, mp 98-101 °C, (8.4:1 mixture). IH NMR (CDC13) (of the major diastereomer B) δ 7.7 (m, 3H), 7.39 (dd, IH), 7.30 (t, IH), 7.15 (m, 3H), 7.02 (d, IH) 4.00 (q, IH), 3.92 (s, 3H), 3.75 (s, 3H), 3.20 (s, 3H), 2.19 (s, 3H), 1.60 (d, 3H).
Step B: Preparation of (aS)-2,4-dihvdro-4-(2-hvdroxy-6-methylphenyl)-5-methoxy-2- methyl-3H- 2,4-triazol-3-one To a suspension of 4.0 g of the 8.4:1 mixture of diastereomers in 40 mL of methanol was added 2.0 mL of 30% sodium methoxide in methanol. The mixture was stirred at room temperature for 30 min. The mixture was diluted with 40 mL of water and extracted with dichloromethane (3x40 mL). The aqueous phase was made acidic with IN hydrochloric acid and extracted again with dichloromethane (3x40 mL). These combined extracts were dried (MgSO4), filtered and concentrated by rotary evaporation. The glassy residue was triturated in hexane to give a white solid which was collected by filtration (1.82 g) mp 178-180 °C. •Η NMR (CDC13) δ 7.95 (s,lΗ), 6.85 (t, IH), 6.68 (d, IH), 6.41 (d, IH), 3.92 (s, 3H), 3.48 (s, 3H), 2.12 (s, 3H), optical rotation [α]D 20 = +113.1 (c = 5.53, CH2C12). HPLC analysis [75%> hexanes, 25% isopropyl alcohol, 0.1% acetic acid, 0.7 mL/min elution time 8.5 min] indicates 86% ee.
Step C: Preparation of 4-methylbenzenecarboximidamide hydrochloride
Into a solution of 43.5 g of p-tolunitrile and 22 mL of ethanol in 372 mL of ethyl ether at room temperature was bubbled anhydrous hydrogen chloride gas until the point of saturation. The vessel was tightly stoppered and allowed to stand for three weeks. The resulting solid was collected by filtration to obtain 28.3 g. A second crop (1.7 g) was obtained by concentrating the filtrate by rotary evaporation. The crude solid was treated with 105 mL of 2.0 M ammonia in ethanol at room temperature overnight. The solvent was- removed to obtain 26.4 g of white solid. lU NMR (Me2SO-rf6) δ 9.38 (broad s, 2H), 9.23 (broad s, 2H), 7.77 (d, 2H), 7.43 (d, 2H), 2.41 (s, 3H). Step D: Preparation of 5-chloro-3-(4-methylphenyl)- 1 ,2,4-thiadiazole
The title compound from Step C was dissolved in 300 mL of water. A solution of 28.8 g of trichloromethanesulfenyl chloride and 1.26 g of triethylbenzylammonium chloride in 650 mL of dichloromethane was added. At 0 °C with vigorous stirring, a solution of
24.7 g of sodium hydroxide in 350 mL of water was added at a rate to keep the temperature below 10 °C. After addition was complete, the mixture was stirred for ten minutes, warmed to room temperature and allowed to stir for one hour. The phases were separated and the organic phase washed with 200 mL of water. The combined aqueous phases were extracted with dichloromethane (3x150 mL). The combined organic phases were dried (Mg SO ), filtered and concentrated by rotary evaporation. The crude material was purified by flash chromatography on silica gel (100% hexane to 2% ethyl acetate in hexane gradient as eluant). The second eluting component was obtained as a yellow solid, lH NMR (CDC13) δ 8.13 (d, 2H), 7.28 (d, 2H), 2.42 (s, 3H). Step E: Preparation of (aS)-2.4-dihvdro-5-methoxy-2-methyl-4-r2-methyl-6-rr3-r4- methylphenyl)-L2,4-thiadiazol-5-vnoxy]phenvn-3H-l,2,4-triazol-3-one The title compound from Step B (800 mg) and the title compound from Step D (720 mg) were dissolved in 25 mL of dimethylformamide and 570 mg of potassium carbonate was added. The mixture was stirred at room temperature for 64 h. The mixture was diluted with 25 mL of water and extracted with ethyl ether (3x25 mL). The combined extracts were dried (Mg SO4), filtered and concentrated by rotary evaporation. The crude material was purified by flash chromatography on silica gel (hexane/ethyl acetate 2:1 to 1 : 1 gradient as eluant). The glassy material was triturated in ethyl ether/hexane to give 890 mg of a white solid which was collected by filtration, mp 90-95 °C, lU NMR (CDC13) δ 8.05 (d, 2Η), 7.45 (m, 2H), 7.31 (dd, IH), 7.23 (d, 2H), 3.75 (s, 3H), 3.39 (s, 3H), 2.39 (s, 3H), 2.32 (s, 3H), optical rotation: [α]D 2° = +23.9 (c = 2.55, CH2C12). HPLC analysis [1 : 1 hexanes/2-propanol, 1.0 mL/min, elution time 8.65 min] indicates 82% ee. EXAMPLE 4 Step A: Preparation of (aR)-2,4-dihvdro-4-(2-hvdroxy-6-methylphenvI)-5-methoxy-2- methyl-3H-l,2,4-triazol-3-one To a suspension of 1.34 g of the single Diastereomer A, obtained in Step A, Example 3, in 10 mL of methanol was added 0.6 mL of 30% sodium methoxide in methanol. The mixture was stirred at room temperature for 30 min. The mixture was diluted with 10 mL of water and extracted with dichloromethane (3x15 mL). The aqueous phase was made acidic with IN hydrochloric acid and extracted again with dichloromethane (3x15 mL). These combined extracts were dried (Mg SO4), filtered and concentrated by rotary evaporation. The glassy residue was triturated in hexane to give a white solid which was collected by filtration (600 mg) mp 184 °C, lB NMR (CDC13) δ 7.95 (s,lΗ), 6.85 (t, IH), 6.68 (d, IH), 6.41 (d, IH), 3.92 (s, 3H), 3.48 (s, 3H), 2.12 (s, 3H), optical rotation: [α]D 20 = -138.6 (c = 5.53, CH2C12). HPLC analysis [75% hexanes, 25% isopropyl alcohol, 0.1% acetic acid, 0.7 mL/min, elution time 7.10 min] indicates >95% ee. Step B: Preparation of (aR)-2>4-dihvdro-5-methoxy-2-methyl-4-r2-methyl-6-r[3-r4- methylphenyl)- 1 ,2,4-thiadiazol-5-vπoxylphenyll-3H- 1 ,2,4-triazol-3-one The title compound from Step A (306 mg) and the title compound from Step D, Example 3 (274 mg) were dissolved in 20 mL of dimethylformamide and 200 mg of potassium carbonate was added. The mixture was stirred at room temperature for 64 h. The mixture was diluted with 20 mL of water and extracted with ethyl ether (3x20 mL). The combined extracts were dried (MgSO4), filtered and concentrated by rotary evaporation. The crude material was purified by flash chromatography on silica gel (hexane/ethyl acetate 2:1 to 1:1 gradient as eluant). The glassy material was triturated in ethyl ether/hexane to give 150 mg of a white solid which was collected by filtration, mp 89-90 °C, !H NMR (CDC13) δ 8.05 (d, 2H), 7.45 (m, 2H), 7.31 (dd, IH), 7.23 (d, 2H), 3.75 (s, 3H), 3.39 (s, 3H), 2.39 (s, 3H), 2.32 (s, 3H), optical rotation: [α]D 20 = -25.5 (c = 2.51, CH2C12). HPLC analysis [1 :1 hexanes/2-propanol, 1.0 mL/min, elution time 7.45 min] indicates 99%> ee.
EXAMPLE 5 Preparation of raS)-2,4-dihvdro-5-methoxy-2-methyl-4-(2-methyl-6-phenoxyphenyl)-3H- 1 ,2.4-triazol-3-one
To a solution of the title compound from Step B, Example 3 (0.79 g) in methylene chloride (16 mL) was added triphenylbismuth (2.98 g, Aldrich Chemical Co.), anhydrous cupric acetate (0.61 g), and triethylamine (0.70 g). After stirring at room temperature for 70 h, the crude reaction mixture was directly subjected to flash chromatography purification (silica gel, 30-40% ethyl acetate in hexane) to give the title compound (0.95 g, 90%), melting at 61-64 °C. 1Η NMR (CDC13) δ 7.28 (m,3Η), 7.10 (t,lH), 7.04 (d,lH), 6.99 (d,2H), 6.78 (d,lH), 3.86 (s,3H), 3.38 (s,3H), 2.27 (s,3H). [α]D °= +16.78 (c = 2.55, CH2C12). HPLC analysis [20% isopropyl alcohol / 80% hexane, 0.8 mL/min, elution time 12.04 min] indicates 84% ee.
EXAMPLE 5A Separation of enantiomers of 2.4-dihvdro-5-methoxy-2-methyl-4-(2-methyl-6- phenoxyphenyl)-3H-L2,4-triazol-3-one
A sample of 2,4-dihydro-5-methoxy-2-methyl-4-(2-methyl-6-phenoxyphenyl)-3H- l,2,4-triazol-3-one (650 g) (similarly prepared as in Steps A-E, Example 1) was separated in portions on a Chiralcel OJ ΗPLC column, 50 cm x 10 cm (inner diameter) [7:3 hexanes/ethanol, flow rate 200 mL/min, 25 °C, UV detection at 290 nm, sample concentration 40 mg/mL in 7:3 hexanes/ethanol, 100 mL injection volume] to yield
Enantiomer V (a5)-2,4-dihydro-5-methoxy-2-methyl-4-(2-methyl-6-phenoxyphenyl)-3H- l,2,4-triazol-3-one, same compound as Example 5, elution time 21 min, and Enantiomer VI (aR)-2,4-dihydro-5-methoxy-2-methyl-4-(2-methyl-6-phenoxyphenyl)-3H-l,2,4-triazol-3- one, same compound as Example 6, elution time 27 min. A total of 306 g of Enantiomer V, 95.6% chemical purity, 94% ee, mp 78-80 °C and 279 g of Enantiomer VI, 99.2% chemical purity, 94% ee, mp 82-84 °C were isolated following solvent removal.
EXAMPLE 6 Preparation of (aR)-2.4-dihydro-5-methoxy-2 -methyl-4-(2 -methyl-6-phenoxyphenyl)-3H- l,2,4-triazol-3-one To a solution of the title compound from Step A, Example 4 (0.38 g) in methylene chloride (8 mL) was added triphenylbismuth (1.41 g, Aldrich Chemical Co.), anhydrous cupric acetate (0.29 g), and triethylamine (0.34 g). After stirring at room temperature for 94 h, an additional 0.2 g of triphenylbismuth was added. After a total of 160 h of stirring, the crude reaction mixture was directly subjected to flash chromatography purification (silica gel, 30%) ethyl acetate in hexane) to give the titled compound (0.46 g, 93%), melting at 69-71 °C. lH NMR (CDC13) δ 7.28 (m,3Η), 7.10 (t,lH), 7.04 (d, IH), 6.99 (d,2H), 6.78 (d,lH), 3.86 (s,3H), 3.38 (s,3H), 2.27 (s,3H). [α]D 20= -19.33 (c = 2.55, CH2C12). HPLC analysis [20% isopropyl alcohol / 80% hexane, 0.8 mL/min, elution time 9.8 min] indicates approximately 99% ee. EXAMPLE 7
Step A: Preparation of raS-r2-(R*)11-4-r2-rrr(7.7-dimethyl-6-oxobicvclor2.2.1 Iheptan-
1 - vDmethyl] sulfonylloxy] -6-methylphenyl] -2 ,4-dihvdro-5 -methoxy-2 -methyl- 3H- 2,4-triazol-3-one To a solution of 2,4-dihydro-4-(2-hy__roxy-6-methylphenyl)-5-methoxy-2-methyl-3H- l,2,4-triazol-3-one (similarly prepared as in Steps A-D, Example 1) (20.0 g) in 300 mL of tetrahydrofiiran and 150 mL of dimethylformamide was added (lS)-(+)-10-camphorsulfonyl chloride (27.8 g). To this mixture was added 50% sodium hydride (5.12 g, washed with hexanes and slurried in tetrahydrofiiran). The resulting mixture was stirred at ambient temperature overnight, becoming a thick paste. An additional 150 mL of tetrahydrofuran was added and the mixture was stirred for one week. The reaction mixture was cooled in an ice- water bath and quenched with 100 mL of water, then diluted with 500 mL of ethyl ether. The phases were separated and the organic phase washed with 100 ml water, 100 mL of saturated sodium carbonate solution, 100 mL of water, then 100 mL of saturated sodium chloride solution. The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was triturated in ether and the solid collected by filtration to yield 35.5 g of a white solid. Flash chromatography on silica gel (9: 1 etheπhexane as eluant) afforded 12.85 g of the first eluting component, Diastereomer C, and 10.6 g of the second eluting component, Diastereomer D after concentrating the appropriate fractions. Some mixed fractions were discarded. Diastereomer C *H NMR (CDC13) δ 7.4 (m, 2H), 7.25 (IH), 3.96 (s, 3H), 3.63 (d, 1 H), 3.45 (s, 3H), 3.17 (d, IH), 2.4 (m, 2H), 2.26 (s, 3H), 2.0-2.15 (m, 2H), 1.95 (d, IH), 1.7 (m, IH), 1.45 (m, IH), 1.09 (s, 3H), 0.88 (s, 3H). Diastereomer D !H NMR (CDC13) δ 7.4 (m, 2H), 7.25 (IH), 3.94 (s, 3H), 3.74 (d, 1 H), 3.45 (s, 3H), 3.15 (d, IH), 2.4 (m, 2H), 2.26 (s, 3H), 2.0-2.15 (M, 2H), 1.95 (d, IH), 1.7 (m, IH), 1.45 (m, IH), 1.11 (s, 3H), 0.89 (s, 3H).
Step B: Preparation of (aS)-2,4-dihydro-4-(2-hvdroxy-6-methylphenyl)-5-methoxy-2 - methyl-3H-l .2.4-triazol-3-one Diastereomer C from Step A (12.85 g) was suspended in 100 mL of methanol and 14.6 mL of 30% sodium methoxide in methanol was added. The reaction mixture was stirred at ambient temperature for 4 h. The mixture was concentrated in vacuo to remove most of the methanol and the remainder was diluted with 200 mL of ethyl acetate and washed with 100 mL of IN hydrochloric acid, 50 mL of water, then 100 mL of saturated sodium chloride solution. The organic phase was dried (MgSO ) and concentrated in vacuo to yield 5.1 g of a white solid. Η NMR (CDC13) δ 8.05 (broad s, IH), 6.85 (t, IH), 6.7 (d, IH), 6.4 (d, IH), 3.9 (s, 3H), 3.45 (s, 3H), 2.1 (s, 3H). Step C: Preparation of 5-chloro-4-methyl-2-(methylthio)thiazole
A solution of methyl dithiocarbamate (prepared as in Synthesis, 1985, 948) (20 g) and 1,1-dichloroacetone (23.7 g) dissolved in ethanol (100 mL) was heated at reflux for 18 h. The solution was heated for an additional 12 h, cooled to room temperature and diluted with 300 mL of ethyl acetate, neutralized with saturated aqueous sodium bicarbonate solution. The layers were separated and the organic phase washed with saturated sodium chloride solution, dried (MgSO4), filtered and concentrated to an oil which was flash chromatographed (silica gel, 5% ethyl ether in hexane) to give the titled compound (9.5 g) as an oil. Η NMR (CDC13) δ 2.65 (s,3H), 2.35 (s,3H).
Step D: Preparation of 5-chloro-4-methyl-2-(methylsulfonyl)thiazole
A solution of 2-methylthio-4-methyl-5-chlorothiazole (9.5 g) dissolved in 250 mL of dichloromethane was cooled in an ice water bath and treated with 32% peracetic acid (28.9 g). The mixture was stirred at room temperature overnight, then washed with saturated aqueous sodium bisulfite solution, saturated aqueous sodium bicarbonate solution, then saturated sodium chloride solution, dried (MgSO4), filtered and concentrated to yield a solid, which was triturated in ether/ hexane and collected by filtration (9.75 g) lH NMR (CDC13) δ 3.3 (s,3H), 2.5 (s,3H).
Step E: Preparation of (aS)-4-[2-r(5-chloro-4-methyl-2-thiazolyl)oxy1-6- methylphenyl]-2.4-dihvdro-5-methoxy-2-methyl-3H-1.2,4-triazol-3-one To a solution of 2-methylsulfonyl-4-methyl-5-chlorothiazole (4.44 g) and (aS)-2,4- dihydro-4-(2-hydroxy-6-methylphenyl)-5-methoxy-2-methyl-3H- 1 ,2,4-triazol-3-one (96%) ee), (4.1 g,), (prepared as in Steps A-B) in 60 mL of acetonitrile was added 7.2 g of potassium carbonate. The mixture was heated to reflux for 5 h, stirred at room temperature 72 h, then heated at reflux 3 h. The reaction mixture was cooled, diluted with ethyl acetate, washed with water, then saturated sodium chloride solution, dried (MgSO4), filtered and concentrated. The residue was flash chromatographed (silica gel, 50% ethyl acetate in hexane) to give the titled compound as an oil which was crystallized from ether/hexane to give 3.58 g of white solid, mp 94-95 °C. Η NMR (CDC13) δ 7.35 (t, 1 Η), 7.25 (m, 2Η), 3.85 (s, 3H), 3.4 (s, 3H), 2.25 (s,3H), 2.2 (s,3H). HPLC analysis as above showed the material to be 98% ee [4:1 hexanes/ 2-propanol, flow rate 0.8 mL/min, elution time 13.1 min]. EXAMPLE 8
Step A: Preparation of 4-( l-dimethylethyl)-2-(methylthio)thiazole
A solution of methyl dithiocarbamate (prepared as in Synthesis, 1985, 948) (5.5 g) and 1-bromopinacolone (8.95 g) dissolved in ethanol (100 mL) was heated at reflux for 18 h., cooled to room temperature and the ethanol removed in vαcuo. The residue was suspended in 300 mL of ethyl acetate and neutralized with saturated aqueous sodium bicarbonate solution. The layers were separated and the organic phase, dried (MgSO4), filtered and concentrated to an oil to give the titled compound in quantitative yield. lH NMR (CDC1 ) δ 6.75 (s, IH), 2.67 (s,3H), 1.32 (s, 9H). Step B: Preparation of 5-bromo-4-(l .1 -dimethylethyl)-2-(methylthio)thiazole A solution of 2-methylthio-4-( 1 , 1 -dimethylethyl)thiazole (prepared similarly as above)
(18.2 g) dissolved in 200 mL of benzene was cooled in an ice water bath and treated with bromine (16.4 g), added over 30 min. After the addition, the resulting mixture was stirred an additional 30 min. The resulting solid was collected by filtration and washed with hexanes. The solid was suspended in 300 mL of ethyl ether and treated with saturated aqueous sodium carbonate solution, until all solids dissolved. The mixture was separated and the organic phase washed with aqueous sodium thiosulfate solution, then saturated sodium chloride solution, dried (MgSO4), filtered and concentrated to yield an oil (18.35 g), which was 70% of title compound and 30% of the coπesponding sulfoxide. This material was carried on to Step C without further treatment. *H NMR (CDC13) δ 2.65 (s, 3H), 1.45 (s, 9H). Step C: Preparation of 5-bromo-4-( 1 , 1 -dimethylethyl)-2-(methylsulfonvDthiazole
A solution of the material obtained in Step B (18.35 g) was dissolved in 150 mL of dichloromethane was cooled in an ice water bath and treated with 32% peracetic acid
(1 1.6 g). The mixture was stirred at room temperature overnight, then an additional 25 g of peracetic acid was added and the mixture stirred 4 h. The reaction mixture was washed with saturated aqueous sodium bisulfite solution, saturated aqueous sodium carbonate solution, then saturated sodium chloride solution, dried (MgSO ), filtered and concentrated to yield a pale yellow solid, which was triturated in ether/ hexane and collected by filtration (16.8 g) ]H NMR (CDC13) δ 3.3 (s, 3H), 1.5 (s, 9H).
Step D: Preparation of (aS)-4-r2-rF5-bromo-4-( 1 , 1 -dimethvIethyl)-2-thiazolyl)oxy1-6- methylphenvn-2,4-dihvdro-5-methoxy-2-methyl-3H-l,2,4-triazol-3-one To a solution of 2-methylsulfonyl-4-(l,l-dimethylethyl)-5-bromothiazole (8.76 g) and (aS)-2,4-dihydro-4-(2-hydroxy-6-methylphenyl)-5-methoxy-2-methyl-3H- 1 ,2,4-triazol-3-one (96% ee), (6.9 g,), (prepared as in Steps A-B, Example ) in 150 mL of acetonitrile was added 12.2 g of potassium carbonate. The mixture was heated to reflux for 2 days. The reaction mixture was cooled, concentrated to remove most of the acetonitrile, diluted with ethyl acetate, washed with water, then saturated sodium chloride solution, dried (MgSO4), filtered and concentrated. The residue was flash chromatographed (silica gel, 40-50% ethyl acetate in hexane). The residue was triturated in ether/hexane to give the titled compound as an off- white solid (5.6 g), mp 97-99 °C. Η NMR (CDC13) δ 7.35 (t, 1 Η), 7.25 (m, 2Η), 3.85 (s, 3H), 3.45 (s, 3H), 2.25 (s, 3H), 1.4 (s, 9H). HPLC analysis as above showed the material to be 94%o ee [4:1 hexanes/ 2-propanol, flow rate 0.8 mL/min, elution time 9.4 min]. EXAMPLE 9
Preparation of (aS)-4-\2-\\4-( 1.1 -dimethylethyl)-2-thiazolyl]oxy1-6-methylphenyl]-2,4- dihydro-5-methoxy-2-methyl-3H- 1 ,2,4-triazol-3-one To a solution of the title compound of Step D, Example 8 (5.35 g) in 60 mL of methanol was added 14.9 g of ammonium formate. The solution was sparged with nitrogen for 3 min, then 2.5 g of 10% Palladium on carbon was added. The mixture was stirred at room temperature overnight. The mixture was filtered through Celite®, and the Celite® rinsed thoroughly with ethyl acetate. The filtrate was washed with water, then saturated sodium chloride solution, dried (MgSO4), filtered and concentrated. The residue was triturated in ether/hexane and the resulting solid collected by filtration to give 3.9 g of the title compound as a white solid, mp 104-107 °C. Η NMR (CDC13) δ 7.35 (m, 2 H), 7.2 (d, IH), 6.4 (s, IH), 3.85 (s, 3H), 3.4 (s, 3H), 2.3 (s, 3H), 1.3 (s, 9H). HPLC analysis as above showed the material to be 97% ee. [4: 1 hexanes/ 2-propanol, flow rate 0.8 mL/min, elution time 10.8 min.] EXAMPLE 10 Step A: Preparation of (aS)-2,4-dihydro-5-methoxy-2-methyl-4- 2-methyl-6-
(sulfooxy)phenyl]-3H- 1 ,2,4-triazol-3-one (R)-α-methylbenzenemethanamine In a 500 mL round-bottomed flask, equipped with a condenser, addition funnel, thermometer and nitrogen inlet, sulfur trioxide NN-dimethylformamide complex (39.16 g, 255.6 mmol) was added as a solid to a slurry of 2,4-dihydro-4-(2-hydroxy-6-methylphenyl)- 5-methoxy-2-methyl-3H-l,2,4-triazol-3-one (50.00 g, 212.5 mmol) in methylene chloride/chloroform (250 mL/50 mL) (methylene chloride was distilled from phosphorus pentoxide). The resulting homogeneous light brown solution was refluxed under nitrogen for 1 hour. Η ΝMR analysis showed a 95:5 ratio of the sulfate to unreacted 2,4-dihydro-4- (2-hydroxy-6-methylphenyl)-5-methoxy-2-methyl-3H-l,2,4-triazol-3-one, so an additional 1.63 g of sulfur trioxide NN-dimethylformamide complex (10.64 mmol, 0.05 eq) was added to the reaction. A solution of (R)-(+)-α-methylbenzylamine (98%> purity, 96% ee, passed through a pad of neutral alumina prior to use, 41.30 g, 340.8 mmol) in 20 mL of methylene chloride was then added dropwise to the reaction mixture over about 20 minutes. This slightly exothermic reaction was maintained between 25-30 °C with an ice bath. After the addition was complete, the solution was refluxed for 15 minutes whereupon a gray solid precipitated from the reaction mixture. The hot solution was filtered and the solids rinsed with 50 mL of methylene chloride. The filtrate was concentrated in vacuo until about 260 mL of methylene chloride had been removed and then 350 mL of toluene was added to the viscous residue. The resulting two-phase (liquid/liquid) mixture was heated to 60 °C whereupon white solids precipitated. The hot mixture was filtered and the solids washed with two 20 mL portions of toluene. lH ΝMR analysis of the solids showed a 95:5 ratio of (aS)-2,4-dihydro-5-methoxy-2-methyl-4-[2-methyl-6-(sulfooxy)phenyl]-3H-l,2,4-triazol-3- one α-methylbenzenemethanamine to the other diastereomeric sulfate. The solids were triturated with an additional 250 mL of toluene at 60 °C, filtered, washed with 50 mL toluene followed by two 40 mL portions of hexanes, then dried in vacuo (0.2 torr) overnight. *Η ΝMR analysis showed a 97:3 ratio of diastereomers and the presence of 0.36 equivalent of toluene. Yield 32.45 g (65% of theoretical based on a formulation of (aS)-2,4-dihydro-5- methoxy-2-methyl-4-[2-methyl-6-(sulfooxy)phenyl]-3H- 1 ,2,4-triazol-3-one α- methylbenzenemethanamine _(0.36 equivalent of toluene), MW = 469.7 g/mol), mp 121-129 °C, [α]D 20 = +1.3 (c = 10.2 g/100 mL CΗC13). In CDC13, the ratio of diastereomers can be obtained via integration of their respective ΝMe singlets ((aS)-2,4-dihydro-5-methoxy-2- methyl-4-[2-methyl-6-(sulfooxy)phenyl]-3H-l,2,4-triazol-3-one α- methylbenzenemethanamine: δ 3.27, undesired diastereomer: δ 3.31). 'Η ΝMR (CDC13) δ 7.42 (d, 7.5 Ηz, 1Η, ArΗ), 7.2-7.4 (m, ArΗ), 7.15 (d, 9.4 Ηz, 1Η, ArΗ), 7.09 (d, 7.7 Ηz, 1Η, ArΗ), 3.92 (q, 6.9 Ηz, 1Η, CΗ(amine)), 3.89 (s, 3H, OCH3), 3.27 (s, 3H, ΝCH3), 2.35 (s, CH3(toluene)), 2.18 (s, 3H, ArCH3), 1.43 (d, 6.7 Hz, 3H, CH3(amine)). The NH resonances were not clearly observed but may be broadened under the aromatic region. Elemental Analysis: Found, C 54.41%, H 5.75%, N 1 1.51%, S 6.94%; Calculated for Ci ιH12N3O6S.C8H12N with 6% toluene by weight, C 54.60 %, H 5.73%, N 12.07%,
Figure imgf000064_0001
CRYSTAL DATA: C26 H32 S η N4 from CH3CN/anisole , colorless , needle , -0.05 x 0.05 x 0.22mm, orthorhombic, P2ι2j2 j (No. 19), a = 12.363(2)A, b = 25.388(4)A, c = 7.791(1)A, T = -70°C, Vol = 2445.4A3,
Z = 4, Formula weight = 544.63, Density = 1.479g/cc, μ(Mo) = 1.79cm" 1
DATA COLLECTION: Rigaku RTJ300, R-AXIS image plate area detector, MoKalpha radiation .filament size
= 12.0 x 2.0mm, anode power = 55kV x 240mA, crystal to plate distance = 85.0mm, 105μ pixel raster, number of frames = 43, oscillation range = 4.0%deg;, exposure time = 25.0 min/frame, box sum integration, data collected = 8910, 2-theta range = 3.2° - 48.2°, maximum hkl = 13 29 8, no absorption correction, 2677 duplicates, 6.0% R-merge, 1868 unique reflections with I> 2.5sig(I),
SOLUTION AND REFINEMENT: Structure solved by direct methods using teXsan(SIR-92), refined using Z program suite(Calabrese), refinement by full-matrix least squares on F, scattering factors from Int. Tables for X-ray Crystallography, Vol IV, including anomalous terms for S , biweight ~ [sigma 2(I)+0.0009I 2]" 1, 2, refined 39 of 63 atoms, 30 atoms refined anisotropic, 307 parameters, data/parameter ratio = 6.07, final Rl =
0.063, Rw = 0.047, error of fit = 1.48, max shift/error = 0.01, largest residual density = 0.35e/A3, near C35.
TABLE I. Fractional Coordinates (X I 0000) and Isotropic Thermal Parameters ATOM X Y Z BISO
S(12) 5301( 2) 1632( 1) 1415( 3) 4.2( 1)'
0(2) 1981( 4) 1952( 2) 319( 7) 3.8( 2)' ATOM X Y Z BISO
0(5) 3081(4) 1135(2) 5261(7) 3.8( 2)'
0(12) 4730( 4) 1151(2) 2482( 6) 4.2( 2)'
0(13) 6276( 5) 1419(2) 775( 8) 7.2( 2)'
0(14) 5474( 6) 2005( 2) 2796( 8) 7.6( 2)'
0(15) 4543( 5) 1798(2) 160(8) 6.3( 2)'
N(l) 2583( 5) 1416(2) 2577( 9) 3.2( 2)'
N(3) 2242( 4) 2232( 2) 3104(7) 2.9( 2)'
N(4) 2581(4) 2009( 2) 4680( 8) 3.2( 2)'
N(28) 2720( 4) 2639( 2) -2181(7) 3.4( 2)'
C(2) 2251(6) 1889(3) 1802(13) 3.3( 3)'
C(3) 1976( 6) 2791(2) 3043( 9) 3.9( 2)'
C(5) 2773( 6) 1526(3) 4223(11) 3.5( 3)'
C(6) 3266( 8) 1275( 3) 7013(12) 6.2( 3)'
C(ll) 2898( 6) 948( 2) 1677(10) 3.5( 2)'
C(12) 4014( 6) 821(3) 1608(11) 3.5( 2)'
C(13) 4359( 6) 365( 3) 807(10) 4.2( 3)'
C(14) 3588( 8) 38(3) 84(11) 4.6( 3)'
C(15) 2518(8) 166( 3) 146(10) 4.4( 3)'
C(16) 2141(6) 622( 2) 923( 9) 3.2( 2)'
C(17) 963( 6) 758( 3) 946(11) 5.0( 3)'
C(21) 4095( 5) 3203( 2) -3498(11) 3.1(2)'
C(22) 4758( 6) 3034( 3) -4865(11) 4.0( 2)'
C(23) 4985( 5) 3380( 3) -6192(11) 4.3( 3)'
C(24) 4580( 6) 3879( 3) -6246(12) 4.8( 3)'
C(25) 3911(7) 4038( 3) -4933(12) 4.7( 3)'
C(26) 3687( 6) 3704( 3) -3604(11) 4.1(2)'
C(27) 3884( 6) 2826( 3) -2060(11) 3.4( 3)'
C(29) 4046( 6) 3066( 3) -340(13) 4.9( 3)'
C(31) 8899(13) -490( 7) 1274(29) 4.2( 4)
C(32) 8574(18) -703( 9) 2406(33) 7.4( 5)
C(33) 7834(16) -358( 8) 3229(29) 7.8( 5)
C(34) 7481(17) 74(8) 2167(26) 7.1(5)
C(35) 7853(17) 230( 7) 566(29) 7.0( 5)
C(36) 8544(18) -104(8) -380(27) 7.4( 5)
C(37) 8683(19) -40( 9) 1522(32) 8.8( 6)
C(38) 9051(19) -1002(10) 1356(38) 9.9( 6)
C(39) 8946(25) -551(13) 166(51) 12.7(10)
H(3) 1651 2884 1999 4.1
H(3') 2614 2991 3274 4.1
H(3") 1491 2861 3975 4.1
H(6) 3883 1504 7096 5.7
H(6') 3521 1004 7756 5.7
H(6") 2678 1468 7509 5.7
H(13) 5115 286 785 4.4
H(14) 3834 -278 -442 4.5
H(15) 2039 -78 -375 4.8
H(17) 749 1014 144 5.0 ATOM X BISO
H(17) 713 856 2130 5.0
H(17") 399 494 1111 5.0
H(22) 5072 2688 -4903 3.9
TABLE I. Fractional Coordinates (XI OOOO) and Isotropic Thermal Parameters
H(23) 5385 3270 -7144 4.6
H(24) 4767 4129 -7093 4.9
H(25) 3586 4385 -4888 5.1
H(26) . 3178 3800 -2711 4.4
H(27) 4332 2525 -2165 3.5
H(28) 2702 2270 -1753 5.1
H(28') 2508 2618 -3360 5.1
H(28") 2262 2839 -1545 5.1
H(29) 4772 3173 -197 6.1
H(29') 3857 2818 523 6.1
H(29") 3583 3368 -233 6.1
TABLE II Anisotropic Thermal Parameters (A2 X . 000) exρ[-19.739(Ul lhha*a*. ..+2(U12hka*b*...))]
ATOM Ull U22 U33 U12 U13 U23
S(12) 53(2) 50(1) 58(2) -16( 1) 5(2) 5(1)
0(2) 51(4) 44(3) 49(5) -4(3) -9(3) 5(3)
0(5) 74(4) 41(3) 31(4) -3(3) 3(3) 1(2)
0(12) 50(3) 53(3) 58(4) -18(3) -6(3) 16(3)
0(13) 57(4) 105( 5) 110(6) 8(3) 26(4) 23(4)
0(14) 134( 6) 85(4) 68(5) -50( 4) 13(5) -10(3)
0(15) 69(4) 72(4) 98(5) -12(3) -16(4) 48(3)
N(l) 47(5) 27(3) 48(5) -1(3) -13(4) 2(3)
N(3) 41(4) 31(3) 37(5) 11(3) 7(3) 16(3)
N(4) 40(4) 31(3) 50(5) -1(3) -2(3) 4(3)
N(28) 28(4) 53(4) 48(5) -9(3) -6(3) 8(3)
C(2) 38(5) 43(5) 45(7) -5(4) 1(5) 3(4)
C(3) 49(5) 37(4) 62(6) 0(4) -6(4) -3(4)
C(5) 50(6) 22(4) 59(7) -6(4) -5(4) 10(4)
C(6) 121(8) 55(6) 60(7) 26(5) 2(6) 23(4)
C(ll) 54(6) 28(4) 50(6) -5(4) 5(5) 17(4)
C(12) 44(5) 43(5) 48(6) -18(4) -11(5) 17(4)
C(13) 51(6) 45(5) 62(7) 20(4) 0(4) 7(4)
C(14) 70(7) 38(5) 66(7) 9(4) -18(5) -10(4)
C(15) 81(7) 34(4) 53(6) -7(4) -11(5) -5(4)
C(16) 41(5) 39(4) 41(6) -12(4) -7(4) 6(3)
C(17) 50(6) 61(5) 80(8) -1(4) -11(5) 23(5)
C(21) 32(4) 41(5) 44(6) -4(3) -2(5) -13(4)
C(22) 47(5) 47(4) 57(6) -2(4) -15(5) 20(4)
C(23) 35(5) 69(5) 60(7) -1(4) 9(4) -2(5)
C(24) 59(6) 54(5) 71(7) -12(5) 4(6) 7(5)
C(25) 77(6) 36(5) 67(7) 3(4) 1(6) 0(5)
C(26) 63(5) 35(5) 59(6) 9(4) 1(5) 5(4)
C(27) 43(5) 25(4) 59(7) 5(3) -5(4) 1(4)
C(29) 50(6) 53(5) 84(8) -11(4) 9(5) 15(5) TABLE III. Interatomic Distances (A)
S(12)-0(12) 1.637(5) C(31)-C(37) 1.188(22)
S(12)-0(13) 1.413(6) C(31)-C(38) 1.316(28)
S(12)-0(14) 1.450(6) C(31)-C(39) 0.879 (38)
S(12)-0(15) 1.418(6) C(32)-C(33) 1.420(27)
0(2)-C(2) 1.213(9) C(32)-C(38) 1.263(30)
0(5)-C(5) 1.336(8) C(33)-C(34) 1.441(26)
0(5)-C(6) 1.429(9) C(34)-C(35) 1.387(23)
0(12)-C(12) 1.395(8) C(34)-C(37) 1.594(29)
N(3)-N(4) 1.416(7) C(35)-C(36) 1.411(26)
N(l)-C(2) 1.404(9) C(35)-C(37) 1.441(27)
N(l)-C(5) 1.334(8) C(36)-C(37) 1.501(29)
N(l)-C(ll) 1.433(9) C(36)-C(39) 1.312 (3 J)
N(3)-C(2) 1.337(9) C(37)-C(39) 1.705(39)
N(3)-C(3) 1.460(8) C(38)-C(39) 1.479(38)
N(4)-C(5) 1.297(8) C(3)-H(3) 0.937 (0)
N(28)-C(27) 1.519(8) C(3)-H(3') 0.955 (0)
N(28)-H(28) 0.994 (0) C(3)-H(3") 0.958 (0)
N(28)-H(28') 0.957 (0) C(6)-H(6) 0.962 (0)
N(28)-H(28") 0.907 (0) C(6)-H(6-) 0.953 (0)
C(ll)-C(12) 1.418(9) C(6)-H(6") 0.958 (0)
C(ll)-C(16) 1.381 (9) C(13)-H(13) 0.956 (0)
C(12)-C(13) 1.384(10) C(14)-H(14) 0.950 (0)
C(13)-C(14) 1.383(10) C(15)-H(15) 0.948 (0)
C(14)-C(15) 1.364(10) C(17)-H(17) 0.939 (0)
C(15)-C(16) 1.387(9) C(17)-H(17') 1.004(0)
C(16)-C(17) 1.497(10) C(17)-H(17") 0.976 (0)
C(21)-C(22) 1.411(10) C(22)-H(22) 0.961 (0)
C(21)-C(26) 1.371 (8) C(23)-H(23) 0.934 (0)
C(21)-C(27) 1.496(10) C(24)-H(24) 0.944 (0)
C(22)-C(23) 1.386(10) C(25)-H(25) 0.968 (0)
C(23)-C(24) 1.362(9) C(26)-H(26) 0.971 (0)
C(24)-C(25) 1.376(11) C(27)-H(27) 0.947 (0)
C(25)-C(26) 1.367(11) C(29)-H(29) 0.945 (0)
C(27)-C(29) 1.486(10) C(29)-H(29') 0.950 (0)
C(31)-C(32) 1.109(24) C(29)-H(29") 0.959 (0)
C(31)-C(36) 1.678(28)
TABLE IV. Intramolecular Angles (Deg)
0(12)-S(12)-0(13) 105.2 (3) C(27)-N(28)-H(28') 110 (0)
0(12)-S(12)-0(14) 100.0 (3) C(27)-N(28)-H(28") 112(0)
0(12)-S(12)-0(15) 106.7 (3) H(28)-N(28)-H(28') 105 (0)
0(13)-S(12)-0(14) 112.7 (4) H(28)-N(28)-H(28") 109(0)
0(13)-S(12)-0(15) 115.7 (4) H(28')-N(28)-H(28") 113 (0)
0(14)-S(12)-0(15) 114.5(4) 0(2)-C(2)-N(l) 127.1 (7)
S(12)-0(12)-C(12) 118.2(5) 0(2)-C(2)-N(3) 129.3 (7)
C(5)-0(5)-C(6) 116.0(6) 0(5)-C(5)-N(l) 118.4(6)
N(4)-N(3)-C(2) 113.3(5) 0(5)-C(5)-N(4) 126.0(8)
N(4)-N(3)-C(3) 119.0(5) 0(12)-C(12)-C(11) 117.6(7)
N(3)-N(4)-C(5) 101.2(6) 0(12)-C(12)-C(13) 121.8(7) C(2)-N(l)-C(5) 106.6(6) 0(5)-C(6)-H(6) 110(0)
C(2)-N(l)-C(ll) 125.2 (7) 0(5)-C(6)-H(6') 117(0)
C(5)-N(l)-C(ll) 126.7 (6) 0(5)-C(6)-H(6") 113(0)
C(2)-N(3)-C(3) 127.7(6) N(l)-C(2)-N(3) 103.5 (7)
C(27)-N(28)-H(28) 107 (0) N(l)-C(5)-N(4) 115.5(6)
N(l)-C(ll)-C(12) 118.1(6) C(31)-C(37)-C(36) 76(2)
N(l)-C(ll)-C(16) 121.4(7) C(31)-C(37)-C(39) 29(2)
N(28)-C(27)-C(21 ) 108.6(6) C(34)-C(37)-C(35) 54(1)
N(28)-C(27)-C(29 ) 108.1(6) C(34)-C(37)-C(36) 103(2)
N(3)-C(3)-H(3) 112(0) C(34)-C(37)-C(39) 121 (2)
N(3)-C(3)-H(3') 109(0) C(35)-C(37)-C(36) 57(1)
N(3)-C(3)-H(3") 107 (0) C(35)-C(37)-C(39) 100 (2)
N(28)-C(27)-H(27 ) 107(0) C(36)-C(37)-C(39) 48(1)
C(12)-C(ll)-C(16) 120.5 (7) C(31)-C(38)-C(32) 51(1)
C(ll)-C(12)-C(13) 120.5 (7) C(31)-C(38)-C(39) 36(2)
C(12)-C(13)-C(14) 118.3(7) C(32)-C(38)-C(39) 84(2)
C(13)-C(14)-C(15) 120.7 (7) C(31)-C(39)-C(36) 98(3)
C(14)-C(15)-C(16) 122.8 (7) C(31)-C(39)-C(37) 41(2)
C(ll)-C(16)-C(15) 117.3(7) C(31)-C(39)-C(38) 62(3)
C(ll)-C(16)-C(17) 121.1(7) C(36)-C(39)-C(37) 58(2)
C(15)-C(16)-C(17) 121.7(7) C(36)-C(39)-C(38) 155 (3)
C(22)-C(21)-C(26) 116.7(7) C(37)-C(39)-C(38) 103 (3)
C(22)-C(21)-C(27) 118.2(6) C(12)-C(13)-H(13) 119(0)
C(26)-C(21)-C(27) 125.1 (7) C(14)-C(13)-H(13) 123 (0)
C(21)-C(22)-C(23) 119.2(7) C(13)-C(14)-H(14) 117(0)
C(22)-C(23)-C(24) 122.6 (7) C(15)-C(14)-H(14) 122 (0)
C(23)-C(24)-C(25) 118.1(7) C(14)-C(15)-H(15) 116(0)
C(24)-C(25)-C(26) 120.2 (7) C(16)-C(15)-H(15) 122 (0)
C(21)-C(26)-C(25) 123.2(8) C(16)-C(17)-H(17) 115(0)
C(21)-C(27)-C(29) 112.9(6) C(16)-C(17)-H(17') 112(0)
C(32)-C(31)-C(36) 143 (2) C(16)-C(17)-H(17") 122 (0)
C(32)-C(31)-C(37) 105 (3) C(21)-C(22)-H(22) 122 (0)
C(32)-C(31)-C(38) 62(2) C(23)-C(22)-H(22) 118(0)
C(32)-C(31)-C(39) 136(4) C(22)-C(23)-H(23) 121 (0)
C(36)-C(31)-C(37) 60(2) C(24)-C(23)-H(23) 117(0)
C(36)-C(31)-C(38) 131 (2) C(23)-C(24)-H(24) 124 (0)
C(36)-C(31)-C(39) 51(3) C(25)-C(24)-H(24) 118(0)
C(37)-C(31)-C(38) 167 (3) C(24)-C(25)-H(25) 123 (0)
C(37)-C(31)-C(39) 110(3) C(26)-C(25)-H(25) 117(0)
C(38)-C(31)-C(39) 82(3) C(21)-C(26)-H(26) 116(0)
C(31)-C(32)-C(33) 107(2) C(25)-C(26)-H(26) 121 (0)
C(31)-C(32)-C(38) 67(2) C(21)-C(27)-H(27) 110(0)
C(33)-C(32)-C(38) 165 (3) C(29)-C(27)-H(27) 109 (0)
C(32)-C(33)-C(34) 114(2) C(27)-C(29)-H(29) 111(0)
C(33)-C(34)-C(35) 129(2) C(27)-C(29)-H(29') 109(0)
C(33)-C(34)-C(37) 76(2) C(27)-C(29)-H(29") 109 (0)
C(35)-C(34)-C(37) 57(1) H(3)-C(3)-H(3') 113(0)
C(34)-C(35)-C(36) 120 (2) H(3)-C(3)-H(3") 110(0) C(34)-C(35)-C(37) 69(2) H(3')-C(3)-H(3") 106(0)
C(36)-C(35)-C(37) 63(1) H(6)-C(6)-H(6') 98(0)
C(31)-C(36)-C(35) 96(2) H(6)-C(6)-H(6") 105 (0)
C(31)-C(36)-C(37) 43(1) H(6')-C(6)-H(6") 112(0)
C(31)-C(36)-C(39) 31(2) H(17)-C(17)-H(17') 111(0)
C(35)-C(36)-C(37) 59(1) H(17)-C(17)-H(17") 111(0)
C(35)-C(36)-C(39) 125 (2) H(17')-C(17)-H(17") 80(0)
C(37)-C(36)-C(39) 74(2) H(29)-C(29)-H(29') 110(0)
C(31)-C(37)-C(34) 116(2) H(29)-C(29)-H(29") 109(0)
C(31)-C(37)-C(35) 122(2) H(29')-C(29)-H(29") 109(0)
TABLE V. Intramolecular Non-Bonding Distances (A)
S(12)...N(1) 3.523 (6)
S(12)...C(2) 3.838 (8)
S(12)...C(5) 3.825 (8)
0(2) 0(15) 3.193 (8)
0(5) 0(12) 2.975 (7)
0(12)...N(4) 3.839 (8)
0(14)...N(1) 3.878 (9)
0(14)...N(4) 3.865 (8)
0(15)...N(1) 3.218 (8)
0(15)...N(3) 3.817 (8)
0(2) C(16) 3.414 (8)
0(2) C(17) 3.317 (8)
0(5) C(12) 3.173 (10)
0(5) C(16) 3.804 (9)
0(12)...C(2) 3.631 (9)
0(12)...C(5) 2.934 (9)
0(13)...C(13) 3.576(11)
0(14)...C(5) 3.723 (9)
0(15)...C(2) 3.117 (9)
0(15)...C(11) 3.190 (8)
0(15)...C(13) 3.680 (9)
C(2) C(17) 3.349(10)
TABLE VI. Intermolecular Distances (A)
0(2) N(28) 2.769 (7)
0(13)...N(28)c 3.180 (9)
0(14)...N(28)c 2.961 (8)
0(5) C(15)a 3.387 (8)
0(12)...C(38)b 3.394(30)
0(12)...C(39)b 3.060(36)
0(13)...C(32)d 3.198(26)
0(14)...C(22)e 3.305(10)
0(15)...C(6)f 3.204(12)
0(15)...C(27) 3.235 (8)
0(15)...C(29) 3.302 (9)
0(2) H(28) 2.013 (0)
N(4) N(28)e 2.927 (8) C(3) C(38)g 3.347 (25)
C(32)...C(35)b 3.258 (34)
C(33)...C(34)b 3.176 (31)
C(33)...C(35)b 2.035 (29)
C(33)...C(36)b 2.334 (29)
C(33)...C(37)b 3.335 (32)
C(34)...C(35)b 2.789 (25)
C(34)...C(36)b 2.295 (28)
C(34)...C(39)b 3.170 (43)
Symmetry Operation Codes a 1/2 - X, -Y, l/2+Z e X, Y, 1+Z b 3/2 - X , - Y , l/2+Z f X , Y , - 1+Z c l/2+X , l/2 - Y, - Z g 1 - X, 1 /2+Y , 1/2 - Z d 3/2 -X, - Y, - 1/2+Z
Step B: Preparation of (a-Sy2,4-dihvdro-4-f2-hvdroxy-6-methvIphenv0-5-methoxy-2- methyl-3H- 1 ,2,4-triazol-3-one In a round bottomed 300 mL flask equipped with a condenser, (aS)-2,4-dihydro-5- methoxy-2-methyl-4-[2-methyl-6-(sulfooxy)phenyl]-3H- 1 ,2,4-triazol-3-one α- methylbenzenemethanamine (containing 0.36 equivalents of toluene, 32.45 g, 69.1 mmol, 94% diastereomeric excess) was heated to 60 °C in 100 mL of 2 N sulfuric acid for three hours. The initially thick slurry dissolved upon heating and then (aS)-2,4-dihydro-4-(2- hydroxy-6-methylphenyl)-5-methoxy-2-methyl-3H- 1 ,2,4-triazol-3-one slowly precipitated from the solution. The reaction mixture was cooled to room temperature and extracted with three 200 mL portions of dichloromethane. The organic extracts were extracted once with 30 mL of water, dried with MgSO4, filtered and concentrated to dryness in vacuo to give (aS)-2,4-dihydro-4-(2-hydroxy-6-methylphenyl)-5-methoxy-2-methyl-3H-l,2,4-triazol-3-one as a white solid. The solid was further dried in vacuo (0.2 torr) for about 1 hour. Yield 16.53 g (99% from (aS)-2,4-dihydro-5-methoxy-2-methyl-4-[2-methyl-6-(sulfooxy)phenyl]- 3H-l,2,4-triazol-3-one (R)-α-methylbenzenemethanamine). ΗPLC analysis (Chirobiotic T column purchased from Astec (i.e., Advanced Separations Technologies, Inc.)), 80/20 Ηexanes/EtOΗ, 1.0 mL/min, 40 °C; 9.64 min (aS)-2,4-dihydro-4-(2-hydroxy-6- methylphenyl)-5-methoxy-2-methyl-3H-l,2,4-triazol-3-one, 1 1.3 min (aR)-2,4-dihydro-4-(2- hydroxy-6-methylphenyl)-5-methoxy-2-methyl-3H-l,2,4-triazol-3-one showed 94% ee.
Η NMR analysis showed the presence of 0.086 equivalent of toluene in addition to (aS)-2,4- dihydro-4-(2-hydroxy-6-methylphenyl)-5-methoxy-2-methyl-3H-l,2,4-triazol-3-one.
JΗ NMR (CDC13) δ 6.79 (t, 7.9 Hz, IH, ArH), 6.65 (d, 7.3 Hz, IH, ArH), 6.31 (d, 8.0 Hz,
IH, ArH), 3.91 (s, 3H, OCH3), 3.46 (s, 3H, NCH3), 2.11 (s, 3H, ArCH3). EXAMPLE 1 1
Step A: Preparation of 2-isocvanato-l ,3-dimethylbenzene
To 1.1 L of ethyl acetate, cooled in an ice-water bath under nitrogen atmosphere was added condensed phosgene (693 g). A solution of 2,6-dimethylaniline (424.5 g) in 250 mL of ethyl acetate was added dropwise. A slight exotherm occurred and a precipitate formed during the addition. After addition was complete, the cooling bath was removed and the slurry heated to reflux, monitoring the reaction by IR. Heating was continued until a clear solution resulted. After 2 h, IR analysis showed a strong cyano band at 2270 cm-1. The ethyl acetate was then removed by distillation at atmospheric pressure, then the product was distilled (7 mm Hg, 80 °C) to yield the title product as a clear colorless oil, (472.9 g, 92% yield) IR 2270 cm- 1, lH NMR (CDC13) δ 6.9 (m, 3H), 2.3 (s, 6H). Step B: Preparation of l-(chloromethyl)-2-isocvanato-3-methylbenzene
The title compound from Step A (424.4 g) and VAZO® 88 (1,1'- azobis(cyclohexanecarbonitrile) (4.0 g) were heated to 80 °C and chlorine (102.6 g), condensed with dry ice condenser , was added over 2 h. After the addition was complete the reaction was held at 80 °C for 15 min, then distilled under reduced pressure to remove unreacted starting material (310 g , 79% pure). The crude product was collect from the pot residue and saved for further handling. The recovered starting material was recycled with 3.5 g VAZO® 88 and 61.4 g chlorine as above. After distillation, 213.2 g of starting material was recovered and the crude product was combined with the crude product from the first cycle and distilled (7 mm Hg, 127-135 °C) to obtain 223.2 g of colorless oil (90% pure). Both fractions from this distillation were recombined and redistilled through a Vigreaux column (7 mm Hg, 130-135 °C) to obtain the title material (237.1 g, 93% pure) as a clear colorless oil, Η NMR (CDC13) δ 7.0-7.25 (m, 3H), 4.6 (s, 3H), 2.3 (s, 3H).
Step C: Preparation of 5-chloro-4- 2-(chloromethyl)-6-methylphenyll-2,4-dihvdro-2- methyl-3H- 1 ,2,4-triazol-3-one The crude material from Step B (237.6 g) was dissolved in 3 L of ethyl acetate. The solution was cooled to 10-15 °C and 1,1-dimethylhydrazine was added dropwise, resulting in a white suspension. The addition funnel was rinsed into the reaction vessel with 250 mL of ethyl acetate, the cooling bath was removed and the slurry held at room temperature until used in a second operation. To 1 L of ethyl acetate in a separate vessel was added 322 g of condensed phosgene. This phosgene solution was heated to reflux and the slurry described above was added via a masterflex peristolic pump over 1.5 h. After about 2/3 of the slurry was added, the remaining slurry was diluted with 1 L of ethyl acetate to facilitate the transfer. After all the slurry was added, the slurry vessel was rinsed into the reactor with 1 L of ethyl acetate. The reaction mixture was heated until a clear solution resulted, about 2. h. The reaction mixture was transferred into distillation vessel, followed by a rinse with 1 L of ethyl acetate. Atmospheric distillation removed about 5 L of ethyl acetate and the remaining solution was allowed to cool to room temperature overnight. The solution was diluted with 2 L of hexane and the resulting solid collected by filtration and washed with warm water (3x) then dried under nitrogen on the filter overnight to provide 220.9 g (66% yield from Step B) of fluffy white solids, !H NMR (CDC13) δ 7.4 (m, 3H), 4.45(AB quartet, 2H), 3.5 (s, 3H), 2.17 (s, 3H).
Step D: Preparation of 2,9-dimethyl-5H-r 1 ,2.4"jtriazolor4,3-αir3, 1 Ibenzothiazin-
U2H)-one To a solution of 5-chloro-4-[2-(chloromethyl)-6-methylphenyl]-2,4-dihydro-2-methyl-
3H-l,2,4-triazol-3-one (832 g), prepared similarly as in Steps A-C above, in 4 L of ethanol was added thiourea (281 g) and sodium bromide (9 g) and the resulting mixture was heated to reflux overnight. To the refluxing mixture was added 50% sodium hydroxide (735 g) dropwise over 45 min, then the mixture was heated at reflux for an additional 1 h. The reaction mixture was cooled to room temperature then added to 4 L of ice/water and the mixture was stirred for 15 min. The resulting solids were collected by filtration and rinsed with water, then dried under vacuum in an inert atmosphere to yield the title compound (620 g, 83% yield) as a pale yellow solid, mp 155-157 °C. lH NMR (CDC13) δ 7.3 (d, 1Η), 7.2 (t, 1 Η), 7.13 (d, 1Η), 3.9 (broad s, 2Η), 3.52 (s, 3H), 2.43 (s, 3H). Step E: Preparation of 2,9-dimethyl-5H-[ 1 ,2,4]triazolor4,3-fll \3 Λ lbenzothiazin- l(2H)-one 4,4-dioxide To a suspension of 2,9-dimethyl-5H-[l,2,4]triazolo[4,3-__][3,l]benzothiazin-l(2H)-one (400 g) in 1.6 L of acetic acid was added an aqueous solution of sodium tungstate (17.6 g in 10 mL) and the mixture heated to 55 °C. Hydrogen peroxide (30%, 425 g) was added dropwise over a 1 h period while maintaining a temperature about 70 °C. Initial oxidation to the sulfoxide was rapid. The clear solution resulting after the addition of hydrogen peroxide was maintained at 75-80 °C for 2.5 h. As the reaction progressed, the title compound precipitated as a white solid. The reaction mixture was cooled to 40 °C and was diluted with ice/water. The solids were removed by filtration, rinsed with water and dried under vacuum in an inert atmosphere to yield the title compound (443 g, 83% yield) as a white solid, mp >240 °C. ϊH NMR (CDC13) δ 7.41 (d, IH), 7.32 (t, 1 H), 7.2 (d, IH), 4.2 (broadened s, 2H), 3.68 (s, 3H), 2.5 (s, 3H).
Step F: Preparation of 4-r2-r(bromosulfonyl)methyll-6-methylphenyll-2,4-dihydro-5- methoxy-2-methyl-3H- 1.2.4-triazol-3-one To a suspension of 2,9-dimethyl-5H-[l,2,4]triazolo[4,3-_.][3,l]benzothiazin-l(2H)-one
4,4-dioxide (800 g), prepared similarly as in Steps E above, in 2.4 L of methanol was added sodium methoxide (25% in methanol, 829 mL) dropwise over 25 min, giving an exotherm to 34 °C. The mixture was heated to 60 °C for 1 h, giving an orange solution. Monitoring by thin-layer chromatography showed no starting material. The majority of the methanol was removed by rotary evaporation to yield an orange semisolid, which was dissolved inl .7 L of water and brought to pΗ = 5 with 48% ΗBr (approximately 100 mL). The aqueous solution was diluted with 1.7 L of dichloromethane and cooled in an ice/water bath. Bromine (150 mL was added dropwise over 45 min resulting in a pale orange mixture, which was stirred for 45 min. The phases were separated and the organic phase was washed with water, dried (MgSO ), filtered and concentrated. The residue was triturated in petroleum ether and the resulting solid collected by filtration to give 946 g of the title compound as an off-white solid, mp 1 19-122 °C. lU NMR (CDC13) δ 7.4-7.5 (m, 3 H), 5.1(AB quartet, 2H), 3.95 (s, 3H), 3.5 (s, 3H), 2.2 (s, 3H).
Step G: Preparation of 4-F2-(bromomethyl)-6-methylphenyl]-2,4-dihydro-5-methoxy-
2-methyl-3H- 1 ,2,4-triazol-3-one To a suspension of 4-[2-[(bromosulfonyl)methyl]-6-methylphenyl]-2,4-dihydro-5- methoxy-2-rnethyl-3H-l,2,4-triazol-3-one (946 g) in 2.2 L of toluene was added tetrabutylammonium bromide (80 g). The mixture was heated to 60 °C overnight, resulting in an amber solution. The reaction mixture was cooled and added to 4 L of ice/water and the phases separated. The organic phase was washed with water, dried (MgSO^, filtered and concentrated. The crude product was purified by applying to 700 g of silica gel and eluting, first with hexanes and then 2: 1 hexanes/ethyl acetate to recover the product. Removal of solvents gave 616 g of the title compound as an off-white solid, mp 115-116 °C. lH NMR (CDC13) δ 7.3-7.4 (m, 3 Η), 4.4(AB quartet, 2Η), 3.97 (s, 3H), 3.5 (s, 3H), 2.2 (s, 3H). Step H: Preparation of l-r4-(trifluoromethyl)-2-pyridinyl1ethanone
To a solution of 4-(trifluoromethyl)-pyridine (247.5 g) in 2 L of dichloromethane was added pyruvic acid (220 g), 2775 mL of water, 140 mL of concentrated sulfuric acid and silver nitrate (6.75 g). Ammonium persulfate (549 g) was added portionwise to the two- phase solution over about 4 h with significant foaming and gas evolution and a slight exotherm. After the addition was complete, the mixture was stirred until gas evolution stopped (about 1 h); monitoring by TLC showed complete reaction. The reaction mixture was diluted with water and the phases separated. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with aqueous sodium bicarbonate, dried (MgSO^), filtered and concentrated to an amber oil, using gentle vacuum and no heat. The crude product (335 g) was further concentrated by distillation at atmospheric pressure through a 7 inch Vigreaux column to remove additional dichloromethane. Removal of solvents gave 292.8 g of the title compound as an amber oil. lU NMR (CDC13) δ 8.75 (d, IH), 7.9 (s, IH), 7.48 (d, IH), 2.5 (s, 3H).
Step I: Preparation of l-[4-(trifluoromethyl)-2-pyridinyl1ethanone oxime
To a solution of hydroxylamine hydrochloride (11.5 g) in 60 mL of methanol was added a solution of potassium hydroxide (9.26 g) in 35 mL of methanol. Stir at room temperature for 30 min. and remove the resulting solids by filtration. The filtrate was added dropwise to a solution of the title compound from Step H (28.6 g) in 30 mL of methanol. The reaction mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation to yield a white solid. The crude product was dissolved in ethyl ether and washed with water , dried (MgSO4), filtered and concentrated to give 25 g of the title compound as a tan solid, mp 85-86 °C. Η NMR (CDC13) δ 9.15 (br s, IH), 8.8 (d, IH), 8.1
(s, IH), 7.5 (m, lH), 2.4 (s, 3H).
Step J: Preparation of 2.4-dihvdro-5-methoxy-2-methyl-4-r2-methyl-6-|~|"[T 1 4-
(trifluoromethyl)-2-pyridinyllethylidene1amino]oxylmethyllphenyll-3H- 1.2.4- triazol-3-one
To a suspension of l-[4-(trifluoromethyl)-2-pyridinyl]ethanone oxime (22.5 g), the title compound from Step I, in 100 mL of toluene was added aqueous sodium hydroxide (20%, 20.6 g), the title compound from Step G (30 g) and tetrabutylammonium bromide (80 g). The mixture was heated to 50 °C for 3 h. Monitoring by TLC showed complete reaction. The reaction mixture was cooled and diluted with water and the phases separated. The organic phase was washed with water, dried (MgSO^, filtered and concentrated to an amber oil. The crude product was purified by applying to silica gel and eluting with 1 : 1 hexanes/ethyl acetate to recover the product. Removal of solvents gave 29 g of the title compound as an off-white solid, mp 108-111 °C. *Η NMR (CDC13) δ 8.75 (d, IH), 8.1 (s, IH), 7.48 (d, IH), 7.4 (m, 2H), 7.3 (m, IH), 5.2 (AB quartet, 2H), 3.9 (s, 3H), 3.4 (s, 3H), 2.3 (s, 3H), 2.2 (s, 3H).
Step K: Separation of enantiomers of 2.4-dihydro-5-methoxy-2-methyl-4-r2-methyl-6- rrrri-r4-(trifluoromethylV2-pyridinyllethylidenelaminoloxy1methyllphenyl]- 3H- 1 ,2,4-triazol-3-one A sample of 2,4-dihydro-5-methoxy-2-methyl-4-[2-methyl-6-[[[[l-[4-
(trifluoromethyl)-2-pyridinyl]ethylidene]amino]oxy]methyl]phenyl]-3H-l,2,4-triazol-3-one (25 g) was separated in portions on a Chiralpak AD ΗPLC column, 32 cm x 8 cm (inner diameter) [98:2 hexanes/ethanol, flow rate 200 mL/min, 35 °C, UV detection at 240 nm, sample concentration 5 mg/mL in 98:2 hexanes/ethanol, 40 mL injection volume] to yield Enantiomer VII (a5)-2,4-dihydro-5-methoxy-2-methyl-4-[2-methyl-6-[[[[ 1 -[4-
(trifluoromethyl)-2-pyridinyl]ethylidene]amino]oxy]methyl]phenyl]-3H-l,2,4-triazol-3-one, elution time 33 min and Enantiomer VIII (aR)-2,4-dihydro-5-methoxy-2-methyl-4-[2-methyl- 6-[[[[ 1 -[4-(trifluoromethyl)-2-pyridinyl]ethylidene]amino]oxy]methyl]phenyl]-3H- 1 ,2,4- triazol-3-one, elution time 39 min. A total of 9.5 g of Enantiomer VII, 99.5% chemical purity, >99% ee, mp 126-128 °C and 10.2 g of Enantiomer VIII, 97.3% chemical purity, 96.5% ee were isolated following solvent removal.
EXAMPLE 12 Step A: Preparation of 2.4-dihvdro-4-[2-(hvdroxymethyl)-6-methylphenyl1-5- methoxy-2-methyl-3H- 1.2,4-triazol-3-one To a solution of 4-[2-(bromomethyl)-6-methylphenyl]-2,4-dihydro-5-methoxy-2- methyl-3H-l,2,4-triazol-3-one, prepared as in Step G, Example 1 1, (50 g) in 500 mL of -dioxane and 500 mL of water was added calcium carbonate (80.2 g), and the mixture was heated to reflux 2 h. The dioxane was removed by rotary evaporation and the residue was diluted with 400 mL of IN hydrochloric acid. The pH was adjusted to 3 by the addition of concentrated hydrochloric acid and ice was added to cool. The aqueous mixture was extracted with dichloromethane (3 X 200 mL). The combined organic phases were washed with 500 mL aqueous sodium bicarbonate, dried (MgSO^, filtered and concentrated to yield a pale yellow solid. The crude product was triturated in hexanes and filtered to yield the title compound (34.1 g) as a white solid, mp 132-134 °C. lH NMR (CDC13) δ 7.35-7.43 (m, 2H), 7.3(m, IH), 4.4 (AB quartet, 2H), 3.94 (s, 3H), 3.48 (s, 3H), 3.3 (dd, IH), 2.15 (s, 3H). Step B: Preparation of faS-.2-(R*ϊl1-4-r2-ITr [Y7,7-dimethyl-6- oxobicvclor2.2.1 Iheptan- 1 -yl)methyllsulfonvnoxy1methyll-6-methylphenyl1- 2.4-dihvdro-5-methoxy-2-methyl-3H-1.2.4-triazol-3-one
To a solution of 2,4-dihydro-4-[2-(hydroxymethyl)-6-methylphenyl]-5-methoxy-2-methyl- 3H-l,2,4-triazol-3-one, prepared as in Step A, (62.0 g) in 1000 mL of tetrahydrofiiran was added 87.4 g of (15)-(+)-camphorsulfonyl chloride and then 52 mL of triethylamine dropwise with ice-bath cooling. The resulting mixture was stirred at room temperature for 18 h. Monitoring by thin layer chromatography showed complete reaction. The solvents were removed by rotary evaporation and the residue was taken up in 500 mL of dichloromethane and washed with 500 mL of IN ΗC1, then 500 mL of water. The organic phase was dried (MgSO4), filtered and concentrated to give 120.4 g of an orange oil. Analysis by JΗ NMR showed a 1:1 ratio of diastereomers. The crude product was taken up in 500 mL of n- chlorobutane and refrigerated for 72 h. The precipitated crystals were collected by filtration and dried under vacuum to yield 59.3 g of white crystals, mp 121-127 °C. lH NMR showed approximately a 9: 1 ratio of diastereomers (major diastereomer is Diastereomer E) with approximately 0.5 mole-equivalents of n-chlorobutane incorporated into the crystals. The mother liquors were concentrated to yield 63 g of orange oil. Analysis by !H NMR showed the oil to be >95% pure for a single diastereomer (Diastereomer F). The oil was triturated in ether/hexanes to obtain 49.3 g of the title compound as a white solid, mp 104-110 °C. [α]D = +64.0 (c = 5.62, CH2C12)
Diastereomer E: !H NMR (CDC13) δ 7.4 (m, 3H), 5.21 (AB quartet, 2H), 3.97 (s, 3H), 3.47 (s, 3H), 3.46 (d, IH), 2.85 (d, IH), 2.4 (m, 2H), 2.18 (s, 3H), 2.1 (m, 2H), 1.93 (d, IH), 1.6 (m, IH), 1.4 (m, IH), 1.07 (s, 3H), 0.81 (s, 3H).
Diastereomer F: !H NMR (CDC13) δ 7.4 (m, 3H), 5.19 (AB quartet, 2H), 3.95 (s, 3H), 3.52 (d, IH), 3.47 (s, 3H), 2.94 (d, IH), 2.4 (m, 2H), 2.18 (s, 3H), 2.1 (m, 2H), 1.93 (d, IH), 1.6 (m, IH), 1.4 (m, IH), 1.08 (s, 3H), 0.86 (s, 3H). Step C: Preparation of (aR -2.4-dihvdro-5-methoxy-2-methyl-4-r2-methyl-6-[rf I" 1 -F3- (trifluoromethyl phenyllethylidene1aminoloxylmethyllphenyl]-3H- 1.2,4- triazol-3-one To a solution of l-[3-(trifluoromethyl)phenyl]ethanone oxime in 10 mL of tetrahydrofiiran was added 40 mg of sodium hydride (50% oil dispersion). Gas evolution was observed and the mixture was stirred at room temperature for 20 min. A solution of Diastereomer E, from Step B, in 10 mL of tetrahydrofiiran was added and the mixture stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate (2x25 mL). The combined extracts were dried (MgSO4), filtered and concentrated to an amber oil. The crude product was purified by applying to silica gel and eluting with 1 : 1 hexanes/ethyl acetate to recover the product. Removal of solvents gave 240 mg of the title compound as a colorless oil. lH NMR (CDCI3) δ 7.86 (br s, IH), 7.8 (d,lH), 7.6 (d, IH), 7.45 (t, IH), 7.38 (m, 2H), 7.3(m, IH), 5.18 (AB quartet, 2H), 3.89 (s, 3H), 3.41 (s, 3H), 2.22 (s, 3H), 2.18 (s, 3H). [α]D = -57.1 (c= 4.98, CH2C12). HPLC analysis as described in • Example 1 using a Chiralpak AD column (25 cm x 0.46 cm (inner diameter)) showed the material to be 96% ee [4:1 hexanes/ 2-propanol, flow rate 0.8 mL/min, elution time 10.3 min].
Step D: Preparation of (aS)-2.4-dihvdro-5-methoxy-2-methyl-4-r2-methyl-6-rrrri-r3-
(trifluoromethyl)phenvnethylidene]amino1oxy]methyl]phenyl]-3H-1.2.4- triazol-3-one
By a procedure similar to that described in Step C, 310 mg of Diastereomer F (approx. 90% pure), obtained similarly as in Step B was converted to 190 mg of the title compound as a colorless oil. Η NMR (CDC13) δ 7.86 (br s, 1Η), 7.8 (d,lΗ), 7.6 (d, IH), 7.45 (t, IH), 7.38 (m, 2H), 7.3(m, IH), 5.18 (AB quartet, 2H), 3.89 (s, 3H), 3.41 (s, 3H), 2.22 (s, 3H), 2.18 (s, 3H). [α]D = +53.0 (c= 5.0, CH2C12). HPLC analysis as described in Example lusing a Chiralpak AD column (25 cm x 0.46 cm (inner diameter)) showed the material to be 83% ee [4:1 hexanes/ 2-propanol, flow rate 0.8 mL/min, elution time 8.2 min].
EXAMPLE 13 Preparation of (aS)-2.4-dihvdro-5-methoxy-2-methyl-4-[2-methyl-6-[rr[ 1 -[4- (trifluoromethvπ-2-pyridinyl1ethylidenelamino1oxy]methyl1phenyll-3H-l,2,4-triazol-3-one To a solution of l-[4-(trifluoromethyl)-2-pyridyl]ethanone oxime (100 mg) in 10 mL of tetrahydrofiiran was added 30 mg of sodium hydride (50% oil dispersion). Gas evolution was observed and the mixture was stirred at room temperature for 20 min. A solution of Diastereomer F (230 mg), from Example 12, Step B, in 5 mL of tetrahydrofiiran was added and the mixture stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate (2x25 mL). The combined extracts were dried (MgSO ), filtered and concentrated to an amber oil. The crude product was purified by applying to silica gel and eluting with 1 : 1 hexanes/ethyl acetate to recover the product. Removal of solvents gave the title compound as a colorless oil. Trituration in ether/hexanes gave 110 mg of the title compound as a white crystalline solid, mp 125-129 °C. Η NMR (CDC13) δ 8.73 (d, IH), 8.10 (s, IH) 7.3-7.45 (m, 4H), 5.22 (AB quartet, 2H), 3.89 (s, 3H), 3.42 (s, 3H), 2.31 (s, 3H), 2.18 (s, 3H). [α]D = +65.9 (c = 3.68, CH2C12). HPLC analysis as described in Example 1 using a Chiralpak AD column (25 cm x 0.46 cm (inner diameter)) showed the material to be 95% ee [92.5% hexanes/ 7.5% ethanol, flow rate 1.0 mL/min, elution time 5.7 min]. (Under the same conditions the minor enantiomer eluted at 6.2 min.) This material corresponds to the Enantiomer VII, Example 1 1 , Step K.
EXAMPLE 14 Preparation of (aS)-4-[2-(iodomethyl)-6-methylphenyl1-2.4-dihvdro-5-methoxy-2-methyl-
3H- 1 ,2,4-triazol-3-one To a solution of Diastereomer F (930 mg), from Example 12, Step B, in 20 mL of acetone was added 330 mg of sodium iodide and the resulting solution stirred at room temperature for 4 h. During that time a solid precipitated out. The solvent was removed by rotary evaporation and the residue taken up in ethyl acetate and water and saturated sodium bisulfite solution to decolorize. The phases were separated and the aqueous phase extracted with ethyl acetate. The combined extracts were dried (MgSO4), filtered and concentrated to an amber oil. On standing, the oil partially solidified. The material was triturated in ether/hexane and the solids collected to yield 460 mg of the title compound as a pale yellow solid, mp 92-96 °C. lU NMR (CDC13) δ 7.3 (m, 3Η), 4.33 (AB quartet, 2H), 3.97 (s, 3H), 3.50 (s, 3H), 2.15 (s, 3H). [α]D = +151.9 (c= 6.1, CH2C12). HPLC analysis as described in Example 1 using a Chiralpak AD column (25 cm x 0.46 cm (inner diameter)) showed the material to be 92% ee [90% hexanes/ 10% ethanol, flow rate 0.8 mL/min, elution time 8.7 min]. (Under the same conditions the other enantiomer eluted at 8.0 min.) EXAMPLE 15
Preparation of (aS)-2.4-dihvdro-4-[2-(hvdroxymethyl)-6-methylphenyl]-5-methoxy-2- methyl-3H- 1 ,2.4-triazol-3-one To a solution of Diastereomer F (930 mg), from Example 12, Step B, in 8 mL of 1,4-dioxane and 8 mL of water was added 1.0 g of calcium carbonate. The mixture was heated for 5 h at reflux. The mixture was diluted with ethyl acetate and neutralized with
IN hydrochloric acid. The phases were separated and the aqueous phase extracted with ethyl acetate. The combined extracts were dried (MgSO ), filtered and concentrated to a colorless oil. The crude product was purified by applying to silica gel and eluting with 1 :2 hexanes/ethyl acetate to recover the product. Removal of solvents gave the title compound as a colorless oil which solidified on standing. Trituration in hexanes gave 230 mg of the title compound as a white crystalline solid, mp 119-121 °C. !Η NMR δ 7.4 (m, 2H), 7.3 (m, IH), 4.46 (m, 2H), 3.94 (s, 3H), 3.48 (s, 3H), 2.16 (s, 3H). [α]D = +100.3 (c= 4.68, CH2C12). HPLC analysis as described in Example 1 using a Chiralpak AD column (25 cm x 0.46 cm (inner diameter)) showed the material to be >98% ee [90% hexanes/ 10% ethanol, flow rate 0.8 mL/min, elution time 1 1.4 min]. (Under the same conditions the other enantiomer eluted at 10.4 min.)
By the procedures described herein together with methods known in the art, the following compounds of Tables 1 to 26 can be prepared. The following abbreviations are used in the Tables which follow: t = tertiary. Me = methyl, Et = ethyl, /Pr = isopropyl, Bu = butyl, CF3 = trifluoromethyl, OMe = methoxy, OCHF2 = difluoromethoxy, SCH3 = methylthio, SCF3 = trifluoromethylthio, SCHF2 = difluoromethylthio, OCF3 = trifluoromethoxy, F = fluorine, Cl = chlorine, Br = bromine, I = iodine, and CN = cyano.
Structure for Tables 1 a. 1 b and 1 c
Figure imgf000078_0001
Table la
V = H, Y = -O-
Phenyl 3-OMe-phenyl 4-CF3-ρhenyl
3-Me-phenyl 3-F-phenyl 3-OCF3-phenyl
4-Me-phenyl 3-SCHF2-phenyl 3-SCH3-phenyl
2-Me-phenyl 4-SCHF2-phenyl 4-SCH3-phenyl
3-cyclohexyl-phenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
5-CF3-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 2-(5,6,7,8-tetrahydro)naphthalenyl 2-(3 ,3,3-trifluoroethoxyl)-4-
6-(3,3,3-tri_luoroethoxyl)-4- 4-(3,3,3-tri_luoroethoxyl)-2- pyrimidinyl pyrimidinyl pyrimidinyl 3,5-diMe-phenyl 2-naphthalenyl 4-.-Bu-phenyl 4-OCF3-phenyl 3- -Bu-phenyl 4-SCF3-phenyl 6-(3,3,3-trifluoroethoxyl)-2- 3-SCF3-phenyl 4,6-diMe-2-pyridinyl pyrazinyl 4-CF3-6-Me-2-pyridinyl 3,5-di(CF3)-phenyl 3-CF3-phenyl 3-I-phenyl 3-( 1 -propynyl)-phenyl 3-(3,3-diMe-l-butynyl)- 3-(2-cyclopropylethynyl)phenyl phenyl
V = H, Y = -CH20-
Z phenyl 3-CF3-phenyl 2-Me-5-/Pr-phenyl
2- e-4-OCH3-phenyl 4-0CF3-phenyl 2-Me-5-CF3-phenyl 3-OCHF2-phenyl 4-0CHF2-phenyl 3,5-di(CF3)-phenyl 2-Me-4-OCHF2-phenyl 6-CF3-2-pyridinyl 3-OCF3-phenyl
4-CF3-2-pyridinyl 4-Me-2-pyridinyl 2-Me-4-OCF3-phenyl
5-Me-2-pyridinyl 3,6-diMe-2-pyridinyl 5-CF3-2-pyridinyl
4, 6-diMe-2-pyridiny 1 6-OCF3-2-pyridinyl 4-CF3-6-Me-2 -pyridinyl
3-Me-2-pyridinyl 4-Cl-2-pyrimidinyl 6-Me-2-pyridinyl
4-Cl-2-pyrimidinyl 3-Et-phenyl 2,6-Me2-4-pyridinyl
2,4,6-triMe-phenyl 3-Cl-2-pyridinyl 6-Cl-4-pyrimidinyl
1-napthalenyl 2,3,6-triMe-phenyl 6-Cl-2-pyrazinyl
4-CF3-2-pyrimidinyl 6-CF3-4-pyrimidinyl 2-.Pr-phenyl
3-Me-2-pyridinyl 4-Cl-2-pyridinyl 2-Me-phenyl
2,5-diMe-phenyl 2,4-diCl-phenyl 2-Me-4-Cl-phenyl
2-Cl-phenyl 2,4-diMe-phenyl 2,5-diCl-phenyl
4-CF3-5-Br-2-thiazolyl l-Ph-l//-pyrazol-3-yl l-(4-Cl-Ph)-l f-pyrazol-3-yl l-(4-Me-Ph)-l_¥-pyrazol-3-yl l-(3-Me-Ph)-l_¥-pyrazol-3-yl 1-Ph-l//- 1 ,2,4-triazol-3-yl l-(4-Cl-Ph)- IH- 1 ,2,4-triazol-3-yl 1 -(4-Me-Ph)- 1 H- 1 ,2,4-triazol-3-yl 1 -(3-Me-Ph)- IH- 1 ,2,4-triazol-3-yl
V = H, Y = -OCH2-
Z 2-Me-phenyl 2,5-diMe-phenyl 3-CF3-phenyl 4-CF3-phenyl 4-Me-phenyl 4-.-Bu-phenyl 3-Cl-phenyl 4-Cl-phenyl 2-Me-5-Cl-ρhenyl 3-r-Bu-phenyl 2-naphthalenyl 1-naphthalenyl 3-pyridinyl 4-pyridinyl 6-Me-2-pyridinyl 2-(5,6,7,8 tetrahydro)naphthalenyl
V = H, Y = -CH20-N=C(CH3)-
Z
3-Me-phenyl 4-CF3-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Br-phenyl 3,5-di(CF3)-phenyl
4-0CHF2-phenyl 4-r-Bu-phenyl 3-.-Bu-phenyl
5-CF3-2-pyridinyl 4-OCF3-phenyl 3-OCHF -phenyl
5-Me-2- pyridinyl 4-CF3-6-Me-2-pyridinyl 4-Me-2- pyridinyl
4,6-diMe-2-pyridinyl 6-Me-2-pyridinyl 6-CF3-2-pyridinyl
6-OMe-2-pyridinyl 2,6-Me2-4-pyridinyl 2,6-diCl-4-pyridinyl
5-OCF3-2-pyridinyl 4-OMe-2-pyridinyl 4-OCF3-2-pyridinyl
5-OCHF2-2-ρyridinyl 6-OCF3-2-pyridinyl 4-OCHF2-pyridinyl
3-(3,3,3 trifluoroethoxy)-phenyl 6-OCHF2-2-pyridinyl 3-Et-phenyl
1-naphthalenyl 2-( 1 ,2,3,4-tetrahydro)naphthalenyl /-Bu 3-SMe-phenyl 3-ethynyl-phenyl 3-CF3-phenyl
3,5-diCl-phenyl 3-OCF3-phenyl 4-CF3-2-pyridinyl
4-CF3-6-Cl-2-pyridinyl
V = H, Y = -CH=NOCH(CH3)-
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-ρhenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl
4-Me-ρhenyl 2-naphthalenyl 4-OCHF2-phenyl
3-OCHF2-phenyl 4-CF3-2-pyridinyl 5-CF3-2-ρyridinyl
6-CF3-2-pyridinyl 4-Me-2-pyridinyl 5-Me-2-pyridinyl
6-Me-2-pyridinyl 4-CF3-6-Me-2-pyridinyl 4-OCF3-2-pyridinyl
5-OCF3-2-pyridinyl 6-OCF3-2-pyridinyl 4-OCHF2-2-pyridinyl
5-OCHF2-2-pyridinyl 6-OCHF2-2-pyridinyl 3-.-Bu-phenyl
4-_-Bu-phenyl
V = H, Y = -CH2-SC(Et)=N
Z 4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl 3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl 4-Me-phenyl 3,5-diMe-ρhenyl 2-naphthalenyl 6-Me-2-pyridinyl 4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-Cl-2-pyridinyl 4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl 5-CF3-2-pyridinyl 5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl
V = H, Y = -CH2-SC(=S)NMe-
4-CF -phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl
4-Me-phenyl 3,5-diMe-phenyl 2-naphthalenyl
6-Me-2-pyridinyl 4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl
5-Cl-2-pyridinyl 4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl
5-CF -2-pyridinyl 5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl V = H, Y = -CH2SC(SMe)=N-
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF3-phenyl 4-CF3-phenyl 3-OCF3 -phenyl
4-OCF3-phenyl 3,5-di(CF3)-phenyl CH2CH2-/-Bu
/-Bu 2-naphthalenyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-Cl-2-pyridinyl
4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl 5-CF3-2-pyridinyl
5-Br-6-Me-2-pyridinyI 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = H, Y = -CH2S-
Z 2-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl 2,5-diMe-phenyl 2-Et-phenyl 3-Cl-phenyl 2-Cl-ρhenyl 2,5-diCl-phenyl 4,6-diMe-2-pyrimidinyl 4-Me- 1 ,2,4-triazol-3-yl 2-naphthalenyl 1 -Me-2-imidazolyl 4-Me-2-pyrimidinyl 5-Me- 1 ,3 ,4-thiadiazol- 2-yl 4-CF3-2-pyridinyl 4-Ph-5-Me-2-thiazolyl
V = H, Y = -CH2ON=C(CH3)CH2S Z _
3-Me-phenyl 2-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl 3-Cl-phenyl 4-Cl-phenyl 2-Et-phenyl 2,5-diMe-phenyl 2-naphthalenyl
V = H, Y = -CH2ON= (CH3)CH20-
Z Z 3-Me-phenyl 2-Me-phenyl 4-Me-phenyl 3-CF3-ρhenyl 4-CF3 -phenyl 4-Cl-phenyl 3-Cl-phenyl 3,5-diMe-phenyl 2,5-diMe-phenyl 2-Me-5-/Pr-phenyl 3-Et-phenyl 6-CF3-2-pyridinyl 4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-Me-2-pyridinyl 5-Me-2-pyridinyl 4-Me-2-pyridinyl 1-naphthalenyl 2-naphthalenyl
V = H, Y = -CH2CH2-
Z z
2-Me-phenyl 2,5-diMe-phenyl 3-CF3-phenyl
4-CF3-phenyl 3-Cl-ρhenyl 4-Cl-phenyl 3-OCF3-phenyl 4-OCF3-phenyl 2-Et-phenyl 2-Me-5-Cl-phenyl 2-naphthalenyl 3,6-diMe-2-pyridinyl
V = H, Y = -CH=C(CH3)- z z
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3-OCF3-phenyl
4-OCF3-phenyl 3-CF3-phenyl 4-CF3 -phenyl
2-naphthalenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = H, Y = -CH=N-N=C(CH3)-
3-Me-phenyl 4-Me-phenyl 3-CF3 -phenyl
4-CF3-phenyl 3-OCF3-phenyl 4-OCF3-phenyl
3,5-diMe-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 4-CF3-2-pyridinyl 5-CF3-2-pyridinyl
6-CF3-2-pyridinyl 4-Me-2-pyridinyl 5-Me-2-pyridinyl
6-Me-2-pyridinyl 2-naphthalenyl 4,6-diMe-2-pyridinyl
3-Et-phenyl /-Bu Phenyl
V = H, Y = -CH2ON (CH3)C(=NOCH3)-
Z Z 3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl 3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl 3-CF3-phenyl 4-CF3-phenyl 3,5-di(CF3)-phenyl 3-OCF3-phenyl 4-OCF3-ρhenyl CH3 /-Bu 2-naphthalenyl 4-/-Bu-phenyl
4-Me-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl 4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-CF3-2-pyridinyl 4,6-diMe-2-pyridinyl 4-CF -2-pyrimidinyl 6-CF3 -2-pyrimidinyl Phenyl 4-Br-phenyl 4-I-phenyl 4-F-phenyl
V = H, Y = -CH=N-N(CH3)-
Z Z
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyF
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl 3-CF3-phenyl 4-CF3-phenyl 3-OCF3-phenyl 4-OCF3-phenyl 2-naphthalenyl 4-/-Bu-phenyl 4-Me-2 -pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl 4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-CF3-2-pyridinyl
4,6-diMe-2-pyridinyl 4-CF3-2-pyrimidinyl
V = H, Y = -CH20C(SMe)=N-
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Me-phenyl 4-Me-phenyl
3,5-diMe-phenyl 2-naρhthalenyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-CF3-2-pyridinyl
5-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = H, Y = -CH2OC(=S)NMe-
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Me-phenyl 4-Me-phenyl
3,5-diMe-phenyl 2-naphthalenyl 6-_v_e-2-pyridinyl
4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-CF3-2-pyridinyl
5-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = H, Y = -SCH2- Z
2-Me-phenyl 2,5-diMe-phenyl 3-CF3 -phenyl
4-CF3-phenyl 4-Me-phenyl 4-/-Bu-phenyl
3-Cl-phenyl 4-Cl-phenyl 2-Me-5-Cl-phenyl
3-/-Bu-phenyl 2-naphthalenyl 1-naphthalenyl
3-pyridinyl 4-pyridinyl 6-Me-2-pyridinyl
2-(5,6,7,8-tetrahydro)naphthalenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = H
Y Y Z -CH20-N=C(SCH3)- 3-CF3-phenyl -CH20-N=C(cyclopropyl)- 3-CF3-phenyl -CH20-N=C(SCH3)- 3-0CF3-phenyl -CH20-N=C(cyclopropyl)- 3-OCF3-phenyl Y Z
-CH20-N=C(SCH3)- 3-Me-phenyl -CH20-N=C(cyclopropyl)- 3-Me-phenyl -CH20-N=C(SCH3)- 4-CF3 -phenyl -CH20-N=C(cyclopropyl)- 4-CF3-phenyl -CH20-N=C(SCH3)- 4-OCF3-phenyl -CH20-N=C(cyclopropyl)- 4-OCF3-phenyl -CH20-N=C(SCH3)- 4-Me-phenyl -CH20-N=C(cyclopropyl)- 4-Me-phenyl -CH20-N=C(SCH3)- 3-Cl-phenyl -CH20-N=C(cycIopropyl)- 3-Cl-phenyl -CH20-N=C(SCH3)- 3,5-diCl-phenyl -CH20-N=C(cyclopropyl)- 3.5-diCl-phenyl
Table lb
V = 3-CH3, Y = -O-
Z Phenyl 3-OMe-phenyl 4-CF3-phenyl 3-Me-phenyl 3-F-phenyl 3-OCF3-phenyl 4-Me-phenyl 3-SCHF -phenyl 3-SCH3-phenyl 2-Me-ρhenyl 4-SCHF2-phenyl 4-SCH3-phenyl 3-cyclohexyl-phenyl 4-CF3-2-pyridinyl 6-CF3 -2-pyridinyl 5-CF3-2-ρyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl 4-Me-2-pyridinyl 2-(5,6,7,8-tetrahydro)naphthalenyl 2-(3,3,3-trifluoroethoxyl)-4- 6-(3,3,3-trifluoroethoxyl)-4- 4-(3,3,3-trifluoroethoxyl)-2- pyrimidinyl pyrimidinyl pyrimidinyl 3,5-diMe-phenyl 2-naphthalenyl 4-/-Bu-phenyl 4-OCF3-phenyl 3-/-Bu-phenyl 4-SCF3-phenyl 6-(3,3,3-trifluoroethoxyl)-2- 3-SCF3-phenyl 4,6-diMe-2-pyridinyl pyrazinyl 4-CF3-6-Me-2-pyridinyl 3,5-di(CF3)-phenyl 3-CF3-phenyl 3-I-phenyl 3-( 1 -propynyl)-phenyl 3-(3,3-diMe-l-butynyl)- 3-(2-cyclopropylethynyl)phenyl phenyl
V = 3-CH3, Y = -CH20- Z phenyl 3-CF3-phenyl 2-Me-5-;Pr-phenyl
2-Me-4-OCH3-phenyl 4-OCF3-phenyl 2-Me-5-CF3-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3,5-di(CF3)-phenyl
2-Me-4-OCHF2-phenyl 6-CF3-2-pyridinyl 3-OCF3-phenyl
4-CF3-2-ρyridinyl 4-Me-2-pyridinyl 2-Me-4-OCF3 -phenyl
5-Me-2-pyridinyl 3,6-diMe-2-pyridinyl 5-CF3-2-pyridinyl
4,6-diMe-2 -pyridinyl 6-OCF3-2-pyridinyl 4-CF3-6-Me-2-pyridinyl
3-Me-2-pyridinyl 4-Cl-2-pyrimidinyl 6-Me-2-pyridinyl
4-Cl-2-pyrimidinyl 3-Et-phenyl 2,6-Me2-4-pyridinyl 2,4,6-triMe-phenyl 3-Cl-2-pyridinyl 6-Cl-4-pyrimidinyl
1-napthalenyl 2,3,6-triMe-phenyl 6-Cl-2-pyrazinyl
4-CF3-2-pyrimidinyl 6-CF3-4-pyrimidinyl 2- Pr-phenyl
3-Me-2-pyridinyl 4-Cl-2-pyridinyl 2-Me-phenyl
2,5-diMe-phenyl 2,4-diCl-phenyl 2-Me-4-Cl-phenyl
2-Cl-phenyl 2,4-diMe-phenyl 2,5-diCl-phenyl
4-CF3-5-Br-2-thiazolyl l-Ph-l/Y-pyrazol-3-yl 1 -(4-Cl-Ph)- 1 / -pyrazol-3-yl l-(4-Me-Ph)-l_Y-pyrazol-3-yl l-(3-Me-Ph)-l /-pyrazol-3-yl 1 -Ph- 1 H- 1 ,2,4-triazol-3-yl
1 -(4-Cl-Ph)- 1 H- 1 ,2,4-triazol-3-yl 1 -(4-Me-Ph)- IH- 1 ,2,4-triazol-3-yl 1 -(3-Me-Ph)- \H- 1 ,2,4-triazol-3-yl
V = 3-CH3, Y = -OCH2-
Z 2-Me-phenyl 2,5-diMe-ρhenyl 3-CF3-phenyl 4-CF3-phenyl 4-Me-phenyl 4-/-Bu-phenyl 3-Cl-phenyl 4-Cl-phenyl 2-Me-5-Cl-phenyl 3-/-Bu-phenyl 2-naρhthalenyl 1-naphthalenyl 3-pyridinyl 4-pyridinyl 6-Me-2-pyridinyl 2-(5,6,7,8 tetrahydro)naphthalenyl
V = 3-CH3, Y = -CH20-N=C(CH3)-
Z 3- e-phenyl 4-CF3-phenyl 3,5-diMe-phenyl 3-Cl-phenyl 4-Br-phenyl 3,5-di(CF3)-phenyl 4-OCHF2-phenyl 4-/-Bu-phenyl 3-/-Bu-phenyl 5-CF3-2-pyridinyl 4-OCF3-phenyl 3-OCHF2-phenyl 5-Me-2- pyridinyl 4-CF3-6-Me-2 -pyridinyl 4-Me-2- pyridinyl 4,6-diMe-2-pyridinyl 6-Me-2-pyridinyl 6-CF3-2-pyridinyl 6-OMe-2-pyridinyl 2,6-Me2-4-pyridinyl 2,6-diCl-4-pyridinyl 5-OCF3-2-ρyridinyl 4-OMe-2-pyridinyl 4-OCF3-2-pyridinyl 5-OCHF2-2-pyridinyl 6-OCF3-2-pyridinyl 4-OCHF2-pyridinyl 3-(3,3,3 trifluoroethoxy)-phenyl 6-OCHF2-2-pyridinyl 3-Et-phenyl 1-naphthalenyl 2-( 1 ,2,3,4-tetrahydro)naphthalenyl /-Bu 3-SMe-phenyl 3-ethynyl-phenyl 3-CF3-phenyl 3,5-diCl-phenyl 3-OCF3-phenyl 4-CF3-2-pyridinyl 4-CF3-6-Cl-2-pyridinyl V = 3-CH3, Y = -CH =NOCH(CH3)-
Z 4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl 3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl 4-Me-phenyl 2-naphthalenyl 4-OCHF2-phenyl 3-OCHF2-phenyl 4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-CF3-2-pyridinyl 4-Me-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl 4-CF3-6-Me-2-pyridinyl 4-OCF3-2-pyridinyl 5-OCF3-2-pyridinyl 6-OCF3-2-pyridinyl 4-OCHF2-2-pyridinyl 5-OCHF -2-pyridinyl 6-OCHF2-2-pyridinyl 3-/-Bu-phenyl 4-/-Bu-phenyl
V = 3-CH3, Y = -CH2-SC(Et)=N-
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-ρhenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl
4-Me-phenyl 3,5-diMe-phenyl 2-naphthalenyl
6-Me-2-pyridinyl 4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl
5-Cl-2-pyridinyl 4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl
5-CF3-2-pyridinyl 5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl
V = 3-CH3, Y = -CH2-SC(=S)NMe-
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl
4-Me-phenyl 3,5-diMe-phenyl 2-naphthalenyl
6-Me-2-pyridinyl 4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl
5-Cl-2-pyridinyl 4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl
5-CF3-2-pyridinyl 5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl
V = 3-CH3, Y = -CH2SC(SMe)=N- z z
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF3-phenyl 4-CF3-phenyl 3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl CH2CH2-/-Bu
/-Bu 2-naphthalenyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-Cl-2-pyridinyl
4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl 5-CF3-2-pyridinyl
5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = 3-CH3, Y = -CH2S-
Z 2-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl 2,5-diMe-phenyl 2-Et-phenyl 3-Cl-phenyl 2-Cl-phenyl 2,5-diCl-phenyl 4,6-diMe-2-pyrimidinyl 4-Me- 1 ,2,4-triazol-3-yl 2-naphthalenyl 1 -Me-2-imidazolyl 4-Me-2-pyrimidinyl 5-Me- 1 ,3,4-thiadiazol-2-yl 4-CF3-2-pyridinyl 4-Ph-5-Me-2 -thiazolyl
V = 3-CH3, Y = -CH2ON=C(CH3)CH2S-
Z Z Z
3-Me-phenyl 2-Me-phenyl 3-CF3-phenyl
4-CF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
2-Et-phenyl 2,5-diMe-phenyl 2-naphthalenyl
V = 3-CH3, Y = -CH2ON=C(CH3)CH20-
3-Me-phenyl 2-Me-phenyl 4-Me-phenyl
3-CF3-phenyl 4-CF3-phenyl 4-Cl-phenyl
3-Cl-phenyl 3,5-diMe-phenyl 2,5-diMe-phenyl
2-Me-5- Pr-phenyl 3-Et-ρhenyl 6-CF3-2-pyridinyl
4-CF3-2-ρyridinyl 5-CF3-2-ρyridinyl 6-Me-2-pyridinyl
5-Me-2-pyridinyl 4-Me-2-pyridinyl 1-naphthalenyl
2-naphthalenyl
V = 3-CH3, Y = -CH2CH2-
Z Z
2-Me-phenyl 2,5-diMe-phenyl 3-CF -ρhenyl
4-CF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3-0CF3-phenyl 4-0CF3-phenyl 2-Et-phenyl
2-Me-5-Cl-phenyl 2-naphthalenyl 3 , 6-diMe-2-pyridiny 1 V = 3-CH3, Y = -CH=C(CH3)-
Z z
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3-OCF3-phenyl
4-OCF3-phenyl 3-CF3-phenyl 4-CF3-phenyl
2-naphthalenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = 3-CH3, Y = -CH=N-N=C(CH3)-
Z Z
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl
4-CF3-phenyl 3-OCF3-phenyl 4-OCF3-phenyl
3,5-diMe-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 4-CF3-2-pyridinyl 5-CF3-2-pyridinyl
6-CF3-2-pyridinyl 4-Me-2-pyridinyl 5-Me-2-pyridinyl
6-Me-2-pyridinyl 2-naphthalenyl 4,6-diMe-2-pyridinyl
3-Et-phenyl /-Bu Phenyl
V = 3-CH3, Y = -CH2ON=C(CH3)C(=NOCH3)-
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF3-phenyl 4-CF3-phenyl 3,5-di(CF3)-phenyl
3-OCF3-phenyl 4-OCF3-phenyl CH3
/-Bu 2-naρhthalenyl 4-/-Bu-phenyl
4-Me-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl
4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-CF3-2-pyridinyl
4,6-diMe-2-pyridinyl 4-CF3-2-pyrimidinyl 6-CF -2-pyrimidinyl
Phenyl 4-Br-phenyl 4-I-phenyl
4-F-phenyl
V = 3-CH3, Y = -CH=N-N(CH3)-
3-Me-phenyl 4-Me-ρhenyl 3,5-diMe-phenyl 3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl 3-CF3-phenyl 4-CF3-phenyl 3-OCF3-phenyl 4-OCF3-phenyl 2-naphthalenyl 4-/-Bu-phenyl 4-Me-2 -pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl z z
4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-CF3-2-pyridinyl
4.6-diMe-2-pyridinyl 4-CF3-2-pyrimidinyl
V = 3-CH3, Y = -CH2OC(SMe)=N-
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Me-ρhenyl 4-Me-phenyl
3,5-diMe-phenyl 2-naphthalenyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-CF -2-pyridinyl
5-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = 3-CH3, Y = -CH2OC(=S)NMe-
Z
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Me-phenyl 4-Me-phenyl
3,5-diMe-phenyl 2-naρhthalenyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-CF3-2-pyridinyl
5-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3 -2-pyridinyl
V = 3-CH3, Y = -SCH2-
2-Me-phenyl 2,5-diMe-phenyl 3-CF -phenyl
4-CF3-phenyl 4-Me-phenyl 4-/-Bu-phenyl
3-Cl-phenyl 4-Cl-phenyl 2-Me-5-Cl-phenyl
3-/-Bu-phenyl 2-naphthalenyl 1-naphthalenyl
3-pyridinyl 4-pyridinyl 6-Me-2-pyridinyl
2-(5,6,7,8-tetrahydro)naphthalenyl 4-CF3 -2-pyridinyl 6-CF3-2-pyridinyl
V = 3-CH3
Y Y Z -CH20-N=C(SCH3)- 3-CF3-phenyl -CH20-N=C(cyclopropyl)- 3-CF3-phenyl -CH20-N=C(SCH3)- 3-OCF3-phenyl -CH20-N=C(cyclopropyl)- 3-OCF3-phenyl -CH20-N=C(SCH3)- 3-Me-phenyl -CH20-N=C(cyclopropyl)- 3-Me-phenyl -CH20-N=C(SCH3)- 4-CF3-phenyl -CH20-N=C(cyclopropyl)- 4-CF3-phenyl -CH20-N=C(SCH3)- 4-OCF3-phenyl -CH20-N=C(cyclopropyl)- 4-OCF3-phenyl Y z
-CH20-N=C(SCH3)- 4-Me-phenyl -CH20-N=C(cyclopropyl)- 4-Me-phenyl -CH20-N=C(SCH3)- 3-Cl-phenyl -CH20-N=C(cyclopropyl)- 3-Cl-phenyl -CH20-N=C(SCH3)- 3,5-diCl-phenyl -CH 0-N=C(cyclopropyl)- 3,5-diCl-phenyl
Table lc
V = 4-CH3, Y = -0-
Z Phenyl 3-OMe-phenyl 4-CF3-ρhenyl 3-Me-phenyl 3-F-phenyl 3-OCF3-phenyl 4-Me-phenyl 3-SCHF2-phenyl 3-SCH3-phenyl 2-Me-phenyl 4-SCHF2-phenyl 4-SCH3 -phenyl 3-cyclohexyl-phenyl 4-CF3-2-pyridinyl 6-CF -2-ρyridinyl 5-CF3-2-ρyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl 4-Me-2-pyridinyl 2-(5,6,7,8-tetrahydro)naphthalenyl 2-(3,3,3-trifluoroethoxyl)-4- 6-(3,3,3-trifluoroethoxyl)-4- 4-(3,3,3-trifluoroethoxyl)-2- pyrimidinyl pyrimidinyl pyrimidinyl 3,5-diMe-phenyl 2-naphthalenyl 4-/-Bu-phenyl 4-OCF3-phenyl 3-/-Bu-phenyl 4-SCF3-phenyl 6-(3,3,3-trifluoroethoxyl)-2- 3-SCF3-phenyl 4,6-diMe-2-pyridinyl pyrazinyl 4-CF3-6-Me-2-ρyridinyl 3,5-di(CF3)-phenyl 3-CF3-phenyl 3-I-phenyl 3-( 1 -propynyl)-phenyl 3-(3,3-diMe-l-butynyl)- 3-(2-cycloproρylethynyl)phenyl phenyl
V = 4-CH3, Y = -CH20- Z phenyl 3-CF3-phenyl 2-Me-5- Pr-phenyl
2-Me-4-OCH3-phenyl 4-OCF3-phenyl 2-Me-5-CF3-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3,5-di(CF3)-phenyl
2-Me-4-OCHF2-phenyl 6-CF3-2-pyridinyl 3-OCF3-phenyl
4-CF3-2-pyridinyl 4-Me-2-pyridinyl 2-Me-4-OCF3-phenyl
5-Me-2-pyridinyl 3 ,6-diMe-2-pyridinyl 5-CF3-2-pyridinyl
4,6-diMe-2-pyridinyl 6-OCF3 -2-pyridinyl 4-CF -6-Me-2-pyridinyl
3-Me-2-pyridinyl 4-Cl-2-pyrimidinyl 6-Me-2-pyridinyl
4-Cl-2-pyrimidinyl 3-Et-phenyl 2,6-Me2-4-pyridinyl
2,4,6-triMe-phenyl 3-Cl-2-pyridinyl 6-Cl-4-pyrimidinyl
1-napthalenyl 2,3,6-triMe-phenyl 6-Cl-2-pyrazinyl
4-CF3-2-pyrimidinyl 6-CF3-4-pyrimidinyl 2- Pr-phenyl 3-Me-2-pyπdιnyl 4-Cl-2-pyπdιnyl 2-Me-phenyl
2,5-diMe-phenyl 2,4-dιCl-phenyl 2-Me-4-Cl-phenyl
2-Cl-phenyl 2,4-dιMe-phenyl 2,5-diCl-phenyl
4-CF3-5-Br-2-thιazolyl l-Ph-l//-pyrazol-3-yl 1 -(4-Cl-Ph)- 1 tf-pyrazol-3-yl
1 -(4-Me-Ph)- 1 tf-pyrazol-3-yl 1 -(3-Me-Ph)- 1 //-pyrazol-3-yl l-Ph-l//-l,2,4-triazol-3-yl
1 -(4-Cl-Ph)- 1 H- 1 ,2,4-tπazol-3-yl 1 -(4-Me-Ph)- 1 H- 1 ,2.4-tπazol-3-y 1 l-(3-Me-Ph)- l//-l,2,4-tπazol-3-yl
V = 4-CH3, Y = -OCH2-
Z 2-Me-phenyl 2,5-diMe-phenyl 3-CF3-phenyl 4-CF3-phenyl 4-Me-phenyl 4-/-Bu-phenyl 3-Cl-phenyl 4-Cl-phenyl 2-Me-5-Cl-phenyl 3-/-Bu-phenyl 2-naphthalenyl 1-naphthalenyl 3-pyridinyl 4-pyridinyl 6-Me-2-pyridinyl 2-(5,6,7,8 tetrahydro)naphthalenyl
V = 4-CH3, Y = -CH20-N=C(CH3)-
Z 3-Me-phenyl 4-CF3 -phenyl 3,5-diMe-phenyl 3-Cl-phenyl 4-Br-phenyl 3,5-di(CF3)-phenyl 4-OCHF2-phenyl 4-/-Bu-phenyl 3-/-Bu-phenyl 5-CF3-2-pyridinyl 4-OCF3-phenyl 3-OCHF -phenyl 5-Me-2- pyridinyl 4-CF -6-Me-2 -pyridinyl 4-Me-2- pyridinyl 4,6-d_Me-2-pyridinyl 6-Me-2-pyridinyl 6-CF3-2-pyridinyl 6-OMe-2-pyridinyl 2,6-Me2-4-pyridinyl 2,6-diCl-4-pyridinyl 5-OCF3 -2-pyridinyl 4-OMe-2-pyridinyl 4-OCF3-2-pyridinyl 5-OCHF -2-pyridinyl 6-OCF3-2-pyridinyl 4-OCHF2-pyridinyl 3-(3,3,3 trifluoroethoxy)-phenyl 6-OCHF2-2-pyridinyl 3-Et-phenyl 1-naphthalenyl 2-( 1 ,2,3 ,4-tetrahydro)naphthaleny 1 /-Bu 3-SMe-phenyl 3-ethynyl-phenyl 3-CF3-phenyl 3,5-diCl-phenyl 3-OCF3-phenyl 4-CF3-2-pyridinyl 4-CF3-6-Cl-2-pyridinyl
V = 4-CH3, Y = -CH=NOCH(CH3)-
Z Z 4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl 3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl
4-Me-phenyl 2-naphthalenyl 4-OCHF2-phenyl
3-OCHF2-phenyl 4-CF3-2-pyridinyl 5-CF3-2-pyridinyl
6-CF -2-pyridinyl 4-Me-2-pyridinyl 5-Me-2-pyridinyl
6-Me-2-pyridinyl 4-CF3-6-Me-2-pyridinyl 4-OCF3-2-pyridinyl
5-OCF3-2-pyridinyl 6-OCF3-2-pyridinyl 4-OCHF2-2-pyridinyl
5-OCHF2-2-pyridinyl 6-OCHF -2-pyridinyl 3-r-Bu-phenyl
4-/-Bu-phenyl
V = 4-CH3, Y = -CH2-SC(Et)=N-
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl
4-Me-phenyl 3,5-diMe-phenyl 2-naphthalenyl
6-Me-2-pyridinyl 4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl
5-Cl-2-pyridinyl 4,6-diCl-2-pyridinyl 5-Me-2 -pyridinyl
5-CF3-2-pyridinyl 5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl
V = 4-CH3, Y = -CH2-SC(=S)NMe-
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl
4-Me-phenyl 3,5-diMe-ρhenyl 2-naphthalenyl
6-Me-2-pyridinyl 4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl
5-Cl-2-pyridinyl 4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl
5-CF3-2-pyridinyl 5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl
V = 4-CH3, Y = -CH2SC(SMe)=N-
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF3-phenyl 4-CF3-ρhenyl 3-OCF3-phenyl
4-OCF3-phenyl 3,5-di(CF3)-phenyl CH2CH2-/-Bu
/-Bu 2-naphthalenyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-Cl-2-pyridinyl Z Z
4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl 5-CF3-2-ρyridinyl
5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = 4-CH3, Y = -CH2S-
Z 2-Me-phenyl 3-CF -phenyl 4-CF3-phenyl 2,5-diMe-phenyl 2-Et-phenyl 3-Cl-phenyl 2-Cl-phenyl 2,5-diCl-phenyl 4,6-diMe-2-pyrimidinyl 4-Me-l,2,4-triazol-3-yl 2-naphthalenyl l-Me-2-imidazolyl 4-Me-2-pyrimidinyl 5-Me- 1 ,3,4-thiadiazol-2-yl 4-CF -2-pyridinyl 4-Ph-5-Me-2-thiazolyl
V = 4-CH3, Y = -CH2ON=C(CH3)CH2S- z z z
3-Me-ρhenyl 2-Me-phenyl 3-CF3-phenyl
4-CF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
2-Et-phenyl 2,5-diMe-phenyl 2-naphthalenyl
V = 4-CH3, Y = -CH2ON=C(CH3)CH 0-
3-Me-phenyl 2-Me-phenyl 4-Me-phenyl
3-CF3-phenyl 4-CF3-phenyl 4-Cl-ρhenyl
3-Cl-phenyl 3,5-diMe-phenyl 2,5-diMe-phenyl
2-Me-5-/Pr-phenyl 3-Et-phenyl 6-CF -2-pyridinyl
4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-Me-2-pyridinyl
5-Me-2-pyridinyl 4-Me-2-pyridinyl 1-naphthalenyl
2-naphthalenyl
V = 4-CH3, Y = -CH2CH2-
Z Z
2-Me-phenyl 2,5-diMe-phenyl 3-CF3-phenyl
4-CF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3-0CF3-phenyl 4-OCF3-ρhenyl 2-Et-phenyl
2-Me-5-Cl-phenyl 2-naphthalenyl 3,6-diMe-2-pyridinyl V = 4-CH3, Y = -CH=C(CH3)- z z
3-Mc-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3-OCF3-phenyl
4-OCF3-phenyl 3-CF3-ρhenyl 4-CF3-phenyl
2-naphthalenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = 4-CH3, Y = -CH=N-N=C(CH3)-
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl
4-CF3-phenyl 3-OCF3-phenyl 4-OCF3-phenyl
3,5-diMe-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 4-CF3-2-pyridinyl 5-CF -2-pyridinyl
6-CF3-2-pyridinyl 4-Me-2-pyridinyl 5-Me-2-pyridinyl
6-Me-2-pyridinyl 2-naρhthalenyl 4,6-diMe-2-pyridinyl
3-Et-phenyl /-Bu Phenyl
V = 4-CH3, Y = -CH2ON=C(CH3)C(=NOCH3)-
Z
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF3-phenyl 4-CF3-phenyl 3,5-di(CF3)-phenyl
3-OCF3-phenyl 4-OCF3-phenyl CH3
/-Bu 2-naphthalenyl 4-/-Bu-phenyl
4-Me-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl
4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-CF3-2-pyridinyl
4,6-diMe-2-pyridinyl 4-CF3-2-pyrimidinyl 6-CF3-2-pyrimidinyl
Phenyl 4-Br-phenyl 4-I-phenyl
4-F-ρhenyl
V = 4-CH3, Y = -CH=N-N(CH3)-
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF3-phenyl 4-CF3-phenyl 3-OCF3-phenyl
4-OCF3-phenyl 2-naρhthalenyl 4-/-Bu-phenyl
4-Me-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl z z
4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-CF3-2-pyridinyl
4,6-diMe-2-pyridinyl 4-CF3-2-pyrimidinyl
V = 4-CH3, Y = -CH2OC(SMe)=N-
4-CF3-phenyl 3-CF3-phenyl 4-OCF3 -phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Me-ρhenyl 4-Me-phenyl
3,5-diMe-phenyl 2-naphthalenyl 6-Me-2-pyridinyl
4-Me-2-ρyridinyl 4,6-diMe-2-pyridinyl 5-CF3-2-pyridinyl
5-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = 4-CH3, Y = -CH2OC(=S)NMe-
4-CF -phenyl 3-CF3-ρhenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Me-phenyl 4-Me-phenyl
3,5-diMe-phenyl 2-naphthalenyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 4,6-di e-2-pyridinyl 5-CF3-2-pyridinyl
5-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = 4-CH3, Y = -SCH2-
Z 2-Me-phenyl 2,5-diMe-phenyl 3-CF3-phenyl 4-CF3-phenyl 4-Me-phenyl 4-/-Bu-phenyl 3-Cl-phenyl 4-Cl-phenyl 2-Me-5-Cl-phenyl 3-/-Bu-phenyl 2-naphthalenyl 1-naphthalenyl 3-pyridinyl 4-pyridinyl 6-Me-2-pyridinyl 2-(5,6,7,8-tetrahydro)naphthalenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = 4-CH3
Y -CH20-N=C(SCH3)- 3-CF3-phenyl -CH20-N=C(cyclopropyl)- 3-CF3 -phenyl -CH20-N=C(SCH3)- 3-OCF3-phenyl -CH20-N=C(cyclopropyl)- 3-OCF3-phenyl -CH20-N=C(SCH3)- 3-Me-phenyl -CH20-N=C(cyclopropyl)- 3-Me-phenyl -CH20-N=C(SCH3)- 4-CF3-phenyl -CH20-N=C(cyclopropyl)- 4-CF3-phenyl -CH20-N=C(SCH3)- 4-OCF3-phenyl -CH20-N=C(cyclopropyl)- 4-OCF3-phenyl Y Y z -CH20-N=C(SCH3)- 4-Me-phenyl -CH20-N=C(cyclopropyl)- 4-Me-phenyl -CH20-N=C(SCH3)- 3-Cl-phenyl -CH20-N=C(cyclopropyl)- 3-Cl-phenyl -CH20-N=C(SCH3)- 3,5-diCl-phenyl -CH20-N=C(cyclopropyl)- 3,5-diCl-ρhenyl
Structure for Tables 2a, 2b and 2c
Figure imgf000096_0001
Table 2a
V = H
__£ S2 E__ E
3-Me-phenyl 4- Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-ρhenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
Table 2b v = 3-CH3
R__ S2 B2
3-Me-phenyl 4- Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3 -phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C-_CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl Table 2c
V = 4-CH3 ? E__ s2
3-Me-phenyl 4- Me-phenyl 3-CF3-phenyl 4-CF -phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3 -phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl .
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
Structure for Tables 3 a. 3b and
Figure imgf000097_0001
Table 3 a
V = H, R10 = H
R_! s£ R_! s2
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3-ρhenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-ρhenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cycloρropyl-phenyl
H CH3 I Br
V = H, R10 = Br
R9 R£ E? R_!
3-Me-phenyl 4-Me-phenyl 3-CF3-ρhenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl Bl R? R£ Bl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cycloρropyl-phenyl
H CH3 I Br
V = H, RI 0 = CH3
Bl S? R E?
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-ρhenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 I Br
V = H, R10 = I
Bl Bl Bl Bl
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF -phenyl
3-OCF3-phenyl 4-OCF3 -phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 I Br
Table 3b
V = 3-CH3, R10 = H
E__ Bl s2 Bl
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3 -phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-ρhenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3.5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 I Br V = 3-CH3, R10 = Br
Bl Bl R__ R__ 3-Me-phenyl 4-Me-phenyl 3-CF -phenyl 4-CF3-phenyl 3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl 3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl 3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl 3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl . /-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl H CH3
V = 3-CH3, R10 = CH3
Bl R Bl Bl 3-Me-phenyl 4-Me-phenyl 3-CF3 -phenyl 4-CF3-phenyl 3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl 3-OCHF -phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl 3-SCHF -phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl 3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl /-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl H CH3 Br
V = 3-CH3, R10 = I
Bl Bl R_! Bl
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3-ρhenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-ρhenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C__CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 I Br
Table 3 c
V = 4-CH3, R10 = H
Bl Bl Bl Bl
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3-ρhenyl 3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl Bl Bl R E__
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF -phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 1 Br
V = 4-CH3, R10 = Br
Bl Bl Bl Bl
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C__CH-phenyl 4-C__CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 Br
V = 4-CH3, R10 = CH3
Bl Bl Bl Rr.
3-Me-phenyl 4-Me-phenyl 3-CF3-ρhenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF -phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-ρhenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C__CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cycloρropyl-phenyl
H CH3 I Br
V = 4-CH3, R10 = I
R_! R__ Bl R?
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-ρhenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3 -phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3.4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl R9 R^ R__ R__
/-Bu CF3 3,5-diF-phenyl 3-cycloproρyl-phenyl H CH3 I Br
Figure imgf000101_0001
Table 4a
Figure imgf000101_0002
6'-Cl
5'-F
6'-F
4'-F
H
2',6'-diCl
Figure imgf000101_0003
2',6,-diF
Table 4b
Figure imgf000101_0004
6'-Cl
5'-F
6'-F
4'-F
H
2',6'-diCl
Figure imgf000101_0005
2',6'-diF Table 4c
Figure imgf000101_0006
R12 R 13 Rl2 R 13 R 12 Si!
2'-Cl H 2'-Cl 4\6'-diF 2'-F 6'-F
2'-F H 4'-Br 2',6'-diF 2'-F 4'-F
2'-OMe H 4*-I 2',6'-diF 2'-Et H
2'-Br H 2'-F 3',6'-diF 4'-Me 2',6'-diCl
2'-SMe H 2'-F 4,,5,-diF 4'-Me 2',6'-diF
Structure for Tables 5a, 5b and 5c
Figure imgf000102_0001
Table 5a
V = H
R12 R13 R_2 Ell R12 Ell
H 2'-< N 2'-F 4',6'-diF 2'-Cl 6 -C1
2'-Me H 2'-F ;5,6'-tήF 2'-F 5'-F
2*-Cl H 2'-Cl 4',6'-diF 2"-F 6"-F
2'-F H 4'-Br 2,,6'-diF 2'-F 4'-F
2'-OMe H 4'-I 2',6'-diF 2'-Et H
2'-Br H 2'-F 3',6'-diF 4'-Me 2,,6'-diCl
2'-SMe H 2'-F 4',5,-diF 4'-Me 2,,6'-diF
Table 5b
Figure imgf000102_0002
Table 5c
Figure imgf000103_0001
Structure for Tables 6a, 6b and 6c
Figure imgf000103_0002
V = H, Y = -O-
Phenyl 3-OMe-phenyl 4-CF3 -phenyl
3-Me-phenyl 3-F-phenyl 3-OCF3-phenyl
4-Me-phenyl 3-SCHF2-phenyl 3-SCH3-phenyl
2-Me-phenyl 4-SCHF2-phenyl 4-SCH3-phenyl
3-cyclohexyl-phenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
5-CF3-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 2-(5,6,7,8-tetrahydro)naphthalenyl 2-(3,3,3-trifluoroethoxyl)-4-
6-(3 ,3 ,3-trifluoroethoxyl)-4- 4-(3,3,3-trifluoroethoxyl)-2- pyrimidinyl pyrimidinyl pyrimidinyl 3,5-diMe-phenyl 2-naphthalenyl 4-/-Bu-phenyl 4-OCF3-phenyl 3-/-Bu-phenyl 4-SCF3-phenyl 6-(3,3,3-trifluoroethoxyl)-2- 3-SCF3-phenyl 4,6-diMe-2-pyridinyl pyrazinyl 4-CF3-6-Me-2-pyridinyl 3,5-di(CF3)-phenyl 3-CF3-phenyl 3-I-phenyl 3-( 1 -propynyl)-phenyl 3-(3,3-diMe-l-butynyl)- 3-(2-cyclopropylethynyl)phenyl phenyl V = H, Y = -CH20-
Z phenyl 3-CF3-phenyl 2-Me-5-/Pr-phenyl
2-Me-4-0CH3-phenyl 4-0CF3-phenyl 2-Me-5-CF3-phenyl 3-OCHF2-phenyl 4-OCHF2-phenyl 3,5-di(CF3)-phenyl 2-Me-4-OCHF2-phenyl 6-CF3-2-pyridinyl 3-OCF3-phenyl 4-CF3-2-pyridinyl 4-Me-2-pyridinyl 2-Me-4-OCF3-phenyl 5-Me-2-pyridinyl 3,6-diMe-2-pyridinyl 5-CF3-2-pyridinyl 4,6-diMe-2-pyridinyl 6-OCF3-2-pyridinyl 4-CF3 -6-Me-2-ρyridinyl 3-Me-2-pyridinyl 4-Cl-2-pyrimidinyl 6-Me-2-pyridinyl 4-Cl-2-pyrimidinyl 3-Et-phenyl 2,6-Me2-4-pyridinyl 2,4,6-triMe-phenyl 3-Cl-2-pyridinyl 6-Cl-4-pyrimidinyl 1-napthalenyl 2,3 ,6-triMe-phenyl 6-Cl-2-pyrazinyl 4-CF3 -2-pyrimidinyl 6-CF3-4-pyrimidinyl 2- Pr-phenyl 3-Me-2-pyridinyl 4-Cl-2-pyridinyl 2-Me-phenyl 2,5-diMe-phenyl 2,4-diCl-phenyl 2-Me-4-Cl-ρhenyl 2-Cl-phenyl 2,4-diMe-phenyl 2,5-diCl-phenyl 4-CF3-5-Br-2-thiazolyl l-Ph-l /-pyrazol-3-yl 1 -(4-Cl-Ph)- 1 #-pyrazol-3-yl l-(4-Me-Ph)- l f-pyrazol-3-yl l-(3-Me-Ph)-l f-pyrazol-3-yl 1 -Ph- IH- 1 ,2,4-triazol-3-yl 1 -(4-Cl-Ph)- IH- 1 ,2,4-triazol-3-yl 1 -(4-Me-Ph)- 1 H- 1 ,2,4-triazol-3-yl 1 -(3-Me-Ph)- IH- 1 ,2,4-triazol-3-yl
V = H, Y = -OCH2- Z
2-Me-phenyl 2,5-diMe-phenyl 3-CF3-ρhenyl
4_CF3-phenyl 4-Me-phenyl 4-/-Bu-phenyl
3-Cl-phenyl 4-Cl-phenyl 2-Me-5-Cl-phenyl
3-/-Bu-phenyl 2-naphthalenyl 1-naphthalenyl
3-pyridinyl 4-pyridinyl 6-Me-2-pyridinyl
2-(5,6,7,8 tetrahydro)naphthalenyl
V = H, Y = -CH20-N=C(CH3)-
Z 3-Me-phenyl 4-CF3-phenyl 3,5-diMe-phenyl 3-Cl-ρhenyl 4-Br-phenyl 3,5-di(CF3)-phenyl 4-OCHF2-phenyl 4-/-Bu-phenyl 3-/-Bu-phenyl 5-CF3-2-pyridinyl 4-OCF3-phenyl 3-OCHF2-phenyl 5-Me-2- pyridinyl 4-CF3-6-Me-2-pyridinyl 4-Me-2- pyridinyl 4,6-diMe-2-pyridinyl 6-Me-2-pyridinyl 6-CF3-2-pyridinyl
6-OMe-2-pyridinyl 2,6-Me2-4-pyridinyl 2,6-diCl-4-pyridinyl
5-OCF3-2-pyridinyl 4-OMe-2-pyridinyl 4-OCF3-2-pyridinyl
5-OCHF2-2-pyridinyl 6-OCF3-2-pyridinyl 4-OCHF2-pyridinyl
3-(3,3,3 trifluoroethoxy)-phenyl 6-OCHF2-2-pyridinyl 3-Et-phenyl
1-naphthalenyl 2-( l,2,3,4-tetrahydro)naphthalenyl /-Bu
3-SMe-phenyl 3-ethynyl-phenyl 3-CF3-ρhenyl
3,5-diCl-phenyl 3-OCF3-phenyl 4-CF3-2-pyridinyl
4-CF3-6-Cl-2-pyridinyl
V = H, Y = -CH=NOCH(CH3)-
Z
4-CF3 -phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl
4-Me-phenyl 2-naphthalenyl 4-OCHF2-phenyl
3-OCHF2-phenyl 4-CF3-2-pyridinyl 5-CF3-2-pyridinyl
6-CF3-2-pyridinyl 4-Me-2-pyridinyl 5-Me-2-pyridinyl
6-Me-2-pyridinyl 4-CF3-6-Me-2-pyridinyl 4-OCF3-2-pyridinyl
5-OCF3-2-pyridinyl 6-OCF3 -2-pyridinyl 4-OCHF2-2-pyridinyl
5-OCHF2-2-pyridinyl 6-OCHF2-2-pyridinyl 3-/-Bu-phenyl
4-/-Bu-phenyl
V = H, Y = -CH2-SC(Et)=N-
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-ρhenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl
4-Me-phenyl 3,5-diMe-phenyl 2-naphthalenyl
6-Me-2-pyridinyl 4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl
5-Cl-2-pyridinyl 4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl
5-CF3-2-pyridinyl 5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl
V = H, Y = -CH2-SC(=S)NMe-
Z z
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl
4-Me-phenyl 3,5-diMe-phenyl 2-naphthalenyl
6-Me-2-pyridinyl 4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl
5-Cl-2-pyridinyl 4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl
5-CF3-2-pyridinyl 5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl
V = H, Y = -CH2SC(SMe)=N-
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF3-phenyl 4-CF3-phenyl 3-OCF3-phenyl
4-OCF3-phenyl 3,5-di(CF3)-phenyl CH2CH2-/-Bu
/-Bu 2-naρhthalenyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-Cl-2-pyridinyl
4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl 5-CF3-2-pyridinyl
5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = H, Y = -CH2S-
Z 2-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl 2,5-diMe-phenyl 2-Et-phenyl 3-Cl-phenyl 2-Cl-phenyl 2,5-diCl-phenyl 4,6-diMe-2-pyrimidinyl 4-Me- 1 ,2,4-triazol-3-yl 2-naphthalenyl 1 -Me-2-imidazolyl 4-Me-2-pyrimidinyl 5-Me- 1 ,3,4-thiadiazol-2-yl 4-CF3-2-pyridinyl 4-Ph-5-Me-2-thiazolyl
V = H, Y = -CH2ON=C(CH3)CH2S-
Z Z Z
3-Me-phenyl 2-Me-phenyl 3-CF3-phenyl
4-CF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
2-Et-phenyl 2,5-diMe-phenyl 2-naphthalenyl
V = H, Y = -CH2ON=C(CH3)CH20- z z
3-Me-phenyl 2-Me-phenyl 4-Me-phenyl
3-CF3-phenyl 4-CF3-phenyl 4-Cl-phenyl
3-Cl-phenyl 3,5-diMe-phenyl 2,5-diMe-phenyl Z Z
2-Me-5-(Pr-phenyl 3-Et-phenyl 6-CF3-2-pyridinyl 4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-Me-2-pyridinyl 5-Me-2-pyridinyl 4-Me-2-pyridinyl 1-naphthalenyl 2-naphthalenyl
V = H, Y = -CH2CH2-
2-Me-phenyl 2,5-diMe-phenyl 3-CF3-phenyl 4-CF3-phenyl 3-Cl-phenyl 4-Cl-phenyl 3-OCF3-phenyl 4-OCF3-phenyl 2-Et-phenyl 2-Me-5-Cl-phenyl 2-naphthalenyl 3,6-diMe-2-pyridinyl
V = H, Y = -CH=C(CH3)-
Z Z Z
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3-OCF3-phenyl
4-OCF3-phenyl 3-CF3-phenyl 4-CF3-phenyl
2-naphthalenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = H, Y = -CH=N-N=C(CH3)-
Z Z
3-Me-ρhenyl 4-Me-phenyl 3-CF3-phenyl
4-CF3 -phenyl 3-OCF3-phenyl 4-OCF3-phenyl
3,5-diMe-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 4-CF3-2-pyridinyl 5-CF3-2-pyridinyl
6-CF3-2-pyridinyl 4-Me-2-pyridinyl 5-Me-2-pyridinyl
6-Me-2-pyridinyl 2-naphthalenyl 4,6-diMe-2-pyridinyl
3-Et-phenyl /-Bu Phenyl
V = H, Y = -CH2ON=C(CH3)C(=NOCH3)-
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF3 -phenyl 4-CF3-phenyl 3,5-di(CF3)-phenyl
3-OCF3-phenyl 4-OCF3-phenyl CH3
/-Bu 2-naphthalenyl 4-/-Bu-phenyl
4-Me-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl Z Z Z
4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-CF3-2-pyridinyl
4,6-diMe-2-pyridinyl 4-CF3-2-pyrimidinyl 6-CF -2-pyrimidinyl
Phenyl 4-Br-phenyl 4-I-phenyl 4-F-phenyl
V = H, Y = -CH=N-N(CH3)-
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl 3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl 3-CF3 -phenyl 4-CF3-phenyl 3-OCF3-phenyl 4-OCF3-phenyl 2-naphthalenyl 4-/-Bu-phenyl 4-Me-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl 4-CF3 -2-pyridinyl 5-CF3-2-pyridinyl 6-CF3-2-pyridinyl
4,6-diMe-2-pyridinyl 4-CF3-2-pyrimidinyl
V = H, Y = -CH2OC(SMe)=N-
4-CF3 -phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-ρhenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Me-phenyl 4-Me-phenyl
3,5-diMe-phenyl 2-naρhthalenyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-CF3 -2-pyridinyl
5-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF -2-pyridinyl
V = H, Y = -CH2OC(=S)NMe-
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Me-phenyl 4-Me-phenyl
3,5-diMe-phenyl 2-naphthalenyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 4,6-diMe-2 -pyridinyl 5-CF3-2-pyridinyl
5-Me-2-pyridinyl 4-CF3 -2-pyridinyl 6-CF3-2-pyridinyl
V = H, Y = -SCH2- Z
2-Me-phenyl 2,5-diMe-phenyl 3-CF3-phenyl 4_CF3-phenyl 4-Me-phenyl 4-/-Bu-phenyl 3-Cl-phenyl 4-Cl-phenyl 2-Me-5-Cl-phenyl
3-/-Bu-phenyl 2-naphthalenyl 1-naphthalenyl
3-pyridinyl 4-pyridinyl 6-Me-2-pyridinyl
2-(5,6,7,8-tetrahydro)naphthalenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = H
Y Y
-CH20-N= =C(SCH3)- 3-CF3-phenyl -CH20-N= C(cyclopropyl)- 3-CF3-phenyl -CH20-N^ =C(SCH3)- 3-OCF3-phenyl -CH20-N= C(cyclopropyl)- 3-OCF3-phenyl -CH20-N= =C(SCH3)- 3-Me-phenyl -CH20-N= C(cycloρropyl)- 3-Me-phenyl -CH20-N= =C(SCH3)- 4-CF3-phenyl -CH20-N= C(cyclopropyl)- 4-CF3-phenyl -CH20-N= =C(SCH3)- 4-OCF3-phenyl -CH20-N= C(cyclopropyl)- 4-OCF3-phenyl -CH20-N= =C(SCH3)- 4-Me-phenyl -CH20-N= C(cycloρropyl)- 4-Me-phenyl -CH20-N= =C(SCH3)- 3-Cl-phenyl -CH20-N= C(cyclopropyl)- 3-Cl-phenyl -CH20-N= (SCH3)- 3,5-diCl-phenyl -CH20-N= C(cyclopropyl)- 3,5-diCl-phenyl
Table 6b
V = 3-CH3, Y = -O-
Z Phenyl 3-OMe-ρhenyl 4-CF3-phenyl 3-Me-phenyl 3-F-phenyl 3-OCF3-phenyl 4-Me-phenyl 3-SCHF2-phenyl 3-SCH3-phenyl 2-Me-phenyl 4-SCHF -phenyl 4-SCH3-phenyl 3-cyclohexyl-phenyl 4-CF3-2-pyridinyl 6-CF -2-pyridiny 1 5-CF3-2-pyridinyl 5-Me-2-ρyridinyl 6-Me-2-pyridinyl 4-Me-2-pyridinyl 2-(5,6,7,8-tetrahydro)naphthalenyl 2-(3,3,3-trifluoroethoxyl)-4- 6-(3,3,3-trifluoroethoxyl)-4- 4-(3,3,3-trifluoroethoxyl)-2- pyrimidinyl pyrimidinyl pyrimidinyl 3,5-diMe-phenyl 2-naphthalenyl 4-/-Bu-phenyl 4-OCF3-phenyl 3-/-Bu-phenyl 4-SCF3-phenyl 6-(3,3,3-trifluoroethoxyl)-2- 3-SCF3-phenyl 4,6-diMe-2-pyridinyl pyrazinyl 4-CF3-6-Me-2-pyridinyl 3,5-di(CF3)-phenyl 3-CF3-phenyl 3-I-phenyl 3-( 1 -propynyl)-pheny 1 3-(3,3-diMe-l-butynyl)- 3-(2-cyclopropylethynyl)phenyl phenyl [08
V = 3-CH3, Y = -CH20-
Z phenyl 3-CF -phenyl 2-Me-5-/Pr-phenyl
2-Me-4-OCH3-phenyl 4-0CF3-phenyl 2-Me-5-CF3-phenyl 3-OCHF2-phenyl 4-0CHF2-phenyl 3,5-di(CF3)-phenyl 2-Me-4-OCHF2-phenyl 6-CF3-2-pyridinyl 3-OCF3-phenyl 4-CF3-2-pyridinyl 4-Me-2-pyridinyl 2-Me-4-OCF3-phenyl 5-Me-2-pyridinyl 3,6-diMe-2-pyridinyl 5-CF3-2-pyridinyl 4,6-diMe-2-pyridinyl 6-OCF3 -2-pyridinyl 4-CF -6-Me-2-pyridinyl 3-Me-2-pyridinyl 4-Cl-2-pyrimidinyl 6-Me-2-pyridinyl 4-Cl-2-pyrimidinyl 3-Et-phenyl 2,6-Me2-4-pyridinyl 2,4,6-triMe-phenyl 3-Cl-2-pyridinyl 6-Cl-4-pyrimidinyl 1-napthalenyl 2,3,6-triMe-phenyl 6-Cl-2-pyrazinyl 4-CF3-2-pyrimidinyl 6-CF3-4-pyrimidinyl 2-/Pr-phenyl 3-Me-2-pyridinyl 4-Cl-2-pyridinyl 2-Me-phenyl 2,5-diMe-phenyl 2,4-diCl-phenyl 2-Me-4-Cl-phenyl 2-Cl-phenyl 2,4-diMe-phenyl 2,5-diCl-phenyl 4-CF3-5-Br-2-thiazolyl l-Ph-l_Y-pyrazol-3-yl 1 -(4-Cl-Ph)- 1 / -pyrazol-3-yl 1 -(4-Me-Ph)- l_ -pyrazol-3-yl l-(3-Me-Ph)-l /-pyrazol-3-yl 1 -P -ΪH- 1 ,2,4-triazol-3-yl 1 -(4-Cl-Ph)- IH- 1 ,2,4-triazol-3-yl 1 -(4-Me-Ph)- IH- 1 ,2,4-triazol-3-yl 1 -(3-Me-Ph)- IH- 1 ,2,4-triazol-3-yl
V = 3-CH3, Y = -OCH2-
Z 2-Me-phenyl 2,5-diMe-phenyl 3-CF3 -phenyl 4-CF -phenyl 4-Me-phenyl 4-/-Bu-phenyl 3-Cl-phenyl 4-Cl-phenyl 2-Me-5-Cl-phenyl 3-/-Bu-phenyl 2-naphthalenyl 1-naphthalenyl 3-pyridinyl 4-pyridinyl 6-Me-2-pyridinyl 2-(5,6,7,8 tetrahydro)naphthalenyl
V = 3-CH3, Y = -CH20-N=C(CH3)-
Z Z
3-Me-phenyl 4-CF3-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Br-phenyl 3,5-di(CF3)-phenyl
4-OCHF2-phenyl 4-/-Bu-phenyl 3-/-Bu-phenyl
5-CF3-2-pyridinyl 4-OCF3-phenyl 3-OCHF2-ρhenyl
5-Me-2- pyridinyl 4-CF3-6-Me-2-pyridinyl 4-Me-2- pyridinyl
4, 6-diMe-2-pyridiny 1 6-Me-2-pyridiny 1 6-CF3-2-pyridinyl 6-OMe-2-pyridinyl 2,6-Me2-4-pyridinyl 2,6-diCl-4-pyridinyl
5-OCF3-2-pyridinyl 4-OMe-2-pyridinyl 4-OCF3-2-pyridinyl
5-OCHF2-2-pyridinyl 6-OCF3-2-pyridinyl 4-OCHF2-pyridinyl
3-(3,3,3 trifluoroethoxy)-phenyl 6-OCHF2-2-pyridinyl 3-Et-phenyl
1-naphthalenyl 2-( 1 ,2,3,4-tetrahydro)naphthalenyl /-Bu
3-SMe-phenyl 3-ethynyl-phenyl 3-CF3-phenyl
3,5-diCl-phenyl 3-OCF3-phenyl 4-CF3-2-pyridinyl
4-CF3-6-Cl-2-pyridinyl
V = 3-CH3, Y = -CH= =NOCH(CH3)-
Z Z 4-CF3 -phenyl 3-CF3-phenyl 4-OCF3-phenyl 3-OCF3-ρhenyl 3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-ρhenyl 3,5-di(CF3)-phenyl 3-Me-phenyl 4-Me-phenyl 2-naρhthalenyl 4-OCHF2-phenyl 3-OCHF2-phenyl 4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-CF3-2-pyridinyl 4-Me-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl 4-CF3-6-Me-2-pyridinyl 4-OCF3-2-pyridinyl 5-OCF3 -2-pyridinyl 6-OCF3-2-pyridinyl 4-OCHF2-2-pyridinyl 5-OCHF2-2-pyridinyl 6-OCHF2-2-pyridinyl 3-/-Bu-phenyl 4-z-Bu-phenyl
V = 3-CH3, Y = -CH2-SC(Et)=N-
4-CF3-phenyl 3-CF3 -phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-ρhenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl
4-Me-phenyl 3,5-diMe-ρhenyl 2-naphthalenyl
6-Me-2 -pyridinyl 4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl
5-Cl-2-pyridinyl 4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl
5-CF3-2-pyridinyl 5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl
V = 3-CH3, Y = -CH2-SC(=S)NMe- z z
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-ρhenyl 4-Cl-phenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl Z Z
4-Me-phenyl 3,5-diMe-phenyl 2-naρhthalenyl 6-Me-2-pyridinyl 4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-Cl-2-pyridinyl 4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl 5-CF3-2-pyridinyl 5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl
V = 3-CH3, Y = -CH2SC(SMe)=N-
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF3-phenyl 4-CF3-phenyl 3-OCF3-phenyl
4-OCF3-phenyl 3,5-di(CF3)-phenyl CH2CH2-/-Bu
/-Bu 2-naphthalenyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-Cl-2-pyridinyl
4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl 5-CF3-2-pyridinyl
5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3 -2-pyridinyl
V = 3-CH3, Y = -CH2S-
2-Me-phenyl 3-CF -phenyl 4-CF3 -phenyl
2,5-diMe-phenyl 2-Et-ρhenyl 3-Cl-phenyl
2-Cl-phenyl 2,5-diCl-phenyl 4,6-diMe-2-pyrimidinyl
4-Me- 1 ,2,4-triazol-3-yl 2-naphthalenyl 1 -Me-2-imidazolyl
4-Me-2-pyrimidinyl 5-Me- 1 ,3,4-thiadiazol-2-yl 4-CF3-2-pyridinyl
4-Ph-5-Me-2-thiazolyl
V = 3-CH3, Y = -CH2ON=C(CH3)CH2S-
Z Z Z
3-Me-phenyl 2-Me-phenyl 3-CF3-phenyl
4-CF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
2-Et-phenyl 2,5-diMe-phenyl 2-naphthalenyl
V = 3-CH3, Y = -CH2ON=C(CH3)CH20-
Z Z Z
3-Me-phenyl 2-Me-phenyl 4-Me-phenyl
3-CF3-phenyl 4-CF3-phenyl 4-Cl-phenyl
3-Cl-phenyl 3,5-diMe-phenyl 2,5-diMe-phenyl
2-Me-5-;Pr-phenyl 3-Et-phenyl 6-CF3-2-pyridinyl 1 1
Z Z
4-CF3-2-pyridinyl 5-CF -2-pyridinyl 6-Me-2-pyridinyl
5-Me-2-pyridinyl 4-Me-2-pyridinyl 1-naphthalenyl
2-naphthalenyl
V = 3-CH3, Y = -CH2CH2-
2-Me-phenyl 2,5-diMe-phenyl 3-CF3-phenyI 4-CF3-ρhenyl 3-Cl-phenyl 4-Cl-phenyl 3-OCF3-phenyl 4-OCF3-phenyl 2-Et-phenyl 2-Me-5-Cl-phenyl 2-naphthalenyl 3,6-diMe-2-pyridinyl
V = 3-CH3, Y = -CH=C(CH3)- z z z
3-Me-phenyl 4-Me-ρhenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3-OCF3-phenyl
4-OCF3-phenyl 3-CF3-ρhenyl 4-CF3-phenyl
2-naphthalenyl 4-CF -2-pyridinyl 6-CF3-2-pyridinyl
V = 3-CH3, Y = -CH=N-N=C(CH3)-
Z Z
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl
4-CF3-phenyl 3-OCF3-phenyl 4-OCF3-ρhenyl
3,5-diMe-phenyl 3-Cl-ρhenyl 4-Cl-phenyl
3,5-diCl-phenyl 4-CF3-2-pyridinyl 5-CF3-2-pyridinyl
6-CF3-2-pyridinyl 4-Me-2-pyridinyl 5-Me-2-pyridinyl
6-Me-2-pyridinyl 2-naphthalenyl 4,6-diMe-2-pyridinyl
3-Et-phenyl /-Bu Phenyl
V = 3-CH3, Y = -CH2ON=C(CH3)C(=NOCH3)-
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF3-phenyl 4-CF3-phenyl 3,5-di(CF3)-phenyl
3-OCF3-phenyl 4-OCF3-phenyl CH3
/-Bu 2-naphthalenyl 4-/-Bu-ρhenyl
4-Me-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl 12 z z
4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-CF3-2-pyridinyl
4,6-diMe-2-pyridinyl 4-CF3-2-pyrimidinyl 6-CF3-2-pyrimidinyl
Phenyl 4-Br-phenyl 4-I-phenyl 4-F-phenyl
V = 3-CH3, Y = -CH=N-N(CH3)-
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-ρhenyl 3,5-diCl-phenyl
3-CF3-phenyl 4-CF3-phenyl 3-OCF3-phenyl
4-OCF3-phenyl 2-naphthalenyl 4-/-Bu-phenyl
4-Me-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl
4-CF3-2-ρyridinyl 5-CF3-2-pyridinyl 6-CF3-2-pyridinyl
4,6-diMe-2-pyridinyl 4-CF3-2-pyrimidinyl
V = 3-CH3, Y = -CH2OC(SMe)=N-
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Me-phenyl 4-Me-phenyl
3,5-diMe-phenyl 2-naphthalenyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-CF -2-pyridinyl
5-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF -2-pyridinyl
V = 3-CH3, Y = -CH2OC(=S)NMe-
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Me-phenyl 4-Me-phenyl
3,5-diMe-phenyl 2-naρhthalenyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-CF3-2-pyridinyl
5-Me-2-pyridinyl 4-CF -2-pyridinyl 6-CF3-2-pyridinyl
V = 3-CH3, Y = -SCH2- Z
2-Me-phenyl 2,5-diMe-phenyl 3-CF3-phenyl 4-CF3 -phenyl 4-Me-phenyl 4-/-Bu-phenyl 3-Cl-phenyl 4-Cl-phenyl 2-Me-5-Cl-phenyl
3-/-Bu-phenyl 2-naphthalenyl 1-naphthalenyl
3-pyridinyl 4-pyridinyl 6-Me-2-pyridinyl
2-(5.6,7,8-tetrahydro)naphthalenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = 3-CH3
Y Y -CH20-N=C(SCH3)- 3-CF3-phenyl -CH20-N= (cyclopropyl)- 3-CF -phenyl -CH20-N=C(SCH3 3-OCF3-phenyl -CH20-N= :C(cyclopropyl)- 3-OCF3-phenyl -CH20-N=C(SCH3)- 3-Me-phenyl -CH20-N= C(cyclopropyl)- 3-Me-phenyl -CH20-N=C(SCH3)- 4-CF3-phenyl -CH20-N= C(cyclopropyl)- 4-CF3-phenyl -CH20-N=C(SCH3)- 4-OCF3-phenyl -CH20-N= C(cyclopropyl)- 4-OCF3-phenyl -CH20-N=C(SCH3)- 4-Me-phenyl -CH20-N= C(cycloproρyl)- 4-Me-phenyl -CH20-N=C(SCH3)- 3-Cl-phenyl -CH20-N= C(cyclopropyl)- 3-Cl-phenyl -CH20-N=C(SCH3)- 3,5-diCl-phenyl -CH20-N= C(cyclopropyl)- 3,5-diCl-phenyl
Table 6c
V = 4-CH3, Y = -O-
Z Phenyl 3-OMe-phenyl 4-CF3-phenyl 3-Me-phenyl 3-F-phenyl 3-OCF3-phenyl 4-Me-phenyl 3-SCHF2-phenyl 3-SCH3-phenyl 2-Me-phenyl 4-SCHF2-phenyl 4-SCH3-phenyl 3-cyclohexyl-phenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl 5-CF3-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-ρyridinyl 4-Me-2-pyridinyl 2-(5,6,7,8-tetrahydro)naphthalenyl 2-(3,3,3-trifluoroethoxyl)-4- 6-(3 ,3 ,3-trifluoroethoxyl)-4- 4-(3,3,3-trifluoroethoxyl)-2- pyrimidinyl pyrimidinyl pyrimidinyl 3,5-diMe-phenyl 2-naphthalenyl 4-/-Bu-phenyl 4-OCF3-phenyl 3- -Bu-phenyl 4-SCF3-phenyl 6-(3,3,3-trifluoroethoxyl)-2- 3-SCF3-phenyl 4,6-diMe-2-pyridinyl pyrazinyl 4-CF3-6-Me-2-pyridinyl 3,5-di(CF3)-phenyl 3-CF3 -phenyl 3-I-phenyl 3-( 1 -propynyl)-phenyl 3-(3,3-diMe-l-butynyl)- 3-(2-cyclopropylethynyl)phenyl phenyl 14
V = 4-CH3, Y = -CH20-
Z phenyl 3-CF3-phenyl 2-Me-5- Pr-phenyl
2-Me-4-0CH3-phenyl 4-0CF3-phenyl 2-Me-5-CF3-phenyl 3-OCHF2-phenyl 4-0CHF2-phenyl 3,5-di(CF3)-phenyl 2-Me-4-0CHF2-phenyl 6-CF3-2-pyridinyl 3-OCF3-phenyl 4-CF -2-pyridinyl 4-Me-2-pyridinyl 2-Me-4-OCF3-phenyl 5-Me-2-pyridinyl 3 , 6-diMe-2-pyridiny 1 5-CF3-2-pyridinyl 4,6-diMe-2-pyridinyl 6-OCF3-2-pyridinyl 4-CF3-6-Me-2-pyridinyl 3-Me-2-pyridinyl 4-Cl-2-pyrimidinyl 6-Me-2-pyridinyl 4-Cl-2-pyrimidinyl 3-Et-phenyl 2,6-Me2-4-pyridinyl 2,4,6-triMe-phenyl 3-Cl-2-pyridinyl 6-Cl-4-pyrimidinyl 1-napthalenyl 2,3,6-triMe-phenyl 6-Cl-2-pyrazinyl 4-CF -2-pyrimidinyl 6-CF3-4-pyrimidinyl 2-z'Pr-phenyl 3-Me-2-pyridinyl 4-Cl-2-pyridinyl 2-Me-phenyl 2,5-diMe-phenyl 2,4-diCl-phenyl 2-Me-4-Cl-phenyl 2-Cl-phenyl 2,4-diMe-phenyl 2,5-diCl-phenyl 4-CF3-5-Br-2-thiazolyl l-Ph-l_7-pyrazol-3-yl 1 -(4-Cl-Ph)- 1 //-pyrazol-3-yl 1 -(4-Me-Ph)- l-Y-pyrazol-3-yl l-(3-Me-Ph)- l -pyrazol-3-yl 1 -Ph- IH- 1 ,2,4-triazol-3-yl l-(4-Cl-Ph)- \H- 1 ,2,4-triazol-3-yl 1 -(4-Me-Ph)- 1 H- 1 ,2,4-triazol-3-y 1 1 -(3-Me-Ph)- 1 H- 1 ,2,4-triazol-3-yl
V = 4-CH3, Y = -OCH2-
Z 2-Me-phenyl 2,5-diMe-phenyl 3-CF3-phenyl 4-CF3-phenyl 4-Me-phenyl 4-/-Bu-phenyl 3-Cl-phenyl 4-Cl-phenyl 2-Me-5-Cl-phenyl 3-/-Bu-phenyl 2-naphthalenyl 1-naphthalenyl 3-pyridinyl 4-pyridinyl 6-Me-2-pyridinyl 2-(5,6,7,8 tetrahydro)naphthalenyl
V = 4-CH3, Y = -CH20-N=C(CH3)-
Z 3-Me-ρhenyl 4-CF3 -phenyl 3,5-diMe-phenyl 3-Cl-phenyl 4-Br-phenyl 3,5-di(CF3)-phenyl 4-OCHF2-phenyl 4-/-Bu-phenyl 3-/-Bu-phenyl 5-CF3-2-pyridinyl 4-OCF3 -phenyl 3-OCHF2-phenyl 5-Me-2- pyridinyl 4-CF3-6-Me-2 -pyridinyl 4-Me-2- pyridinyl 4,6-diMe-2-pyridinyl 6-Me-2-pyridinyl 6-CF3-2-pyridinyl 6-OMe-2-pyridinyl 2,6-Me2-4-pyridinyl 2,6-diCl-4-pyridinyl
5-OCF3-2-pyridinyl 4-OMe-2-pyridinyl 4-OCF3-2-pyridinyl
5-OCHF2-2-pyridinyl 6-OCF3-2-pyridinyl 4-OCHF2-pyridinyl
3-(3,3,3 trifluoroethoxy)-phenyl 6-OCHF2-2-pyridinyl 3-Et-phenyl
1-naphthalenyl 2-( 1 ,2,3,4-tetrahydro)naphthalenyl /-Bu
3-SMe-phenyl 3-ethynyl-phenyl 3-CF3-phenyl
3,5-diCl-phenyl 3-OCF3-phenyl 4-CF3-2-pyridinyl
4-CF3-6-Cl-2-pyridinyl
V = 4-CH3, Y = -CH =NOCH(CH3)-
Z 4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl 3-OCF3-phenyl 3-Cl-ρhenyl 4-Cl-phenyl 3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl 4-Me-phenyl 2-naphthalenyl 4-OCHF2-phenyl 3-OCHF2-phenyl 4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-CF3-2-pyridinyl 4-Me-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2 -pyridinyl 4-CF3 -6-Me-2-pyridinyl 4-OCF3-2-pyridinyl 5-OCF3-2-pyridinyl 6-OCF3-2-pyridinyl 4-OCHF2-2-pyridinyl 5-OCHF2-2-pyridinyl 6-OCHF2-2-pyridinyl 3-/-Bu-phenyl 4-/-Bu-phenyl
V = 4-CH3, Y = -CH2-SC(Et)=N-
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl
4-Me-phenyl 3,5-diMe-phenyl 2-naρhthalenyl
6-Me-2-pyridinyl 4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl
5-Cl-2-pyridinyl 4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl
5-CF3 -2-pyridiny 1 5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl
V = 4-CH3, Y = -CH2-SC(=S)NMe- z z z
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl Z Z
4-Me-phenyl 3.5-diMe-phenyl 2-naphthalenyl 6-Me-2-pyridinyl 4-Me-2 -pyridinyl 4,6-diMe-2-pyridinyl 5-Cl-2-pyridinyl 4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl 5-CF3-2-pyridinyl 5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl
V = 4-CH3, Y = -CH2SC(SMe)=N-
3-Me-ρhenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF3-phenyl 4-CF3-phenyl 3-OCF3-phenyl
4-OCF3-phenyl 3,5-di(CF3)-phenyl CH2CH2-/-Bu
/-Bu 2-naphthalenyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-Cl-2-pyridinyl
4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl 5-CF3-2-pyridinyl
5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = 4-CH3, Y = -CH2S-
2-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
2,5-diMe-phenyl 2-Et-phenyl 3-Cl-phenyl
2-Cl-phenyl 2,5-diCl-phenyl 4,6-diMe-2-pyrimidinyl
4-Me- 1 ,2,4-triazol-3-yl 2-naphthalenyl l-Me-2-imidazolyl
4-Me-2-pyrimidinyl 5-Me- 1 ,3,4-thiadiazol-2-yl 4-CF3-2-pyridinyl
4-Ph-5-Me-2-thiazolyl
V = 4-CH3, Y = -CH2ON=C(CH3)CH2S-
Z Z Z
3-Me-phenyl 2-Me-phenyl 3-CF3-phenyl
4-CF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
2-Et-phenyl 2,5-diMe-phenyl 2-naphthalenyl
V = 4-CH3, Y = -CH2ON=C(CH3)CH20-
Z Z Z
3-Me-phenyl 2-Me-phenyl 4-Me-phenyl
3-CF3-phenyl 4-CF3-phenyl 4-Cl-phenyl
3-Cl-phenyl 3,5-diMe-phenyl 2,5-diMe-phenyl
2-Me-5-/Pr-phenyl 3-Et-phenyl 6-CF3-2-pyridinyl Z Z
4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-Me-2-pyridinyl
5-Me-2-pyridinyl 4-Me-2-pyridinyl 1-naphthalenyl
2-naphthalenyl
V = 4-CH3, Y = -CH2CH2-
2-Me-phenyl 2,5-diMe-phenyl 3-CF3-phenyl 4-CF3-phenyl 3-Cl-phenyl 4-Cl-phenyl 3-OCF3-phenyl 4-OCF3-phenyl 2-Et-phenyl 2-Me-5-Cl-phenyl 2-naphthalenyl 3,6-diMe-2-pyridinyl
V = 4-CH3, Y = -CH=C(CH3)-
Z Z Z
3-Me-phenyl 4-Me-phenyl 3,5-diMe-ρhenyl
3-Cl-phenyl 4-Cl-phenyl 3-OCF3-phenyl
4-OCF3-phenyl 3-CF3-phenyl 4-CF3-phenyl
2-naphthalenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = 4-CH3, Y = -CH=N-N=C(CH3)-
Z
3-Me-ρhenyl 4-Me-phenyl 3-CF3-phenyl
4-CF3 -phenyl 3-OCF3-phenyl 4-OCF3-phenyl
3,5-diMe-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 4-CF3-2-pyridinyl 5-CF3-2-pyridinyl
6-CF3-2-pyridinyl 4-Me-2-pyridinyl 5-Me-2-pyridinyl
6-Me-2-pyridinyl 2-naphthalenyl 4,6-diMe-2-pyridinyl
3-Et-phenyl /-Bu Phenyl
V = 4-CH3, Y = -CH2ON=C(CH3)C(=NOCH3)-
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF3-phenyl 4-CF3-phenyl 3,5-di(CF3)-phenyl
3-OCF3-phenyl 4-OCF3-phenyl CH3
/-Bu 2-naphthalenyl 4-/_Bu-phenyl
4-Me-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl
4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-CF3 -2-pyridiny 1 18
z z
4,6-diMe-2-pyridinyl 4-CF3-2-pyrimidinyl 6-C F -2-pyrimidinyl
Phenyl 4-Br-phenyl 4-I-phenyl 4-F-phenyl
V = 4-CH3, Y = -CH=N-N(CH3)-
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF3-phenyl 4-CF3-phenyl 3-OCF3-phenyl
4-OCF3-phenyl 2-naphthalenyl 4-/-Bu-phenyl
4-Me-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl
4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-CF3-2-pyridinyl
4,6-diMe-2-pyridinyl 4-CF3-2-pyrimidinyl
V = 4-CH3, Y = -CH2OC(SMe)=N-
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-ρhenyl
3,5-diCl-phenyl 3-Me-phenyl 4-Me-phenyl
3,5-diMe-phenyl 2-naρhthalenyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-CF3-2-pyridinyl
5-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = 4-CH3, Y = -CH2OC(=S)NMe-
4-CF3 -phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-ρhenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Me-phenyl 4-Me-phenyl
3,5-diMe-phenyl 2-naρhthalenyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-CF3-2-pyridinyl
5-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = 4-CH3, Y = -SCH2-
Z 2-Me-phenyl 2,5-diMe-phenyl 3-CF -phenyl 4-CF3-phenyl 4-Me-phenyl 4-/-Bu-phenyl 3-Cl-phenyl 4-Cl-phenyl 2-Me-5-Cl-phenyl 19
3-/-Bu-phenyl 2-naphthalenyl 1-naphthalenyl
3-pyridinyl 4-pyridinyl 6-Me-2-pyridinyl
2-(5,6,7,8-tetrahydro)naphthalenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = 4-CH3
Y Z Y Z
-CH20-N=C(SCH3)- 3-CF -phenyl -CH20-N=C(cyclopropyl)- 3-CF3-phenyl
-CH20-N=C(SCH3)- 3-OCF3-phenyl -CH20-N=C(cyclopropyl)- 3-0CF3-phenyl
-CH20-N=C(SCH3)- 3-Me-phenyl -CH 0-N=C(cyclopropyl)- 3-Me-phenyl
-CH20-N=C(SCH3)- 4-CF3-phenyl -CH20-N=C(cyclopropyl)- 4-CF3-phenyl
-CH20-N=C(SCH3)- 4-OCF3 -phenyl -CH20-N=C(cyclopropyl)- 4-OCF3-phenyl
-CH20-N=C(SCH3)- 4-Me-phenyl -CH20-N=C(cyclopropyl)- 4-Me-phenyl
-CH20-N=C(SCH3)- 3-Cl-phenyl -CH20-N=C(cyclopropyl)- 3-Cl-phenyl
-CH20-N=C(SCH3)- 3,5-diCl-phenyl -CH20-N=C(cyclopropyl)- 3,5-diCl-phenyl
Structure for Tables 7a, 7b and 7c
Figure imgf000121_0001
Table 7a
V = H
Er. Bl Bl E?
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3 -phenyl
3-OCF3-phenyl 4-0CF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-0CHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 ■ 3,5-diF-phenyl 3-cyclopropyl-phenyl Table 7b
V = 3-CH3
Er! Er! Bl S__
3-Me-phenyl 4- Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF -phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-dιCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C__CH-phenyl 4-C__CH-phenyl .
/-Bu CF3 3,5-diF-phenyl 3-cycloproρyl-phenyl
Table 7c
V = 4-CH3
Bl E! Er! Er.
3-Me-phenyl 4- Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-ρhenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3 -phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C__CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cycloρropyl-phenyl
Figure imgf000122_0001
1 'able 8a
V = H, R10 = H
E? Bl Bl Er!
3-Me-phenyl 4-Me-ρhenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl Er! ! Bl Bl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 I Br
V = H, R10 = Br
E! S? £__ Bl
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3.5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-ρhenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 I Br
V = H, R10 = CH3
Er! E* Er! Er!
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3 -phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 I Br
V = H, R10 = I
El E2 Er! E£
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3 -phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C__CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 I Br Table 8b
•"
V = 3-CH3, R10 = H
Er! Er. Er! Bl
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF -phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl .
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 I Br
V = 3-CH3, R10 = Br
Er! Er! Er! Er!
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF -phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-ρhenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C__CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-ρhenyl
H CH3
V = 3-CH3, R10 = CH3
El Er! Bl Er!
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF -ρhenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C=CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 I Br
V = 3-CH3, R10 = I
El Bl Er! Er!
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3 -phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl El Er! E£ Er!
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 I Br
Table 8c
V = 4-CH3, R10 = H
El Er! Bl E2
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3 -phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C__CH-phenyl 4-C__CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-ρhenyl
H CH3 I Br
V = 4-CH3, R10 = Br
El Er! Er! Er!
3-Me-phenyl 4-Me-phenyl 3-CF3 -phenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3 -phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cycloproρyl-phenyl
H CH3 Br
V = 4-CH3, R10 = CH3
El Bl Bl Er!
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3 -phenyl
3-OCF3-phenyl 4-OCF3 -phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF -phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl R9 R9 R9 R9
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-pheny
H CH3 I Br
V = 4-CH3, R10 = 1
El E? E? Bl
3 -Me -phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C_-CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 I Br
Structure for Tables 9a, 9b and 9c
Figure imgf000126_0001
Table 9a
V = H
Eli R13 R12 R13 R12 R13
H 2'-( _:N 2'-F 4',6'-diF 2"-Cl 6'-Cl
2'-Me H 2'-F 3y5,6'-triF 2'-F 5'-F
2'-Cl H 2'-Cl 4\6'-diF 2'-F 6'-F
2'-F H 4'-Br 2',6'-diF 2'-F 4'-F
2'-OMe H 4'-I 2',6'-diF 2'-Et H
2'-Br H 2'-F 3',6'-diF 4'-Me 2',6'-diCl
2"-SMe H 2'-F 4',5'-diF 4'-Me 2',6'-diF
Table 9b
V = 3-CH3
EH EH B R13 RI2 R13
H 2'-CN 2'-F 4',6'-diF 2 -Cl 6'-Cl 2
2
2
2
2
2
Figure imgf000127_0001
Table 9c
V = 4-CH3
R12 Ell Ell Ell Rl2 R13
H 2'-CN 2'-F 4',6'-diF 2'-Cl 6'-Cl
2'-Me H 2'-F 3',5',6'-tήF 2'-F 5'-F
2'-Cl H 2'-Cl 4,,6,-diF 2'-F 6'-F
2'-F H 4'-Br 2',6'-diF 2'-F 4'-F
2'-OMe H 4'-I 2',6'-diF 2'-Et H
2'-Br H 2'-F 3 6'-dϊF 4'-Me 2',6'-diCl
2'-SMe H 2'-F 4',5'-diF 4'-Me 2',6-diF
Stπ icture for Tables 1 Oa, 1 Ob and 1 Oc
Figure imgf000127_0002
Table 10a
Figure imgf000127_0003
Table 10b
V = 3-CH3
Ell Ell R12 Ell Ell Ell
H 2'-< N 2'-F 4',6'-diF 2'-Cl 6'-Cl
2'-Me H 2'-F 3\5\6'-triF 2'-F 5'-F
2'-Cl H 2'-Cl 4',6'-diF 2'-F 6'-F
2'-F H 4'-Br 2',6'-diF 2'-F 4'-F
2'-OMe H 4'-I 2',6'-diF 2'-Et H
2'-Br H 2'-F 3',6'-diF 4'-Me 2',6'-diCl
2'-SMe H 2'-F 4\5'-diF 4'-Me 2',6'-diF
Table 10c
V = 4-CH3
Ell Ell R12 R13 Ell Ell
H 2'-CN 2'-F 4',6'-diF 2'-Cl 6'-Cl
2'-Me H 2'-F 3\5',6,-triF 2'-F 5'-F
2'-Cl H 2'-Cl 4',6'-diF 2'-F 6'-F
2'-F H 4'-Br 2',6'-diF 2'-F 4'-F
2'-OMe H 4'-I 2,,6'-diF 2'-Et H
2'-Br H 2'-F 3',6'-diF 4'-Me 2',6'-diCl
2'-SMe H 2'-F 4',5'-diF 4'-Me 2',6'-diF
Structure for Tables 11a. 1 lb an d l lc
Figure imgf000128_0001
Table 11a v = H, Y = -O-
Phenyl 3-OMe-phenyl . 4-CF3-phenyl
3-Me-phenyl 3-F-phenyl 3-OCF3-phenyl
4-Me-phenyl 3-SCHF2-phenyl 3-SCH3-phenyl
2-Me-phenyl 4-SCHF2-phenyl 4-SCH3-phenyl
3-cyclohexyl-phenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl 5-CF3-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 2-(5,6_7,8-tetrahydro)naphthalenyl 2-(3,3,3-trifluoroethoxyl)-4-
6-(3,3,3-trifluoroethoxyl)-4- 4-(3,3,3-trifluoroethoxyl)-2- pyrimidinyl pyrimidinyl pyrimidinyl 3,5-diMe-phenyl
2-naphthalenyl 4-/-Bu-phenyl 4-OCF3-phenyl
3-/-Bu-phenyl 4-SCF3-phenyl 6-(3,3,3-trifluoroethoxyl)-2-
3-SCF3-phenyl 4,6-diMe-2-pyridinyl pyrazinyl
4-CF -6-Me-2-pyridinyl 3,5-di(CF3)-phenyl 3-CF3-phenyl
3-I-phenyl 3-( 1 -ρropynyl)-ρhenyl 3-(3,3-diMe-l-butynyl)-
3-(2-cyclopropylethynyl)phenyl phenyl
V = H, Y = -CH20-
Z Z Z phenyl 3-CF -phenyl 2-Me-5- Pr-ρhenyl
2-Me-4-OCH3-phenyl 4-OCF3-phenyl 2-Me-5-CF3-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3,5-di(CF3)-phenyl
2-Me-4-OCHF2-phenyl 6-CF3 -2-pyridinyl 3-OCF3 -phenyl
4-CF3 -2-pyridinyl 4-Me-2-pyridinyl 2-Me-4-OCF3-phenyl
5-Me-2-pyridinyl 3,6-diMe-2-pyridinyl 5-CF3-2-pyridinyl
4,6-diMe-2-pyridinyl 6-OCF3-2-pyridinyl 4-CF3-6-Me-2-pyridinyl
3-Me-2-pyridinyl 4-Cl-2-pyrimidinyl 6-Me-2-pyridinyl
4-Cl-2-pyrimidinyl 3-Et-phenyl 2,6-Me2-4-pyridinyl
2,4,6-triMe-ρhenyl 3-Cl-2-pyridinyl 6-Cl-4-pyrimidinyl
1-napthalenyl 2,3 ,6-triMe-phenyl 6-Cl-2-pyrazinyl
4-CF3-2-pyrimidinyl 6-CF3-4-pyrimidinyl 2-/Pr-phenyl
3-Me-2-pyridinyl 4-Cl-2-pyridinyl 2-Me-phenyl
2,5-diMe-phenyl 2,4-diCl-phenyl 2-Me-4-Cl-phenyl
2-Cl-phenyl 2,4-diMe-phenyl 2,5-diCl-phenyl
4-CF3-5-Br-2-thiazolyl l-Ph-l_Y-pyrazol-3-yl 1 -(4-Cl-Ph)- l /-pyrazol-3-yl l-(4-Me-Ph)-l/ -pyrazol-3-yl 1 -(3-Me-Ph)- l /-pyrazol-3-yl 1 -Ph- IH- 1 ,2,4-triazol-3-yl l-(4-Cl-Ph IH- 1 ,2,4-triazol-3-yl 1 -(4-Me-Ph)- IH- 1 ,2,4-triazol-3-yl 1 -(3-Me-Ph)- IH- 1 ,2,4-triazol-3-yl
V = H, Y = -OCH2-
Z Z Z
2-Me-phenyl 2,5-diMe-phenyl 3-CF3-phenyl
4-CF3-phenyl 4-Me-phenyl 4-/-Bu-phenyl
3-Cl-phenyl 4-Cl-phenyl 2-Me-5-Cl-phenyl 3-/-Bu-phenyl 2-naphthalenyl 1-naphthalenyl
3-pyridinyl 4-pyridinyl 6-Me-2-pyridinyl
2-(5, 6,7,8 tetrahydro)naphthalenyl
V = H, Y = -CH20-N=C(CH3)-
Z 3-Me-phenyl 4-CF3-phenyl 3,5-diMe-phenyl 3-Cl-phenyl 4-Br-phenyl 3,5-di(CF3)-phenyl 4-OCHF2-phenyl 4-/-Bu-phenyl 3-/-Bu-phenyl 5-CF3-2-pyridinyl 4-OCF3-phenyl 3-OCHF2-phenyl 5-Me-2- pyridinyl 4-CF3-6-Me-2-pyridinyl 4-Me-2- pyridinyl 4,6-diMe-2-pyridinyl 6-Me-2-pyridinyl 6-CF3-2-pyridinyl 6-OMe-2-pyridinyl 2,6-Me2-4-pyridinyl 2,6-diCl-4-pyridinyl 5-OCF3-2-pyridinyl 4-OMe-2-pyridinyl 4-OCF3-2-pyridinyl 5-OCHF2-2-pyridinyl 6-OCF3 -2-pyridinyl 4-OCHF -pyridinyl 3-(3,3,3 trifluoroethoxy)-phenyl 6-OCHF2-2-pyridinyl 3-Et-phenyl 1-naphthalenyl 2-( 1 ,2,3,4-tetrahydro)naphthalenyl /-Bu 3-SMe-ρhenyl 3-ethynyl-phenyl 3-CF3-phenyl 3,5-diCl-phenyl 3-OCF3-phenyl 4-CF -2-pyridinyl 4-CF3-6-Cl-2-pyridinyl
V = H, Y = -CH=NOCH(CH3)-
Z
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl
4-Me-phenyl 2-naphthalenyl 4-OCHF2-phenyl
3-OCHF2-phenyl 4-CF3-2-pyridinyl 5-CF3-2-pyridinyl
6-CF3 -2-pyridinyl 4-Me-2-pyridinyl 5-Me-2-pyridinyl
6-Me-2-pyridinyl 4-CF3 -6-Me-2-pyridinyl 4-OCF3-2-pyridinyl
5-OCF3-2-pyridinyl 6-OCF3-2-pyridinyl 4-OCHF2-2-pyridinyl
5-OCHF2-2-pyridinyl 6-OCHF2-2-pyridinyl 3-/-Bu-phenyl
4-/-Bu-phenyl [ 29
V = H, Y = -CH2-SC(Et)=N-
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl
4-Me-phenyl 3,5-diMe-phenyl 2-naphthalenyl
6-Me-2-pyridinyl 4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl
5-Cl-2-pyridinyl 4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl
5-CF3-2 -pyridinyl 5-Br-6-Me-2-pyridinyl 4-CF3 -2-pyridinyl
V = H, Y = -CH2-SC(=S)NMe-
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl
4-Me-phenyl 3,5-diMe-phenyl 2-naphthalenyl
6-Me-2-pyridinyl 4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl
5-Cl-2-pyridinyl 4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl
5-CF3-2-pyridinyl 5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl
V = H, Y = -CH2SC(SMe)=N-
3-Me-phenyl 4-Me-ρhenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF3-phenyl 4-CF3-phenyl 3-OCF3-phenyl
4-OCF3-phenyl 3,5-di(CF3)-phenyl CH2CH2-/-Bu
/-Bu 2-naphthalenyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-Cl-2-pyridinyl
4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl 5-CF3-2-pyridinyl
5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = H, Y = -CH2S-
Z 2-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl 2,5-diMe-phenyl 2-Et-phenyl 3-Cl-phenyl 2-Cl-phenyl 2,5-diCl-phenyl 4,6-diMe-2-pyrimidinyl 4-Me- 1 ,2,4-triazol-3-yl 2-πaphthalenyl l-Me-2-imidazolyI
4-Me-2-pyrimidinyl 5-Me- 1 ,3,4-thiadiazol-2-yl 4-CF -2-pyridinyl
4-Ph-5-Me-2-thiazolyl
V = H, Y = -CH2ON=C(CH3)CH2S-
Z Z Z
3-Me-phenyl 2-Me-phenyl 3-CF3-phenyl
4-CF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
2-Et-phenyl 2,5-diMe-phenyl 2-naphthalenyl
V = H, Y = -CH2ON=C(CH3)CH20-
Z Z Z
3-Me-phenyl 2-Me-phenyl 4-Me-phenyl
3-CF3-ρhenyl 4-CF3-phenyl 4-Cl-phenyl
3-Cl-phenyl 3,5-diMe-phenyl 2,5-diMe-phenyl
2-Me-5-.Pr-phenyl 3-Et-phenyl 6-CF3-2-pyridinyl
4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-Me-2-pyridinyl
5-Me-2-pyridinyl 4-Me-2-pyridinyl 1-naphthalenyl
2-naphthalenyl
V = H, Y = -CH2CH2-
2-Me-phenyl 2,5-diMe-phenyl 3-CF -phenyl 4-CF3-phenyl 3-Cl-phenyl 4-Cl-phenyl 3-OCF3-phenyl 4-OCF3-phenyl 2-Et-phenyl 2-Me-5-Cl-phenyl 2-naρhthalenyl 3,6-diMe-2-pyridinyl
V = H, Y = -CH=C(CH3)- z z z
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-ρhenyl 3-OCF3-phenyl
4-OCF3-phenyl 3-CF3-phenyl 4-CF3-phenyl
2-naphthalenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl [ 3 1
V = H, Y = -CH=N-N=C(CH3)-
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl
4-CF3-phenyl 3-OCF3-phenyl 4-OCF3-phenyl
3,5-diMe-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 4-CF -2-pyridinyl 5-CF3-2-pyridinyl
6-CF3-2-pyridinyl 4-Me-2-pyridinyl 5-Me-2-pyridinyl
6-Me-2-pyridinyl 2-naphthalenyl 4,6-diMe-2-pyridinyl
3-Et-phenyl /-Bu Phenyl
V = H, Y = -CH2ON= =C(CH3)C(=NOCH3)-
Z Z 3-Me-ρhenyl 4-Me-ρhenyl 3,5-diMe-phenyl 3-Cl-ρhenyl 4-Cl-phenyl 3,5-diCl-phenyl 3-CF3-phenyl 4-CF3-phenyl 3,5-di(CF3)-phenyl 3-OCF3-phenyl 4-OCF3-phenyl CH3 /-Bu 2-naphthalenyl 4-/-Bu-phenyl
4-Me-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl 4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-CF3 -2-pyridiny 1 4,6-diMe-2-pyridinyl 4-CF3-2-pyrimidinyl 6-CF3 -2-pyrimidinyl Phenyl 4-Br-phenyl 4-I-phenyl 4-F-phenyl
V = H, Y = -CH=N-N(CH3)-
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF3>phenyl 4-CF3-phenyl 3-OCF3-phenyl
4-OCF3-phenyl 2-naphthalenyl 4-/-Bu-phenyl
4-Me-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl
4-CF3 -2-pyridinyl 5-CF3-2-pyridinyl 6-CF3 -2-pyridinyl
4,6-diMe-2-pyridinyl 4-CF3-2-pyrimidinyl
V = H, Y = -CH2OC(SMe)=N-
Z Z
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl 2-naphthalenyl 6-Me-2-pyridinyl 4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-CF3-2-pyridinyl 5-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = H, Y = -CH2OC(=S)NMe-
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Me-phenyl 4-Me-phenyl
3,5-diMe-phenyl 2-naphthalenyl ' 6-Me-2-pyridinyl
4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-CF3-2-pyridinyl
5-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = H, Y = -SCH2-
Z z z
2-Me-phenyl 2,5-diMe-phenyl 3-CF3-phenyl
4-CF3-phenyl 4-Me-phenyl 4-/-Bu-phenyl
3-Cl-ρhenyl 4-Cl-phenyl 2-Me-5-Cl-phenyl
3-/-Bu-phenyl 2-naphthalenyl 1-naphthalenyl
3-pyridinyl 4-pyridinyl 6-Me-2-pyridinyl
2-(5,6,7,8-tetrahydro)naphthalenyl 4-CF3-2 -pyridinyl 6-CF3-2-pyridinyl
V = H
Y Z Y Z
-CH20-N=C(SCH3)- 3-CF3-phenyl -CH20-N=C(cyclopropyl)- 3-CF3-phenyl
-CH20-N=C(SCH3)- 3-OCF3-phenyl -CH 0-N=C(cyclopropyl)- 3-OCF3-phenyl
-CH20-N=C(SCH3)- 3-Me-phenyl -CH20-N=C(cyclopropyl)- 3-Me-phenyl
-CH20-N=C(SCH3)- 4-CF3-phenyl -CH20-N=C(cyclopropyl)- 4-CF3 -phenyl
-CH20-N=C(SCH3)- 4-OCF3-phenyl -CH20-N=C(cyclopropyl)- 4-OCF3-phenyl
-CH20-N=C(SCH3 4-Me-phenyl -CH20-N=C(cyclopropyl)- 4-Me-phenyl
-CH20-N=C(SCH3)- 3-Cl-phenyl -CH20-N=C(cyclopropyl)- 3-Cl-phenyl
-CH20-N=C(SCH3)- 3,5-diCl-phenyl -CH20-N=C(cyclopropyl)- 3,5-diCl-ρhenyl Table l ib
V = 3-CH3, Y = -0- z
Phenyl 3-OMe-phenyl 4-CF -phenyl
3-Me-phenyl 3-F-phenyl 3-OCF3-phenyl
4-Me-ρhenyl 3-SCHF2-phenyl 3-SCH3-phenyl
2-Me-phenyl 4-SCHF2-phenyl 4-SCH3-phenyl
3-cyclohexyl-ρhenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
5-CF3-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 2-(5,6,7,8-tetrahydro)naphthalenyl 2-(3,3,3-trifluoroethoxyl)-4-
6-(3,3,3-trifluoroethoxyl)-4- 4-(3,3,3-trifluoroethoxyl)-2- pyrimidinyl pyrimidinyl pyrimidinyl 3,5-diMe-phenyl 2-naphthalenyl 4-/-Bu-phenyl 4-OCF3-phenyl 3-/-Bu-phenyl 4-SCF3-phenyl 6-(3,3,3-trifluoroethoxyl)-2- 3-SCF3-phenyl 4,6-diMe-2-pyridinyl pyrazinyl 4-CF3-6-Me-2-pyridinyl 3,5-di(CF3)-phenyl 3-CF3-phenyl 3-I-phenyl 3-( 1 -propynyl)-phenyl 3-(3,3-diMe-l-butynyl)- 3-(2-cyclopropylethynyl)phenyl phenyl
V = 3-CH3, Y = -CH20- Z phenyl 3-CF3-phenyl 2-Me-5- Pr-phenyl
2-Me-4-OCH3-phenyl 4-OCF3-phenyl 2-Me-5-CF3-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3,5-di(CF3)-phenyl
2-Me-4-OCHF2-phenyl 6-CF3-2-pyridinyl 3-OCF3-phenyl
4-CF3-2-pyridinyl 4-Me-2-pyridinyl 2-Me-4-OCF3-phenyl
5-Me-2-pyridinyl 3,6-diMe-2-pyridinyl 5-CF3-2-pyridinyl
4,6-diMe-2-pyridinyl 6-OCF3-2-pyridinyl 4-CF3-6-Me-2-pyridinyl
3-Me-2-pyridinyl 4-Cl-2-pyrimidinyl 6-Me-2-pyridinyl
4-Cl-2-pyrimidinyl 3-Et-phenyl 2,6-Me2-4-pyridinyl
2,4,6-triMe-phenyl 3-Cl-2-pyridinyl 6-Cl-4-pyrimidinyl
1-napthalenyl 2,3,6-triMe-phenyl 6-Cl-2-pyrazinyl
4-CF3-2-pyrimidinyl 6-CF3 -4-pyrimidinyl 2- Pr-ρhenyl
3-Me-2-pyridinyl 4-Cl-2-pyridinyl 2-Me-phenyl
2,5-diMe-phenyl 2,4-diCl-phenyl 2-Me-4-Cl-phenyl
2-Cl-phenyl 2,4-diMe-phenyl 2,5-diCl-phenyl
4-CF3-5-Br-2-thiazolyl l-Ph-l -pyrazol-3-yl l-(4-Cl-Ph)-l /-pyrazol-3-yl 1 -(4-Me-Ph)- 1 / -pyrazol-3-yl 1 -(3-Me-Ph)- 1 /-pyrazol-3-yl l-Ph-l -l,2,4-triazol-3-yl 1 -(4-Cl-Ph)- IH- 1 ,2,4-triazol-3-yl 1 -(4-Me-Ph)- 1 H- 1 ,2,4-triazol-3-yl 1 -(3-Me-Ph)- 1 H- 1 ,2,4-triazol-3-yl
V = 3-CH3, Y = -OCH2-
Z 2-Me-phenyl 2,5-diMe-phenyl 3-CF3-phenyl 4-CF3-phenyl 4-Me-phenyl 4-/-Bu-ρhenyl 3-Cl-phenyl 4-Cl-phenyl 2-Me-5-Cl-phenyl 3-/-Bu-phenyl 2-naphthalenyl 1-naphthalenyl 3-pyridinyl 4-pyridinyl 6-Me-2-pyridinyl 2-(5,6,7,8 tetrahydro)naphthalenyl
V = 3-CH3, Y = -CH20-N=C(CH3)-
Z 3-Me-phenyl 4-CF -phenyl 3,5-diMe-phenyl 3-Cl-phenyl 4-Br-phenyl 3,5-di(CF3)-phenyl 4-OCHF2-phenyl 4-/-Bu-phenyl 3-/-Bu-phenyl 5-CF3-2-pyridinyl 4-OCF3-phenyl 3-OCHF -phenyl 5-Me-2- pyridinyl 4-CF3-6-Me-2-pyridinyl 4-Me-2- pyridinyl 4,6-diMe-2-pyridinyl 6-Me-2-pyridinyl 6-CF3-2-pyridinyl 6-OMe-2-pyridinyl 2,6-Me2-4-pyridinyl 2,6-diCl-4-pyridinyl 5-OCF3-2-pyridinyl 4-OMe-2-pyridinyl 4-OCF3-2-pyridinyl 5-OCHF2-2-pyridinyl 6-OCF -2-pyridinyl 4-OCHF2-pyridinyl 3-(3,3,3 trifluoroethoxy)-phenyl 6-OCHF2-2-pyridinyl 3-Et-phenyl 1-naphthalenyl 2-( 1 ,2,3 ,4-te trahydro)naphthalenyl /-Bu 3-SMe-phenyl 3-ethynyl-phenyl 3-CF3 -phenyl 3,5-diCl-phenyl 3-OCF3-ρhenyl 4-CF3-2-pyridinyl 4-CF3-6-Cl-2-pyridinyl
V = 3-CH3, Y = -CH=NOCH(CH3)-
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl
4-Me-phenyl 2-naphthalenyl 4-OCHF2-phenyl
3-OCHF2-phenyl 4-CF3-2-pyridinyl 5-CF3-2-pyridinyl
6-CF3-2-pyridinyl 4-Me-2-pyridinyl 5-Me-2-pyridinyl z z z
6-Me-2-pyridinyl 4-CF3-6-Me-2-pyridinyl 4-OCF3-2-pyridinyl
5-OCF3-2-pyridinyl 6-OCF3-2-pyridinyl 4-OCHF2-2-pyridinyl
5-OCHF2-2-pyridinyl 6-OCHF2-2-pyridinyl 3- -Bu-phenyl 4-/-Bu-phenyl
V = 3-CH3, Y = -CH2-SC(Et)=N-
4-CF3-phenyl 3-CF -phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl
4-Me-phenyl 3,5-diMe-phenyl 2-naphthalenyl
6-Me-2-pyridinyl 4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl
5-Cl-2-ρyridinyl 4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl
5-CF3-2-pyridinyl 5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl
V = 3-CH3, Y = -CH2-SC(=S)NMe-
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl
4-Me-phenyl 3,5-diMe-phenyl 2-naphthalenyl
6-Me-2-pyridinyl 4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl
5-Cl-2-pyridinyl 4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl
5-CF3 -2-pyridinyl 5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl
V = 3-CH3, Y = -CH2SC(SMe)=N-
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF3-phenyl 4-CF3-phenyl 3-OCF3-phenyl
4-OCF3-phenyl 3,5-di(CF3)-phenyl CH2CH2-/-Bu
/-Bu 2-naphthalenyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 4,6-diMe-2 -pyridinyl 5-Cl-2-pyridinyl
4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl 5-CF3-2-pyridinyl
5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl V = 3-CH3, Y = -CH2S-
Z 2-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl 2,5-diMe-phenyl 2-Et-phenyl 3-Cl-phenyl 2-Cl-phenyl 2,5-diCl-phenyl 4,6-diMe-2-pyrimidinyl 4-Me- 1 ,2,4-triazol-3-yl 2-naphthalenyl 1 -Me-2-imidazolyl 4-Me-2-pyrimidinyl 5-Me- 1 ,3,4-thiadiazol-2-yl 4-CF3-2-pyridinyl 4-Ph-5-Me-2-thiazolyl
V = 3-CH3, Y = -CH2ON=C(CH3)CH2S- z z z
3-Me-phenyl 2-Me-phenyl 3-CF3-phenyl
4-CF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
2-Et-phenyl 2,5-diMe-phenyl 2-naphthalenyl
V = 3-CH3, Y = -CH2ON=C(CH3)CH20-
3-Me-phenyl 2-Me-phenyl 4-Me-phenyl
3-CF -phenyl 4-CF3-phenyl 4-Cl-phenyl
3-Cl-phenyl 3,5-diMe-phenyl 2,5-diMe-phenyl
2-Me-5-;Pr-phenyl 3-Et-phenyl 6-CF3-2-pyridinyl
4-CF3-2-pyridinyl 5-CF -2-ρyridinyl 6-Me-2-pyridinyl
5-Me-2-pyridinyl 4-Me-2-pyridinyl 1-naphthalenyl
2-naphthalenyl
V = 3-CH3, Y = -CH2CH2-
2-Me-phenyl 2,5-diMe-phenyl 3-CF3 -phenyl 4-CF3-phenyl 3-Cl-phenyl 4-Cl-phenyl 3-OCF3-ρhenyl 4-OCF3-phenyl 2-Et-phenyl 2-Me-5-Cl-phenyl 2-naphthalenyl 3,6-diMe-2 -pyridinyl
V = 3-CH3, Y = -CH=C(CH3)- z z
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3-OCF3-phenyl
4-OCF3-phenyl 3-CF3-phenyl 4-CF3-phenyl
2-naphthalenyl 4-CF -2-pyridinyl 6-CF -2-pyridinyl V = 3-CH3, Y = -CH=N-N=C(CH3)-
3-Me-phenyl 4-Me-phenyl 3-CF -phenyl
4-CF3-phenyl 3-OCF3-phenyl 4-OCF3-phenyl
3,5-diMe-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 4-CF3-2-pyridinyl 5-CF3-2-pyridinyl
6-CF3-2-pyridinyl 4-Me-2-pyridinyl 5-Me-2-pyridinyl
6-Me-2-pyridinyl 2-naphthalenyl 4,6-diMe-2-pyridinyl
3-Et-phenyl /-Bu Phenyl
V = 3-CH3, Y = -CH2ON=C(CH3)C(=NOCH3)-
3-Me-phenyl 4-Me-phenyl 3,5-diMe-ρhenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-ρhenyl
3-CF3-phenyl 4-CF3-phenyl 3,5-di(CF3)-phenyl
3-OCF3-phenyl 4-OCF3-phenyl CH3
/-Bu 2-naphthalenyl 4-/-Bu-phenyl
4-Me-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl
4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-CF3-2-pyridinyl
4,6-diMe-2-pyridinyl 4-CF3-2-pyrimidinyl 6-CF3-2-pyrimidinyl
Phenyl 4-Br-ρhenyl 4-I-phenyl
4-F-phenyl
V = 3-CH3, Y = -CH=N-N(CH3)-
Z
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF3-phenyl 4-CF3-phenyl 3-OCF3-phenyl
4-OCF3-phenyl 2-naphthalenyl 4-/-Bu-phenyl
4-Me-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl
4-CF -2-pyridinyl 5-CF3-2-pyridinyl 6-CF -2-pyridinyl
4,6-diMe-2-pyridinyl 4-CF3-2-pyrimidinyl
V = 3-CH3, Y = -CH2OC(SMe)=N-
Z Z
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl 3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl 2-naphthalenyl 6-Me-2-pyridinyl 4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-CF3-2-pyridinyl 5-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = 3-CH3, Y = -CH2OC(=S)NMe-
4-CF3 -phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-ρhenyl
3,5-diCl-phenyl 3-Me-phenyl 4-Me-phenyl
3,5-diMe-phenyl 2-naρhthalenyl 6-Me-2-ρyridinyl
4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-CF3-2-pyridinyl
5-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = 3-CH3, Y = -SCH2- Z
2-Me-phenyl 2,5-diMe-phenyl 3-CF3-phenyl
4-CF3-phenyl 4-Me-phenyl 4-/-Bu-phenyl
3-Cl-phenyl 4-Cl-phenyl 2-Me-5-Cl-phenyl
3-/-Bu-phenyl 2-naphthaleny I 1-naphthalenyl
3-pyridinyl 4-pyridinyl 6-Me-2-pyridinyl
2-(5,6,7,8-tetrahydro)naphthalenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = 3-CH3
Y Z Y Z
-CH20-N=C(SCH3)- 3-CF3-phenyl -CH20-N=C(cyclopropyl)- 3-CF3 -phenyl
-CH20-N=C(SCH3)- 3-OCF3-phenyl -CH20-N=C(cyclopropyl)- 3-OCF3-phenyl
-CH20-N=C(SCH3> 3-Me-phenyl -CH20-N=C(cyclopropyl)- 3-Me-phenyl
-CH20-N=C(SCH3)- 4-CF3-phenyl -CH20-N=C(cyclopropyl)- 4-CF3-phenyl
-CH20-N=C(SCH3)- 4-OCF3-phenyl -CH20-N=C(cyclopropyl)- 4-OCF3-phenyl
-CH20-N=C(SCH3)- 4-Me-phenyl -CH20-N=C(cyclopropyl)- 4-Me-phenyl
-CH20-N=C(SCH3)- 3-Cl-phenyl -CH20-N=C(cyclopropyl)- 3-Cl-ρhenyl
-CH20-N=C(SCH3)- 3,5-diCl-phenyl -CH20-N=C(cyclopropyl)- 3,5-diCl-phenyl Table l ie
V = 4-CH3, Y = -0-
Z Phenyl 3-OMe-phenyl 4-CF3-phenyl 3-Me-phenyl 3-F-phenyl 3-OCF3-phenyl 4-Me-phenyl 3-SCHF2-phenyl 3-SCH3-phenyl 2-Me-phenyl 4-SCHF2-phenyl 4-SCH3-phenyl 3-cyclohexyl-phenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl 5-CF3-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl 4-Me-2-pyridinyl 2-(5,6,7,8-tetrahydro)naphthalenyl 2-(3,3,3-trifluoroethoxyl)-4- 6-(3 ,3 ,3-trifluoroethoxyl)-4- 4-(3,3,3-trifluoroethoxyl)-2- pyrimidinyl pyrimidinyl pyrimidinyl 3,5-diMe-phenyl 2-naphthalenyl 4-/-Bu-phenyl 4-OCF3-phenyl 3-/-Bu-phenyl 4-SCF3-phenyl 6-(3,3,3-trifluoroethoxyl)-2- 3-SCF3-phenyl 4,6-diMe-2-pyridinyl pyrazinyl 4-CF3-6-Me-2-pyridinyl 3,5-di(CF3)-phenyl 3-CF3-phenyl 3-I-phenyl 3-( 1 -propynyl)-phenyl 3-(3,3-diMe-l-butynyl)- 3-(2-cyclopropylethynyl)phenyl phenyl
V = 4-CH3, Y = -CH20-
Z phenyl 3-CF3-phenyl 2-Me-5-/Pr-phenyl
2-Me-4-OCH3-ρhenyl 4-OCF3-phenyl 2-Me-5-CF3-phenyl 3-OCHF2-phenyl 4-OCHF2-phenyl 3,5-di(CF3)-phenyl 2-Me-4-OCHF2-phenyl 6-CF3-2-pyridinyl 3-OCF3-phenyl 4-CF3-2-pyridinyl 4-Me-2-pyridinyl 2-Me-4-OCF3-phenyl 5-Me-2-pyridinyl 3,6-diMe-2-pyridinyl 5-CF3-2-pyridinyl 4,6-diMe-2-pyridinyl 6-OCF -2-pyridinyl 4-CF3-6-Me-2-pyridinyl 3-Me-2-pyridinyl 4-Cl-2-pyrimidinyl 6-Me-2-pyridinyl 4-Cl-2-pyrimidinyl 3-Et-ρhenyl 2,6-Me -4-pyridinyl 2,4,6-triMe-phenyl 3-Cl-2-pyridinyl 6-Cl-4-pyrimidinyl 1-napthalenyl 2,3,6-triMe-phenyl 6-Cl-2-pyrazinyl 4-CF3-2-pyrimidinyl 6-CF3-4-pyrimidinyl 2-;'Pr-phenyl 3-Me-2-pyridinyl 4-Cl-2-pyridinyl 2-Me-phenyl 2,5-diMe-phenyl 2,4-diCl-phenyl 2-Me-4-Cl-phenyl 2-Cl-phenyl 2,4-diMe-phenyl 2,5-diCl-phenyl 4-CF3-5-Br-2-thiazolyl l-Ph-l//-pyrazol-3-yl 1 -(4-Cl-Ph)- 1 //-pyrazol-3-yl 1 -(4-Me-Ph)- 1 / -pyrazol-3-y 1 l-(3-Me-Ph)- l.Y-pyrazol-3-yl l-Ph-l - l,2,4-triazol-3-yl 1 -(4-Cl-Ph)- \H- 1 ,2,4-triazol-3-yl l-(4-Me-Ph)-l/Y- l,2-4-triazol-3-yl 1 -(3-Me-Ph)- IH- 1 ,2,4-triazol-3-yl
V = 4-CH3, Y = -OCH2-
Z 2-Me-phenyl 2,5-diMe-phenyl 3-CF3-phenyl 4-CF3-phenyl 4-Me-phenyl 4-/-Bu-phenyl 3-Cl-phenyl 4-Cl-phenyl 2-Me-5-Cl-phenyl 3-/-Bu-phenyl 2-naphthalenyl 1-naphthalenyl 3-pyridinyl 4-pyridinyl 6-Me-2-pyridinyl 2-(5,6,7,8 tetrahydro)naphthalenyl
V = 4-CH3, Y = -CH20-N=C(CH3)-
Z 3-Me-phenyl 4-CF3-phenyl 3,5-diMe-phenyl 3-Cl-phenyl 4-Br-phenyl 3,5-di(CF3)-phenyl 4-OCHF -phenyl 4-/-Bu-phenyl 3-/-Bu-phenyl 5-CF3-2-pyridinyl 4-OCF3-phenyl 3-OCHF2-phenyl 5-Me-2- pyridinyl 4-CF3-6-Me-2-pyridinyl 4-Me-2- pyridinyl 4,6-diMe-2-pyridinyl 6-Me-2-pyridinyl 6-CF3-2-pyridinyl 6-OMe-2-pyridinyl 2,6-Me2-4-pyridinyl 2,6-diCl-4-pyridinyl 5-OCF3-2-pyridinyl 4-OMe-2-pyridinyl 4-OCF3-2-pyridinyl 5-OCHF2-2-pyridinyl 6-OCF3-2-pyridinyl 4-OCHF2-pyridinyl 3-(3,3,3 trifluoroethoxy)-phenyl 6-OCHF -2-pyridinyl 3-Et-phenyl 1-naphthalenyl 2-( l,2,3,4-tetrahydro)naphthalenyl /-Bu 3-SMe-phenyl 3-ethynyl-phenyl 3-CF3-phenyl 3,5-diCl-phenyl 3-OCF3-phenyl 4-CF3-2-pyridinyl 4-CF3-6-Cl-2-pyridinyl
V = 4-CH3, Y = -CH=NOCH(CH3)-
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl
4-Me-phenyl 2-naphthalenyl 4-OCHF2-phenyl
3-OCHF2-phenyl 4-CF3-2-pyridinyl 5-CF3-2-pyridinyl
6-CF3-2-pyridinyl 4-Me-2-pyridinyl 5-Me-2-pyridinyl [41
6-Me-2-pyridinyl 4-CF3-6-Me-2-pyridinyl 4-OCF3-2-pyridinyl 5-OCF3-2-pyridinyl 6-OCF3-2-pyridinyl 4-OCHF2-2-pyridinyl 5-OCHF2-2-pyridinyl 6-OCHF2-2-pyridinyl 3-/-Bu-phenyl 4-/-Bu-ρhenyl
V = 4-CH3, Y = -CH2-SC(Et)=N-
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl
4-Me-phenyl 3,5-diMe-phenyl 2-naphthalenyl
6-Me-2-pyridinyl 4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl
5-Cl-2-pyridinyl 4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl
5-CF3-2-pyridinyl 5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl
V = 4-CH3, Y = -CH2-SC(=S)NMe-
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl
4-Me-phenyl 3,5-diMe-phenyl 2-naphthalenyl
6-Me-2-pyridinyl 4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl
5-Cl-2-pyridinyl 4,6-diCl-2-pyridinyl 5-Me-2-ρyridinyl
5-CF3-2-pyridinyl 5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl
V = 4-CH3, Y = -CH2SC(SMe)=N-
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF -phenyl 4-CF3-phenyl 3-OCF3-phenyl
4-OCF3-phenyl 3,5-di(CF3)-phenyl CH2CH2-/-Bu
/-Bu 2-naphthalenyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 4,6-diMe-2 -pyridinyl 5-Cl-2-pyridinyl
4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl 5-CF3-2-pyridinyl
5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl V = 4-CH3, Y = -CH2S-
2-Me-phenyl 3-CF3-phenyl 4-CF3 -phenyl
2,5-diMe-phenyl 2-Et-ρhenyl 3-Cl-phenyl
2-Cl-phenyl 2,5-diCl-phenyl 4,6-diMe-2-pyrimidinyl
4-Me- l,2,4-triazol-3-yl 2-naphthalenyl l-Me-2-imidazolyl
4-Me-2-pyrimidinyl 5-Me- 1 ,3,4-thiadiazol-2-yl 4-CF3-2-pyridinyl
4-Ph-5-Me-2-thiazolyl
V = 4-CH3, Y = -CH2ON=C(CH3)CH2S-
3-Me-phenyl 2-Me-phenyl 3-CF3-phenyl
4-CF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
2-Et-phenyl 2,5-diMe-phenyl 2-naphthalenyl
V = 4-CH3, Y = -CH2ON=C(CH3)CH20-
3-Me-phenyl 2-Me-phenyl 4-Me-ρhenyl
3-CF3-phenyl 4-CF3-phenyl 4-Cl-phenyl
3-Cl-phenyl 3,5-diMe-phenyl 2,5-diMe-phenyl
2-Me-5-/Pr-phenyl 3-Et-phenyl 6-CF3-2-pyridinyl
4-CF3 -2-pyridinyl 5-CF3-2-pyridinyl 6-Me-2-pyridinyl
5-Me-2-pyridinyl 4-Me-2-pyridinyl 1-naphthalenyl
2-naphthalenyl
V = 4-CH3, Y = -CH2CH2-
2-Me-phenyl 2,5-diMe-phenyl 3-CF3-phenyl 4-CF3-phenyl 3-Cl-phenyl 4-Cl-phenyl 3-OCF3-phenyl 4-OCF3-ρhenyl 2-Et-phenyl 2-Me-5-Cl-phenyl 2-naphthalenyl 3,6-diMe-2 -pyridinyl
V = 4-CH3, Y = -CH=C(CH3)-
Z Z
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phcnyl 3-OCF3-phenyl
4-OCF3-phenyI 3-CF3-phenyl 4-CF3-phenyl
2-naphthalenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl V = 4-CH3, Y = -CH=N-N=C(CH3)-
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl
4-CF3-ρhenyl 3-OCF3-phenyl 4-OCF3-phenyl
3,5-diMe-ρhenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 4-CF3-2-pyridinyl 5-CF3-2-pyridinyl
6-CF3-2-pyridinyl 4-Me-2-pyridinyl 5-Me-2-pyridinyl
6-Me-2-pyridinyl 2-naphthalenyl 4,6-diMe-2-pyridinyl
3-Et-ρhenyl /-Bu Phenyl
V = 4-CH3, Y = -CH2ON=C(CH3)C(=NOCH3)-
Z
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF3-phenyl 4-CF3-phenyl 3,5-di(CF3)-phenyl
3-OCF3-phenyl 4-OCF3-phenyl CH3
/-Bu 2-naphthalenyl 4-/-Bu-phenyl
4-Me-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl
4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-CF3-2-pyridinyl
4,6-diMe-2-pyridinyl 4-CF3 -2-pyrimidinyl 6-CF3-2-pyrimidinyl
Phenyl 4-Br-phenyl 4-I-phenyl
4-F-phenyl
V = 4-CH3, Y = -CH=N-N(CH3)-
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF3-phenyl 4-CF3-phenyl 3-OCF3-phenyl
4-OCF3-phenyl 2-naphthalenyl 4-/-Bu-phenyl
4-Me-2 -pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl
4-CF3-2-pyridinyl 5-CF -2-pyridinyl 6-CF3-2-pyridinyl
4,6-diMe-2-pyridinyl 4-CF3-2-pyrimidinyl
V = 4-CH3, Y = -CH2OC(SMe)=N-
Z Z
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl Z Z
3,5-diCl-phenyl 3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl 2-naphthalenyl 6-Me-2-pyridinyl 4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-CF3-2-pyridinyl 5-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = 4-CH3, Y = -CH2OC(=S)NMe-
4-CF -phenyl 3-CF3-ρhenyl 4-OCF3-phenyl
3-OCF3 -phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Me-phenyl 4-Me-phenyl
3,5-diMe-phenyl 2-naphthalenyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-CF3-2-pyridinyl
5-Me-2-pyridinyl 4-CF -2-pyridinyl 6-CF3-2-pyridinyl
V = 4-CH3, Y = -SCH2-
2-Me-phenyl 2,5-diMe-phenyl 3-CF3-phenyl
4-CF3-phenyl 4-Me-phenyl 4-/-Bu-phenyl
3-Cl-phenyl 4-Cl-phenyl 2-Me-5-Cl-phenyl
3-/-Bu-ρhenyl 2-naphthalenyl 1-naphthalenyl
3-pyridinyl 4-pyridinyl 6-Me-2-pyridinyl
2-(5,6,7,8-tetrahydro)naphthalenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = 4-CH3 z
-CH20-N=C(SCH3)- 3-CF3-phenyl -CH20-N=C(cyclopropyl)- 3-CF3-phenyl
-CH20-N=C(SCH3)- 3-OCF3-phenyl -CH 0-N=C(cyclopropyl)- 3-0CF3-phenyl
-CH20-N=C(SCH3 3-Me-phenyl -CH20-N=C(cyclopropyl)- 3-Me-phenyl
-CH20-N=C(SCH3)- 4-CF3-ρhenyl -CH20-N=C(cyclopropyl)- 4-CF3-phenyl
-CH20-N=C(SCH3)- 4-OCF3-phenyl -CH20-N=C(cyclopropyl)- 4-OCF3-phenyl
-CH20-N=C(SCH3)- 4-Me-phenyl -CH20-N=C(cyclopropyl)- 4-Me-phenyl
-CH20-N=C(SCH3)- 3-Cl-phenyl -CH20-N=C(cyclopropyl)- 3-Cl-phenyl
-CH20-N=C(SCH3)- 3,5-diCl-phenyl -CH20-N=C(cyclopropyl)- 3,5-diCl-phenyl Structure for Tables 12a, 12b and 12c
Figure imgf000147_0001
Table 12a
V = H
Bl R? R Bl
3-Me-phenyl 4- Me-phenyl 3-CF3-phenyl 4-CF -phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-ρhenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C__CH-phenyl 4-C-_CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
Table 12b
V = 3-CH3
Bl R? R9 Bl
3-Me-phenyl 4- Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-ρhenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-ρhenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
Table 12c
V = 4-CH3
Bl R? R9 Bl
3 -Me-phenyl 4- Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl E£ Bl Bl Bl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
Figure imgf000148_0001
Table 13a
V = H, R10 = H
E? E__ E Bl
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 I Br
V = H, R10 = Br
Bl R9 R9 Bl
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3>phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-ρhenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3 -phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C__CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cycloρropyl-phenyl
H CH3 I Br [47
V = H. R 10 = CH3
Bl E_! Bl E
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3 -phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phe.nyl
H CH3 Br
V = H, R10 = I
Bl Bl E.. Bl 3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl 3-OCF3-phenyl 4-OCF3-ρhenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl 3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl 3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl 3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C__CH-phenyl /-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl H CH3 I Br
Table 13b
V = 3-CH3, R10 = H
Bl Bl E_! Bl 3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl 3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl 3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl 3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-ρhenyl 3-Cl-4-Me-phenyl 3,4-diCl-ρhenyl 3-Br-phenyl 3-SMe-phenyl 4-SMe-phenyl 3-C=CH-phenyl 4-C≡CH-phenyl /-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-ρhenyl H CH3 Br
V = 3-CH3, R10 = Br Er. Bl Bl Bl
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF -phenyl 3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl E£ Bl Er! Bl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF -phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-ρhenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3
V = 3-CH3, R10 = CH3
Bl Bl Bl Bl
3-Me-ρhenyl 4-Me-phenyl 3-CF3-phenyl 4-CF -phenyl
3-OCF3-phenyl 4-OCF3 -phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 I Br
V = 3-CH3, R10 = I
E_! Bl Er! Er!
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3-ρhenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF -phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-ρhenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-ρhenyl
H CH3 I Br
Table 13c
V = 4-CH3, R10 = H
E£ Er! Bl Er!
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl E_! Er! Er! Er!
3-S Me-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 I Br
V = 4-CH3, R10 = Br
Er! Er! Er! Er!
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3-ρhenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-ρhenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-ρhenyl 4-SMe-phenyl 3-C__CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 Br
V = 4-CH3, R10 = CH3
Er! Bl Er! Bl
3-Me-phenyl 4-Me-ρhenyl 3-CF3-phenyl 4-CF3 -phenyl
3-OCF3 -phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF -phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-ρhenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 I Br
V = 4-CH3, R10 = I
Bl Bl Er! Er!
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3 -phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C__CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cycloρropyl-phenyl
H CH3 I Br Structure for Tables 14a, 14b and 14c
Figure imgf000152_0001
Table 14a
V = H
Ell R13 R12 Ell R12 EH
H 2'- CN 2'-F 4',6,-diF 2'-Cl 6'-Cl
2'-Me H 2'-F y,'5,6'-tήF 2'-F 5'-F
2'-Cl H 2'-Cl 4',6'-diF 2'-F 6'-F
2'-F H 4'-Br 2',6'-diF 2'-F 4'-F
2'-OMe H 4'-I 2',6'-diF 2'-Et H
2'-Br H 2'-F 3',6'-diF 4'-Me 2',6'-diCl
2'-SMe H 2'-F 4',5'-diF 4'-Me 2',6'-diF
Table 14b
Figure imgf000152_0002
Table 14c
V = 4-CH3
Ell I 13 R 12 Ell R 12 R 13
H 2'-CN 2'-F 4',6'-diF 2'-Cl 6'-Cl
2'-Me H 2'-F 3,,5',6,-triF 2'-F 5'-F
2'-Cl H 2'-Cl 4'.6'-diF 2'-F 6'-F
2'-F H 4'-Br 2',6'-diF 2'-F 4'-F
2'-OMe H 4'-I 2',6'-diF 2'-Et H 2'- 2'-
Figure imgf000153_0001
Structure for Tables 15a, 15b and 15c
Figure imgf000153_0002
Table 15a
V = H
Ell R 13 R 12 Ell R12 Ell H 2'-CN 2'-F 4',6'-diF 2'-Cl 6*-Cl
2'-Me H 2'-F 375,6'--riF 2'-F 5'-F 2'-Cl H 2'-Cl 4',6'-diF 2'-F 6'-F 2'-F H 4'-Br 2',6 -diF 2'-F 4'-F 2'-OMe H 4'-I 2',6'-diF 2'-Et H 2'-Br H 2'-F 3',6'-diF 4"-Me 2\6'-diCl 2'-SMe H 2'-F 4',5'-diF 4'-Me 2',6'-diF
Table 15b
V = 3-CH3
R12 I .13 R12 R13 .12 Ell
H 2'-CN 2'-F 4',6'-diF 2'-Cl 6'-Cl
2'-Me H 2'-F 3',5',&-tήΕ 2'-F 5'-F
2'-Cl H 2'-Cl 4',6'-diF 2'-F 6'-F
2'-F H 4'-Br 2',6'-diF 2'-F 4'-F
2'-OMe H 4'-I 2',6'-diF 2'-Et H
2'-Br H 2'-F 3',6'-diF 4'-Me 2,,6'-diCl
2'-SMe H 2'-F 4',5'-diF 4'-Me 2',6'-diF Table 15c
Figure imgf000154_0001
Structure for Tables 16a, 16b and 16c
Figure imgf000154_0002
Table 16a
V = H, Y = -O-
Phenyl 3-OMe-phenyl 4-CF3 -phenyl
3-Me-phenyl 3-F-phenyl 3-OCF3-phenyl
4-Me-phenyl 3-SCHF2-phenyl 3-SCH3-phenyl
2-Me-phenyl 4-SCHF2-phenyl 4-SCH3-phenyl
3-cyclohexyl-phenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
5-CF3-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 2-(5,6,7,8-tetrahydro)naphthalenyl 2-(3,3,3-trifluoroethoxyl)-4-
6-(3,3,3-trifluoroethoxyl)-4- 4-(3,3,3-trifluoroethoxyl)-2- pyrimidinyl pyrimidinyl pyrimidinyl 3,5-diMe-phenyl 2-naphthalenyl 4-/-Bu-phenyl 4-OCF3-phenyl 3-/-Bu-phenyl 4-SCF3-phenyl 6-(3,3,3-trifluoroethoxyl)-2- 3-SCF3-phenyl 4,6-diMe-2-pyridinyl pyrazinyl 4-CF3-6-Me-2 -pyridinyl 3,5-di(CF3)-phenyl 3-CF3-phenyl 3-I-phenyl 3-( 1 -propynyl)-phenyl 3-(3,3-diMe-l-butynyl)- 3-(2-cyclopropylethynyl)phenyl phenyl V = H. Y = -CH20-
Z phenyl 3-CF3-phenyl 2-Me-5-;Pr-phenyl
2-Me-4-OCH3-phenyl 4-0CF3-phenyl 2-Me-5-CF3-phenyl 3-OCHF2-phenyl 4-0CHF2-phenyl 3,5-dι(CF3)-phenyl 2-Me-4-0CHF2-phenyl 6-CF3-2-pyπdιnyl 3-OCF3-phenyl 4-CF -2-pyπdιnyl 4-Me-2-pyπdιnyl 2-Me-4-OCF3-phenyl 5-Me-2-pyπdιnyl 3,6-dιMe-2-pyπdmyl 5-CF3-2-pyπdιnyl 4,6-dιMe-2-pyndιnyl 6-OCF3 -2-pyπdιny 1 4-CF3-6-Me-2 -pyridinyl 3-Me-2-pyπdmyl 4-Cl-2-pyπmιdmyl 6-Me-2-pyndmyl 4-Cl-2-ρyπmιdmyl 3-Et-phenyl 2,6-Me2-4-pyndmyl 2,4,6-tπMe-phenyl 3-Cl-2-pyndmyl 6-Cl-4-pyπmιdmyl 1-napthalenyl 2,3,6-tπMe-phenyl 6-Cl-2-pyrazmyl 4-CF3-2-pynmιdmyl 6-CF3-4-pyπmιdmyl 2- Pr-phenyl 3-Me-2-pyπdmyl 4-Cl-2-pyπdmyl 2-Me-phenyl 2,5-dιMe-phenyl 2,4-dιCl-phenyl 2-Me-4-Cl-phenyl 2-Cl-phenyl 2,4-dιMe-phenyl 2,5-dιCl-phenyl 4-CF3-5-Br-2-thιazolyl l-Ph-l /-pyrazol-3-yl l-(4-Cl-Ph)- l_Y-pyrazol-3-yl 1 -(4-Me-Ph)- l_Y-pyrazol-3-yl 1 -(3-Me-Ph)- l_Y-pyrazol-3-yl l-Ph-l/ -l,2,4-tπazol-3-yl 1 -(4-Cl-Ph)- IH- 1 ,2,4-tπazol-3-yl 1 -(4-Me-Ph)- IH- 1 ,2,4-tπazol-3-yl l-(3-Me-Ph)- 1 H- 1 ,2,4-tπazol-3-yl
V = H, Y = -OCH2-
Z 2-Me-phenyl 2,5-dιMe-phenyl 3-CF3-ρhenyl 4-CF3 -phenyl 4-Me-phenyl 4-/-Bu-ρhenyl 3-Cl-phenyl 4-Cl-phenyl 2-Me-5-Cl-phenyl 3-/-Bu-phenyl 2-naρhthalenyl 1-naρhthalenyl 3-pyndmyl 4-pyπdιnyl 6-Me-2-pyπdιnyl 2-(5,6,7,8 tetrahydro)naρhthalenyl
V - H, Y = -CH20-N=C(CH3)-
Z 3-Me-phenyl 4-CF3-phenyl 3,5-dιMe-phenyl 3-Cl-phenyl 4-Br-phenyl 3,5-dι(CF3)-phenyl 4-OCHF2-phenyl 4-/-Bu-phenyl 3-/-Bu-phenyl 5-CF3-2-pyπdmyl 4-OCF3-phenyl 3-OCHF2-phenyl 5-Me-2- pyridinyl 4-CF3-6-Me-2-pyπdιnyl 4-Me-2- pyridinyl 4,6-dιMe-2-pyπdιnyl 6-Me-2-pyndιnyl 6-CF3-2-pyndιnyl 6-OMe-2-pyridinyl 2,6-Me2-4-pyridinyl 2,6-diCl-4-pyridinyl
5-OCF3-2-pyridinyl 4-OMe-2-pyridinyl 4-OCF3-2-pyridinyl
5-OCHF2-2-pyridinyl 6-OCF3-2-pyridinyl 4-OCHF2-pyridinyl
3-(3,3,3 trifluoroethoxy)-phenyl 6-OCHF -2-pyridinyl 3-Et-phenyl
1-naphthalenyl 2-( 1 ,2,3.4-tetrahydro)naphthalenyl /-Bu
3-SMe-phenyl 3-ethynyl-phenyl 3-CF -phenyl
3,5-diCl-phenyl 3-OCF3-phenyl 4-CF3 -2-pyridiny 1
4-CF3-6-Cl-2-pyridinyl
V = H, Y = -CH=NOCH(CH3)-
4-CF -phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl
4-Me-phenyl 2-naphthalenyl 4-OCHF2-phenyl
3-OCHF2-phenyl 4-CF3-2-pyridinyl 5-CF3-2-pyridinyl
6-CF -2-pyridinyl 4-Me-2-pyridinyl 5-Me-2-pyridinyl
6-Me-2-pyridinyl 4-CF3 -6-Me-2-pyridinyl 4-OCF3-2-pyridinyl
5-OCF3-2-pyridinyl 6-OCF3-2-pyridinyl 4-OCHF2-2-pyridinyl
5-OCHF2-2-pyridinyl 6-OCHF2-2-pyridinyl 3-/-Bu-phenyl
4-/-Bu-phenyl
V = H, Y = -CH2-SC(Et)=N-
4-CF3 -phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl
4-Me-phenyl 3,5-diMe-phenyl 2-naphthalenyl
6-Me-2-pyridinyl 4-Me-2-pyridinyl 4, 6-diMe-2-pyridinyl
5-Cl-2-pyridinyl 4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl
5-CF3-2-pyridinyl 5-Br-6-Me-2-pyridinyl 4-CF3 -2-pyridinyl
V = H, Y = -CH2-SC(=S)NMe- z z z
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl Z Z
4-Me-phenyl 3,5-diMe-ρhenyl 2-naphthalenyl 6-Me-2-pyridinyl 4-Me-2-pyridinyl 4.6-diMe-2-pyridinyl 5-Cl-2-pyridinyl 4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl 5-CF3-2-pyridinyl 5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl
V = H, Y = -CH2SC(SMe)=N-
3-Me-phenyl 4-Me-phenyl 3,5-diMe-ρhenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF3-phenyl 4-CF3-phenyl 3-OCF3-ρhenyl
4-OCF3-phenyl 3,5-di(CF3)-phenyl CH2CH2-/-Bu
/-Bu 2-naphthalenyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-Cl-2-pyridinyl
4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl 5-CF3-2-pyridinyl
5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = H, Y = -CH2S-
Z 2-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl 2,5-diMe-phenyl 2-Et-phenyl 3-Cl-ρhenyl 2-Cl-phenyl 2,5-diCl-phenyl 4,6-diMe-2-pyrimidinyl 4-Me- 1 ,2,4-triazol-3-yl 2-naphthalenyl 1 -Me-2-imidazolyl 4-Me-2-pyrimidinyl 5-Me- 1 ,3,4-thiadiazol-2-yl 4-CF3-2-pyridinyl 4-Ph-5-Me-2-thiazolyl
V = H, Y = -CH2ON=C(CH3)CH2S-
Z Z Z
3-Me-phenyl 2-Me-phenyl 3-CF3-phenyl
4-CF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
2-Et-phenyl 2,5-diMe-phenyl 2-naρhthalenyl
V = H, Y = -CH2ON=C(CH3)CH20- z z
3-Me-phenyl 2-Me-phenyl 4-Me-phenyl
3-CF3-phenyl 4-CF3-phenyl 4-Cl-phenyl
3-Cl-phenyl 3,5-diMe-phenyl 2,5-diMe-phenyl
2-Me-5-/Pr-phenyl 3-Et-phenyl 6-CF3-2-pyridinyl Z Z
4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-Me-2-pyridinyl
5-Me-2-pyridinyl 4-Me-2-pyridinyl 1-naphthalenyl
2-naphthalenyl
V = H, Y = -CH2CH2-
2-Me-phenyl 2,5-diMe-phenyl 3-CF3-phenyl 4-CF3-phenyl 3-Cl-phenyl 4-Cl-phenyl 3-OCF3-phenyl 4-OCF3-phenyl 2-Et-phenyl 2-Me-5-Cl-phenyl 2-naphthalenyl 3,6-diMe-2-pyridinyl
V = H, Y = -CH=C(CH3)- z z
3-Me-phenyl 4-Me-ρhenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3-OCF3-phenyl
4-OCF3-ρhenyl 3-CF3-phenyl 4-CF3-phenyl
2-naphthalenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = H, Y = -CH=N-N=C(CH3)-
Z
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl
4-CF3-phenyl 3-OCF3-ρhenyl 4-OCF3-phenyl
3,5-diMe-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 4-CF3-2-pyridinyl 5-CF3-2-pyridinyl
6-CF3-2-pyridinyl 4-Me-2-pyridinyl 5-Me-2-pyridinyl
6-Me-2-pyridinyl 2-naphthalenyl 4, 6-diMe-2-pyridinyl
3-Et-phenyl /-Bu Phenyl
V = H, Y = -CH2ON=C(CH3)C(=NOCH3)-
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF3-phenyl 4-CF3 -phenyl 3,5-di(CF3)-phenyl
3-OCF3-phenyl 4-OCF3-phenyl CH3
/-Bu 2-naphthalenyl 4-/-Bu-phenyl
4-Me-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl
4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-CF3-2-pyridinyl : 57
z z z
4,6-diMe-2-pyridinyl 4-CF3-2-pyrimidinyl 6-CF3-2-pyrimidinyl
Phenyl 4-Br-phenyl 4-I-phenyl 4-F-phenyl
V = H, Y = -CH=N-N(CH3)-
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF3-phenyl 4-CF3 -phenyl 3-OCF3-phenyl
4-OCF3-phenyl 2-naphthalenyl 4-/-Bu-phenyl
4-Me-2 -pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl
4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-CF -2-pyridinyl
4,6-diMe-2-pyridinyl 4-CF3-2-pyrimidinyl
V = H, Y = -CH2OC(SMe)=N-
4-CF3-ρhenyl 3-CF3-ρhenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Me-phenyl 4-Me-phenyl
3,5-diMe-phenyl 2-naphthalenyl 6-Me-2 -pyridinyl
4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-CF3-2-pyridinyl
5-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = H, Y = -CH2OC(=S)NMe-
4-CF3-ρhenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Me-phenyl 4-Me-phenyl
3,5-diMe-phenyl 2-naρhthalenyl 6-Me-2-ρyridinyl
4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-CF3-2-pyridinyl
5-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V - H, Y = -SCH2- Z 2-Me-phenyl 2,5-diMe-phenyl 3-CF3-phenyl 4-CF3-phenyl 4-Me-phenyl 4-/-Bu-phenyl 3-Cl-phenyl 4-Cl-phenyl 2-Me-5-Cl-phenyl [ 58
3-/-Bu-phenyl 2-naphthalenyl 1 -naphthalenyl
3-pyridinyl 4-pyridinyl 6-Me-2-pyridinyl
2-(5,6,7,8-tetrahydro)naphthalenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = H
Y Z Y Z
-CH20-N=C(SCH3)- 3-CF3-phenyl -CH20-N=C(cyclopropyl)- 3-CF3-phenyl
-CH20-N=C(SCH3)- 3-OCF -phenyl -CH20-N=C(cyclopropyl)- 3-OCF3-phenyl
-CH20-N=C(SCH3)- 3-Me-phenyl -CH20-N=C(cyclopropyl)- 3-Me-phenyl
-CH20-N=C(SCH3)- 4-CF3-phenyl -CH20-N=C(cyclopropyl)- 4-CF3-phenyl
-CH20-N=C(SCH3)- 4-OCF3-phenyl -CH20-N=C(cyclopropyl)- 4-OCF3-phenyl
-CH20-N=C(SCH3> 4-Me-phenyl -CH20-N=C(cyclopropyl)- 4-Me-phenyl
-CH20-N=C(SCH3)- 3-Cl-phenyl -CH20-N=C(cyclopropyl)- 3-Cl-phenyl
-CH20-N=C(SCH3)- 3,5-diCl-phenyl -CH20-N=C(cyclopropyl)- 3,5-diCl-phenyl
Table 16b
V = 3-CH3, Y = -0-
Z Z Z
Phenyl 3-OMe-phenyl 4-CF3 -phenyl
3-Me-phenyl 3-F-phenyl 3-OCF3-phenyl
4-Me-phenyl 3-SCHF2-phenyl 3-SCH3-phenyl
2-Me-phenyl 4-SCHF2-phenyl 4-SCH3-phenyl
3-cyclohexyl-phenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
5-CF3-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 2-(5,6,7,8-tetrahydro)naρhthalenyl 2-(3,3,3-trifluoroethoxyl)-4
6-(3 ,3 ,3- trifluoroethoxyι)-4 4-(3,3,3-trifluoroethoxyl)-2- pyrimidinyl pyrimidinyl pyrimidinyl 3,5-diMe-phenyl
2-naphthalenyl 4-/-Bu-phenyl 4-OCF3-phenyl
3-/-Bu-phenyi 4-SCF3-phenyl 6-(3,3,3-trifluoroethoxyl)-2
3-SCF3-phenyl 4,6-diMe-2-pyridinyl pyrazinyl
4-CF3-6-Me-2-pyridinyl 3,5-di(CF3)-phenyl 3-CF3-phenyl
3-I-phenyl 3-(l-propynyl)-phenyl 3-(3,3-diMe-l-butynyl)-
3-(2-cycloproρylethynyl)ph enyl phenyl
V = 3-CH3, Y = -CH20-
Z Z Z phenyl 3-CF3-phenyl 2-Me-5- Pr-phenyl 2-Me-4-OCH3-phenyl 4-OCF3-phenyl 2-Me-5-CF3-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3,5-dι(CF3)-phenyl
2-Me-4-OCHF2-phenyl 6-CF3-2-pyπdιnyl 3-OCF3-phenyl
4-CF3-2-pyπdιnyl 4-Me-2-pyπdιnyl 2-Me-4-OCF3-phenyl
5-Me-2-pyndmyl 3,6-dιMe-2-pyπdιnyl 5-CF3 -2-pyπdιny 1
4,6-dιMe-2-pyπdιnyl 6-OCF3-2-pyπdιnyl 4-CF3-6-Me-2-pyπdmyl
3-Me-2-pyπdmyl 4-Cl-2-pyrιmιdmyl 6-Me-2-pyπdιnyl
4-Cl-2-ρyrιmιdιnyl 3-Et-phenyl 2,6-Me2-4-pyπdιnyl
2,4,6-tπMe-phenyl 3-Cl-2-pyndmyl 6-Cl-4-pyπmιdmyl
1-napthalenyl 2,3,6-tπMe-phenyl 6-Cl-2-pyrazmyl
4-CF3-2-pyπmιdmyl 6-CF3-4-pynmιdmyl 2-τPr-phenyl
3-Me-2-pyπdmyl 4-Cl-2-pyπdmyl 2-Me-phenyl
2,5-dιMe-phenyl 2,4-dιCl-ρhenyl 2-Me-4-Cl-phenyl
2-Cl-phenyl 2,4-dιMe-phenyl 2,5-dιCl-phenyl
4-CF3-5-Br-2-thιazolyl l-Ph-l/ -pyrazol-3-yl l-(4-Cl-Ph)-l -pyrazol-3-yl l-(4-Me-Ph)-ltf-pyrazol-3-yl 1 -(3-Me-Ph)- ltf-pyrazol-3-yl 1-Ph- 1H-1 ,2,4-tπazol-3-yl l-(4-Cl-Ph)- IH- 1 ,2,4-tπazol-3-yl 1 -(4-Me-Ph)- IH- 1 ,2,4-tπazol-3-yl 1 -(3-Me-Ph)- IH- 1 ,2,4-tπazol-3-yl
V = 3-CH3, Y = -OCH2-
Z 2-Me-phenyl 2,5-dιMe-phenyl 3-CF3-phenyl 4-CF3 -phenyl 4-Me-phenyl 4-/-Bu-phenyl 3-Cl-phenyl 4-Cl-phenyl 2-Me-5-Cl-phenyl 3-/-Bu-phenyl 2-naphthalenyl 1-naρhthalenyl 3-pyndιnyl 4-pyndmyl 6-Me-2-pyndmyl 2-(5,6,7,8 tetrahydro)naphthalenyl
V = 3-CH3, Y - -CH20-N=C(CH3)-
3-Me-phenyl 4-CF3-phenyl 3,5-dιMe-phenyl
3-Cl-phenyl 4-Br-phenyl 3,5-dι(CF3)-phenyl
4-OCHF2-phenyl 4-/-Bu-phenyl 3-/-Bu-phenyl
5-CF3-2-pyπdmyl 4-OCF3-phenyl 3-OCHF2-phenyl
5-Me-2- pyndinyl 4-CF3-6-Me-2-pyndιnyl 4-Me-2- pyridmyl
4,6-dιMe-2-pyπdιnyl 6-Me-2-pyndιnyl 6-CF3-2-pyπdmyl
6-OMe-2-pyndιnyl 2,6-Me -4-pyπdιnyl 2,6-dιCl-4-pyπdmyl
5-OCF3-2-pyπdmyl 4-OMe-2-pyπdmyl 4-OCF3-2-pyπdιnyl [ 60
5-OCHF2-2-pyridinyl 6-OCF3-2-pyridinyl 4-OCHF2-pyridinyl
3-(3,3,3 trifluoroethoxy)-phenyl 6-OCHF2-2-pyridinyl 3-Et-phenyl
1-naphthalenyl 2-( 1 ,2,3,4-tetrahydro)naphthaleny 1 /-Bu
3-SMe-phenyl 3-ethynyl-phenyl 3-CF -phenyl
3,5-diCl-phenyl 3-OCF3-phenyl 4-CF -2-pyridinyl
4-CF3-6-Cl-2-pyridinyl
V = 3-CH3, Y = -CH =NOCH(CH3)-
Z 4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl 3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl 4-Me-phenyl 2-naphthalenyl 4-OCHF2-phenyl 3-OCHF2-phenyl 4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-CF3-2-pyridinyl 4-Me-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl 4-CF3-6-Me-2-pyridinyl 4-OCF3-2-pyridinyl 5-OCF3-2-pyridinyl 6-OCF3-2-pyridinyl 4-OCHF2-2-pyridinyl 5-OCHF2-2-pyridinyl 6-OCHF2-2-pyridinyl 3-/-Bu-phenyl 4-/-Bu-phenyl
V = 3-CH3, Y = -CH2-SC(Et)=N-
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl
4-Me-phenyl 3,5-diMe-phenyl 2-naphthalenyl
6-Me-2-pyridinyl 4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl
5-Cl-2-pyridinyl 4,6-diCl-2-pyridinyl 5-Me-2-ρyridinyl
5-CF3-2-pyridinyl 5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl
V = 3-CH3, Y = -CH2-SC(=S)NMe-
Z Z Z
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl
4-Me-phenyl 3,5-diMe-phenyl 2-naphthalenyl Z Z
6-Me-2-pyridinyl 4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl
5-Cl-2-pyridinyl 4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl
5-CF3-2-pyridinyl 5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl
V = 3-CH3, Y = -CH2SC(SMe)=N-
3-Me-phenyl 4-Me-ρhenyl 3.5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF3-phenyl 4-CF3-phenyl 3-OCF3-ρhenyl
4-OCF3-phenyl 3,5-di(CF3)-phenyl CH2CH2-/-Bu
/-Bu 2-naphthalenyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-Cl-2-pyridinyl
4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl 5-CF3-2-pyridinyl
5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = 3-CH3, Y = -CH2S-
2-Me-ρhenyl 3-CF3-phenyl 4-CF3-phenyl
2,5-diMe-phenyl 2-Et-phenyl 3-Cl-ρhenyl
2-Cl-phenyl 2,5-diCl-phenyl 4,6-diMe-2-pyrimidinyl
4-Me- 1 ,2,4-triazol-3-yl 2-naphthalenyl 1 -Me-2-imidazolyl
4-Me-2-pyrimidinyl 5-Me- l,3,4-thiadiazol-2-yl 4-CF3-2-pyridinyl
4-Ph-5-Me-2-thiazolyl
V = 3-CH3, Y = -CH2ON=C(CH3)CH2S-
Z Z Z
3-Me-phenyl 2-Me-phenyl 3-CF3-phenyl
4-CF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
2-Et-phenyl 2,5-diMe-phenyl 2-naphthalenyl
V = 3-CH3, Y = -CH2ON=C(CH3)CH20-
Z Z Z
3-Me-phenyl 2-Me-phenyl 4-Me-phenyl
3-CF3-phenyl 4-CF -phenyl 4-Cl-ρhenyl
3-Cl-phenyl 3,5-diMe-phenyl 2,5-diMe-phenyl
2-Me-5-/Pr-phenyl 3-Et-phenyl 6-CF3-2-pyridinyl Z Z
4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-Me-2-pyridinyl
5-Me-2-pyridinyl 4-Me-2-pyridinyl 1-naphthalenyl
2-naphthalenyl
V = 3-CH3, Y = -CH2CH2-
Z 2-Me-phenyl 2,5-diMe-phenyl 3-CF3-phenyl 4-CF3-phenyl 3-Cl-phenyl 4-Cl-phenyl 3-OCF3-phenyl 4-OCF3-phenyl 2-Et-phenyl 2-Me-5-Cl-phenyl 2-naphthalenyl 3,6-diMe-2-pyridinyl
V = 3-CH3, Y = -CH=C(CH3)- z Z Z
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3-OCF3-phenyl
4-OCF3-phenyl 3-CF3-phenyl 4-CF3-phenyl
2-naphthalenyl 4-CF3-2-ρyridinyl 6-CF3 -2-pyridin)
V = 3-CH3, Y = -CH=N-N=C(CH3
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl
4-CF3-phenyl 3-OCF3-phenyl 4-OCF3-phenyl
3,5-diMe-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 4-CF -2-pyridinyl 5-CF3-2-pyridinyl
6-CF3-2-pyridinyl 4-Me-2-pyridinyl 5-Me-2-pyridinyl
6-Me-2-pyridinyl 2-naphthalenyl 4,6-diMe-2-pyridinyl
3-Et-phenyl /-Bu Phenyl
V = 3-CH3, Y = -CH2ON=C(CH3)C(=NOCH3)-
3-Me-phenyl 4-Me-phenyl 3,5-dLMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF3-ρhenyl 4-CF -phenyl 3,5-di(CF3)-phenyl
3-OCF3-phenyl 4-OCF3-phenyl CH3
/-Bu 2-naphthalenyl 4-/-Bu-phenyl
4-Me-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl
4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-CF3-2-pyridinyl z z z
4,6-diMe-2-pyridinyl 4-CF3-2-pyrimidinyl 6-CF3-2-pyrimidinyl
Phenyl 4-Br-phenyl 4-I-phenyl 4-F-phenyl
V = 3-CH3, Y = -CH=N-N(CH3)-
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF3-phenyl 4-CF3-phenyl 3-OCF3 -phenyl
4-OCF3-phenyl 2-naphthalenyl 4-/-Bu-phenyl
4-Me-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl
4-CF3 -2-pyridiny 1 5-CF3 -2-pyridinyl 6-CF3-2-pyridinyl
4,6-diMe-2-pyridinyl 4-CF3-2-pyrimidinyl
V = 3-CH3, Y = -CH2OC(SMe)=N-
4-CF3-phenyl 3-CF3-ρhenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Me-phenyl 4-Me-phenyl
3,5-diMe-phenyl 2-naρhthalenyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-CF3-2-pyridinyl
5-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = 3-CH3, Y = -CH2OC(=S)NMe-
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-ρhenyl 3-Me-phenyl 4-Me-phenyl
3,5-diMe-phenyl 2-naphthalenyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl 5-CF3-2-ρyridinyl
5-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = 3-CH3, Y = -SCH2-
Z 2-Me-phenyl 2,5-diMe-phenyl 3-CF3-phenyl 4-CF3-phenyl 4-Me-phenyl 4-/-Bu-phenyl 3-Cl-phenyl 4-Cl-phenyl 2-Me-5-Cl-phenyl 3-/-Bu-phenyl 2-naphthalenyl 1-naphthalenyl
3-pyridinyl 4-pyridinyl 6-Me-2-pyridinyl
2-(5,6,7.8-tetrahydro)naphthalenyl 4-CF -2-pyridinyl 6-CF3-2-pyridinyl
V = 3-CH3
Y Y
-CH20-N=C(SCH3)- 3-CF3-phenyl -CH20-N= =C(cycloρropyl)- 3-CF -phenyl
-CH20-N=C(SCH3)- 3-OCF3-phenyl -CH20-N= =C(cyclopropyl)- 3-0CF3-phenyl
-CH20-N=C(SCH3)- 3-Me-phenyl -CH20-N= =C(cyclopropyl)- 3-Me-phenyl
-CH20-N=C(SCH3)- 4-CF3-phenyl -CH20-N= =C(cyclopropyl)- 4-CF3-phenyl
-CH20-N=C(SCH3)- 4-OCF3-phenyl -CH20-N= =C(cyclopropyl)- 4-0CF3-phenyl
-CH20-N=C(SCH3)- 4-Me-phenyl -CH20-N= =C(cyclopropyl)- 4-Me-phenyl
-CH20-N=C(SCH3)- 3-Cl-phenyl -CH20-N= =C(cyclopropyl)- 3-Cl-phenyl
-CH20-N=C(SCH3)- 3,5-diCl-phenyl -CH20-N= =C(cyclopropyl)- 3,5-diCl-phenyl
Table 16c
V = 4-CH3, Y = -O-
Z Z Z
Phenyl 3-OMe-phenyl 4-CF3-phenyl
3-Me-phenyl 3-F-phenyl 3-0CF3-phenyl
4-Me-phenyl 3-SCHF2-phenyl 3-SCH3 -phenyl
2-Me-phenyl 4-SCHF2-phenyl 4-SCH3-phenyl
3-cyclohexyl-phenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
5-CF3-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 2-(5,6,7,8-tetrahydro)naphthalenyl 2-(3, 3,3-trifluoroethoxyl)-4
6-(3 ,3 ,3-trifluoroethoxyl)-4 4-(3,3,3-tri_luoroethoxyl)- 2- pyrimidinyl pyrimidinyl pyrimidinyl 3,5-diMe-phenyl
2-naphthalenyl 4-/-Bu-phenyl 4-OCF3-phenyl
3-/-Bu-phenyl 4-SCF3-phenyl 6-(3,3,3-trifluoroethoxyl)-2-
3-SCF3-phenyl 4,6-diMe-2-pyridinyl pyrazinyl
4-CF3-6-Me-2-pyridinyl 3,5-di(CF3)-phenyl 3-CF3-phenyl
3-I-phenyl 3-( 1 -propynyl)-phenyl 3-(3,3-diMe-l-butynyl)-
3-(2-cyclopropylethynyl)phenyl phenyl
V = 4-CH3, Y = -CH20-
Z Z Z phenyl 3-CF -phenyl 2-Me-5-/Pr-phenyl 2-Me-4-OCH3-phenyl 4-OCF3-phenyl 2-Me-5-CF3-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3,5-di(CF3)-phenyl
2-Me-4-OCHF2-phenyl 6-CF3-2-pyridinyl 3-OCF3-phenyl
4-CF3-2-pyridinyl 4-Me-2-pyridinyl 2-Me-4-OCF3-phenyl
5-Me-2-pyridinyl 3 , 6-diMe-2-pyridiny 1 5-CF3-2-pyridinyl
4,6-diMe-2-pyridinyl 6-OCF3-2-pyridinyl 4-CF3-6-Me-2-pyridinyl
3-Me-2-pyridinyl 4-Cl-2-pyrimidinyl 6-Me-2-pyridinyl
4-Cl-2-pyrimidinyl 3-Et-phenyl 2,6-Me2-4-pyridinyl
2,4,6-triMe-phenyl 3-Cl-2-pyridinyl 6-Cl-4-pyrimidinyl
1-napthalenyl 2,3,6-triMe-phenyl 6-Cl-2-pyrazinyl
4-CF -2-pyrimidinyl 6-CF3-4-pyrimidinyl 2-zPr-phenyl
3-Me-2-pyridinyl 4-Cl-2-pyridinyl 2-Me-phenyl
2,5-diMe-phenyl 2,4-diCl-phenyl 2-Me-4-Cl-phenyl
2-Cl-phenyl 2,4-diMe-phenyl 2,5-diCl-phenyl
4-CF3-5-Br-2-thiazolyl l-Ph-l_¥-pyrazol-3-yl 1 -(4-Cl-Ph)- l -pyrazol-3-yl l-(4-Me-Ph)-l/ -pyrazol-3-yl 1 -(3-Me-Ph)- l_¥-pyrazol-3-yl 1 -Ph- 1 H- 1 ,2,4-triazol-3-yl l-(4-Cl-Ph)- IH- 1 ,2,4-triazol-3-yl 1 -(4-Me-Ph)- IH- 1 ,2,4-triazol-3-yl 1 -(3-Me-Ph)- IH- 1 ,2,4-triazol-3-yl
V = 4-CH3, Y = -OCH2-
2-Me-phenyl 2,5-diMe-phenyl 3-CF3-phenyl
4-CF3 -phenyl 4-Me-ρhenyl 4-/-Bu-phenyl
3-Cl-phenyl 4-Cl-phenyl 2-Me-5-Cl-phenyl
3-/-Bu-phenyl 2-naphthalenyl 1-naphthalenyl
3-pyridinyl 4-pyridinyl 6-Me-2-pyridinyl
2-(5,6,7,8 tetrahydro)naphthalenyl
V = 4-CH3, Y = -CH20-N=C(CH3)-
3-Me-phenyl 4-CF3-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Br-phenyl 3,5-di(CF3)-phenyl
4-OCHF2-phenyl 4-/-Bu-phenyl 3-/-Bu-phenyl
5-CF3-2-pyridinyl 4-OCF3-phenyl 3-OCHF2-phenyl
5-Me-2- pyridinyl 4-CF3 -6-Me-2-pyridiny 1 4-Me-2- pyridinyl
4,6-diMe-2-pyridinyl 6-Me-2-pyridinyl 6-CF -2-pyridinyl
6-OMe-2-pyridinyl 2,6-Me -4-pyridinyl 2,6-diCl-4-pyridinyl
5-OCF3-2-pyridinyl 4-OMe-2-pyridinyl 4-OCF3-2-pyridinyl 5-OCHF2-2-pyridinyl 6-OCF3-2-pyridinyl 4-OCHF2-pyridinyl
3-(3.3,3 trifluoroethoxy)-phenyl 6-OCHF2-2-pyridinyl 3-Et-phenyl
1 -naphthalenyl 2-( l,2,3,4-tetrahydro)naphthalenyl /-Bu
3-SMe-phenyl 3-ethynyl-phenyl 3-CF3-phenyl
3,5-diCl-phenyl 3-OCF3-phenyl 4-CF3-2-pyridinyl
4-CF3-6-Cl-2-pyridinyl
V = 4-CH3, Y = -CH= =NOCH(CH3)-
Z Z 4-CF3-phenyl 3-CF -phenyl 4-OCF3-phenyl 3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl 4-Me-phenyl 2-naphthalenyl 4-OCHF2-phenyl 3-OCHF2-phenyl 4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-CF -2-pyridinyl 4-Me-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl 4-CF3-6-Me-2-pyridinyl 4-OCF3-2-pyridinyl 5-OCF -2-pyridinyl 6-OCF3 -2-pyridinyl 4-OCHF -2-pyridinyl 5-OCHF2-2-pyridinyl 6-OCHF -2-pyridinyl 3-/-Bu-phenyl 4-/-Bu-phenyl
V = 4-CH3, Y = -CH2-SC(Et)=N-
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl
4-Me-phenyl 3,5-diMe-phenyl 2-naphthalenyl
6-Me-2 -pyridinyl 4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl
5-Cl-2-pyridinyl 4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl
5-CF3-2-pyridinyl 5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl
V = 4-CH3, γ = -CH2-SC(=S)NMe- z z z
4-CF3-phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-ρhenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3,5-di(CF3)-phenyl 3-Me-phenyl
4-Me-phenyl 3,5-diMe-phenyl 2-naphthalenyl z z
6-Me-2-pyridinyl 4-Me-2-pyridinyl 4,6-diMe-2-pyridinyl
5-Cl-2-pyridinyl 4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl
5-CF3-2-pyridinyl 5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl
V = 4-CH3, Y = -CH2SC(SMe)=N-
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF3-phenyl 4-CF3-phenyl 3-OCF3-phenyl
4-OCF3-phenyl 3,5-di(CF3)-phenyl CH2CH2-/-Bu
/-Bu 2-naphthalenyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 4,6-diMe-2 -pyridinyl 5-Cl-2-pyridinyl
4,6-diCl-2-pyridinyl 5-Me-2-pyridinyl 5-CF3-2-pyridinyl
5-Br-6-Me-2-pyridinyl 4-CF3-2-pyridinyl 6-CF3 -2-pyridinyl
V = 4-CH3, Y = -CH2S- Z
2-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
2,5-diMe-phenyl 2-Et-phenyl 3-Cl-phenyl
2-Cl-ρhenyl 2,5-diCl-phenyl 4,6-diMe-2-pyrimidinyl
4-Me-l,2,4-triazol-3-yl 2-naphthalenyl 1 -Me-2-imidazolyl
4-Me-2-pyrimidinyl 5-Me- 1 ,3 ,4-thiadiazol-2-yl 4-CF3-2-pyridinyl
4-Ph-5-Me-2-thiazolyl
V = 4-CH3, Y = -CH2ON=C(CH3)CH2S-
Z Z Z
3-Me-phenyl 2-Me-phenyl 3-CF3-phenyl
4-CF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
2-Et-phenyl 2,5-diMe-phenyl 2-naphthalenyl
V = 4-CH3, Y = -CH2ON=C(CH3)CH20-
3-Me-phenyl 2-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl 4-Cl-phenyl 3-Cl-phenyl 3,5-diMe-phenyl 2,5-diMe-phenyl 2-Me-5-;Pr-phenyl 3-Et-phenyl 6-CF3-2-pyridinyl Z Z
4-CF -2-pyridinyl 5-CF3-2-pyridinyl 6-Me-2-pyridinyl
5-Mc-2-pyridinyl 4-Me-2-pyridinyl 1-naphthalenyl
2-naphthalenyl
V = 4-CH3, Y = -CH2CH2-
2-Me-phenyl 2,5-diMe-phenyl 3-CF -phenyl 4-CF3-phenyl 3-Cl-phenyl 4-Cl-phenyl 3-OCF3-phenyl 4-OCF3-phenyl 2-Et-phenyl 2-Me-5-Cl-phenyl 2-naphthalenyl 3,6-diMe-2-pyridinyl
V = 4-CH3, Y = -CH=C(CH3)-
Z Z Z
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3-OCF3-phenyl
4-OCF3-phenyl 3-CF3-phenyl 4-CF3-phenyl
2-naρhthalenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = 4-CH3, Y = -CH=N-N=C(CH3)- z Z
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl
4-CF -phenyl 3-OCF3-phenyl 4-OCF3-phenyl
3,5-diMe-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 4-CF3-2-pyridinyl 5-CF3-2-pyridinyl
6-CF3-2-pyridinyl 4-Me-2-pyridinyl 5-Me-2-ρyridinyl
6-Me-2-pyridinyl 2-naphthalenyl 4,6-diMe-2-ρyridinyl
3-Et-phenyl /-Bu Phenyl
V = 4-CH3, Y = -CH2ON=C(CH3)C(=NOCH3
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-ρhenyl
3-CF3-phenyl 4-CF3-phenyl 3,5-di(CF3)-phenyl
3-OCF3-phenyl 4-OCF3 -phenyl CH3
/-Bu 2-naphthalenyl 4-/-Bu-phenyl
4-Me-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl
4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-CF3-2-pyridinyl z z
4,6-dιMe-2-pyπdmyl 4-CF3-2-pyπmιdmyl 6-CF3-2-pynmιdmyl
Phenyl 4-Br-phenyl 4-I-phenyl 4-F-phenyl
V = 4-CH3, Y = -CH=N-N(CH3>
Z 3-Me-phenyl 4-Me-phenyl 3,5-dιMe-phenyl 3-Cl-phenyl 4-Cl-phenyl 3,5-dιCl-phenyl 3-CF3-phenyl 4-CF3-phenyl 3-OCF3-phenyl 4-OCF3-phenyl 2-naphthalenyl 4-/-Bu-phenyl 4-Me-2-pyπdmyl 5-Me-2-pyπdmyl 6-Me-2-pyndmyl 4-CF3-2-pyπdmyl 5-CF3-2-ρyπdιnyl 6-CF3-2-pyndmyl
4,6-dιMe-2-pyπdmyl 4-CF -2-pyπmιdmyl
V = 4-CH3, Y = -CH2OC(SMe)=N-
4-CF3 -phenyl 3-CF3 -phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-dιCl-phenyl 3-Me-phenyl 4-Me-phenyl
3,5-dιMe-phenyl 2-naρhthalenyl 6-Me-2-pyndmyl
4-Me-2-pyπdmyl 4,6-dιMe-2-pyπdmyl 5-CF3-2-pyπdmyl
5-Me-2-pyndmyl 4-CF3-2-pyπdmyl 6-CF3-2-pyπdmyl
V = 4-CH3, Y = -CH2OC(=S)NMe-
4-CF3 -phenyl 3-CF3-phenyl 4-OCF3-phenyl
3-OCF3-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-dιCl-ρhenyl 3-Me-phenyl 4-Me-phenyl
3,5-dιMe-phenyl 2-naphthalenyl 6-Me-2-pyndmyl
4-Me-2-pyndmyl 4,6-dιMe-2-pyπdmyl 5-CF3-2-pyπdιnyl
5-Me-2-pyπdmyl 4-CF3-2-pyπdιnyl 6-CF3-2-pyπdmyl
V = 4-CH3, Y = -SCH2-
Z 2-Me-phenyl 2,5-dιMe-phenyl 3-CF3-phenyl 4-CF3-phenyl 4-Me-phenyl 4-/-Bu-phenyl 3-Cl-phenyl 4-Cl-phenyl 2-Me-5-Cl-phenyl ! 70
3-/-Bu-phenyl 2-naphthalenyl 1-naphthalenyl
3-pyridinyl 4-pyridinyl 6-Me-2-pyridinyI
2-(5,6,7,8-tetrahydro)naphthalenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl
V = 4-CH3
Y
-CH20-N=C(SCH3)- 3-CF3-phenyl _ CH20-N=C(cyclopropyl)- 3-CF3-phenyl
-CH20-N=C(SCH3)- 3-OCF3-phenyl -CH20-N=C(cyclopropyl)- 3-0CF3-phenyl
-CH20-N=C(SCH3)- 3-Me-phenyl -CH20-N=C(cyclopropyl)- 3-Me-phenyl
-CH20-N=C(SCH3)- 4-CF3-phenyl -CH20-N=C(cyclopropyl)- 4-CF3-phenyl
-CH20-N=C(SCH3)- 4-OCF3-phenyl -CH20-N=C(cyclopropyl)- 4-OCF3-phenyl
-CH20-N=C(SCH3)- 4-Me-phenyl -CH20-N=C(cyclopropyl)- 4-Me-phenyl
-CH20-N=C(SCH3)- 3-Cl-phenyl -CH20-N=C(cyclopropyl)- 3-Cl-phenyl
-CH20-N=C(SCH3)- 3,5-diCl-phenyl -CH20-N=C(cyclopropyl)- 3,5-diCl-phenyl
Structure for Tables 17a, 17b and 17c
Figure imgf000172_0001
Table 17a
V = H
Bl Bl E£ Bl
3-Me-ρhenyl 4- Me-phenyl 3-CF3-phenyl 4_CF3-phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-ρhenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C__CH-ρhenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl Table 17b
V = 3-CH3
Bl Bl B ?
3-Me-phenyl 4- Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl .
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
Table 17c
V = 4-CH3
Bl Bl E£ E
3 -Me-phenyl 4- Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3 -phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3 -phenyl
3-SCHF2-phenyl 4-SCHF -phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCI-phenyl 3_Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-ρhenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
Structure for Tables 18a. 18b and 18c
Figure imgf000173_0001
T able 18a
V = H, R , 110 = H
E_! Bl Bl Bl
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF -phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl E__ E__ Bl Bl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 I Br
V = H, R10 = Br
Bl Bl E__ Bl 3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl 3-OCF3 -phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-ρhenyl 3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl 3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl 3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C__CH-phenyl /-Bu CF3 3,5-diF-ρhenyl 3-cyclopropyl-phenyl H CH3 Br
V = H, R10 = CH3
E£ ____: Bl Bl
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 I Br
V = H, R10 = I
Bl Bl Bl s2
3-Me-phenyl 4-Me-ρhenyl 3-CF -phenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-ρhenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-ρhenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 I Br Table 18b
V = 3-CH3, R10 = H s2 E_! Er! Er!
3-Me-phenyl 4-Me-ρhenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3 -phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3 -phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl ' 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl .
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-ρhenyl
H CH3 I Br
V = 3-CH3, R10 = Br
Bl Er! Bl Er!
3-Me-phenyl 4-Me-phenyl 3-CF3 -phenyl 4-CF3-ρhenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-ρhenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3
V = 3-CH3, R10 = CH3
Bl Bl Bl Er!
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-ρhenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyI 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C__CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 I Br
V = 3-CH3, R10 = I
B2 Bl Bl Bl
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl .74
Er! R__ Er! E
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 I Br
Table 18c
V = 4-CH3, R10 = H
Er! Bl Er! Er!
3-Me-ρhenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF -phenyl 3-Cl-ρhenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 I Br
V = 4-CH3, R10 = Br
Bl Bl Bl Bl
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3 -phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-ρhenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3 -phenyl
3-SCHF2-phenyl 4-SCHF -phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-ρhenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 Br
V = 4-CH3, R10 = CH3
Bl Er! Er! Er!
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF3-phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF2-phenyl 4-SCHF2-phenyl 3-Cl-phenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl Bl Er! R? Er!
3-SMe-phenyl 4-SMe-phenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 I Br
V = 4-CH3, R10 = I
Er! Er! Er! Er.
3-Me-phenyl 4-Me-phenyl 3-CF3-phenyl 4-CF -phenyl
3-OCF3-phenyl 4-OCF3-phenyl 3,5-di(CF3)-phenyl 3,5-diMe-phenyl
3-OCHF2-phenyl 4-OCHF2-phenyl 3-SCF3-phenyl 4-SCF3-phenyl
3-SCHF -phenyl 4-SCHF2-phenyl 3-Cl-ρhenyl 4-Cl-phenyl
3,5-diCl-phenyl 3-Cl-4-Me-phenyl 3,4-diCl-phenyl 3-Br-phenyl
3-SMe-phenyl 4-SMe-ρhenyl 3-C≡CH-phenyl 4-C≡CH-phenyl
/-Bu CF3 3,5-diF-phenyl 3-cyclopropyl-phenyl
H CH3 Br
Structure for Tables 19a, 19b and 19c
Figure imgf000177_0001
Table 19a
Figure imgf000177_0002
Table 19b
V = 3-CH3
R12 I R 13 Ri Ell R 12 R13
H 2'-CN 2'-F 4',6'-diF 2'-Cl 6'-Cl
2'-Me H 2"-F 3',5',6'-triF 2'-F 5'-F
2'-Cl H 2'-Cl 4',6'-diF 2'-F 6'-F
2'-F H 4'-Br 2',6'-diF 2'-F 4'-F
2'-0Me H 4'-I 2',6'-diF 2'-Et H
2'-Br H 2'-F 3',6'-diF 4'-Me 2',6'-diCl
2'-SMe H 2'-F 4',5'-diF 4'-Me 2',6'-diF
Table 19c
V = 4-CH3
Ell I R 13 Rl2 Ell R 12 Ell
H 2'-CN 2'-F 4',6'-diF 2'-Cl 6'-Cl
2'-Me H 2'-F 3',5',6'-triF 2'-F 5'-F
2 -C1 H 2'-Cl 4',6'-diF 2'-F 6'-F
2'-F H 4'-Br 2,,6'-diF 2'-F 4'-F
2'-OMe H 4'-I 2',6'-diF 2'-Et H
2'-Br H 2'-F 3',6'-diF 4'-Me 2',6'-diCl
2'-SMe H 2'-F 4',5'-diF 4'-Me 2',6'-diF
Structure for Tables 20a. 20b and 20c
Figure imgf000178_0001
Table 20a
V = H
R12 Ell Eli R13 R12 R 13
H 2'- CN 2'-F ' 4',6'-diF 2'-Cl 6 -C1
2'-Me H 2'-F 3','5,6'-triF 2'-F 5'-F
2'-Cl H 2'-Cl 4',6'-diF 2'-F 6'-F
2'-F H 4'-Br 2',6'-diF 2'-F 4'-F
2'-OMe H 4'-I 2',6'-diF 2'-Et H [ 77
R_2 13 R 12 R13 R 12 Ell 2'-Br H 2'-F 3\6'-diF 4'-Me 2',6'-diCl
2'-SMe H 2--F 4',5'-diF 4'-Me 2',6'-diF
Table 20b
V = 3-CH3
R12 Ell Ell Ell Ell Ell
H 2'- CN 2'-F 4',6'-diF 2'-Cl 6 -C1
2'-Me H 2'-F 3,,5',6'-triF 2'-F 5'-F
2'-Cl H 2'-Cl 4',6'-diF 2'-F 6'-F
2'-F H 4'-Br 2',6'-diF 2'-F 4'-F
2'-OMe H 4'-I 2',6'-diF 2'-Et H
2'-Br H 2'-F 3',6'-diF 4'-Me 2',6'-diCl
2'-SMe H 2'-F 4,,5'-diF 4'-Me 2',6,-diF
Table 20c
Figure imgf000179_0001
Structure for Table 21
Figure imgf000179_0002
V = H, Y = -O-
Phenyl 3-OMe-phenyl 4-CF3-phenyl 3-Me-phenyl 3-F-phenyl 3-OCF3-phenyl 4-Me-phenyl 3-SCHF -phenyl 3-SCH3-phenyl 2-Me-phenyl 4-SCHF2-phenyl 4-SCH3-phenyl 3-cyclohexyl-phenyl 4-CF3-2-pyridinyl 6-CF3-2-pyridinyl 5-CF3-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl 4-Me-2-pyridinyl 2-(5,6,7,8-tetrahydro)naρhthalenyl 2-(3,3,3-trifluoroethoxyl)-4- 6-(3,3,3-trifluoroethoxyl)-4- 4-(3,3,3-trifluoroethoxyl)-2- pyrimidinyl pyrimidinyl pyrimidinyl 3,5-diMe-phenyl 2-naphthalenyl 4-/-Bu-phenyl 4-OCF3-phenyl 3-/-Bu-phenyl 4-SCF3-phenyl 6-(3 ,3 ,3-trifluoroethoxyl)-2- 3-SCF3-phenyl 4,6-diMe-2 -pyridinyl pyrazinyl 4-CF3-6-Me-2-pyridinyl 3,5-di(CF3)-phenyl 3-CF3-phenyl 3-I-phenyl 3-( 1 -propynyl)-phenyl 3-(3,3-diMe-l-butynyl)- 3-(2-cyclopropylethynyl)phenyl phenyl
V = H, Y = -CH20- Z phenyl 3-CF3-phenyl 2-Me-5- Pr-phenyl
2-Me-4-OCH3-phenyl 4-OCF3-phenyl 2-Me-5-CF3-phenyl
3-OCHF -phenyl 4-OCHF2-phenyl 3,5-di(CF3)-phenyl
2-Me-4-OCHF2-phenyl 6-CF3-2-pyridinyl 3-OCF3-phenyl
4-CF3-2-pyridinyl 4-Me-2-pyridinyl 2-Me-4-OCF3-phenyl
5-Me-2-pyridinyl 3,6-diMe-2-pyridinyl 5-CF3-2-pyridinyl
4,6-diMe-2-pyridinyl 6-OCF3-2-pyridinyl 4-CF3-6-Me-2-pyridinyl
3-Me-2-pyridinyl 4-Cl-2-pyrimidinyl 6-Me-2-pyridinyl
4-Cl-2-pyrimidinyl 3-Et-phenyl 2,6-Me2-4-pyridinyl
2,4,6-triMe-phenyl 3-Cl-2-pyridinyl 6-Cl-4-pyrimidinyl
1-napthalenyl 2,3,6-triMe-phenyl 6-Cl-2-pyrazinyl
4-CF3-2-pyrimidinyl 6-CF3-4-pyrimidinyl 2-.Pr-phenyl
3-Me-2-pyridinyl 4-Cl-2-pyridinyl 2-Me-phenyl
2,5-diMe-phenyl 2,4-diCl-phenyl 2-Me-4-Cl-phenyl
2-Cl-ρhenyl 2,4-diMe-phenyl 2,5-diCl-phenyl
4-CF3-5-Br-2-thiazolyl l-Ph-l.Y-pyrazol-3-yl 1 -(4-Cl-Ph)- l /-pyrazol-3-yl l-(4-Me-Ph)-l /-pyrazol-3-yl 1 -(3-Me-Ph)- l.7-pyr__-θl-3-yl 1 -Ph- 1 H- 1 ,2,4-triazol-3-yl
1 -(4-Cl-Ph)- IH- 1 ,2,4-triazol-3-yl l-(4-Me-Ph)- \H- 1 ,2,4-triazol-3-yl 1 -(3-Me-Ph)- \H- 1 ,2,4-triazol-3-yl
V = H, Y = -CH20-N=C(CH3)-
Z 3-Me-phenyl 4-CF3-phenyl 3,5-diMe-phenyl 3-Cl-phenyl 4-Br-phenyl 3,5-di(CF3)-phenyl 4-OCHF2-phenyl 4-/-Bu-phenyl 3-/-Bu-phenyl
5-CF3-2-pyridinyl 4-OCF3-phenyl 3-OCHF2-phenyl
5-Me-2- pyridinyl 4-CF3-6-Me-2-pyridinyl 4-Me-2- pyridinyl
4,6-diMe-2-pyridinyl 6-Me-2-pyridinyl 6-CF3-2-pyridinyl
6-OMe-2-pyridinyl 2,6-Me2-4-pyridinyl 2,6-diCl-4-pyridinyl
5-OCF3-2-pyridinyl 4-OMe-2-pyridinyl 4-OCF3-2-pyridinyl
5-OCHF2-2-pyridinyl 6-OCF3-2-pyridinyl 4-OCHF -pyridinyl
3-(3,3,3 trifluoroethoxy)-phenyl 6-OCHF2-2-pyridinyl 3-Et-phenyl
1-naphthalenyl 2-( 1 ,2,3,4-tetrahydro)naphthalenyl /-Bu
3-SMe-phenyl 3-ethynyl-phenyl 3-CF3-phenyl
3,5-diCl-phenyl 3-OCF3-phenyl 4-CF3-2-pyridinyl
4-CF3-6-Cl-2-pyridinyl
V = H, Y = -CH2ON: =C(CH3)C(=NOCH3)-
Z Z 3-Me-phenyl 4-Me-phenyl 3,5-diMe-ρhenyl 3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl 3-CF3-phenyl 4-CF3-phenyl 3,5-di(CF3)-phenyl 3-OCF3-phenyl 4-OCF3-phenyl CH3 /-Bu 2-naphthalenyl 4-/-Bu-phenyl
4-Me-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl 4-CF3-2-pyridinyl 5-CF3-2-pyridinyl 6-CF3-2-pyridinyl 4,6-diMe-2-pyridinyl 4-CF3-2-pyrimidinyl 6-CF3-2-pyrimidinyl Phenyl 4-Br-phenyl 4-I-phenyl 4-F-phenyl
Structure for Table 22
Figure imgf000181_0001
V = H, Y = -O-
Phenyl 3-OMe-phenyl 4-CF3-phenyl
3-Me-phenyl 3-F-phenyl 3-OCF3-phenyl
4-Me-phenyl 3-SCHF2-phenyl 3-SCH3-phenyl 2-Me-ρhenyl 4-SCHF2-phenyl 4-SCH3-phenyl
3-cyclohexyl-phenyl 4-CF3-2-pyridinyl 6-CF -2-pyridinyl
5-CF3-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl
4-Me-2-pyridinyl 2-(5,6,7,8-tetrahydro)naρhthalenyl 2-(3,3,3-trifluoroethoxyl)-4-
6-(3,3,3-trifluoroethoxyl)-4- 4-(3,3,3-trifluoroethoxyl)-2- pyrimidinyl pyrimidinyl pyrimidinyl 3,5-diMe-phenyl 2-naphthalenyl 4-/-Bu-phenyl 4-OCF3-phenyl 3-/-Bu-phenyl 4-SCF -phenyl 6-(3 ,3 ,3-trifluoroethoxyl)-2- 3-SCF3-phenyl 4,6-diMe-2-pyridinyl pyrazinyl 4-CF3-6-Me-2-ρyridinyl 3,5-di(CF3)-phenyl 3-CF3-phenyl 3-I-phenyl 3-( 1 -propynyl)-phenyl 3-(3,3-diMe-l-butynyl)- 3-(2-cyclopropylethynyl)phenyl phenyl
V = H, Y = -CH20-
Z phenyl 3-CF3-ρhenyl 2-Me-5-zPr-phenyl
2-Me-4-OCH3-phenyl 4-OCF3-phenyl 2-Me-5-CF3-phenyl 3-OCHF2-phenyl 4-OCHF2-phenyl 3,5-di(CF3)-phenyl 2-Me-4-OCHF2-phenyl 6-CF3 -2-pyridinyl 3-OCF3-phenyl 4-CF -2-pyridinyl 4-Me-2-pyridinyl 2-Me-4-OCF3-phenyl 5-Me-2-pyridinyl 3,6-diMe-2-pyridinyl 5-CF3-2-pyridinyl 4,6-diMe-2-pyridinyl 6-OCF3-2-pyridinyl 4-CF3-6-Me-2-pyridinyl 3-Me-2-pyridinyl 4-Cl-2-pyrimidinyl 6-Me-2-pyridinyl 4-Cl-2-pyrimidinyl 3-Et-phenyl 2,6-Me2-4-pyridinyl 2,4,6-triMe-phenyl 3-Cl-2-pyridinyl 6-Cl-4-pyrimidinyl 1-napthalenyl 2,3,6-triMe-phenyl 6-Cl-2-pyrazinyl 4-CF3-2-pyrimidinyl 6-CF -4-pyrimidinyl 2-zPr-ρhenyl 3-Me-2-pyridinyl 4-Cl-2-pyridinyl 2-Me-phenyl 2,5-diMe-phenyl 2,4-diCl-phenyl 2-Me-4-Cl-phenyl 2-Cl-phenyl 2,4-diMe-phenyl 2,5-diCl-phenyl 4-CF3-5-Br-2-thiazolyl l-Ph-l//-pyrazol-3-yl 1 _(4-Cl-Ph)- l/ -pyrazol-3-yl 1 -(4-Me-Ph)- l_ -pyrazol-3-y I 1 -(3-Me-Ph)- l#-pyrazol-3-yl 1 -Ph- 1 H- 1 ,2,4-triazol-3-yl 1 -(4-Cl-Ph)- IH- 1 ,2,4-triazol-3-yl 1 -(4-Me-Ph)- \H- 1 ,2,4-triazol-3-yl 1 -(3-Me-Ph)- IH- 1 ,2,4-triazol-3-yl
V = H, Y = -CH20-N=C(CH3)-
Z 3-Me-phenyl 4-CF3-phenyl 3,5-diMe-phenyl 3-Cl-phenyl 4-Br-phenyl 3,5-di(CF3)-phenyl
4-OCHF2-phenyl 4-/-Bu-phenyl 3-/-Bu-phenyl
5-CF3-2-pyridinyl 4-OCF3-phenyl 3-OCHF2-phenyl
5-Me-2- pyridinyl 4-CF3-6-Me-2-pyridinyl 4-Me-2- pyridinyl
4,6-diMe-2-pyridinyl 6-Me-2-pyridinyl 6-CF3-2-pyridinyl
6-OMe-2-pyridinyl 2,6-Me -4-pyridinyl 2.6-diCl-4-pyridinyl
5-OCF3-2-pyridinyl 4-OMe-2-pyridinyl 4-OCF3-2-pyridinyl
5-OCHF -2-pyridinyl 6-OCF3-2-pyridinyl 4-OCHF2-pyridinyl
3-(3,3,3 trifluoroethoxy)-phenyl 6-OCHF2-2-pyridinyl 3-Et-phenyl
1-naphthalenyl 2-( 1 ,2,3,4-tetrahydro)naphthalenyl /-Bu
3-SMe-phenyl 3-ethynyl-phenyl 3-CF3-phenyl
3,5-diCl-phenyl 3-OCF -phenyl 4-CF3 -2-pyridinyl
4-CF3-6-Cl-2-pyridiny 1
V = H, Y = -CH2ON=C(CH3)C(=NOCH3)-
Z z z
3-Me-phenyl 4-Me-phenyl 3,5-diMe-phenyl
3-Cl-phenyl 4-Cl-phenyl 3,5-diCl-phenyl
3-CF3-phenyl 4-CF3-phenyl 3,5-di(CF3)-phenyl
3-OCF3-phenyl 4-OCF3-phenyl CH3
/-Bu 2-naphthalenyl 4-/-Bu-phenyl
4-Me-2-pyridinyl 5-Me-2-pyridinyl 6-Me-2-pyridinyl
4-CF3-2-ρyridinyl 5-CF3-2-pyridinyl 6-CF3-2-pyridinyl
4,6-diMe-2-pyridinyl 4-CF3-2-pyrimidinyl 6-CF3-2-pyrimidinyl
Phenyl 4-Br-phenyl 4-I-phenyl
4-F-phenyl
Table 23
Figure imgf000183_0001
v ya V ya v ya
H -OH H -CH2C1 H -CH2Br
H -CH(CH3)Br H -CH2I H -CH2OH -CH3 -OH 3-CH3 -CH2C1 3-CH3 -CH2Br -CH3 -CH(CH3)Br 3-CH3 -CH2I 3-CH3 -CH2OH -CH3 -OH 4-CH3 -CH2C1 4-CH3 -CH2Br -CH3 -CH(CH3)Br 4-CH3 -CH-.I 4-CH3 -CH2OH
Table 24
Figure imgf000184_0001
V ya v yj» V ya
H -OH H -CH2C1 H -CH2Br
H -CH(CH3)Br H -CH2I H -CH2OH -CH3 -OH 3-CH3 -CH2C1 3-CH3 -CH2Br -CH3 -CH(CH3)Br 3-CH3 -CH2I 3-CH3 -CH2OH
-CH2Br -CH3 -OH 4-CH3 -CH2C1 4-CH3 -CH3 -CH(CH3)Br 4-CH3 -CH2I 4-CH3 -CH2OH
Table 2 5
Figure imgf000184_0002
V X! V γ3 V X
H -OH H -CH2C1 H -CH2Br
H -CH(CH3)Br H -CH2I H -CH2OH -CH3 -OH 3-CH3 -CH2C1 3-CH3 -CH2Br -CH3 -CH(CH3)Br 3-CH3 -CH2I 3-CH3 -CH2OH -CH3 -OH 4-CH3 -CH2C1 4-CH3 -CH2Br -CH3 -CH(CH3)Br 4-CH3 -CH2I 4-CH3 -CH2OH Table 26
Figure imgf000185_0001
Formulation/Utilitv
Compositions of this invention will generally be used as a formulation including an agriculturally suitable carrier comprising at least one of a liquid diluent, a solid diluent or a surfactant. The formulation 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.
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 Water-soluble 5-90 0-94 1-15 Granules, Tablets and Powders.
Suspensions, Emulsions, Solutions 5-50 40-95 0-15 (including Emulsifiable Concentrates)
Dusts 1-25 70-99 0-5
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, rung, 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 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-D.
Example A
Wettable Powder
Compound 5 65.0% dodecylphenol polyethylene glycol ether 2.0% sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0% montmorillonite (calcined) 23.0%.
Example B
Granule
Compound 7 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 7 25.0% anhydrous sodium sulfate 10.0% crude calcium ligninsulfonate 5.0% sodium alkylnaphthalenesulfonate 1.0% calcium magnesium bentonite 59.0%. Example D Emulsifiable Concentrate
Compound 5 20.0% blend of oil soluble sulfonates and polyoxyethylene ethers 10.0% isophorone 70.0%.
The compounds of this invention are useful as plant disease control agents. The present invention therefore further comprises a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof to be protected, or to the plant seed or seedling to be protected, an effective amount of a compound of the invention or a fungicidal composition containing said compound. The compounds and compositions of this invention provide control of diseases caused by a broad spectrum of fungal plant pathogens in the Basidiomycete, Ascomycete, Oomycete and Deuteromycete classes. They are effective in controlling a broad spectrum of plant diseases, particularly foliar pathogens of ornamental, vegetable, field, cereal, and fruit crops. These pathogens include Plasmopara viticola, Phytophthora infestans, Peronospora tabacina, Pseudoperonospora cubensis, Pythium aphanidermatum, Alternaria brassicae, Septoria nodorum, Septoria tritici, Cercosporidium personatum, Cercospora arachidicola, Pseudocercosporella herpotrichoides, Cercospora beticola, Botrytis cinerea, Monilinia fructicola, Pyricularia oryzae, Podosphaera leucotricha, Venturia inaequalis, Erysiphe graminis, Uncinula necatur, Puccinia recondita, Puccinia graminis, Hemileia vastatrix, Puccinia striiformis, Puccinia arachidis, Rhizoctonia solani, Sphaerotheca fuliginea, Fusarium oxysporum, Verticillium dahliae, Pythium aphanidermatum, Phytophthora megasperma, Sclerotinia sclerotiorum, Sclerotium rolfsii, Erysiphe polygon!, Pyrenophora teres, Gaeumannomyces graminis, Rynchosporium secalis, Fusarium roseum, Bremia lactucae and other generea and species closely related to these pathogens.
The compounds of this invention also 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 frugiperda), black bean aphid (Aphis fabae), green peach aphid (Myzus persica), cotton aphid (Aphis gossypii), Russian wheat aphid (Diuraphis noxia), 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 lurida), 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 pacificus, Tetranychus turkestani, Byrobia rubrioculus, Panonychus ulmi, Panonychus citri, Eotetranychus carpini borealis, Eotetranychus, hicoriae, Eotetranychus sexmaculatus, Eotetranychus yumensis,
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, azinphos-methyl, bifenthrin, buprofezin, carbofuran, chlorfenapyr, chlorpyrifos, chlorpyrifos-methyl, cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, deltamethrin, diafenthiuron, diazinon, diflubeπzuron, dimethoate, esfenvalerate, fenoxycarb, fenpropathrin, fenvalerate, fipronil, flucythrinate, tau-fluvalinate, fonophos, imidacloprid, isofenphos, malathion, metaldehyde, methamidophos, methidathion, methomyl, methoprene, methoxychlor, methyl 7-chloro-2,5-dihydro-2-[[N-(methoxycarbonyl)-N-[4- (trifluoromethoxy)phenyl]amino]carbonyl]indeno[ 1 ,2-e][ 1 ,3,4]oxadiazine-4a(3H)- carboxylate (DPX-JW062), monocrotophos, oxamyl, parathion, parathion-methyl, permethrin, phorate, phosalone, phosmet, phosphamidon, pirimicarb, profenofos, rotenone, sulprofos, tebufenozide, tefluthrin, terbufos, tetrachlorvinphos, 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, (S)-3,5-dihydro-5-methyl- 2-(methylthio)-5-phenyl-3-(phenylamino)-4H-imidazol-4-one, dimethomo h, 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, quinoxyfen, 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, Bacillus thuringiensis delta endotoxin, baculovirus, and entomopathogenic bacteria, virus and fungi.
In certain instances, combinations with other fungicides or 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 plant diseases caused by fungal plant pathogens (e.g., lower use rate or broader spectrum of plant pathogens controlled) or resistance management are fungicidal formulations (e.g., mixtures) comprising a composition of this invention including a fungicide selected from the group azoxystrobin, benomyl, carbendazim, carpropamid, copper salts, cymoxanil, cyproconazole, cyprodinil, dimethomorph, epoxiconazole, famoxadone, fenpropidin, fenpropimorph, flusilazole, flutolanil, fosetyl- aluminum, kasugamycin, kresoxim-methyl, mancozeb, metalaxyl, oxadixyl, pencycuron, probenazole, propiconazole, pyroquilon, quinoxyfen, spiroxamine, tricyclazole and validamycin. Specifically preferred mixtures (compound numbers refer to compounds in
Index Tables A-D) are selected from the group: compound 7 and azoxystrobin; compound 7 and benomyl; compound 7 and carbendazim; compound 7 and carpropamid; compound 7 and copper salts; compound 7 and cymoxanil; compound 7 and cyproconazole; compound 7 and cyprodinil; compound 7 and dimethomorph; compound 7 and epoxiconazole; compound 7 and famoxadone; compound 7 and fenpropidin; compound 7 and fenpropimorph; compound 7 and flusilazole; compound 7 and flutolanil; compound 7 and fosetyl-aluminum; compound 7 and kasugamycin; compound 7 and kresoxim-methyl; compound 7 and mancozeb; compound 7 and metalaxyl; compound 7 and oxadixyl; compound 7 and pencycuron; compound 7 and probenazole; compound 7 and propiconazole; compound 7 and pyroquilon; compound 7 and quinoxyfen; compound 7 and spiroxamine; compound 7 and tricyclazole; and compound 7 and validamycin; compound 13 and azoxystrobin; compound 13 and benomyl; compound 13 and carbendazim; compound 13 and carpropamid; compound 13 and copper salts; compound 13 and cymoxanil; compound 13 and cyproconazole; compound 13 and cyprodinil; compound 13 and dimethomorph; compound 13 and epoxiconazole; compound 13 and famoxadone; compound 13 and fenpropidin; compound 13 and fenpropimorph; compound 13 and flusilazole; compound 13 and flutolanil; compound 13 and fosetyl-aluminum; compound 13 and kasugamycin; compound 13 and kresoxim-methyl; compound 13 and mancozeb; compound 13 and metalaxyl; compound 13 and oxadixyl; compound 13 and pencycuron; compound 13 and probenazole; compound 13 and propiconazole; compound 13 and pyroquilon; compound 13 and quinoxyfen; compound 13 and spiroxamine; compound 13 and tricyclazole; and compound 13 and validamycin; compound 21 and azoxystrobin; compound 21 and benomyl; compound 21 and carbendazim; compound 21 and carpropamid; compound 21 and copper salts; compound 21 and cymoxanil; compound 21 and cyproconazole; compound 21 and cyprodinil; compound 21 and dimethomorph; compound 21 and epoxiconazole; compound 21 and famoxadone; compound 21 and fenpropidin; compound 21 and fenpropimorph; compound 21 and flusilazole; compound 21 and flutolanil; compound 21 and fosetyl-aluminum; compound 21 and kasugamycin; compound 21 and kresoxim-methyl; compound 21 and mancozeb; compound 21 and metalaxyl; compound 21 and oxadixyl; compound 21 and pencycuron; compound 21 and probenazole; compound 21 and propiconazole; compound 21 and pyroquilon; compound 21 and quinoxyfen; compound 21 and spiroxamine; compound 21 and tricyclazole; and compound 21 and validamycin; compound 25 and azoxystrobin; compound 25 and benomyl; compound 25 and carbendazim; compound 25 and carpropamid; compound 25 and copper salts; compound 25 and cymoxanil; compound 25 and cyproconazole; compound 25 and cyprodinil; compound 25 and dimethomorph; compound 25 and epoxiconazole; compound 25 and famoxadone; compound 25 and fenpropidin; compound 25 and fenpropimorph; compound 25 and flusilazole; compound 25 and flutolanil; compound 25 and fosetyl-aluminum; compound 25 and kasugamycin; compound 25 and kresoxim-methyl; compound 25 and mancozeb; compound 25 and metalaxyl; compound 25 and oxadixyl; compound 25 and pencycuron; compound 25 and probenazole; compound 25 and propiconazole; compound 25 and pyroquilon; compound 25 and quinoxyfen; compound 25 and spiroxamine; compound 25 and tricyclazole; and compound 25 and validamycin.
Plant disease control is ordinarily accomplished by applying an effective amount of a compound of this invention either pre- or post-infection, to the portion of the plant to be protected such as the roots, stems, foliage, fruit, seeds, tubers or bulbs, or to the media (soil or sand) in which the plants to be protected are growing. The compounds can also be applied to the seed to protect the seed and seedling.
For plant disease control, rates of application for these compounds can be influenced by many factors of the environment and should be determined under actual use conditions. Foliage can normally be protected when treated at a rate of from less than 1 g/ha to
5,000 g/ha of active ingredient. Seed and seedlings can normally be protected when seed is treated at a rate of from 0.1 to 10 g per kilogram of seed.
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 incoφorated into baits that are consumed by the arthropods or in devices such as traps and the like.
For the control arthropod pests, 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 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 pathogens and arthropod pests. For the tests on arthropod pests, "control efficacy" represents inhibition of arthropod development (including mortality) that causes significantly reduced feeding. The pathogen and arthropod pest control protection afforded by the compounds is not limited, however, to these species. See Index Table A-E for compound descriptions. The following abbreviations are used in the Index Tables which follow: Ph = phenyl CH3 = methyl, CF3 = trifluoromethyl and I = iodine. The abbreviation "Ex." stands for "Example" and is followed by a number indicating in which example the compound is prepared. The abbreviation "Compd. No." stands for "Compound Number". The abbreviation "Confϊg." stands for "Configuration".
INDEX TABLE A
Figure imgf000193_0001
Compd. Z mo (°C) Retention Rotation2 % ee Confie.
No. Time3 (MD20)
1 Ex. 1 3-CF3-Ph 9.8 min 97 S
2 Ex. 1 3-CF3-Ph 8.2 min 99 R
3 Ex. 2 3-I-Ph 97-101 12.2 min 99 S
4 Ex. 2 3-I-Ph 97-101 9.9 min 97.5 R
5 Ex. 3 3-(4-CH3-Ph)- •1,2,4- 90-95 8.65 min +23.9 (c = 2.55, 82 S thiadiazol-5-yl CH2C12)
6 Ex. 4 3-(4-CH3-Ph)- 1,2,4- 89-90 7.45 min -25.5 (c = 2.51, 99 R thiadiazol-5-yl CH2C12)
7 Ex. 5 Ph 61-64 12.04 min + 16.78 (c = 2.55, 84 S CH2C12) Compd. mp (°C) Retention Rotation3 % ee Config No. Tιmea (MD20)
Ex. 6 Ph 69-71 9.8 mm • 19.33 (c = 2.55. 99 CH->C1?)
9 Ex. 1A 3 3--CCFF33--PPhh 72-74 9.8 mm 94 S 10 3 3--CCFF33--PPhh 73-75 8.2 min 99 R
1 1 Ex. 7 4-CH3-5-Cl-thιazol- 94-95 13.1 min 98 S
2-yl
12 4-CH3-5-Cl-thiazol- 90-93 10.9 min 99 R
2-yl
13 Ex. 8 4-/-Bu-5-Br-thiazol- 97-99 9.4 min + 15.9 (c = 2.66, 94
2-yl CH2C12)
14 Ex. 9 4-/-Bu-thiazol-2-yl 104-107 10.8 min 97 15 4-(3,5-diF-phenyl)- o oiill** 95
5-Br-thiazol-2-yl
16 4-(3,5-diF-phenyl)- gguumm 1 122..55°° mmmin 95
5-CH3-thiazol-2- yi
17 5-Br-thiazol-2-yl 79-80 14.3 min 95 S 18 4-CH3-Ph 72-76 11.1 min +21.23 (2.52, 97 S CH2C12)
19 4-CH3-Ph 72-77.5 8.8 min -20.7 (2.54, 99 R CH2C12)
20 3-((CH3)3CC__C)-Ph 134-135 +35.0 (1.15, >95 CH2C12) a See Examples for details.
*> 4:1 Hexanes/2-propanol, flow rate 1 mL min.
♦See Index Table D for lR NMR data.
INDEX TABLE B
Figure imgf000195_0001
Compd. Z mn (°C) Retention Rotation3 % ee Confie.
No. Time3 (MD20)
21 Ex. 11 4-CF -2-pyridinyl 126-128 33 min >99 S
22 Ex. 13 4-CF -2-pyridinyl 125-129 5.7 min +65.9 (c = 3.68, 95 S
CH2C12)
23 Ex. 1 1 4-CF3 -2-pyridinyl 39 min 96.5 R
24 Ex. 12 3-CF3-Ph oil* 10.3 min 57.1 (c = 4.98, 96 R CH2C12)
25 Ex. 12 3-CF3-Ph oil* 8.2 min +53 (c = 5.0, 83 S
CH2C12)
See Index Table D for !H NMR data.
INDEX TABLE C
Figure imgf000195_0002
Compd. No. mp (°C) Rotation3 % ee Config.
(MD20)
26 2,5-di(CH3)-Ph 158-160 +54.4 (c = +3.18, >95 CH2C12)
27 2-CH3-5-CH(CH3)2-Ph oil* +49.2 (c = 4.32, >95 CH2C12)
"See Index Table D for lR NMR data.
INDEX TABLE D
Cmpd No. *H NMR Data (CDC13 solution unless indicated otherwise)0
15 δ 7.5 (m, 2H), 7.4 (t, IH), 7.35 (d, IH). 7.25 (d, IH), 6.8 ( . IH), 3.85 (s, 3H), 3.4 (s, 3H), 2.3 (s, 3H) Cmpd No ^H NMR Data (CDCI3 solution unless indicated otherwise)0
16 δ 7.35 (m, 2H), 7.2 (d, IH), 7.15 (m, 2H), 6.75 (m, 1H), 3.85 (s, 3H), 3.4
(s, 3H), 2.5 (s, 3H), 2.3 (s, 3H)
24 δ 7.86 (s, IH), 7.8 (d, IH), 7.6 (d, IH), 7.45 (t, IH), 7.38 (m, 2H), 7.3 (m, IH), 5.18 (ABq, 2H), 3.89 (s. 3H), 3.41 (s, 3H), 2.22 (s, 3H). 2.18 (s. 3H)
25 δ 7.86 (s, IH), 7.8 (d, IH). 7 6 (d, IH), 7.45 (t, IH), 7.38 (m, 2H), 7.3 (m, IH), 5.18 (ABq, 2H), 3.89 (s. 3H), 3 41 (s, 3H), 2.22 (s, 3H). 2.18 (s, 3H)
27 δ 7.45 (d, IH), 7.38 (t, I H), 7.29 (d, IH), 7.05 (d, IH), 6.74 (d, IH), 6.65
(s, IH), 4.96 (ABq, 2H), 3.89 (s, 3H), 3.44 (s, 3H), 2.8 (m, IH), 2.19 (s,
3H), 2.18 (s, 3H), 1.20 (d, 6H) c ^H NMR data are in ppm downfield from tetramethylsilane. Couplings are designated by (s)-singlet, (d)-doublet, (t)-triplet, (q)-quartet, (m)-multiplet, (ABq)-AB quartet, (dd)-doublet of doublets.
BIOLOGICAL EXAMPLES OF THE INVENTION
Test compounds were first dissolved in acetone in an amount equal to 3% of the final volume and then suspended at a concentration of 200 ppm in purified water containing
250 ppm of the surfactant Trem® 014 (polyhydric alcohol esters). The resulting test suspensions were then used in the following tests. Spraying these 200 ppm test suspensions to the point of run-off on the test plants is the equivalent of a rate of 500 g/ha.
TEST A The test suspension was sprayed to the point of run-off on wheat seedlings. The following day the seedlings were inoculated with a spore dust of Erysiphe graminis f sp. tritici, (the causal agent of wheat powdery mildew) and incubated in a growth chamber at 20°C for 7 days, after which disease ratings were made.
TEST B The test suspension was sprayed to the point of run-off on wheat seedlings. The following day the seedlings were inoculated with a spore suspension of Puccinia recondita
(the causal agent of wheat leaf rust) and incubated in a saturated atmosphere at 20°C for
24 h, and then moved to a growth chamber at 20°C for 6 days, after which disease ratings were made. TEST C
The test suspension was sprayed to the point of run-off on rice seedlings. The following day the seedlings were inoculated with a spore suspension of Pyricularia oryzae
(the causal agent of rice blast) and incubated in a saturated atmosphere at 27°C for 24 h, and then moved to a growth chamber at 30°C for 5 days, after which disease ratings were made. TEST D
The test suspension was sprayed to the point of run-off on tomato seedlings. The following day the seedlings were inoculated with a spore suspension of Phytophthora infestans (the causal agent of potato and tomato late blight) and incubated in a saturated atmosphere at 20°C for 24 h. and then moved to a growth chamber at 20°C for 5 days, after which disease ratings were made.
TEST E The test suspension was sprayed to the point of run-off on grape seedlings. The following day the seedlings were inoculated with a spore suspension of Plasmopara viticola (the causal agent of grape downy mildew) and incubated in a saturated atmosphere at 20°C for 24 h, moved to a growth chamber at 20°C for 6 days, and then incubated in a saturated atmosphere at 20°C for 24 h, after which disease ratings were made.
TEST F The test suspension was sprayed to the point of run-off on cucumber seedlings. The following day the seedlings were inoculated with a spore suspension of Botrytis cinerea (the causal agent of gray mold on many crops) and incubated in a saturated atmosphere at 20°C for 48 h, and moved to a growth chamber at 20°C for 5 days, after which disease ratings were made. Results for Tests A-F are given in Table A. In the table, a rating of 100 indicates 100% disease control and a rating of 0 indicates no disease control (relative to the controls). A dash (--) indicates no test results. ND indicates disease control not determined due to phytotoxicity. # indicates significant activity.
Table A
Cmpd No. Test A Test B Test C Test D Test E Test F
1 99#** 94#** - - - -
2 0** 0** - - - -
3 100#** 100# 100# 100# - 83#
4 46** 99# 99# 76 - 0
5 92#** 98#** 96#* ND 100#* 47
6 0** 0** 17* 77# 4* 47
7 100#** 98#** 29* 94# 35** 83#
8 37** 0** 10* 0 1 1** 0
9 99#** 94#** - - - -
10 0** 0** - - - -
1 1 73#*** 99#*** 18* ND 5»»* 82
12 0*** Q*** 0* 43 10*** 0
13 96#* 100#* 88#* ND 100#* 82
14 96#* 100#* 96#* ND 100#* 0
15 96#* 94#* 83#* ND 100#* 94
16 96#* 99#* 98#* ND 100#* 99#
17 94#* 99#* 35* ND 100#* 0
18 98#* 99#* 53#* ND 97#* 83 Cmpd No. Test A Test B Test C Test D Test E Test F
19 0* 9* 0* 98# 7* 0
21 84#* 100#* 99#* - 100#*
23 51 * 96#* 66#* -- 12*
* Tested at 10 ppm. ** Tested at 2 ppm. *** Tested at 0.4 ppm.
TEST G Southern Corn Rootworm
Test units, each consisting of a 230-mL (8-ounce) plastic cup containing a 6.5-cm2
(1 -square-inch) plug of a wheatgerm diet, were prepared. Solutions of each of the test compounds in 75:25 acetone-distilled water solvent were sprayed into the cup. Spraying was accomplished by passing the cup on a conveyer belt directly beneath a flat fan hydraulic nozzle which discharged the spray at a rate of 0.138 kilograms of active ingredient per hectare (about 0.13 pounds per acre) at 207 kPa (30 p.s. ). After the spray on the cups had dried, five second- instar larvae of the southern corn rootworm (Diabrotica undecimpunctata howardi) were placed into each cup. The cups were held at 27°°Cand 50% relative humidity for 48 hours, after which time mortality readings were taken. The same units were read again at 6-8 days for delayed toxicity.
Results for Test G are given in Table B. In Table B, a rating of 100 indicates 100% insect mortality and a rating of 0 indicates no insect mortality (relative to the controls).
Table B
Cmpd No. Test G
7 100
8 0
18 100
19 0
Figure imgf000199_0001
ComDd. ya mo CC) Retention Rotation3 % ee Confie.
No. Time3 ([α]D 20)
28 Ex.4a OH 184 7.10 min -138.6 (c = 5.53, CH2C12) >95 R
29 Ex. 3b OH 178-180 8.5 min M 13.1 (c = 5.53. CH2C12) 86 S
30 Ex. 14 CH2I 92-96 8.7 min + 151.9 (c = 6.1, CH2C12) 92 S
31 Ex. 15 CH2OH 1 19-121 11.4 min H00.3 (c = 4.68, CH2Cl2) >98 s

Claims

CLAIMS What is claimed is:
1. A composition comprising at least one pesticidal compound selected from Formula I, N-oxides and agriculturally suitable salts thereof,
Figure imgf000200_0001
wherein T is
Figure imgf000200_0002
T2 T3
Tl
Figure imgf000200_0003
j4 T5 or j6
V is H, halogen, CrC3 alkyl, CN, NO2 or CrC3 alkoxy;
U is halogen, C C2 alkyl or CpC2 haloalkyl;
YZ is a group consisting of (a) 5 or more atoms independently selected from the group
C, N, O, S, Si and Ge, provided that at least 2 of said atoms are C, and
(b) additional atoms independently selected from H, F, Cl, Br and I; A is O; S; N; NR3; or CR4; G is C or N; provided that when G is C, then A is O, S or NR3 and the floating double bond is attached to G; and when G is N, then A is N or CR4 and the floating double bond is attached to A; W is O or S; X is OR1 ; S(O)mR'; halogen; C,-C6 alkyl; C C6 haloalkyl; C3-C6 cycloalkyl; cyano;
NH2; NHR1; N(CrC6 alkyDR1; NH(CrC6 alkoxy); or N(C,-C6 alkoxy)Ri; R1 is CrC6 alkyl; CrC6 haloalkyl; C2-C6 alkenyl; C2-C6 haloalkenyl; C2-C6 alkynyl;
C2-C6 haloalkynyl; C3-C6 cycloalkyl; C2-C4 alkylcarbonyl; or C -C4 alkoxycarbonyl;
R2 is H; CrC6 alkyl; CrC6 haloalkyl; C2-C6 alkenyl; C2-C6 haloalkenyl; C2-C6 alkynyl; C2-Cβ haloalkynyl; C3-C6 cycloalkyl; C2-C alkylcarbonyl; C2-C4 alkoxycarbonyl; hydroxy; Cj-C alkoxy; or acetyloxy; R3 is H; CrC6 alkyl; CrC6 haloalkyl; C2-C6 alkenyl; C2-C6 haloalkenyl; C2-C6 alkynyl; C2-C6 haloalkynyl; C3-C6 cycloalkyl; C2-C4 alkylcarbonyl; or C2-C4 alkoxycarbonyl; R4 is H; halogen; CrC6 alkyl; CrC6 haloalkyl; C2-C6 alkenyl; C2-C6 haloalkenyl;
C2-Cg alkynyl; C -Cg haloalkynyl; or C3-C6 cycloalkyl; R5 is CrC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2- haloalkynyl or C3-Cg cycloalkyl; each R6 is H, CrC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, C -C4 alkylcarbonyl, C2-C4 alkoxycarbonyl, hydroxy, CrC2 alkoxy or acetyloxy, provided that at least one
R6 is other than hydroxy, Cγ-C2 alkoxy or acetyloxy; m is 0, 1 or 2; and s is 0 or 1 , characterized by: having at least a 20% enantiomeric excess of the structural atropic isomer type with respect to the relative positions of U, T and YZ corresponding to the structural atropic isomer of 2,4-dihydro-5-methoxy-2-methyl-4-[6-methyl-2-[3- (trifluoromethyl)ρhenoxy]phenyl]-3H-l,2,4-triazol-3-one which has the longer retention time in a chiral separation using a column with a chiral stationary phase having R,R configuration and derived from 4-(3,5- dinitrobenzamido)tetrahydrophenanthrene covalently bound to 5 μm 3-propyl silica with a mobile phase employing a solvent consisting of 80% by volume hexane and 20% by volume 2-propanol.
2. A composition of Claim 1 wherein
V is bonded to the 3- or 4-position of the phenyl ring;
Y is -O-; -S(O)n-; -NR15-; -C(=O)-; -CΗ(OR15)-; -CHR8-; -CHR8CHR8-; -CR8=CR8-; -C=C-; -CHR15O-; -OCHR15-; -CHR15S(O)n-; -S(O)nCHR15-; -CHR1 N-;
-CHR15O-N=C(R7)-; -(R7)C=N-OCH(R15)-; -C(R7)=N-O-; -O-N=C(R7)-; -CHR15OC(=O)N(R15)-; -CHR15OC(=S)N(R15)-; -CHR15OC(=O)O-; -CHR15OC(=S)O-; -CHR15OC(=O)S-; -CHR15OC(=S)S-; -CHRl 5SC(=O)N(R15)-; -CHR15SC(=S)N(R15)-; -CHR1 SC(=O)O-; -CHR15SC(=S)O-; -CHR15SC(=O)S-; -CHR15SC(=S)S-; -CHRI 5SC(=NR15)S-; -CHR15N(R15)C(=O)N(Rl )-; -CHR15O-N(R15)C(=O)N(Rl5)-; -CHR 1 O-N(R • 5)C(=S)N(R 15)-; -CHR ' 5O-N=C(R7)NR l 5-; -CHR15O-N=C(R7)OCH2-; -CHR15O-N=C(R7)-N=N-;
-CHR15O-N=C(R7)-C(=O)-; -CHR15O-N=C(R7)-C(=N-OR15)-; -CHR 15O-N=C(R7)-C(R7)=N-A2-A3-; -CHR 15O-N=C(-C(R7)=N-A2-Z ' )-; -CHR15O-N=C(R7)-CH2O-; -CHR15O-N=C(R7)-CH2S-; -O-CH2CH2O-N=C(R7)-; -CHRl5O-C(R15)=C(R7)-; -CHR15O-C(R7)=N-; -CHR15S-C(R7)=N-; -C(R7)=N-NR15-; -CH=N-N=C(R7)-;
-CHRl N(Rl 5)-N=C(R7)-; -CHR » 5N(COCH3)-N=C(R7)-; -OC(=S)NR15C(=O)-; -CHR8-C(=Wl)-A!-; -CHR8CHR8-C(=Wl)-A1-; -CR8=CR8-C(=Wl)-A1-; -C≡C-C(=Wl)-A1-; -N=CR8-C(=Wl)-A1-; or a direct bond; and the directionality of the Y linkage is defined such that the moiety depicted on the left side of the linkage is bonded to the phenyl ring and the moiety on the right side of the linkage is bonded to Z; ZUs H or -A^Z; Wl is O or S;
A1 is O; S; NR15; or a direct bond; A2 is O; NR15; or a direct bond;
A3 is -C(=O)-; -S(O)2-; or a direct bond; each R7 is independently H; CrC6 alkyl; CrC6 haloalkyl; CrC6 alkoxy; CrC6 haloalkoxy; CrC6 alkylthio; CrC6 alkylsulfinyl; C C6 alkylsulfonyl; CrC6 haloalkylthio; CrC6 haloalkylsulfmyl; CrC6 haloalkylsulfonyl; C2-C6 alkenyl; C2-C6 haloalkenyl; C2-C6 alkynyl; C2-C6 haloalkynyl; CyC6 cycloalkyl; C2-C4 alkylcarbonyl; C2-C4 alkoxycarbonyl; halogen; cyano; nitro; hydroxy; amino; NH(CrC6 alkyl); N(CrC6 alkyl)2; or moφholinyl; each R8 is independently H; 1-2 CH3; C2-C3 alkyl; CrC3 alkoxy; C3-C6 cycloalkyl; formylamino; C2-C alkylcarbonylamino; C2-C4 alkoxycarbonylamino; NH2C(O)NH; (CrC3 alkyl)NHC(O)NH; (CrC3 alkyl)2NC(O)NH;
N(CrC3 alkyl)2; piperidinyl; moφholinyl; 1-2 halogen; cyano; or nitro; each Z is independently selected from: i) CrC10 alkyl, C2-C10 alkenyl, and C2-C10 alkynyl each substituted with R9 and optionally substituted with one or more R10; ii) C3-C8 cycloalkyl, C3-C8 cycloalkenyl and phenyl each substituted with R9 and optionally substituted with one or more R10; iii) a ring system selected from 3 to 14-membered monocyclic, fused bicyclic and fused tricyclic nonaromatic heterocyclic ring systems and 5 to 14-membered monocyclic, fused bicyclic and fused tricyclic aromatic heterocyclic ring systems, each heterocyclic ring system containing 1 to 6 heteroatoms independently selected from the group nitrogen, oxygen, and sulfur, provided that each heterocyclic ring system contains no more than 4 nitrogens, no more than 2 oxygens, and no more than 2 sulfurs, each nonaromatic or aromatic heterocyclic ring system substituted with R9 and optionally substituted with one or more R10; iv) a multicyclic ring system selected from 8 to 14-membered fused-bicyclic and fused-tricyclic ring systems which are an aromatic carbocyclic ring system, a nonaromatic carbocyclic ring system, or a ring system containing one or two nonaromatic rings that each include one or two J1 as ring members and one or two ring members independently selected from C(=O) and S(O)2, and any remaining rings as aromatic carbocyclic rings, each multicyclic ring system substituted with R9 and optionally substituted with one or more R10; and v) adamantyl substituted with R9 and optionally substituted with one or more R10; each J1 is independently selected from the group -CHR13-, -NR13-, -O-, and -S(O)p-; R9 is H; 1-2 halogen; CrC6 alkyl; CrC6 haloalkyl; CrC6 alkoxy; CrC6 haloalkoxy; C2-C6 alkenyl; C2-C6 haloalkenyl; C2-C6 alkynyl; CrC6 alkylthio; CrC6 haloalkyl thio; CrC6 alkylsulfinyl; Cj-Cg alkylsulfonyl; C3-C6 cycloalkyl; C3-C6 alkenyloxy; CO2(CrC6 alkyl); NH(CrC6 alkyl); N(CrC6 alkyl)2;
-C(R18)=NOR17; cyano; nitro; SF5; SiR22R23R24; or GeR22R23R24; or R9 is phenyl, benzyl, benzoyl, phenoxy, pyridinyl, pyridinyloxy, thienyl, thienyloxy, furanyl, pyrimidinyl, or pyrimidinyloxy each optionally substituted with one of R^ R^ or both RH and R12; each R10 is independently halogen; Cj-C4 alkyl; Cj-C4 haloalkyl; CrC4 alkoxy; nitro; or cyano; or when R9 and an R10 are attached to adjacent atoms on Z, R9 and said adjacently attached R10 can be taken together as -OCH2O- or -OCH2CH2O-; each CH2 group of said taken together R9 and R10 optionally substituted with 1-2 halogen; or when Y and an R10 are attached to adjacent atoms on Z and Y is -CHR15O-N=C(R7)-, -O-N=C(R7)-, -O-CH2CH2O-N=C(R7)-, -CHR15O-C(R15)=C(R7)-, -CH=N-N=C(R7)-, -CHR1 N(R15)-N=C(R7)- or -CHR15N(COCH3)-N=C(R7)-, R7 and said adjacently attached R10 can be taken together as -(CH2)r-J- such that J is attached to Z;
J is -CH2-; -CH2CH2-; -OCH2-; -CH2O-; -SCH2-; -CH2S-; -N(R16)CH2-; or
-CH2N(R16)-; each CH2 group of said J optionally substituted with 1 to 2 CH3; R1 1 and R12 are each independently 1 -2 halogen; C C4 alkyl; C rC haloalkyl; C2-C6 alkenyl; C2- haloalkenyl; C2-Cg alkynyl; C2-C6 haloalkynyl; C2-C(, alkoxyalkyl; C2- alkylthioalkyl; C3-C6 alkoxyalkynyl: C7-Cjo tetrahydropyranyloxyalkynyl; benzyloxymethyl; C C alkoxy; C C4 haloalkoxy; C3-Cg alkenyloxy; C3-C6 haloalkenyloxy; C3-Cg alkynyloxy; C3-C6 haloalkynyloxy; C2-C6 alkoxyalkoxy; C5-C9 trialkylsilylalkoxyalkoxy; C2-C6 alkylthioalkoxy; C C4 alkylthio: CrC haloalkylthio; CrC4 alkylsulfinyl;
CrC haloalkylsulfmyl; CrC alkylsulfonyl; C C4 haloalkylsulfonyl; C3-C6 alkenylthio; y (, haloalkenylthio; C2-Cg alkylthioalkylthio; nitro; cyano;- thiocyanato; hydroxy; N(R26)2; SF5; Si(R25)3; Ge(R25)3; (R 5)3Si-C≡C-;
OSi(R25)3; OGe(R25)3; C(=O)R 6; C(=S)R26; C(=O)OR26; C(=S)OR 6;
C(=O)SR26; C(=S)SR 6; C(=O)N(R26)2; C(=S)N(R26)2; OC(=O)R26;
OC(=S)R26; SC(=O)R26; SC(=S)R26; N(R26)C(=O)R26; N(R26)C(=S)R26;
OC(=O)OR27; OC(=O)SR27; OC(=O)N(R26)2; SC(=O)OR27; SC(=O)SR27; S(O)2OR26; S(O)2N(R2<>)2; OS(O)2R27; N(R26)S(O)2R27; or phenyl, phenoxy, benzyl, benzyloxy, phenylsulfonyl, phenylethynyl or pyridinylethynyl, each optionally substituted with halogen, CrC4 alkyl, C C4 haloalkyl, CrC4 alkoxy,
C C haloalkoxy, nitro or cyano; each R13 is independently H; C Cg alkyl; CrC6 haloalkyl; or phenyl optionally substituted with halogen, C j -C4 alkyl, C l -C4 haloalkyl, C j -C4 alkoxy, C 1 -C haloalkoxy, nitro or cyano; each R15 is independently H; C1-C3 alkyl; C3-C6 cycloalkyl; or phenyl or benzyl, each optionally substituted on the phenyl ring with halogen, C C4 alkyl, Cj-C4 haloalkyl, C C alkoxy, CrC4 haloalkoxy, nitro or cyano; or when Y is -CHR15N(R15)C(=O)N(R15)-, the two R15 attached to nitrogen atoms on said group can be taken together as -(CH2)q-; or when Y is -CHR15O-N=C(R7)NR15-, R7 and the adjacently attached R15 can be taken together as -CH2-(CH2)q-; -O-(CH2)q-; -S-(CH2)q-; or -N(C,-C3 alkyl)-(CH2)q-; with the directionality of said linkage defined such that the moiety depicted on the left side of the linkage is bonded to the carbon and the moiety on the right side of the linkage is bonded to the nitrogen; R16, R17, and R18 are each independently H; C C3 alkyl; C3-C6 cycloalkyl; or phenyl optionally substituted with halogen, C C4 alkyl, C C4 haloalkyl, C C4 alkoxy,
C C4 haloalkoxy, nitro or cyano; R22, R23, and R24 are each independently C -C6 alkyl; C2-C6 alkenyl; C { -C4 alkoxy; or phenyl; each R25 is independently Ct-C4 alkyl; C haloalkyl; C2-C4 alkenyl; C rC alkoxy; or phenyl; each R26 is independently H; Cι-C6 alkyl; C[-C6 haloalkyl; 2-C^ alkenyl; C2-C6 haloalkenyl; C -Cg alkynyl; C2-C6 haloalkynyl; C C6 cycloalkyl; or phenyl or benzyl, each optionally substituted on the phenyl ring with halogen, C C alkyl, C [-C4 haloalkyl, C C4 alkoxy, C C4 haloalkoxy, nitro or cyano; R27 is independently Cj-Cg alkyl; C^Cf, haloalkyl; C2-Cg alkenyl; C2- 6 haloalkenyl;
C2- alkynyl; C2- haloalkynyl; C C cycloalkyl; or phenyl or benzyl, each optionally substituted on the phenyl ring with halogen, C C4 alkyl, C C4 haloalkyl, C C4 alkoxy, Cj-C4 haloalkoxy, nitro or cyano; n and p are each independently 0, 1 or 2; r is 0 or 1 ; and q is 2 or 3.
3. A composition of Claim 2 wherein U is CH3; Y is Y is -O-; -S(O)n-; -NR15-; -CHR8-; -CHR CHR8-; -CR =CR8-; -CHR O-;
-OCHR15-; -CHR15S(O)n-; -S(O)nCHR15-; -CHR15N-; -CHR15O-N=C(R7)-;
-(R7)C=N-OCH(R15)-; -CHR1 OC(=S)N(R15)-; -CHR1 SC(=S)N(R15)-;
-CHR15O-N=C(R7)-C(=N-OR15)-; -CHR15O-N=C(R7)-CH2O-;
-CHR15O-N=C(R7)-CH2S-; -CHR15O-C(R7)=N-; -CHR15S-C(R7)=N-; -C(R7)=N-NR15-; -C(R7)=N-N=C(R7)-; or a direct bond; and the directionality of the Y linkage is defined such that the moiety depicted on the left side of the linkage is bonded to the phenyl ring and the moiety on the right side of the linkage is bonded to Z; and Z is naphthalenyl, tetrahydronaphthalenyl, phenyl, or 5- or 6- membered aromatic heterocyclic ring systems each substituted with R9 and optionally substituted with one or more R10.
4. A composition of Claim 3 wherein the projection of the relative positions of U, YZ and the substituents on T for the compounds of Formula I corresponds to
Figure imgf000205_0001
where the groups shown define a distorted tetrahedron, the view is along the bond between the phenyl group and the moiety T, and the solid line represents the foreground and the dashed line the background.
5. A composition of Claim 3 wherein the projection of the relative positions of U, YZ and the substituents on T for the compounds of Formula I corresponds to
Figure imgf000206_0001
where the groups shown define a distorted tetrahedron, the view is along the bond between the phenyl group and the moiety T, and the solid line represents the foreground and the dashed line the background.
6. A composition of Claim 4 wherein
G is N;
A is N;
R2 is CH3;
X is OR1;
R1 is CH3; and
W is O.
The composition of Claim 1 comprising Formula I compounds selected from the group
(aS)-4-[2-(3-fluorophenoxy)-6-methylphenyl]-2,4-dihydro-5-methoxy-2- methyl-3H- 1 ,2,4-triazol-3-one; (aS)-2,4-dihydro-5-methoxy-2-methyl-4-[2-methyl-6-(3- methylphenoxy)phenyl]-3H- 1 ,2,4-triazol-3-one; (aS)-2,4-dihydro-5-methoxy-2-methyl-4-(2-methyl-6-phenoxyphenyl)-3H- l,2,4-triazol-3-one; (aS)-2,4-dihydro-5-methoxy-2-methyl-4-[2-methyl-6-(4- methylphenoxy)phenyl]-3H- 1 ,2,4-triazol-3-one; (aS)-2,4-dihydro-5-methoxy-2-methyl-4-[2-methyl-6-[3-
(trifluoromethyl)phenoxy]phenyl]-3H- 1 ,2,4-triazol-3-one; (aS)-(2,4-dihydro-5-methoxy-2-methyl-4-[2-methyl-6-[[[[ 1 -[4-
(trifluoromethyl)-2-pyridinyl]ethylidene]amino]oxy]methyl]phenyl]-3H- l,2,4-triazol-3-one; (aS)-4-[2-[[[[ l-[2-fluoro-5-
(trifluoromethyl)phenyl]ethylidene]amino]oxy]methyl]-6- methylphenyl]-2,4-dihydro-5-methoxy-2-methyl-3H-l,2,4-triazol-3-one; (aS)-4-[2-[[[[l-(2-fluoro-5-methylphenyl)ethylidene]amino]oxy]methyl]-6- methylphenyl]-2,4-dihydro-5-methoxy-2-methyl-3H- 1 ,2,4-triazol-3-one;
(aS)-4-[2-[3-(2-fluorophenoxy)phenoxy]-6-methylphenyl]-2,4-dihydro-5- methoxy-2-methyl-3H- 1 ,2,4-triazol-3-one; (aS)-4-[2-[[4-(3,5-difluorophenyl)-5-methyl-2-thiazolyl]oxy]-6- methylphenyl]-2,4-dihydro-5-methoxy-2-methyl-3H-l,2,4-triazol-3-one; (aS)-2-[[6-[2-( 1 ,5-dihydro-3-methoxy- 1 -methyl-5-oxo-4H- 1 ,2,4-triazol-4-yl)-
3-methylphenoxy]-4-pyrimidinyl]oxy]benzonitrile; (aS)-4-[2-[[4-( 1 , 1 -dimethylethyl)-2-thiazolyl]oxy]-6-methylphenyl]-2,4- dihydro-5-methoxy-2-methyl-3H- 1 ,2,4-triazol-3-one; (aS)-4-[2-[(5-bromo-2-thiazolyl)oxy]-6-methylphenyl]-2,4-dihydro-5- methoxy-2-methyl-3H-l,2,4-triazol-3-one;
(aS)-2,4-dihydro-4-[2-[(5-iodo-2-thiazolyl)oxy]-6-methylphenyl]-5-methoxy-
2-methyl-3H-l,2,4-triazol-3-one; (aS)-2,4-dihydro-5-methoxy-2-methyl-4-[2-methyl-6-[[6-(2,4,6- trifluorophenoxy)-4-pyrimidinyl]oxy]phenyl]-3H-l,2,4-triazol-3-one; (aS)-2,4-dihydro-5-methoxy-2-methyl-4-[2-methyl-6-[[[[ 1 -[3-
(trifluoromethyl)phenyl]ethylidene]amino]oxy]methyl]phenyl]-3H-
1 ,2,4-triazol-3-one; (aS)-2,4-dihydro-5-methoxy-2-methyl-4-[2-methyl-6-[[2-methyl-5-(l- methylethyl)phenoxy]methyl]phenyl]-3H- 1 ,2,4-triazol-3-one; (aS)-2,4-dihydro-5-methoxy-2-methyl-4-[2-methyl-6-[[[[l-(3- methylphenyl)ethylidene]amino]oxy]methyl]phenyl]-3H-l,2,4-triazol-3- one; (aS)-4-[2-[(2,5-dimethylphenoxy)methyl]-6-methylphenyl]-2,4-dihydro-5- methoxy-2-methyl-3H- 1 ,2,4-triazol-3-one; (aS)-2,4-dihydro-5-methoxy-2-methyl-4-[2-methyl-6-[[[[l-(4- methylphenyl)ethylidene]amino]oxy]methyl]phenyl]-3H-l,2,4-triazol-3- one; and (aS)-4-[2-[[5-bromo-4-(l , 1 -dimethylethyl)-2-thiazolyl)oxy]-6-methylphenyl]-
2,4-dihydro-5-methoxy-2-methyI-3H- 1 ,2,4-triazol-3-one.
8. A fungicidal formulation comprising a composition of Claim 1 and including a fungicide selected from the group azoxystrobin, benomyl, carbendazim, caφropamid, copper salts, cymoxanil, cyproconazole, cyprodinil, dimethomoφh, epoxiconazole, famoxadone, fenpropidin, fenpropimoφh, flusilazole, flutolanil, fosetyl-aluminum, kasugamycin, kresoxim-methyl, mancozeb, metalaxyl, oxadixyl, pencycuron, probenazole, propiconazole, pyroquilon, tricyclazole and validamycin.
9. A fungicidal formulation comprising a fungicidally effective amount of a composition of Claim 1 and including at least one of a surfactant, a solid diluent or a liquid diluent.
10. A method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof, or to the plant seed or seedling, a fungicidally effective amount of a composition of Claim 1.
11. An arthropodicidal formulation comprising an arthropodicidally effective amount of a composition of Claim 1 and including at least one of a surfactant, a solid diluent or a liquid diluent.
12. A method for controlling arthropods comprising contacting the arthropods or their environment with an arthropodicidally effective amount of a composition of Claim 1.
13. A composition comprising at least one intermediate of Formula II
Figure imgf000208_0001
wherein T is
Figure imgf000208_0002
T2 , T3
Tl
Figure imgf000209_0001
T4 ^ T5 or T6 •
V is H, halogen, CrC3 alkyl, CN, NO2 or CrC3 alkoxy; U is halogen, C C2 alkyl or C C2 haloalkyl; Y^ is -OH, -CH2Xa or -CH(CH3)χa; Xa is Cl, Br, I or OH; A is O; S; N; NR3; or CR4;
G is C or N; provided that when G is C, then A is O, S or NR3 and the floating double bond is attached to G; and when G is N, then A is N or CR4 and the floating double bond is attached to A; W is O or S; X is OR1; S O^R1; halogen; CrC6 alkyl; CrC6 haloalkyl; C3-C6 cycloalkyl; cyano;
NH2; NHR1; N(CrC6 alky R1; NH(CrC6 alkoxy); or N(CrC6 alkoxy)R1; R1 is CrC6 alkyl; CrC6 haloalkyl; C2-C6 alkenyl; C2-C6 haloalkenyl; C2-C6 alkynyl;
C2-C6 haloalkynyl; C3-C6 cycloalkyl; C2-C alkylcarbonyl; or C2-C4 alkoxycarbonyl; R2 is H; CrC6 alkyl; CrC6 haloalkyl; C2-C6 alkenyl; C2-C6 haloalkenyl; C2-C6 alkynyl; C2-C6 haloalkynyl; C3-C6 cycloalkyl; C2-C4 alkylcarbonyl; C2-C alkoxycarbonyl; hydroxy; C C alkoxy; or acetyloxy; R3 is H; CrC6 alkyl; CrC6 haloalkyl; C2-C6 alkenyl; C2-C6 haloalkenyl; C2-C6 alkynyl; C2-Cg haloalkynyl; C3-C6 cycloalkyl; C2-C4 alkylcarbonyl; or C2-C4 alkoxycarbonyl;
R4 is H; halogen; CrC6 alkyl; CrC6 haloalkyl; C2-C6 alkenyl; C2-C6 haloalkenyl;
C2-C6 alkynyl; C2-Cg haloalkynyl; or C3-C6 cycloalkyl; R5 is CrC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl,
C2-C6 haloalkynyl or C3-C6 cycloalkyl; each R6 is H, CrC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, C2-C4 alkylcarbonyl, C2-C alkoxycarbonyl, hydroxy, C C2 alkoxy or acetyloxy, provided that at least one
R6 is other than hydroxy, CrC alkoxy or acetyloxy; m is 0, 1 or 2; and s is 0 or 1; characterized by: having at least a 20% enantiomeric excess of the structural atropic isomer which has a projection of the relative positions of U, Ya and the substituents on T for the compounds of Formula II corresponding to
--C02R3
Figure imgf000210_0001
•C0 R 5. or
Figure imgf000210_0003
Figure imgf000210_0002
where the groups shown define a distorted tetrahedron, the view is along the bond between the phenyl group and the moiety T, and the solid line represents the foreground and the dashed line the background.
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JP2008540474A (en) * 2005-05-14 2008-11-20 バイエル・クロツプサイエンス・アクチエンゲゼルシヤフト Substituted aryl oximes
JP2014101347A (en) * 2012-04-27 2014-06-05 Sumitomo Chemical Co Ltd Tetrazolinone compound and its use
CN103923013A (en) * 2014-04-29 2014-07-16 南京工业大学 Pyraclostrobin compounds and application thereof
WO2015056806A1 (en) * 2013-10-17 2015-04-23 住友化学株式会社 Tetrazolinone compound and application for same
CN105636955A (en) * 2013-10-17 2016-06-01 住友化学株式会社 Tetrazolinone compound and application for same
CN106946770A (en) * 2017-03-17 2017-07-14 中国农业大学 High activity imido grpup phenylacetic acid ester compound and its preparation method and application
EP3939961A1 (en) * 2020-07-16 2022-01-19 Basf Se Strobilurin type compounds and their use for combating phytopathogenic fungi
CN114728951A (en) * 2019-11-15 2022-07-08 先正达农作物保护股份公司 Herbicidal thiazole compounds
CN116349686A (en) * 2021-12-27 2023-06-30 沈阳中化农药化工研发有限公司 Fungicidal composition containing substituted triazolinone ether compound and application thereof

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Cited By (17)

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US6489487B1 (en) 1998-08-03 2002-12-03 Sumitomo Chemical Company, Limited Triazolone derivatives, use thereof, and intermediates therefor
US6824830B1 (en) * 1999-10-20 2004-11-30 Aventis Cropscience Gmbh Wood treatment
JP2008540474A (en) * 2005-05-14 2008-11-20 バイエル・クロツプサイエンス・アクチエンゲゼルシヤフト Substituted aryl oximes
JP2014101347A (en) * 2012-04-27 2014-06-05 Sumitomo Chemical Co Ltd Tetrazolinone compound and its use
US10085450B2 (en) 2013-10-17 2018-10-02 Sumitomo Chemical Company, Limited Tetrazolinone compound and use thereof
WO2015056806A1 (en) * 2013-10-17 2015-04-23 住友化学株式会社 Tetrazolinone compound and application for same
CN105636955A (en) * 2013-10-17 2016-06-01 住友化学株式会社 Tetrazolinone compound and application for same
JPWO2015056806A1 (en) * 2013-10-17 2017-03-09 住友化学株式会社 Tetrazolinone compounds and uses thereof
CN105636955B (en) * 2013-10-17 2018-01-12 住友化学株式会社 Terazololine-one compound and application thereof
US10077254B2 (en) 2013-10-17 2018-09-18 Sumitomo Chemical Company, Limited Tetrazolinone compound and use thereof
CN103923013A (en) * 2014-04-29 2014-07-16 南京工业大学 Pyraclostrobin compounds and application thereof
CN106946770A (en) * 2017-03-17 2017-07-14 中国农业大学 High activity imido grpup phenylacetic acid ester compound and its preparation method and application
CN106946770B (en) * 2017-03-17 2020-05-05 中国农业大学 High-activity imido phenylacetate compound and preparation method and application thereof
CN114728951A (en) * 2019-11-15 2022-07-08 先正达农作物保护股份公司 Herbicidal thiazole compounds
EP3939961A1 (en) * 2020-07-16 2022-01-19 Basf Se Strobilurin type compounds and their use for combating phytopathogenic fungi
WO2022013009A1 (en) * 2020-07-16 2022-01-20 Basf Se Strobilurin type compounds and their use for combating phytopathogenic fungi
CN116349686A (en) * 2021-12-27 2023-06-30 沈阳中化农药化工研发有限公司 Fungicidal composition containing substituted triazolinone ether compound and application thereof

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